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Sample records for 1b 1d 1d1

  1. 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. PMID:23325368

  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. Molecular characterization of zebrafish Oatp1d1 (Slco1d1), a novel organic anion-transporting polypeptide.

    PubMed

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

    2013-11-22

    The organic anion-transporting polypeptide (OATP/Oatp) superfamily includes a group of polyspecific transporters that mediate transport of large amphipathic, mostly anionic molecules across cell membranes of eukaryotes. OATPs/Oatps are involved in the disposition and elimination of numerous physiological and foreign compounds. However, in non-mammalian species, the functional properties of Oatps remain unknown. We aimed to elucidate the role of Oatp1d1 in zebrafish to gain insights into the functional and structural evolution of the OATP1/Oatp1 superfamily. We show that diversification of the OATP1/Oatp1 family occurs after the emergence of jawed fish and that the OATP1A/Oatp1a and OATP1B/Oatp1b subfamilies appeared at the root of tetrapods. The Oatp1d subfamily emerged in teleosts and is absent in tetrapods. The zebrafish Oatp1d1 is similar to mammalian OATP1A/Oatp1a and OATP1B/Oatp1b members, with the main physiological role in transport and balance of steroid hormones. Oatp1d1 activity is dependent upon pH gradient, which could indicate bicarbonate exchange as a mode of transport. Our analysis of evolutionary conservation and structural properties revealed that (i) His-79 in intracellular loop 3 is conserved within OATP1/Oatp1 family and is crucial for the transport activity; (ii) N-glycosylation impacts membrane targeting and is conserved within the OATP1/Oatp1 family with Asn-122, Asn-133, Asn-499, and Asn-512 residues involved; (iii) the evolutionarily conserved cholesterol recognition interaction amino acid consensus motif is important for membrane localization; and (iv) Oatp1d1 is present in dimeric and possibly oligomeric form in the cell membrane. In conclusion, we describe the first detailed characterization of a new Oatp transporter in zebrafish, offering important insights into the functional evolution of the OATP1/Oatp1 family and the physiological role of Oatp1d1.

  4. 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

  5. Exercise increases TBC1D1 phosphorylation in human skeletal muscle

    PubMed Central

    Jessen, Niels; An, Ding; Lihn, Aina S.; Nygren, Jonas; Hirshman, Michael F.; Thorell, Anders

    2011-01-01

    Exercise and weight loss are cornerstones in the treatment and prevention of type 2 diabetes, and both interventions function to increase insulin sensitivity and glucose uptake into skeletal muscle. Studies in rodents demonstrate that the underlying mechanism for glucose uptake in muscle involves site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 (TBC1D4) and TBC1D1. Multiple kinases, including Akt and AMPK, phosphorylate TBC1D1 and AS160 on distinct residues, regulating their activity and allowing for GLUT4 translocation. In contrast to extensive rodent-based studies, the regulation of AS160 and TBC1D1 in human skeletal muscle is not well understood. In this study, we determined the effects of dietary intervention and a single bout of exercise on TBC1D1 and AS160 site-specific phosphorylation in human skeletal muscle. Ten obese (BMI 33.4 ± 2.4, M-value 4.3 ± 0.5) subjects were studied at baseline and after a 2-wk dietary intervention. Muscle biopsies were obtained from the subjects in the resting (basal) state and immediately following a 30-min exercise bout (70% V̇o2 max). Muscle lysates were analyzed for AMPK activity and Akt phosphorylation and for TBC1D1 and AS160 phosphorylation on known or putative AMPK and Akt sites as follows: AS160 Ser711 (AMPK), TBC1D1 Ser231 (AMPK), TBC1D1 Ser660 (AMPK), TBC1D1 Ser700 (AMPK), and TBC1D1 Thr590 (Akt). The diet intervention that consisted of a major shift in the macronutrient composition resulted in a 4.2 ± 0.4 kg weight loss (P < 0.001) and a significant increase in insulin sensitivity (M value 5.6 ± 0.6), but surprisingly, there was no effect on expression or phosphorylation of any of the muscle-signaling proteins. Exercise increased muscle AMPKα2 activity but did not increase Akt phosphorylation. Exercise increased phosphorylation on AS160 Ser711, TBC1D1 Ser231, and TBC1D1 Ser660 but had no effect on TBC1D1 Ser700. Exercise did not increase TBC1D1 Thr590 phosphorylation or TBC1D1/AS160 PAS

  6. 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.

  7. TBC1D1 reduces palmitate oxidation by inhibiting β-HAD activity in skeletal muscle.

    PubMed

    Maher, A C; McFarlan, J; Lally, J; Snook, L A; Bonen, A

    2014-11-01

    In skeletal muscle the Rab-GTPase-activating protein TBC1D1 has been implicated in the regulation of fatty acid oxidation by an unknown mechanism. We determined whether TBC1D1 altered fatty acid utilization via changes in protein-mediated fatty acid transport and/or selected enzymes regulating mitochondrial fatty acid oxidation. We also determined the effects of TBC1D1 on glucose transport and oxidation. Electrotransfection of mouse soleus muscles with TBC1D1 cDNA increased TBC1D1 protein after 2 wk (P<0.05), without altering its paralog AS160. TBC1D1 overexpression decreased basal palmitate oxidation (-22%) while blunting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated palmitate oxidation (-18%). There was a tendency to increase fatty acid esterification (+10 nmol·g(-1)·60 min(-1), P=0.07), which reflected the reduction in fatty acid oxidation (-12 nmol·g(-1)·60 min(-1)). Concomitantly, basal (+21%) and AICAR-stimulated glucose oxidation (+8%) were increased in TBC1D1-transfected muscles relative to their respective controls (P<0.05), independent of changes in GLUT4 and glucose transport. The reductions in TBC1D1-mediated fatty acid oxidation could not be attributed to changes in the transporter FAT/CD36, muscle mitochondrial content, CPT1 expression or the expression and phosphorylation of AS160, acetyl-CoA carboxylase, or AMPK. However, TBC1D1 overexpression reduced β-HAD enzyme activity (-18%, P<0.05). In conclusion, TBC1D1-mediated reduction of muscle fatty acid oxidation appears to occur via inhibition of β-HAD activity.

  8. 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.

  9. NR1D1 ameliorates Mycobacterium tuberculosis clearance through regulation of autophagy

    PubMed Central

    Chandra, Vemika; Bhagyaraj, Ella; Nanduri, Ravikanth; Ahuja, Nancy; Gupta, Pawan

    2015-01-01

    NR1D1 (nuclear receptor subfamily 1, group D, member 1), an adopted orphan nuclear receptor, is widely known to orchestrate the expression of genes involved in various biological processes such as adipogenesis, skeletal muscle differentiation, and lipid and glucose metabolism. Emerging evidence suggests that various members of the nuclear receptor superfamily perform a decisive role in the modulation of autophagy. Recently, NR1D1 has been implicated in augmenting the antimycobacterial properties of macrophages and providing protection against Mycobacterium tuberculosis infection by downregulating the expression of the IL10 gene in human macrophages. This antiinfective property of NR1D1 suggests the need for an improved understanding of its role in other host-associated antimycobacterial pathways. The results presented here demonstrate that in human macrophages either ectopic expression of NR1D1 or treatment with its agonist, GSK4112, enhanced the number of acidic vacuoles as well as the level of MAP1LC3-II, a signature molecule for determination of autophagy progression, in a concentration- and time-dependent manner. Conversely, a decrease in NR1D1 in knockdown cells resulted in the reduced expression of lysosomal-associated membrane protein 1, LAMP1, commensurate with a decrease in the level of transcription factor EB, TFEB. This is indicative of that NR1D1 may have a regulatory role in lysosome biogenesis. NR1D1 being a repressor, its positive regulation on LAMP1 and TFEB is suggestive of an indirect byzantine mechanism of action. Its role in the modulation of autophagy and lysosome biogenesis together with its ability to repress IL10 gene expression supports the theory that NR1D1 has a pivotal antimycobacterial function in human macrophages. PMID:26390081

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

    PubMed

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

    2015-08-01

    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.

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

    PubMed

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

    2015-08-01

    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

    ... Federal Register published on April 11, 2000 (65 FR 19477-78). Examining the AD Docket You may examine the.... Discussion On March 17, 2008, the FAA issued AD 2008-07-01, Amendment 39-15442 (73 FR 15866, March 26, 2008... Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and 3. Would not have a...

  13. 75 FR 27411 - Airworthiness Directives; Turbomeca Arriel 1B, 1D, 1D1, and 1S1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-17

    ... INFORMATION: The FAA proposed to amend 14 CFR part 39 by superseding AD 2008-07-01, Amendment 39-15442 (73 FR... the proposed AD in the Federal Register on March 10, 2010 (75 FR 11072). That action proposed to...'' under DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and (3) Will not have...

  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. Amino acid residue 247 in canine sulphotransferase SULT1D1: a new determinant of substrate selectivity.

    PubMed Central

    Tsoi, Carrie; Widersten, Mikael; Morgenstern, Ralf; Swedmark, Stellan

    2004-01-01

    The SULT (sulphotransferase) family plays a critical role in the detoxification and activation of endogenous and exogenous compounds as well as in the regulation of steroid hormone actions and neurotransmitter functions. The structure-activity relationships of the human SULTs have been investigated with focus on the amino acid 146 in hSULT1A3 and its impact on dopamine/PNP (p-nitrophenol) specificity. In the present study, we have generated canine SULT1D1 (cSULT1D1) variants with mutations at amino acid residues in the substrate-binding pocket [A146E (Ala-146-->Glu), A146D, A146Q, I86D or D247L]. These mutation sites were chosen with regard to their possible contribution to the marked dopamine/PNP preference of cSULT1D1. After characterization, we found that the overall sulphation efficiencies for the cSULT1D1 A146 and the I86 mutants were strongly decreased for both substrates compared with wild-type cSULT1D1 but the substrate preference was unchanged. In contrast, the D247L mutant was found to be more than 21-fold better at sulphating PNP (120-fold decrease in K(m) value) but 54-fold less efficient in sulphating dopamine (8-fold increase in K(m) value) and the preference was switched from dopamine to PNP, indicating the importance of this amino acid in the dopamine/PNP preference in cSULT1D1. Our results show that Asp-247 has a pronounced effect on the substrate specificity of cSULT1D1 and thus we have identified a previously unrecognized contributor to active-site selectivity. PMID:14614767

  16. Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle

    PubMed Central

    Cartee, Gregory D.

    2014-01-01

    This review focuses on two paralogue Rab GTPase activating proteins known as TBC1D1 Tre-2/BUB2/cdc 1 domain family (TBC1D) 1 and TBC1D4 (also called Akt Substrate of 160 kDa, AS160) and their roles in controlling skeletal muscle glucose transport in response to the independent and combined effects of insulin and exercise. Convincing evidence implicates Akt2-dependent TBC1D4 phosphorylation on T642 as a key part of the mechanism for insulin-stimulated glucose uptake by skeletal muscle. TBC1D1 phosphorylation on several insulin-responsive sites (including T596, a site corresponding to T642 in TBC1D4) does not appear to be essential for in vivo insulin-stimulated glucose uptake by skeletal muscle. In vivo exercise or ex vivo contraction of muscle result in greater TBC1D1 phosphorylation on S237 that is likely to be secondary to increased AMP-activated protein kinase activity and potentially important for contraction-stimulated glucose uptake. Several studies that evaluated both normal and insulin-resistant skeletal muscle stimulated with a physiological insulin concentration after a single exercise session found that greater post-exercise insulin-stimulated glucose uptake was accompanied by greater TBC1D4 phosphorylation on several sites. In contrast, enhanced post-exercise insulin sensitivity was not accompanied by greater insulin-stimulated TBC1D1 phosphorylation. The mechanism for greater TBC1D4 phosphorylation in insulin-stimulated muscles after acute exercise is uncertain, and a causal link between enhanced TBC1D4 phosphorylation and increased post-exercise insulin sensitivity has yet to be established. In summary, TBC1D1 and TBC1D4 have important, but distinct roles in regulating muscle glucose transport in response to insulin and exercise. PMID:25280670

  17. Inhibition of Human Steroid 5-Reductase (AKR1D1) by Finasteride and Structure of the Enzyme-Inhibitor Complex

    SciTech Connect

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

    2009-01-01

    The {Delta}{sup 4}-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens. The first step in functionalization of the A-ring is mediated in humans by steroid 5{alpha}- or 5{beta}-reductase. Finasteride is a mechanism-based inactivator of 5{alpha}-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia. It is also used for androgen deprivation in hormone-dependent prostate carcinoma, and it has been examined as a chemopreventive agent in prostate cancer. The effect of finasteride on steroid 5{beta}-reductase (AKR1D1) has not been previously reported. We show that finasteride competitively inhibits AKR1D1 with low micromolar affinity but does not act as a mechanism-based inactivator. The structure of the AKR1D1 {center_dot} NADP{sup +} {center_dot} finasteride complex determined at 1.7 {angstrom} resolution shows that it is not possible for NADPH to reduce the {Delta}{sup 1-2}-ene of finasteride because the cofactor and steroid are not proximal to each other. The C3-ketone of finasteride accepts hydrogen bonds from the catalytic residues Tyr-58 and Glu-120 in the active site of AKR1D1, providing an explanation for the competitive inhibition observed. This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.

  18. Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice.

    PubMed

    Hargett, Stefan R; Walker, Natalie N; Keller, Susanna R

    2016-02-15

    The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160(-/-)/Tbc1d1(-/-) mice). Herein, we describe abnormalities in male and female AS160(-/-)/Tbc1d1(-/-) mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160(-/-)/Tbc1d1(-/-) mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160(-/-) and Tbc1d1(-/-) mice also combine in AS160(-/-)/Tbc1d1(-/-) mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160(-/-)/Tbc1d1(-/-) and AS160(-/-) mice. However, in vivo glucose uptake abnormalities in AS160(-/-)/Tbc1d1(-/-) skeletal muscles differ from those observed previously in AS160(-/-) mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160(-/-)/Tbc1d1(-/-) mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1. PMID:26625902

  19. Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice.

    PubMed

    Hargett, Stefan R; Walker, Natalie N; Keller, Susanna R

    2016-02-15

    The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160(-/-)/Tbc1d1(-/-) mice). Herein, we describe abnormalities in male and female AS160(-/-)/Tbc1d1(-/-) mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160(-/-)/Tbc1d1(-/-) mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160(-/-) and Tbc1d1(-/-) mice also combine in AS160(-/-)/Tbc1d1(-/-) mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160(-/-)/Tbc1d1(-/-) and AS160(-/-) mice. However, in vivo glucose uptake abnormalities in AS160(-/-)/Tbc1d1(-/-) skeletal muscles differ from those observed previously in AS160(-/-) mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160(-/-)/Tbc1d1(-/-) mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1.

  20. 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. PMID:24979340

  1. 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.

  2. Numerical simulations of heavily polluted fine-grained sediment remobilization using 1D, 1D+, and 2D channel schematization.

    PubMed

    Kaiglová, Jana; Langhammer, Jakub; Jiřinec, Petr; Janský, Bohumír; Chalupová, Dagmar

    2015-03-01

    This article used various hydrodynamic and sediment transport models to analyze the potential and the limits of different channel schematizations. The main aim was to select and evaluate the most suitable simulation method for fine-grained sediment remobilization assessment. Three types of channel schematization were selected to study the flow potential for remobilizing fine-grained sediment in artificially modified channels. Schematization with a 1D cross-sectional horizontal plan, a 1D+ approach, splitting the riverbed into different functional zones, and full 2D mesh, adopted in MIKE by the DHI modeling suite, was applied to the study. For the case study, a 55-km stretch of the Bílina River, in the Czech Republic, Central Europe, which has been heavily polluted by the chemical and coal mining industry since the mid-twentieth century, was selected. Long-term exposure to direct emissions of toxic pollutants including heavy metals and persistent organic pollutants (POPs) resulted in deposits of pollutants in fine-grained sediments in the riverbed. Simulations, based on three hydrodynamic model schematizations, proved that for events not exceeding the extent of the riverbed profile, the 1D schematization can provide comparable results to a 2D model. The 1D+ schematization can improve accuracy while keeping the benefits of high-speed simulation and low requirements of input DEM data, but the method's suitability is limited by the channel properties. PMID:25687259

  3. 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

    ... Register on December 23, 2009 (74 FR 68194). That NPRM proposed to correct an unsafe condition for the... Procedures (44 FR 11034, February 26, 1979); and 3. Will not have a significant economic impact, positive or... aviation authority of another country to identify and correct an unsafe condition on an aviation...

  4. 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

  5. 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

  6. 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.

  7. An RNAi screen identifies metabolic regulators NR1D1 and PBP as novel survival factors for breast cancer cells with the ERBB2 signature

    PubMed Central

    Kourtidis, Antonis; Jain, Ritu; Carkner, Richard D.; Eifert, Cheryl; Brosnan, M. Julia; Conklin, Douglas S.

    2010-01-01

    Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers, however, therapies targeting this gene have not proven to be as effective as was initially hoped. Transcriptional profiling meta-analyses have shown that there are approximately 150 genes co-overexpressed with ERBB2, suggesting that these genes may represent alternative factors influencing ERBB2-positive tumors. Here we describe an RNA interference-based analysis of these genes that identifies transcriptional regulators of fat synthesis and storage as being critical for the survival of these cells. These transcription factors, NR1D1 and PBP, both reside on ERBB2-containing 17q12-21 amplicons and are part of the ERBB2 expression signature. We show that NR1D1 and PBP act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network that is highly active in ERBB2-positive breast cancer cells. MDH1 and ME1, enzymes that link glycolysis and fatty acid synthesis, are also regulated by NR1D1. The resulting high-level fat production from increased expression of these genes likely contributes to an abnormal cellular energy metabolism based on aerobic glycolysis. Together, these results demonstrate that the cells of this aggressive form of breast cancer are genetically preprogrammed to depend on NR1D1 and PBP for the energy production necessary for survival. PMID:20160030

  8. Crystal Structures of Human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating Protein (RabGAP) Domains Reveal Critical Elements for GLUT4 Translocation

    SciTech Connect

    S Park; W Jin; S Shoelson

    2011-12-31

    We have solved the x-ray crystal structures of the RabGAP domains of human TBC1D1 and human TBC1D4 (AS160), at 2.2 and 3.5 {angstrom} resolution, respectively. Like the yeast Gyp1p RabGAP domain, whose structure was solved previously in complex with mouse Rab33B, the human TBC1D1 and TBC1D4 domains both have 16 {alpha}-helices and no {beta}-sheet elements. We expected the yeast Gyp1p RabGAP/mouse Rab33B structure to predict the corresponding interfaces between cognate mammalian RabGAPs and Rabs, but found that residues were poorly conserved. We further tested the relevance of this model by Ala-scanning mutagenesis, but only one of five substitutions within the inferred binding site of the TBC1D1 RabGAP significantly perturbed catalytic efficiency. In addition, substitution of TBC1D1 residues with corresponding residues from Gyp1p did not enhance catalytic efficiency. We hypothesized that biologically relevant RabGAP/Rab partners utilize additional contacts not described in the yeast Gyp1p/mouse Rab33B structure, which we predicted using our two new human TBC1D1 and TBC1D4 structures. Ala substitution of TBC1D1 Met{sup 930}, corresponding to a residue outside of the Gyp1p/Rab33B contact, substantially reduced catalytic activity. GLUT4 translocation assays confirmed the biological relevance of our findings. Substitutions with lowest RabGAP activity, including catalytically dead RK and Met{sup 930} and Leu{sup 1019} predicted to perturb Rab binding, confirmed that biological activity requires contacts between cognate RabGAPs and Rabs beyond those in the yeast Gyp1p RabGAP/mouse Rab33B structure.

  9. In-Depth Dissection of the P133R Mutation in Steroid 5β-Reductase (AKR1D1): A Molecular Basis of Bile Acid Deficiency.

    PubMed

    Chen, Mo; Jin, Yi; Penning, Trevor M

    2015-10-20

    Human steroid-5β-reductase (aldo-keto reductase 1D1, AKR1D1) stereospecifically reduces Δ(4)-3-ketosteroids to 5β-dihydrosteroids and is essential for steroid hormone metabolism and bile acid biosynthesis. Genetic defects in AKR1D1 cause bile acid deficiency that leads to life threatening neonatal hepatitis and cholestasis. The disease-associated P133R mutation caused significant decreases in catalytic efficiency with both the representative steroid (cortisone) and the bile acid precursor (7α-hydroxycholest-4-en-3-one) substrates. Pro133 is a second shell residue to the steroid binding channel and is distal to both the cofactor binding site and the catalytic center. Strikingly, the P133R mutation caused over a 40-fold increase in Kd values for the NADP(H) cofactors and increased the rate of release of NADP(+) from the enzyme by 2 orders of magnitude when compared to the wild type enzyme. By contrast the effect of the mutation on Kd values for steroids were 10-fold or less. The reduced affinity for the cofactor suggests that the mutant exists largely in the less stable cofactor-free form in the cell. Using stopped-flow spectroscopy, a significant reduction in the rate of the chemical step was observed in multiple turnover reactions catalyzed by the P133R mutant, possibly due to the altered position of NADPH. Thus, impaired NADPH binding and hydride transfer is the molecular basis for bile acid deficiency in patients with the P133R mutation. Results revealed that optimal cofactor binding is vulnerable to distant structural perturbation, which may apply to other disease-associated mutations in AKR1D1, all of which occur at conserved residues and are unstable.

  10. Molecular, physicochemical and rheological characteristics of introgressive Triticale/Triticum monococcum ssp. monococcum lines with wheat 1D/1A chromosome substitution.

    PubMed

    Salmanowicz, Bolesław P; Langner, Monika; Wiśniewska, Halina; Apolinarska, Barbara; Kwiatek, Michał; Błaszczyk, Lidia

    2013-01-01

    Three sets of hexaploid introgressive triticale lines, with Triticum monococcum ssp. monococcum (cultivated einkorn wheat) genes and a bread wheat chromosome 1D substituted for chromosome 1A, and one set of secondary triticale lines were evaluated for grain and flour physicochemical and dough rheological characteristics in two generations (F7 and F8). Genomic in situ hybridization (GISH) and fluorescence in situ hybridization (FISH) confirmed the 1D/1A chromosome substitution. The presence or absence of einkorn high-molecular-weight (HMW) glutenin subunits and the wheat Glu-D1d locus encoding the 5 + 10 subunits was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary zone electrophoresis, and allele-specific molecular markers. Significant differences were found among physicochemical properties (with the exception of the Hagberg falling number) of all introgressive Triticale/T. monococcum lines and the secondary triticale lines. The wheat 1D/1A chromosome substitution also affected these properties. The results showed that in all introgressive triticale lines, the protein and gluten content, Zeleny sedimentation value, and water absorption capacity, were increased. The rheological parameters estimated using micro-farinograph, reomixer, and Kieffer dough extensibility systems also showed an appreciable increase in dough-mixing properties, maximum resistance to extension (Rmax), and dough extensibility. Introgressive Triticale/T. monococcum lines with 5 + 10 subunits have particularly favorable rheological parameters. The results obtained in this study suggest that the cultivated einkorn genome Am, in the context of hexaploid secondary triticale lines and with a wheat 1D/1A substitution, has the potential to improve gluten polymer interactions and be a valuable genetic resource for triticale quality improvement. PMID:23896593

  11. Molecular, physicochemical and rheological characteristics of introgressive Triticale/Triticum monococcum ssp. monococcum lines with wheat 1D/1A chromosome substitution.

    PubMed

    Salmanowicz, Bolesław P; Langner, Monika; Wiśniewska, Halina; Apolinarska, Barbara; Kwiatek, Michał; Błaszczyk, Lidia

    2013-07-26

    Three sets of hexaploid introgressive triticale lines, with Triticum monococcum ssp. monococcum (cultivated einkorn wheat) genes and a bread wheat chromosome 1D substituted for chromosome 1A, and one set of secondary triticale lines were evaluated for grain and flour physicochemical and dough rheological characteristics in two generations (F7 and F8). Genomic in situ hybridization (GISH) and fluorescence in situ hybridization (FISH) confirmed the 1D/1A chromosome substitution. The presence or absence of einkorn high-molecular-weight (HMW) glutenin subunits and the wheat Glu-D1d locus encoding the 5 + 10 subunits was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary zone electrophoresis, and allele-specific molecular markers. Significant differences were found among physicochemical properties (with the exception of the Hagberg falling number) of all introgressive Triticale/T. monococcum lines and the secondary triticale lines. The wheat 1D/1A chromosome substitution also affected these properties. The results showed that in all introgressive triticale lines, the protein and gluten content, Zeleny sedimentation value, and water absorption capacity, were increased. The rheological parameters estimated using micro-farinograph, reomixer, and Kieffer dough extensibility systems also showed an appreciable increase in dough-mixing properties, maximum resistance to extension (Rmax), and dough extensibility. Introgressive Triticale/T. monococcum lines with 5 + 10 subunits have particularly favorable rheological parameters. The results obtained in this study suggest that the cultivated einkorn genome Am, in the context of hexaploid secondary triticale lines and with a wheat 1D/1A substitution, has the potential to improve gluten polymer interactions and be a valuable genetic resource for triticale quality improvement.

  12. Molecular, Physicochemical and Rheological Characteristics of Introgressive Triticale/Triticum monococcum ssp. monococcum Lines with Wheat 1D/1A Chromosome Substitution

    PubMed Central

    Salmanowicz, Bolesław P.; Langner, Monika; Wiśniewska, Halina; Apolinarska, Barbara; Kwiatek, Michał; Błaszczyk, Lidia

    2013-01-01

    Three sets of hexaploid introgressive triticale lines, with Triticum monococcum ssp. monococcum (cultivated einkorn wheat) genes and a bread wheat chromosome 1D substituted for chromosome 1A, and one set of secondary triticale lines were evaluated for grain and flour physicochemical and dough rheological characteristics in two generations (F7 and F8). Genomic in situ hybridization (GISH) and fluorescence in situ hybridization (FISH) confirmed the 1D/1A chromosome substitution. The presence or absence of einkorn high-molecular-weight (HMW) glutenin subunits and the wheat Glu-D1d locus encoding the 5 + 10 subunits was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary zone electrophoresis, and allele-specific molecular markers. Significant differences were found among physicochemical properties (with the exception of the Hagberg falling number) of all introgressive Triticale/T. monococcum lines and the secondary triticale lines. The wheat 1D/1A chromosome substitution also affected these properties. The results showed that in all introgressive triticale lines, the protein and gluten content, Zeleny sedimentation value, and water absorption capacity, were increased. The rheological parameters estimated using micro-farinograph, reomixer, and Kieffer dough extensibility systems also showed an appreciable increase in dough-mixing properties, maximum resistance to extension (Rmax), and dough extensibility. Introgressive Triticale/T. monococcum lines with 5 + 10 subunits have particularly favorable rheological parameters. The results obtained in this study suggest that the cultivated einkorn genome Am, in the context of hexaploid secondary triticale lines and with a wheat 1D/1A substitution, has the potential to improve gluten polymer interactions and be a valuable genetic resource for triticale quality improvement. PMID:23896593

  13. Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT).

    PubMed

    Kosfeld, Anne; Kreuzer, Martin; Daniel, Christoph; Brand, Frank; Schäfer, Anne-Kathrin; Chadt, Alexandra; Weiss, Anna-Carina; Riehmer, Vera; Jeanpierre, Cécile; Klintschar, Michael; Bräsen, Jan Hinrich; Amann, Kerstin; Pape, Lars; Kispert, Andreas; Al-Hasani, Hadi; Haffner, Dieter; Weber, Ruthild G

    2016-01-01

    Congenital anomalies of the kidneys and urinary tract (CAKUT) are genetically highly heterogeneous leaving most cases unclear after mutational analysis of the around 30 causative genes known so far. Assuming that phenotypes frequently showing dominant inheritance, such as CAKUT, can be caused by de novo mutations, de novo analysis of whole-exome sequencing data was done on two patient-parent-trios to identify novel CAKUT genes. In one case, we detected a heterozygous de novo frameshift variant in TBC1D1 encoding a Rab-GTPase-activating protein regulating glucose transporter GLUT4 translocation. Sequence analysis of 100 further CAKUT cases yielded three novel or rare inherited heterozygous TBC1D1 missense variants predicted to be pathogenic. TBC1D1 mutations affected Ser237-phosphorylation or protein stability and thereby act as hypomorphs. Tbc1d1 showed widespread expression in the developing murine urogenital system. A mild CAKUT spectrum phenotype, including anomalies observed in patients carrying TBC1D1 mutations, was found in kidneys of some Tbc1d1 (-/-) mice. Significantly reduced Glut4 levels were detected in kidneys of Tbc1d1 (-/-) mice and the dysplastic kidney of a TBC1D1 mutation carrier versus controls. TBC1D1 and SLC2A4 encoding GLUT4 were highly expressed in human fetal kidney. The patient with the truncating TBC1D1 mutation showed evidence for insulin resistance. These data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT pathogenesis, possibly via a role in glucose homeostasis. PMID:26572137

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. The rate-determining steps of aldo-keto reductases (AKRs), a study on human steroid 5β-reductase (AKR1D1).

    PubMed

    Chen, Mo; Jin, Yi; Penning, Trevor M

    2015-06-01

    Aldo-keto reductases (AKRs) are an expanding family of NAD(P)(H)-dependent oxidoreductases that catalyze the reduction of either carbonyl groups or α,β-unsaturated ketones on a variety of endogenous and exogenous substrates. The enzymes catalyze a sequential ordered bi-bi kinetic mechanism, in which cofactor is bound first and released last. Using human steroid 5β-reductase (AKR1D1) as a representative enzyme, the influence of substrate structure on the rate-limiting steps of AKR catalysis has been previously determined. The rate of the chemistry step was found to differ by two orders of magnitude when different steroid substrates were used in single turnover experiments with AKR1D1. This difference was reflected in multiple turnover experiments. C17-C21 steroid substrates exhibited a fast chemistry step followed by slow product release as suggested by "burst" phase kinetics. By contrast, C27 steroids have a slower chemical step that determines the rate of the reaction and "burst-phase" kinetics are no longer observed. Here we present single turnover kinetic experiments and find that they support the existence of two different binding poses for fast substrates due to their biphasic nature. We also re-interpret the loss of "burst-phase" kinetics in the multiple turnover experiments as due to long range effects of the steroid side-chain interacting with distal parts of the steroid pocket to perturb the reaction trajectory for hydride transfer and thus reduce kcat. The ability of steroid structure and hence binding pose to influence rate determination in steroid transforming AKRs is discussed as a general phenomenon.

  19. 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

  20. Rate of steroid double-bond reduction catalysed by the human steroid 5β-reductase (AKR1D1) is sensitive to steroid structure: implications for steroid metabolism and bile acid synthesis.

    PubMed

    Jin, Yi; Chen, Mo; Penning, Trevor M

    2014-08-15

    Human AKR1D1 (steroid 5β-reductase/aldo-keto reductase 1D1) catalyses the stereospecific reduction of double bonds in Δ4-3-oxosteroids, a unique reaction that introduces a 90° bend at the A/B ring fusion to yield 5β-dihydrosteroids. AKR1D1 is the only enzyme capable of steroid 5β-reduction in humans and plays critical physiological roles. In steroid hormone metabolism, AKR1D1 serves mainly to inactivate the major classes of steroid hormones. AKR1D1 also catalyses key steps of the biosynthetic pathway of bile acids, which regulate lipid emulsification and cholesterol homoeostasis. Interestingly, AKR1D1 displayed a 20-fold variation in the kcat values, with steroid hormone substrates (e.g. aldosterone, testosterone and cortisone) having significantly higher kcat values than steroids with longer side chains (e.g. 7α-hydroxycholestenone, a bile acid precursor). Transient kinetic analysis revealed striking variations up to two orders of magnitude in the rate of the chemistry step (kchem), which resulted in different rate determining steps for the fast and slow substrates. By contrast, similar Kd values were observed for representative fast and slow substrates, suggesting similar rates of release for different steroid products. The release of NADP+ was shown to control the overall turnover for fast substrates, but not for slow substrates. Despite having high kchem values with steroid hormones, the kinetic control of AKR1D1 is consistent with the enzyme catalysing the slowest step in the catabolic sequence of steroid hormone transformation in the liver. The inherent slowness of the conversion of the bile acid precursor by AKR1D1 is also indicative of a regulatory role in bile acid synthesis.

  1. 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 Central

    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

    2014-01-01

    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. PMID:24599455

  2. Decays B(s)→a1(b1)D(s), a1(b1)D(s)* in the perturbative QCD approach

    NASA Astrophysics Data System (ADS)

    Zhang, Zhi-Qing

    2013-04-01

    Within the framework of the perturbative QCD approach, we study the branching ratios of the two-body charmed decays B(s)→a1(b1)D(s), a1(b1)D(s)*, which, including Cabibbo-Kobayashi-Maskawa, allowed and suppressed decays. Our calculations are consistent with the currently available data and the experimental upper limits. Certainly, many of these predicted channels have not been measured by experiments and can be confronted with the future experimental data. We also discuss the polarization factions of the decays B(s)→a1(b1)D(s)*, some of which are sensitive to the distinct Gegenbauer moments of the wave functions and the decay constants of mesons a1 and b1.

  3. 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

    ... to the specified products. That NPRM was published in the Federal Register on June 12, 2009 (74 FR... Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and 3. Will not have a significant... service. The ruptures have been determined to be originated at the pinion teeth root due to...

  4. 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.

  5. Ex vivo induction and expansion of Natural Killer T cells by CD1d1-Ig coated artificial antigen presenting cells

    PubMed Central

    Webb, Tonya J.; Bieler, Joan G.; Schneck, Jonathan P.; Oelke, Mathias

    2009-01-01

    Natural killer T (NKT) cells play a pivotal role in maintaining immune homostasis. They recognize lipid antigen in the context of CD1d molecules and subsequently produce cytokines that activate cells of both the innate and adaptive immune responses. Many studies examining patients with autoimmune disease or cancer have shown that there is a reduction in both NKT cell number and function. Due to the complexities of manipulating NKT cells in vivo, ex vivo expanded effector NKT cells would be an excellent therapeutic modality. To date, immunotherapy utilizing the NKT/CD1d system has been dependent on the use of autologous DC in the presence or absence of a synthetic glycolipid, α-galactocylceramide. Here we report a novel technique that facilitates the growth and analysis of NKT cells through the use of CD1d-expressing aAPC. CD1d-based aAPC can effectively propagate both canonical (iNKT cells) and noncanonical (Vα14−) NKT cells. Importantly, CD1d-Ig aAPC can expand NKT cells from cancer patients. Thus, CD1d-expressing aAPC will enhance our knowledge of NKT cell biology and could potentially be used as a novel tool in adoptive immunotherapeutic strategies. PMID:19446558

  6. Ex vivo induction and expansion of natural killer T cells by CD1d1-Ig coated artificial antigen presenting cells.

    PubMed

    Webb, Tonya J; Bieler, Joan G; Schneck, Jonathan P; Oelke, Mathias

    2009-07-31

    Natural killer T (NKT) cells play a pivotal role in maintaining immune homostasis. They recognize lipid antigen in the context of CD1d molecules and subsequently produce cytokines that activate cells of both the innate and adaptive immune responses. Many studies examining patients with autoimmune disease or cancer have shown that there is a reduction in both NKT cell number and function. Due to the complexities of manipulating NKT cells in vivo, ex vivo expanded effector NKT cells would be an excellent therapeutic modality. To date, immunotherapy utilizing the NKT/CD1d system has been dependent on the use of autologous DC in the presence or absence of a synthetic glycolipid, alpha-galactocylceramide. Here we report a novel technique that facilitates the growth and analysis of NKT cells through the use of CD1d-expressing aAPC. CD1d-based aAPC can effectively propagate both canonical (iNKT cells) and noncanonical (Valpha14(-)) NKT cells. Importantly, CD1d-Ig aAPC can expand NKT cells from cancer patients. Thus, CD1d-expressing aAPC will enhance our knowledge of NKT cell biology and could potentially be used as a novel tool in adoptive immunotherapeutic strategies. PMID:19446558

  7. 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

  8. Mechanisms of action of the 5-HT1B/1D receptor agonists.

    PubMed

    Tepper, Stewart J; Rapoport, Alan M; Sheftell, Fred D

    2002-07-01

    Recent studies of the pathophysiology of migraine provide evidence that the headache phase is associated with multiple physiologic actions. These actions include the release of vasoactive neuropeptides by the trigeminovascular system, vasodilation of intracranial extracerebral vessels, and increased nociceptive neurotransmission within the central trigeminocervical complex. The 5-HT(1B/1D) receptor agonists, collectively known as triptans, are a major advance in the treatment of migraine. The beneficial effects of the triptans in patients with migraine are related to their multiple mechanisms of action at sites implicated in the pathophysiology of migraine. These mechanisms are mediated by 5-HT(1B/1D) receptors and include vasoconstriction of painfully dilated cerebral blood vessels, inhibition of the release of vasoactive neuropeptides by trigeminal nerves, and inhibition of nociceptive neurotransmission. The high affinity of the triptans for 5-HT(1B/1D) receptors and their favorable pharmacologic properties contribute to the beneficial effects of these drugs, including rapid onset of action, effective relief of headache and associated symptoms, and low incidence of adverse effects. PMID:12117355

  9. Profiles of 5-HT 1B/1D agonists in acute migraine with special reference to second generation agents.

    PubMed

    Deleu, D; Hanssens, Y

    1999-06-01

    The efficacy of 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) agonists is related to their inhibitory effects on neurogenic inflammation, mediated through serotoninergic control mechanisms. Recently, a series of oral second generation 5-HT 1B/1D agonists (eletriptan, naratriptan, rizatriptan and zolmitriptan) have been developed and are reviewed in this paper. Their in vitro and in vivo pharmacological properties, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the gold standard in the treatment of acute migraine, sumatriptan. PMID:10427351

  10. 75 FR 3159 - Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-20

    ... Sections 368(a)(1)(D) and 354(b)(1)(B); Correction AGENCY: Internal Revenue Service (IRS), Treasury...) that were published in the Federal Register on Friday, December 18, 2009 (74 FR 67053) providing...)(1)(D) where no stock and/or securities of the acquiring corporation is issued and distributed in...

  11. Cardiovascular characterization of pyrrolo[2,1-d][1,5]benzothiazepine derivatives binding selectively to the peripheral-type benzodiazepine receptor (PBR): from dual PBR affinity and calcium antagonist activity to novel and selective calcium entry blockers.

    PubMed

    Campiani, G; Fiorini, I; De Filippis, M P; Ciani, S M; Garofalo, A; Nacci, V; Giorgi, G; Sega, A; Botta, M; Chiarini, A; Budriesi, R; Bruni, G; Romeo, M R; Manzoni, C; Mennini, T

    1996-07-19

    The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1-d][1,5]-benzothiazepine derivatives (54-68) are described. Selective peripheral-type benzodiazepine receptor (PBR) ligands, such as PK 11195 and Ro 5-4864, have recently been found to possess low but significant inhibitory activity of L-type calcium channels, and this property is implicated in the cardiovascular effects observed with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue. Therefore, several 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepines, potent and selective peripheral-type benzodiazepine receptor ligands recently developed by us (3, 7-20), were subjected to calcium channel receptor binding assay. Some of these compounds showed an unexpected potency in displacing the binding of [3H]nitrendipine from L-type calcium channels, much higher than that reported for PK 11195 and Ro 5-4864 and equal to or higher than that of reference calcium antagonists such as verapamil and (+)-cis-diltiazem. Specifically, in rat cortex homogenate, our prototypic PBR ligand 7-acetoxy-6-(p-methoxyphenyl)pyrrolo[2,1-d][1,5]benzothiazepine (3) showed an IC50 equal to 0.13 nM for inhibition of [3H]nitrendipine binding. Furthermore, in functional studies this compound displayed a clear-cut selectivity for cardiac over vascular tissue. Comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using isolated guinea pig left atria, revealed that 3 displayed higher selectivity than the reference (+)-cis-diltiazem. Thus, the pyrrolobenzothiazepine 3 might represent a new tool for characterizing the relationship between the PBR and cardiac function. Furthermore, we have also investigated the structural dependence of binding to PBR and L-type calcium channels, and

  12. 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).

  13. 75 FR 3160 - Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-20

    ... were the subject of FR Doc. E9-30170, is corrected as follows: 1. On page 67054, column 1, in the... Sections 368(a)(1)(D) and 354(b)(1)(B); Correction AGENCY: Internal Revenue Service (IRS), Treasury. ACTION...) that were published in the Federal Register on Friday, December 18, 2009 (74 FR 67053)...

  14. Rizatriptan, a novel 5-HT1B/1D agonist for migraine: single- and multiple-dose tolerability and pharmacokinetics in healthy subjects.

    PubMed

    Goldberg, M R; Lee, Y; Vyas, K P; Slaughter, D E; Panebianco, D; Ermlich, S J; Shadle, C R; Brucker, M J; McLoughlin, D A; Olah, T V

    2000-01-01

    Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma. PMID:10631625

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

    PubMed Central

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

    2015-01-01

    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. PMID:26019234

  16. 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. PMID:23662895

  17. 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

    2011-03-01

    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.

  18. The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist rizatriptan in healthy volunteers

    PubMed Central

    van Haarst, A D; van Gerven, J M A; Cohen, A F; De Smet, M; Sterrett, A; Birk, K L; Fisher, A L; De Puy, M E; Goldberg, M R; Musson, D G

    1999-01-01

    Aims The new 5-HT1B/1D agonist rizatriptan (MK-0462) has recently been registered for the treatment of migraine. Its primary route of metabolism is via monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor moclobemide may be used in patients with chronic headache syndromes. Hence, this study aimed to investigate the interactions between rizatriptan and moclobemide. Methods In a double-blind, randomized, placebo-controlled, two-period cross-over study 12 healthy, young volunteers (six males, six females) were treated with moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a single dose of rizatriptan (10 mg) was administered, and subsequently blood and urine samples were collected for assay of rizatripan and N-monodesmethyl rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of MAO-A inhibition, were also assessed. Supine and standing blood pressure were measured regularly. Results Both treatments were well tolerated. During moclobemide, the increase in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persistent decrease in DHPG level (43% on average). When rizatriptan was coadministered with moclobemide, the area under the plasma drug concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fold (90% CI, 1.93–2.47) and 5.3-fold (90% CI, 4.81–5.91), respectively, when compared with placebo. Peak plasma drug concentrations for rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI, 1.11–1.80) and 2.6-fold (90% CI, 2.23–3.14), respectively, and half-lives of both were prolonged. Conclusions Moclobemide inhibited the metabolism of rizatriptan and its active N-monodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemide may considerably potentiate rizatriptan action. Concurrent administration of moclobemide and rizatriptan is not recommended

  19. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D- mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new

  20. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D-mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new

  1. Interaction of the alpha-adrenoceptor agonist oxymetazoline with serotonin 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors.

    PubMed

    Schoeffter, P; Hoyer, D

    1991-04-17

    Oxymetazoline was recognized with nanomolar affinity by 5-HT1A, 5-HT1B and 5-HT1D binding sites and mimicked the effects of 5-hydroxytryptamine with about the same potency and intrinsic activity as the endogenous amine in the corresponding functional tests. At 5-HT1C receptors, oxymetazoline behaved as a mixed agonist-antagonist. Clonidine had minimal activity. Methiothepin antagonized the effects of oxymetazoline (7.4 less than pKB less than 8.8). Thus, oxymetazoline is a full and potent agonist at 5-HT1A, 5-HT1B and 5-HT1D receptors and a partial agonist at 5-HT1C receptors.

  2. Differential involvement of 5-HT(1A) and 5-HT(1B/1D) receptors in human interferon-alpha-induced immobility in the mouse forced swimming test.

    PubMed

    Zhang, Hongmei; Wang, Wei; Jiang, Zhenzhou; Shang, Jing; Zhang, Luyong

    2010-01-01

    Although Interferon-alpha (IFN-alpha, CAS 9008-11-1) is a powerful drug in treating several viral infections and certain tumors, a considerable amount of neuropsychiatric side-effects such as depression and anxiety are an unavoidable consequence. Combination with the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine (CAS 56296-78-7) significantly improved the situation. However, the potential 5-HT(1A) receptor- and 5-HT(1B) receptor-signals involved in the antidepressant effects are still unclear. The effects of 5-HT(1A) receptor- and 5-HT(1B) receptor signals were analyzed by using the mouse forced swimming test (FST), a predictive test of antidepressant-like action. The present results indicated that (1) fluoxetine (administrated intragastrically, 30 mg/kg; not subactive dose: 15 mg/kg) significantly reduced IFN-alpha-induced increase of the immobility time in the forced swimming test; (2) 5-HT(1A) receptor- and 5-HT(1B) receptor ligands alone or in combination had no effects on IFN-alpha-induced increase of the immobility time in the FST; (3) surprisingly, WAY 100635 (5-HT(1A) receptor antagonist, 634908-75-1) and 8-OH-DPAT(5-HT(1A) receptor agonist, CAS 78950-78-4) markedly enhanced the antidepressant effect of fluoxetine at the subactive dose (15 mg/kg, i. g.) on the IFN-alpha-treated mice in the FST. Further investigations showed that fluoxetine combined with WAY 100635 and 8-OH-DPAT failed to produce antidepressant effects in the FST. (4) Co-application of CGS 12066A (5-HT(1B) receptor agonist, CAS 109028-09-3) or GR 127935 (5-HT(1B/1D) receptor antagonist, CAS 148642-42-6) with fluoxetine had no synergistic effects on the IFN-alpha-induced increase of immobility time in FST. (5) Interestingly, co-administration of GR 127935, WAY 100635 and fluoxetine significantly reduced the IFN-alpha-induced increase in immobility time of FST, being more effective than co-administration of WAY 100635 and fluoxetine. All results suggest that (1) compared to

  3. Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine.

    PubMed

    Martin, G R

    1997-10-01

    Zolmitriptan (Zomig; formerly 311C90) is a novel 5-hydroxytryptamine (5HT)1B/1D receptor agonist with proven efficacy in the acute treatment of migraine with or without preceding aura. The drug differs from presently available members of this drug class in that it combines 5HT1B/1D receptor partial agonist activity with robust oral pharmacokinetics and an ability to inhibit trigeminovascular activation centrally as well as peripherally in preclinical studies. Consistent with its selectivity for 5HT1B/1D receptors, zolmitriptan produces constriction of various isolated blood vessels, most notably cranial arteries. In anaesthetized animals, these vascular effects manifest as a selective constriction of cranial arterio-venous anastomoses resulting in a redistribution of carotid arterial blood flow. This effect is produced without significant effects on heart rate, blood pressure or blood flow to the brain, heart or lungs. Zolmitriptan also inhibits trigeminal-evoked increases in cerebral blood flow in anaesthetized cats and blocks trigeminal-evoked plasma protein extravasation in the dura of guinea-pigs. These actions are consistent with a pre-junctional inhibition of neuropeptide release from perivascular afferents of the trigeminal nerve, as confirmed by independent studies showing that zolmitriptan blocks elevations of calcitonin-gene-related peptide in jugular venous blood during electrical stimulation of the trigeminal ganglion. In all of these effects, zolmitriptan is three to four times more potent than sumatriptan, but produces the same maximum response. Zolmitriptan crosses the intact blood-brain barrier to inhibit trigeminovascular activation in the brainstem. This was shown initially by the ability of the drug to block a brainstem reflex provoking vasoactive intestinal peptide release from the VIIth cranial (facial) nerve during trigeminal stimulation. Subsequent ex vivo autoradiography confirmed that intravenously injected [3H]zolmitriptan labels a

  4. The involvement of intracellular Ca2+ in 5-HT1B/1D receptor-mediated contraction of the rabbit isolated renal artery

    PubMed Central

    Hill, P B; Dora, K A; Hughes, A D; Garland, C J

    2000-01-01

    5-Hydroxytryptamine1B/1D (5-HT1B/1D) receptor coupling to contraction was investigated in endothelium-denuded rabbit isolated renal arteries, by simultaneously measuring tension and intracellular [Ca2+], and tension in permeabilized smooth muscle cells.In intact arterial segments, 1 nM–10 μM 5-HT failed to induce contraction or increase the fura-2 fluorescence ratio (in the presence of 1 μM ketanserin and prazosin to block 5-HT2 and α1-adrenergic receptors, respectively). However, in vessels pre-exposed to either 20 mM K+ or 30 nM U46619, 5-HT stimulated concentration-dependent increases in both tension and intracellular [Ca2+].1 nM–10 μM U46619 induced concentration-dependent contractions. In the presence of nifedipine (0.3 and 1 μM) the maximal contraction to U46619 (10 μM) was reduced by around 70%. The residual contraction was abolished by the putative receptor operated channel inhibitor, SKF 96365 (2 μM).With 0.3 μM nifedipine present, 100 nM U46619 evoked similar contraction to 30 nM U46619 in the absence of nifedipine, but contraction to 5-HT (1 nM–10 μM) was abolished.In permeabilized arterial segments, 10 mM caffeine, 1 μM IP3 or 100 μM phenylephrine, each evoked transient contractions by releasing Ca2+ from intracellular stores, whereas 5-HT had no effect. In intact arterial segments pre-stimulated with 20 mM K+, 5-HT-evoked contractions were unaffected by 1 μM thapsigargin, which inhibits sarco- and endoplasmic reticulum calcium-ATPases.In vessels permeabilized with α-toxin and then pre-contracted with Ca2+ and GTP, 5-HT evoked further contraction, reflecting increased myofilament Ca2+-sensitivity.Contraction linked to 5-HT1B/1D receptor stimulation in the rabbit renal artery can be explained by an influx of external Ca2+ through voltage-dependent Ca2+ channels and sensitization of the contractile myofilaments to existing levels of Ca2+, with no release of Ca2+ from intracellular stores. PMID

  5. Effects of 5-HT1B/1D receptor agonist rizatriptan on cerebral blood flow and blood volume in normal circulation.

    PubMed

    Okazawa, Hidehiko; Tsuchida, Tatsuro; Pagani, Marco; Mori, Tetsuya; Kobayashi, Masato; Tanaka, Fumiko; Yonekura, Yoshiharu

    2006-01-01

    To investigate the vasoconstrictor effect of 5-hydroxytryptamine (5-HT1B/1D) receptor agonists for migraine treatment, changes in cerebral blood flow (CBF) and blood volume induced by rizatriptan were assessed by positron emission tomography (PET). Eleven healthy volunteers underwent PET studies before and after rizatriptan administration. Dynamic PET data were acquired after bolus injection of H2(15)O to analyze CBF and arterial-to-capillary blood volume (V0) images using the three-weighted integral method. After a baseline scan, three further acquisitions were performed at 40 to 50, 60 and 70 to 80 mins after drug administration. Global and regional differences in CBF and V0 between conditions were compared using absolute values in the whole brain and cortical regions, as well as statistical parametric mapping (SPM) analysis. The global and regional values for CBF and V0 decreased significantly after rizatriptan administration compared with the baseline condition. However, both values recovered to baseline within 80 mins after treatment. The maximal reduction in global CBF and V0 was approximately 13% of baseline value. The greatest decrease in CBF was observed approximately 60 mins after drug administration, whereas the maximal reduction in V0 was observed approximately 5 mins earlier. Statistical parametric mapping did not highlight any regional differences between conditions. Thus, in brain circulation, rizatriptan caused significant CBF and V0 decreases, which are consistent with the vasoconstrictor effect of triptans on the large cerebral arteries. The gradual recovery in the late phase from the maximal CBF and V0 decrease suggests that rizatriptan does not affect the cerebral autoregulatory response in small arteries induced by CBF reduction. PMID:15944648

  6. Influence of β-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol

    PubMed Central

    Goldberg, Michael R; Sciberras, David; De Smet, Marina; Lowry, Richard; Tomasko, Lisa; Lee, Yih; Olah, Timothy V; Zhao, Jamie; Vyas, Kamlesh P; Halpin, Rita; Kari, Prasad H; James (deceased), Ian

    2001-01-01

    Aims Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other β-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between β-adrenoceptor blockers and rizatriptan. Methods Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various β-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured. Results Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0,∞) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the β-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other

  7. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials.

    PubMed

    Ferrari, M D; Goadsby, P J; Roon, K I; Lipton, R B

    2002-10-01

    The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained

  8. Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [3H]eletriptan binding at human 5-HT1B and 5-HT1D receptors.

    PubMed

    Napier, C; Stewart, M; Melrose, H; Hopkins, B; McHarg, A; Wallis, R

    1999-03-01

    The affinity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]-1H-indole) for a range of 5-HT receptors was compared to values obtained for other 5-HT1B/1D receptor agonists known to be effective in the treatment of migraine. Eletriptan, like sumatriptan, zolmitriptan, naratriptan and rizatriptan had highest affinity for the human 5-HT1B, 5-HT1D and putative 5-ht1f receptor. Kinetic studies comparing the binding of [3H]eletriptan and [3H]sumatriptan to the human recombinant 5-HT1B and 5-HT1D receptors expressed in HeLa cells revealed that both radioligands bound with high specificity (>90%) and reached equilibrium within 10-15 min. However, [3H]eletriptan had over 6-fold higher affinity than [3H]sumatriptan at the 5-HT1D receptor (K(D)): 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [3H]sumatriptan at the 5-HT1B receptor (K(D): 3.14 and 11.07 nM, respectively). Association and dissociation rates for both radioligands could only be accurately determined at the 5-HT1D receptor and then only at 4 degrees C. At this temperature, [3H]eletriptan had a significantly (P<0.05) faster association rate (K(on) 0.249 min(-1) nM(-1)) than [3H]sumatriptan (K(on) 0.024 min(-1) nM(-1)) and a significantly (P<0.05) slower off-rate (K(off) 0.027 min(-1) compared to 0.037 min(-1) for [3H]sumatriptan). These data indicate that eletriptan is a potent ligand at the human 5-HT1B, 5-HT1D, and 5-ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache. PMID:10193663

  9. 5-HT-moduline, a 5-HT(1B/1D) receptor endogenous modulator, interacts with dopamine release measured in vivo by microdialysis.

    PubMed

    Bentué-Ferrer, D; Reymann, J M; Rousselle, J C; Massot, O; Bourin, M; Allain, H; Fillion, G

    1998-10-01

    5-Hydroxytryptamine-moduline (5-HT-moduline) is an endogenous tetrapeptide (Leu-Ser-Ala-Leu) recently isolated and characterized from mammalian brain. This compound interacts with 5-HT1B receptors as a non-competitive, high-affinity antagonist and has the properties of an allosteric modulator. 5-HT-moduline could play an important role in the regulation of serotonergic transmission and also, through heteroreceptors, dopaminergic transmission. The aim of this work was to examine the potential ability of 5-HT-moduline to modify the basal extracellular concentration of dopamine and its metabolites (3-methoxytyramine, dihydroxyphenylacetic acid and homovanillic acid), in the rat striatum and to determine its potential interaction with the stimulating activity of a specific 5-HT1B receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl) pyrrolo [3,2-b] pyrid-5-one (CP-93,129), on the release of dopamine. The technique is based on in vivo microdialysis using probes implanted in the striatum of the conscious rat. Results showed that the perfusion of 5-HT-moduline directly into this structure (1.25 mM) increased the striatal level of dopamine by two-fold (104% of the absolute basal release values, P = 0.0015) and that of 3-methoxytyramine by 3-fold (293%, P = 0.0001) without any change in the terminal metabolite concentrations. The intrastriatal administration of CP-93,129 induced a statistically significant, dose-dependent increase of dopamine levels (P < 0.0001). Coperfusion of 5-HT-moduline did not significantly alter the effect of CP-93,129 at 0.1 and 0.5 mM, but appeared to have an additive effect on the lowest dose (P = 0.0406). The results obtained show that 5-HT-moduline directly administered into the striatum increases the release of dopamine in this area. Presumably, this effect results from the desensitization of 5-HT1B receptors located on dopamine terminals. However, the fact that a 5-HT1B receptor agonist (CP-93,129) also increased the release of dopamine in the

  10. 8-NH2-boldine, an antagonist of alpha1A and alpha1B adrenoceptors without affinity for the alpha1D subtype: structural requirements for aporphines at alpha1-adrenoceptor subtypes.

    PubMed

    Ivorra, M Dolores; Valiente, Miguel; Martínez, Sonia; Madrero, Yolanda; Noguera, M Antonia; Cassels, Bruce K; Sobarzo, Eduardo M; D'Ocon, Pilar

    2005-10-01

    Structure-activity analysis of 21 aporphine derivatives was performed by examining their affinities for cloned human alpha (1A), alpha (1B) and alpha (1D) adrenoceptors (AR) using membranes prepared from rat-1 fibroblasts stably expressing each alpha (1)-AR subtype. All the compounds tested competed for [ (125)I]-HEAT binding with steep and monophasic curves. The most interesting compound was 8-NH (2)-boldine, which retains the selective affinity for alpha(1A)-AR (pKi = 6.37 +/- 0.21) vs. alpha(1B)-AR (pKi = 5.53 +/- 0.11) exhibited by 1,2,9,10-tetraoxygenated aporphines, but shows low affinity for alpha(1D)-AR (pKi < 2.5). Binding studies on native adrenoceptors present in rat cerebral cortex confirms the results obtained for human cloned alpha (1)-AR subtypes. The compounds selective for the alpha (1A) subtype discriminate two binding sites in rat cerebral cortex confirming a mixed population of alpha (1A)- and alpha (1B)-AR in this tissue. All compounds are more selective as inhibitors of [ (3)H]-prazosin binding than of [ (3)H]-diltiazem binding to rat cerebral cortical membranes. A close relationship was found between affinities obtained for cloned alpha (1A)-AR and inhibitory potencies on noradrenaline-induced contraction or inositol phosphate accumulation in tail artery, confirming that there is a homogeneous functional population of alpha(1A)-AR in this vessel. On the contrary, a poor correlation seems to exist between the affinity of 8-NH (2)-boldine for cloned alpha (1D)-AR and its potency as an inhibitor of noradrenaline-induced contraction or inositol phosphate accumulation in rat aorta, which confirms that a heterogeneous population of alpha (1)-AR mediates the adrenergic response in this vessel.

  11. Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.

    PubMed

    Borcherding, D C; Tong, W; Hugo, E R; Barnard, D F; Fox, S; LaSance, K; Shaughnessy, E; Ben-Jonathan, N

    2016-06-16

    Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.

  12. Protein Expression for Novel Prognostic Markers (Cyclins D1, D2, D3, B1, B2, ITGβ7, FGFR3, PAX5) Correlate With Previously Reported Gene Expression Profile Patterns in Plasma Cell Myeloma.

    PubMed

    Mansoor, Adnan; Akhter, Ariz; Pournazari, Payam; Mahe, Etienne; Shariff, Sami; Farooq, Fahad; Elyamany, Ghaleb; Shahbani-Rad, Meer-Taher; Rashid-Kolvear, Fariborz

    2015-01-01

    Among plasma cell myeloma (PCM) patients, gene expression profiling (GEP)-based molecular classification has proven to be an independent predictor of survival, after autologous stem cell transplantation. However, GEP has limited routine clinical applicability given its complex methodology, high cost, and limited availability in clinical laboratories. In this study, we have evaluated biomarkers identified from GEP discoveries, utilizing immunohistochemistry (IHC) platform in a cohort of PCM patients. IHC staining for cyclins B1, B2, D1, D2, D3, FGFR3, PAX5, and integrin β7 (ITGβ7) was performed on the bone marrow biopsies of 93 newly diagnosed PCM patients. Expression of FGFR3 was noted in 10 (11%) samples correlating completely with t(4;14)(p16;q32) results (P<0.001); however, the association between FGFR3 and cyclin D2 expression was not significant (P=0.14). ITGβ7 expression was present in 9/93 (9%) patients and all these samples also demonstrated upregulated expression of cyclin D2 (P=0.014). Expression of cyclins D1, D2, and D3 was variable in this cohort. Positive protein expression of cyclin D1 was noted in 30/93 (32%), D2 in 17/93 (18%), and D3 in 5/93 (5%) samples. Coexpression of cyclins D1 and D2 was observed in 13/93 (14%) samples, whereas 28 (30%) samples were negative for all the 3 cyclin D proteins. Cyclin B1 was not expressed in any sample, despite adequate staining in positive controls. Cyclin B2 was expressed in 33/93 (35%) and PAX5 protein was noted in 7/93 (8%) samples. In summary, we have demonstrated that mRNA-based prognostic markers can be detected by routine IHC in decalcified bone marrow samples. This approach may provide a useful tool for the wider adoption of prognostic makers for risk stratification of PCM patients. We anticipate that such an approach might allow patients with high-risk immunoprofiles to be considered for other potential novel therapeutic agents, potentially sparing some patients the toxicity of stem cell transplant.

  13. The Ubiquitin-associated (UBA) Domain of SCCRO/DCUN1D1 Protein Serves as a Feedback Regulator of Biochemical and Oncogenic Activity*

    PubMed Central

    Huang, Guochang; Towe, Christopher W.; Choi, Lydia; Yonekawa, Yoshihiro; Bommeljé, Claire C.; Bains, Sarina; Rechler, Willi; Hao, Bing; Ramanathan, Yegnanarayana; Singh, Bhuvanesh

    2015-01-01

    Amplification of squamous cell carcinoma-related oncogene (SCCRO) activates its function as an oncogene in a wide range of human cancers. The oncogenic activity of SCCRO requires its potentiating neddylation domain, which regulates its E3 activity for neddylation. The contribution of the N-terminal ubiquitin-associated (UBA) domain to SCCRO function remains to be defined. We found that the UBA domain of SCCRO preferentially binds to polyubiquitin chains in a linkage-independent manner. Binding of polyubiquitin chains to the UBA domain inhibits the neddylation activity of SCCRO in vivo by inhibiting SCCRO-promoted nuclear translocation of neddylation components and results in a corresponding decrease in cullin-RING-ligase-promoted ubiquitination. The results of colony formation and xenograft assays showed a mutation in the UBA domain of SCCRO that reduces binding to polyubiquitin chains, significantly enhancing its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frameshift mutation in SCCRO that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of SCCRO, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. Combined, these data suggest that the UBA domain functions as a negative regulator of SCCRO function. Mutations in the UBA domain lead to loss of inhibitory control, which results in increased biochemical and oncogenic activity. The clustering of mutations in the UBA domain of SCCRO suggests that mutations may be a mechanism of oncogene activation in human cancers. PMID:25411243

  14. 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...

  15. 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.

  16. 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.

  17. Early emergence of three dopamine D1 receptor subtypes in vertebrates. Molecular phylogenetic, pharmacological, and functional criteria defining D1A, D1B, and D1C receptors in European eel Anguilla anguilla.

    PubMed

    Cardinaud, B; Sugamori, K S; Coudouel, S; Vincent, J D; Niznik, H B; Vernier, P

    1997-01-31

    The existence of dopamine D1C and D1D receptors in Xenopus and chicken, respectively, challenged the established duality (D1A and D1B) of the dopamine D1 receptor class in vertebrates. To ascertain the molecular diversity of this gene family in early diverging vertebrates, we isolated four receptor-encoding sequences from the European eel Anguilla anguilla. Molecular phylogeny assigned two receptor sequences (D1A1 and D1A2) to the D1A subtype, and a third receptor to the D1B subtype. Additional sequence was orthologous to the Xenopus D1C receptor and to several other previously unclassified fish D1-like receptors. When expressed in COS-7 cells, eel D1A and D1B receptors display affinity profiles for dopaminergic ligands similar to those of other known vertebrate homologues. The D1C receptor exhibits pharmacological characteristics virtually identical to its Xenopus homologue. Functionally, while all eel D1 receptors stimulate adenylate cyclase, the eel D1B receptor exhibits greater constitutive activity than either D1A or D1C receptors. Semiquantitative reverse transcription-polymerase chain reaction reveals the differential distribution of D1A1, D1A2, D1B, and D1C receptor mRNA within the hypothalamic-pituitary axis of the eel brain. Taken together, these data suggest that the D1A, D1B, and D1C receptors arose prior to the evolutionary divergence of fish and tetrapods and exhibit molecular, pharmacological, and functional attributes that unambiguously allow for their classification as distinct D1 receptor subtypes in the vertebrate phylum. PMID:9006917

  18. 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 ...

  19. Phylogeography of E1b1b1b-M81 haplogroup and analysis of its subclades in Morocco.

    PubMed

    Reguig, Ahmed; Harich, Nourdin; Barakat, Abdelhamid; Rouba, Hassan

    2014-01-01

    In this study we analyzed 295 unrelated Berber-speaking men from northern, central, and southern Morocco to characterize frequency of the E1b1b1b-M81 haplogroup and to refine the phylogeny of its subclades: E1b1b1b1-M107, E1b1b1b2-M183, and E1b1b1b2a-M165. For this purpose, we typed four biallelic polymorphisms: M81, M107, M183, and M165. A large majority of the Berber-speaking male lineages belonged to the Y-chromosomal E1b1b1b-M81 haplogroup. The frequency ranged from 79.1% to 98.5% in all localities sampled. E1b1b1b2-M183 was the most dominant subclade in our samples, ranging from 65.1% to 83.1%. In contrast, the E1b1b1b1-M107 and E1b1b1b2a-M165 subclades were not found in our samples. Our results suggest a predominance of the E1b1b1b-M81 haplogroup among Moroccan Berber-speaking males with a decreasing gradient from south to north. The most prevalent subclade in this haplogroup was E1b1b1b2-M183, for which diffferences among these three groups were statistically significant between central and southern groups. PMID:25397701

  20. 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. PMID:25854421

  1. Human autoreactive T cells recognize CD1b and phospholipids

    PubMed Central

    Van Rhijn, Ildiko; van Berlo, Twan; Hilmenyuk, Tamara; Cheng, Tan-Yun; Wolf, Benjamin J.; Tatituri, Raju V. V.; Uldrich, Adam P.; Napolitani, Giorgio; Cerundolo, Vincenzo; Altman, John D.; Willemsen, Peter; Huang, Shouxiong; Rossjohn, Jamie; Besra, Gurdyal S.; Brenner, Michael B.; Godfrey, Dale I.; Moody, D. Branch

    2016-01-01

    In contrast with the common detection of T cells that recognize MHC, CD1a, CD1c, or CD1d proteins, CD1b autoreactive T cells have been difficult to isolate in humans. Here we report the development of polyvalent complexes of CD1b proteins and carbohydrate backbones (dextramers) and their use in identifying CD1b autoreactive T cells from human donors. Activation is mediated by αβ T-cell receptors (TCRs) binding to CD1b-phospholipid complexes, which is sufficient to activate autoreactive responses to CD1b-expressing cells. Using mass spectrometry and T-cell responses to scan through the major classes of phospholipids, we identified phosphatidylglycerol (PG) as the immunodominant lipid antigen. T cells did not discriminate the chemical differences that distinguish mammalian PG from bacterial PG. Whereas most models of T-cell recognition emphasize TCR discrimination of differing self and foreign structures, CD1b autoreactive T cells recognize lipids with dual self and foreign origin. PG is rare in the cellular membranes that carry CD1b proteins. However, bacteria and mitochondria are rich in PG, so these data point to a more general mechanism of immune detection of infection- or stress-associated lipids. PMID:26621732

  2. 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

    2016-02-01

    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 (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. PMID:26812443

  3. 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

  4. Modulation of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) by 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives, ligands of peripheral benzodiazepine receptor (PBR).

    PubMed

    Anderson, Linnea E; Dring, Ann M; Hamel, Laura D; Stoner, Matthew A

    2011-04-25

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate xenobiotic sensing and metabolism through interactions with multiple exogenous and endogenous chemicals. Compounds that activate CAR are often ligands of PXR; attention is therefore given to discovery of new, receptor-specific chemical entities that may be exploited for therapeutic and basic research purposes. Recently, ligands of the peripheral benzodiazepine receptor (PBR), PK11195 and FGIN-1-27, were shown to modulate both CAR and PXR. PBR is a mitochondrial transport protein responsible for multiple regulatory functions, including heme biosynthesis, a major component in cytochrome P450 (CYP) enzymes. To investigate possible new roles for PBR involvement in metabolic regulation, expression of the CAR and PXR target genes, CYP2B6 and CYP3A4, was measured in human hepatocytes following treatment with a targeted PBR ligand set. Luciferase reporter assays with transiently expressed wild-type CAR (CAR1), splice variant CAR3, or PXR in HuH-7 cells were used to further study activation of these receptors. Four structurally related PBR ligands (benzothiazepines) differentially modulate CAR1, CAR3 and PXR activity. Benzothiazepine NF49 is an agonist ligand of CAR3, a partial agonist of PXR, exhibits greater inverse agonist activity on CAR1 than does PK11195, and is a new tool for studying these closely related nuclear receptors.

  5. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 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— (a... pipelines, electric utilities and hydroelectric projects....

  6. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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— (a... pipelines, electric utilities and hydroelectric projects....

  7. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 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— (a... pipelines, electric utilities and hydroelectric projects....

  8. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 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— (a... pipelines, electric utilities and hydroelectric projects....

  9. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 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— (a... pipelines, electric utilities and hydroelectric projects....

  10. 7 CFR 1b.3 - Categorical exclusions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Categorical exclusions. 1b.3 Section 1b.3 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.3 Categorical exclusions... individual or cumulative effect on the human environment and are excluded from the preparation...

  11. 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... environment for present and future generations. (b) Each USDA agency is responsible for compliance with...

  12. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 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... environment for present and future generations. (b) Each USDA agency is responsible for compliance with...

  13. 7 CFR 1b.3 - Categorical exclusions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Categorical exclusions. 1b.3 Section 1b.3 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.3 Categorical exclusions... individual or cumulative effect on the human environment and are excluded from the preparation...

  14. 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....

  15. 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...

  16. 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.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)...

  17. 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,...

  18. 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....

  19. 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...

  20. 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...

  1. 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,...

  2. 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....

  3. 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....

  4. 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...

  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.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....

  7. 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,...

  8. 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...

  9. 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.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)...

  10. 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,...

  11. 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...

  12. 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.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)...

  13. 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...

  14. 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....

  15. 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...

  16. 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...

  17. 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...

  18. 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....

  19. 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...

  20. 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....

  1. 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...

  2. 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....

  3. 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,...

  4. 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...

  5. 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....

  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.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...

  8. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....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) The... by calling (202) 502-8390 or 1-888-889-8030 (toll free), by e-mail at hotline@ferc.gov, or writing...

  9. Construction of HEK293 cells stably expressing wild-type organic anion transporting polypeptide 1B1 (OATP1B1*1a) and variant OATP1B1*1b and OATP1B1*15.

    PubMed

    Chen, M; Qu, B X; Chen, X L; Hu, H H; Jiang, H D; Yu, L S; Zhou, Q; Zeng, S

    2016-06-01

    A transgenic cell line stably expressing the human organic anion transporting polypeptide (OATP1B1) was established. Human Embryonic Kidney 293 (HEK293) cell line stably expressing OATP1B1*1a sequence was amplified through PCR with the extracted total RNA as templates from human liver, then subcloned into the plasmid pMD19-T and verified by sequencing. OATP1B1*1b/OATP1B1*15 mutant sequences were obtained by site-directed mutation PCR with pMD19-T/ OATP1B1*1a as templates. The plasmids pcDNA3.1(+)/OATP1B1*1a, *1b and *15 were constructed and transfected into HEK293 cell line using Lipofectamine 2000 transfection reagent. Several stable transfected clones were obtained after selection with G418. Using rosuvastatin as a probe substrate of OATP1B1, the intracellular rosuvastatin accumulation in HEK293 and HEK-OATP1B1*1a, *1b and *15 monoclone cells were validated by a ultra-performance liquid chromatography-tandem mass spectrometry. OATP1B1 mRNA and protein expression were detected by RT-PCR and Western blot, respectively. The results from RT-PCR, rosuvastatin uptake and Western blot assay indicated that human OATP1B1 was highly expressed in transfected cells compared with controls. The HEK-293 cell lines stably expressing human OATP1B1-wild and variant (HEK-OATP1B1, *1b and *15) are potential models to study drug transport in vitro. PMID:27455553

  10. Construction of HEK293 cells stably expressing wild-type organic anion transporting polypeptide 1B1 (OATP1B1*1a) and variant OATP1B1*1b and OATP1B1*15.

    PubMed

    Chen, M; Qu, B X; Chen, X L; Hu, H H; Jiang, H D; Yu, L S; Zhou, Q; Zeng, S

    2016-06-01

    A transgenic cell line stably expressing the human organic anion transporting polypeptide (OATP1B1) was established. Human Embryonic Kidney 293 (HEK293) cell line stably expressing OATP1B1*1a sequence was amplified through PCR with the extracted total RNA as templates from human liver, then subcloned into the plasmid pMD19-T and verified by sequencing. OATP1B1*1b/OATP1B1*15 mutant sequences were obtained by site-directed mutation PCR with pMD19-T/ OATP1B1*1a as templates. The plasmids pcDNA3.1(+)/OATP1B1*1a, *1b and *15 were constructed and transfected into HEK293 cell line using Lipofectamine 2000 transfection reagent. Several stable transfected clones were obtained after selection with G418. Using rosuvastatin as a probe substrate of OATP1B1, the intracellular rosuvastatin accumulation in HEK293 and HEK-OATP1B1*1a, *1b and *15 monoclone cells were validated by a ultra-performance liquid chromatography-tandem mass spectrometry. OATP1B1 mRNA and protein expression were detected by RT-PCR and Western blot, respectively. The results from RT-PCR, rosuvastatin uptake and Western blot assay indicated that human OATP1B1 was highly expressed in transfected cells compared with controls. The HEK-293 cell lines stably expressing human OATP1B1-wild and variant (HEK-OATP1B1, *1b and *15) are potential models to study drug transport in vitro.

  11. 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

    ... Internal Revenue Service 26 CFR Part 1 RIN 1545-BF83 Corporate Reorganizations; Distributions Under... published on Friday, December 18, 2009 (74 FR 67053). The regulations provide guidance regarding the... is in need of clarification. List of Subjects in 26 CFR Part 1 Income taxes, Reporting...

  12. 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.

  13. Discovery of novel PTP1b inhibitors.

    PubMed

    Ockey, Denise A; Gadek, Thomas R

    2004-01-19

    A small library of 19 compounds was designed based on unique structural features of PTP1b. Utilizing electrospray ionization mass spectrometry (ESI-MS) to provide binding information about complexes of enzyme and small molecule ligands, two classes of lead compounds were discovered.

  14. 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.

  15. ESA Swarm Mission - Level 1b Products

    NASA Astrophysics Data System (ADS)

    Tøffner-Clausen, Lars; Floberghagen, Rune; Mecozzi, Riccardo; Menard, Yvon

    2014-05-01

    Swarm, a three-satellite constellation to study the dynamics of the Earth's magnetic field and its interactions with the Earth system, has been launched in November 2013. The objective of the Swarm mission is to provide the best ever survey of the geomagnetic field and its temporal evolution, which will bring new insights into the Earth system by improving our understanding of the Earth's interior and environment. The Level 1b Products of the Swarm mission contain time-series of the quality screened, calibrated, corrected, and fully geo-localized measurements of the magnetic field intensity, the magnetic field vector (provided in both instrument and Earth-fixed frames), the plasma density, temperature, and velocity. Additionally, quality screened and pre-calibrated measurements of the nongravitational accelerations are provided. Geo-localization is performed by 24- channel GPS receivers and by means of unique, three head Advanced Stellar Compasses for high-precision satellite attitude information. The Swarm Level 1b data will be provided in daily products separately for each of the three Swarm spacecrafts. This poster will present detailed lists of the contents of the Swarm Level 1b Products and brief descriptions of the processing algorithms used in the generation of these data.

  16. Mutation of Oryza sativa CORONATINE INSENSITIVE 1b (OsCOI1b) delays leaf senescence.

    PubMed

    Lee, Sang-Hwa; Sakuraba, Yasuhito; Lee, Taeyoung; Kim, Kyu-Won; An, Gynheung; Lee, Han Yong; Paek, Nam-Chon

    2015-06-01

    Jasmonic acid (JA) functions in plant development, including senescence and immunity. Arabidopsis thaliana CORONATINE INSENSITIVE 1 encodes a JA receptor and functions in the JA-responsive signaling pathway. The Arabidopsis genome harbors a single COI gene, but the rice (Oryza sativa) genome harbors three COI homologs, OsCOI1a, OsCOI1b, and OsCOI2. Thus, it remains unclear whether each OsCOI has distinct, additive, synergistic, or redundant functions in development. Here, we use the oscoi1b-1 knockout mutants to show that OsCOI1b mainly affects leaf senescence under senescence-promoting conditions. oscoi1b-1 mutants stayed green during dark-induced and natural senescence, with substantial retention of chlorophylls and photosynthetic capacity. Furthermore, several senescence-associated genes were downregulated in oscoi1b-1 mutants, including homologs of Arabidopsis thaliana ETHYLENE INSENSITIVE 3 and ORESARA 1, important regulators of leaf senescence. These results suggest that crosstalk between JA signaling and ethylene signaling affects leaf senescence. The Arabidopsis coi1-1 plants containing 35S:OsCOI1a or 35S:OsCOI1b rescued the delayed leaf senescence during dark incubation, suggesting that both OsCOI1a and OsCOI1b are required for promoting leaf senescence in rice. oscoi1b-1 mutants showed significant decreases in spikelet fertility and grain weight, leading to severe reduction of grain yield, indicating that OsCOI1-mediated JA signaling affects spikelet fertility and grain filling.

  17. Specific inhibition of sensitized protein tyrosine phosphatase 1B (PTP1B) with a biarsenical probe

    PubMed Central

    Davis, Oliver B.; Bishop, Anthony C.

    2012-01-01

    Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of the insulin-receptor and leptin-receptor signaling pathways, and it has therefore emerged as a critical anti-type-II-diabetes and anti-obesity drug target. Toward the goal of generating a covalent modulator of PTP1B activity that can be used for investigating its roles in cell signaling and disease progression, we report that the biarsenical probe FlAsH-EDT2 can be used to inhibit PTP1B variants that contain cysteine point mutations in a key catalytic loop of the enzyme. The site-specific cysteine mutations have little effect on the catalytic activity of the enzyme in the absence of FlAsH-EDT2. Upon addition of FlAsH-EDT2, however, the activity of the engineered PTP1B is strongly inhibited, as assayed with either small-molecule or phosphorylated-peptide PTP substrates. We show that the cysteine-rich PTP1B variants can be targeted with the biarsenical probe in either whole-cell lysates or intact cells. Together, our data provide an example of a biarsenical probe controlling the activity of a protein that does not contain the canonical tetra-cysteine biarsenical-labeling sequence CCXXCC. The targeting of “incomplete” cysteine-rich motifs could provide a general means for controlling protein activity by targeting biarsenical compounds to catalytically important loops in conserved protein domains. PMID:22263876

  18. B-1B excels in conventional role

    SciTech Connect

    Scott, W.B.

    1992-07-01

    A report is presented of an observational flight performed in a USAF B-1B to better understand the operational aspects of the aircraft's new conventional bombing mission as an integral element of a multiaircraft tactical strike package. The basic flight plan consisted of a standard takeoff and climb, cruising to the training area at 22,000 ft, descending for a 400 ft low-level run, making two simulated bomb drops, and climbing back to 25,000 ft for the return to base. Attention is given the new/enhanced avionics, the ALQ-161 defensive electronic warfare system and ripple-release Mk. 82 bombing procedures.

  19. 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.

  20. Interleukin 1B gene (IL1B) variation and internalizing symptoms in maltreated preschoolers.

    PubMed

    Ridout, Kathryn K; Parade, Stephanie H; Seifer, Ronald; Price, Lawrence H; Gelernter, Joel; Feliz, Paloma; Tyrka, Audrey R

    2014-11-01

    Evidence now implicates inflammatory proteins in the neurobiology of internalizing disorders. Genetic factors may influence individual responses to maltreatment; however, little work has examined inflammatory genetic variants in adults and none in children. The present study examined the role of an interleukin 1B gene (IL1B) variant in preschoolers exposed to maltreatment and other forms of adversity in internalizing symptom development. One hundred ninety-eight families were enrolled, with one child (age 3-5 years) from each family. Adversity measures included child protective service documentation of moderate-severe maltreatment in the last 6 months and interview-assessed contextual stressors. Internalizing symptoms were measured using the Child Behavior Checklist and the Diagnostic Infant and Preschool Assessment. Maltreated children had higher major depressive disorder (MDD) and posttraumatic stress disorder symptoms and marginally higher internalizing symptoms on the Child Behavior Checklist. Controlling for age, sex, and race, IL1B genotype was associated with MDD symptoms (p = .002). Contextual stressors were significantly associated with MDD and posttraumatic stress disorder and marginally with internalizing symptoms. The IL1B genotype interacted with contextual stress such that children homozygous for the minor allele had more MDD symptoms (p = .045). These results suggest that genetic variants of IL1B may modulate the development of internalizing symptoms in the face of childhood adversity. PMID:25422961

  1. 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.

  2. DESIGN PACKAGE 1D SYSTEM SAFETY ANALYSIS

    SciTech Connect

    L.R. Eisler

    1995-02-02

    The purpose of this analysis is to systematically identify and evaluate hazards related to the Yucca Mountain Project Exploratory Studies Facility (ESF) Design Package 1D, Surface Facilities, (for a list of design items included in the package 1D system safety analysis see section 3). This process is an integral part of the systems engineering process; whereby safety is considered during planning, design, testing, and construction. A largely qualitative approach was used since a radiological System Safety analysis is not required. The risk assessment in this analysis characterizes the accident scenarios associated with the Design Package 1D structures/systems/components in terms of relative risk and includes recommendations for mitigating all identified risks. The priority for recommending and implementing mitigation control features is: (1) Incorporate measures to reduce risks and hazards into the structure/system/component (S/S/C) design, (2) add safety devices and capabilities to the designs that reduce risk, (3) provide devices that detect and warn personnel of hazardous conditions, and (4) develop procedures and conduct training to increase worker awareness of potential hazards, on methods to reduce exposure to hazards, and on the actions required to avoid accidents or correct hazardous conditions. The scope of this analysis is limited to the Design Package 1D structures/systems/components (S/S/Cs) during normal operations excluding hazards occurring during maintenance and ''off normal'' operations.

  3. ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma

    PubMed Central

    Su, Gloria H.; Bansal, Ravi; Murphy, Kathleen M.; Montgomery, Elizabeth; Yeo, Charles J.; Hruban, Ralph H.; Kern, Scott E.

    2001-01-01

    DPC4 is known to mediate signals initiated by type β transforming growth factor (TGFβ) as well as by other TGFβ superfamily ligands such as activin and BMP (bone morphogenic proteins), but mutational surveys of such non-TGFβ receptors have been negative to date. Here we describe the gene structure and novel somatic mutations of the activin type I receptor, ACVR1B, in pancreatic cancer. ACVR1B has not been described previously as a mutated tumor-suppressor gene. PMID:11248065

  4. 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.

  5. [5-HT1B serotonin receptors and antidepressant effects of selective serotonin reuptake inhibitors ].

    PubMed

    Gardier, A M; Trillat, A C; Malagié, I; David, D; Hascoët, M; Colombel, M C; Jolliet, P; Jacquot, C; Hen, R; Bourin, M

    2001-05-01

    We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiates the effect of a single administration of paroxetine on [5-HT]ext more in the ventral hippocampus than in the frontal cortex. Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs.

  6. 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

    2015-02-01

    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.

  7. 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... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request...

  8. 7 CFR 1b.4 - Exclusion of agencies.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 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...

  9. 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...

  10. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request for... 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...

  11. 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...

  12. 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...

  13. 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....

  14. 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...

  15. 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)...

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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...

  2. 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...

  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.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request for... 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...

  5. 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...

  6. 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, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.8 Requests for...

  7. 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 COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  8. 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 COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  9. 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...

  10. 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....

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request for... 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...

  12. 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...

  13. 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...

  14. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request for... 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...

  15. 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, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.10 By whom conducted....

  16. 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....

  17. 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....

  18. 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...

  19. 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)...

  20. 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...

  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.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....

  3. 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....

  4. 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....

  5. 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)...

  6. 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....

  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.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...

  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.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...

  11. 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)...

  12. 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

  13. 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.

  14. 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.

  15. Association of Neuropeptide Y (NPY), Interleukin-1B (IL1B) Genetic Variants and Correlation of IL1B Transcript Levels with Vitiligo Susceptibility

    PubMed Central

    Laddha, Naresh C.; Dwivedi, Mitesh; Mansuri, Mohmmad Shoab; Singh, Mala; Patel, Hetanshi H.; Agarwal, Nishtha; Shah, Anish M.; Begum, Rasheedunnisa

    2014-01-01

    Background Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels. Objectives Aim of the present study was to explore NPY promoter −399T/C (rs16147) and exon2 +1128T/C (rs16139) polymorphisms as well as IL1B promoter −511C/T (rs16944) polymorphism and to correlate IL1B transcript levels with vitiligo. Methods PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B −511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR. Results Genotype and allele frequencies for NPY −399T/C, +1128T/C and IL1B −511C/T SNPs differed significantly (p<0.0001, p<0.0001; p = 0.0161, p = 0.0035 and p<0.0001, p<0.0001) between patients and controls. ‘TC’ haplotype containing minor alleles of NPY polymorphisms was significantly higher in patients and increased the risk of vitiligo by 2.3 fold (p<0.0001). Transcript levels of IL1B were significantly higher, in patients compared to controls (p = 0.0029), in patients with active than stable vitiligo (p = 0.015), also in female patients than male patients (p = 0.026). Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes. Conclusion Our results suggest that NPY −399T/C, +1128T/C and IL1B −511C/T polymorphisms are associated with vitiligo and IL1B −511C/T SNP influences its transcript levels leading to increased risk for vitiligo in

  16. Protein-Tyrosine Phosphatase 1B Substrates and Metabolic Regulation

    PubMed Central

    Bakke, Jesse; Haj, Fawaz G.

    2014-01-01

    Metabolic homeostasis requires integration of complex signaling networks which, when deregulated, contribute to metabolic syndrome and related disorders. Protein-tyrosine phosphatase 1B (PTP1B) has emerged as a key regulator of signaling networks that are implicated in metabolic diseases such as obesity and type 2 diabetes. In this review, we examine mechanisms that regulate PTP1B-substrate interaction, enzymatic activity and experimental approaches to identify PTP1B substrates. We then highlight findings that implicate PTP1B in metabolic regulation. In particular, insulin and leptin signaling are discussed as well as recently identified PTP1B substrates that are involved in endoplasmic reticulum stress response, cell-cell communication, energy balance and vesicle trafficking. In summary, PTP1B exhibits exquisite substrate specificity and is an outstanding pharmaceutical target for obesity and type 2 diabetes. PMID:25263014

  17. 1D fast coded aperture camera.

    PubMed

    Haw, Magnus; Bellan, Paul

    2015-04-01

    A fast (100 MHz) 1D coded aperture visible light camera has been developed as a prototype for imaging plasma experiments in the EUV/X-ray bands. The system uses printed patterns on transparency sheets as the masked aperture and an 80 channel photodiode array (9 V reverse bias) as the detector. In the low signal limit, the system has demonstrated 40-fold increase in throughput and a signal-to-noise gain of ≈7 over that of a pinhole camera of equivalent parameters. In its present iteration, the camera can only image visible light; however, the only modifications needed to make the system EUV/X-ray sensitive are to acquire appropriate EUV/X-ray photodiodes and to machine a metal masked aperture. PMID:25933861

  18. 1D fast coded aperture camera.

    PubMed

    Haw, Magnus; Bellan, Paul

    2015-04-01

    A fast (100 MHz) 1D coded aperture visible light camera has been developed as a prototype for imaging plasma experiments in the EUV/X-ray bands. The system uses printed patterns on transparency sheets as the masked aperture and an 80 channel photodiode array (9 V reverse bias) as the detector. In the low signal limit, the system has demonstrated 40-fold increase in throughput and a signal-to-noise gain of ≈7 over that of a pinhole camera of equivalent parameters. In its present iteration, the camera can only image visible light; however, the only modifications needed to make the system EUV/X-ray sensitive are to acquire appropriate EUV/X-ray photodiodes and to machine a metal masked aperture.

  19. 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.

  20. New hippolide derivatives with protein tyrosine phosphatase 1B inhibitory activity from the marine sponge Hippospongia lachne.

    PubMed

    Piao, Shu-Juan; Jiao, Wei-Hua; Yang, Fan; Yi, Yang-Hua; Di, Ying-Tong; Han, Bing-Nan; Lin, Hou-Wen

    2014-07-01

    Five new sesterterpenoids, compounds 1-5, have been isolated from the sponge Hippospongia lachne off Yongxing Island in the South China Sea. The structures of compounds 1-5 were elucidated through extensive spectroscopic analysis, including HRMS, 1D, and 2D NMR experiments. The stereochemistry, including absolute configurations of these compounds, was determined by spectroscopic, chemical, and computational methods. Compounds 1 and 5 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibitory activities with IC50 values of 5.2 μM and 8.7 μM, respectively, more potent than previously reported hippolides.

  1. 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.

  2. 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

  3. Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3

    PubMed Central

    Gui, Chunshan; Miao, Yi; Thompson, Lucas; Wahlgren, Bret; Mock, Melissa; Stieger, Bruno; Hagenbuch, Bruno

    2008-01-01

    The pregnane X receptor is a ligand-activated transcription factor that is abundantly expressed in hepatocytes. Numerous drugs are pregnane X receptor ligands. To bind to their receptor they must cross the sinusoidal membrane. Organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are polyspecific transporters expressed at the sinusoidal membrane of human hepatocytes. They mediate transport of a variety of drugs including the pregnane X receptor ligands rifampicin and dexamethasone. To test whether additional pregnane X receptor ligands interact with OATP1B1- and 1B3-mediated transport, we developed Chinese Hamster Ovary (CHO) cell lines stably expressing OATP1B1 or 1B3 at high levels. OATP1B1- and 1B3-mediated estradiol-17β-glucuronide uptake was inhibited by several pregnane X receptor ligands in a concentration dependent way. IC50 values for rifampicin, paclitaxel, mifepristone, and troglitazone were within their respective pharmacological free plasma concentrations. Kinetic analysis revealed that clotrimazole inhibits OATP1B1-mediated estradiol-17β-glucuronide transport with a Ki of 7.7 ± 0.3 μM in a competitive way. However, uptake of OATP1B3-mediated estradiol-17β-glucuronide was stimulated and this stimulation was due to an increased apparent affinity. Transport of estrone-3-sulfate was hardly affected while all other substrates tested were inhibited. Additional azoles like fluconazole, ketoconazole and miconazole did not stimulate OATP1B3-mediated estradiol-17β-glucuronide transport. In summary, these results demonstrate that pregnane X receptor ligands, by inhibiting or stimulating OATP-mediated uptake, can lead to drug-drug interactions at the transporter level. PMID:18321482

  4. MAN1B1 deficiency: an unexpected CDG-II.

    PubMed

    Rymen, Daisy; Peanne, Romain; Millón, María B; Race, Valérie; Sturiale, Luisa; Garozzo, Domenico; Mills, Philippa; Clayton, Peter; Asteggiano, Carla G; Quelhas, Dulce; Cansu, Ali; Martins, Esmeralda; Nassogne, Marie-Cécile; Gonçalves-Rocha, Miguel; Topaloglu, Haluk; Jaeken, Jaak; Foulquier, François; Matthijs, Gert

    2013-01-01

    Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency. PMID:24348268

  5. Two extreme young objects in Barnard 1-b

    SciTech Connect

    Hirano, Naomi; Liu, Fang-chun

    2014-07-01

    Two submillimeter/millimeter sources in the Barnard 1b (B1-b) core, B1-bN and B1-bS, have been studied in dust continuum, H{sup 13}CO{sup +} J = 1-0, CO J = 2-1, {sup 13}CO J = 2-1, and C{sup 18}O J = 2-1. The spectral energy distributions of these sources from the mid-IR to 7 mm are characterized by very cold temperatures of T {sub dust} < 20 K and low bolometric luminosities of 0.15-0.31 L {sub ☉}. The internal luminosities of B1-bN and B1-bS are estimated to be <0.01-0.03 L {sub ☉} and ∼0.1-0.2 L {sub ☉}, respectively. Millimeter interferometric observations have shown that these sources have already formed central compact objects of ∼100 AU sizes. Both B1-bN and B1-bS are driving the CO outflows with low characteristic velocities of ∼2-4 km s{sup –1}. The fractional abundance of H{sup 13}CO{sup +} at the positions of B1-bN and B1-bS is lower than the canonical value by a factor of four to eight. This implies that a significant fraction of CO is depleted onto dust grains in the dense gas surrounding these sources. The observed physical and chemical properties suggest that B1-bN and B1-bS are in an earlier evolutionary stage than most of the known class 0 protostars. In particular, the properties of B1-bN agree with those of the first hydrostatic core predicted by the MHD simulations. The CO outflow was also detected in the mid-IR source located at ∼15'' from B1-bS. Since the dust continuum emission was not detected in this source, the circumstellar material surrounding this source is less than 0.01 M {sub ☉}. It is likely that the envelope of this source was dissipated by the outflow from the protostar that is located to the southwest of B1-b.

  6. [The interactions between natural products and OATP1B1].

    PubMed

    Shi, Mei-zhi; Liu, Yu; Bian, Jia-lin; Jin, Meng; Gui, Chun-shan

    2015-07-01

    Organic anion transporting polypeptide 1B1 (OATP1B1) is an important liver-specific uptake transporter, which mediates transport of numerous endogenous substances and drugs from blood into hepatocytes. To identify and investigate potential modulators of OATP1B1 from natural products, the effect of 21 frequently used natural compounds and extracts on OATP1B1-mediated fluorescein methotrexate transport was studied by using Chinese hamster ovary cells stably expressing OATP1B1 (CHO-OATP1B1) in 96-well plates. This method could be used for the screening of large compound libraries. Our studies showed that some flavonoids (e.g., quercetin, quercitrin, rutin, chrysanthemum flavonoids and mulberrin) and triterpenoids (e.g., glycyrrhetinic acid and glycyrrhizic acid) were inhibitors of OATP1B1 with IC50 values less than 16 µmol · L(-1). The IC50 value of glycyrrhetinic acid on OATP1B1 was comparable to its blood concentration in clinics, indicating an OATPlB1-mediated drug-drug interaction could occur. Structure-activity relationship analysis showed that flavonoids had much higher inhibitory activity than their glycosides. Furthermore, the type and length of saccharides had a significant effect on their activity. In addition, we used OATP1B1 substrates fluvastatin and rosuvastatin as probe drugs to investigate the substrate-dependent effect of several natural compounds on the function of OATP1B1 in vitro. Our results demonstrated that the effect of these natural products on the function of OATPlB1 was substrate-dependent. In summary, this study would be conducive to predicting and avoiding potential OATP1B1-mediated drug-drug and drug-food interactions and thus provide the experimental basis and guidance for rational drug use. PMID:26552146

  7. Aldo-Keto Reductases 1B in Endocrinology and Metabolism

    PubMed Central

    Pastel, Emilie; Pointud, Jean-Christophe; Volat, Fanny; Martinez, Antoine; Lefrançois-Martinez, Anne-Marie

    2012-01-01

    The aldose reductase (AR; human AKR1B1/mouse Akr1b3) has been the focus of many research because of its role in diabetic complications. The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme. However, the issue of AR function in non-diabetic condition remains unresolved. AR-like enzymes (AKR1B10, Akr1b7, and Akr1b8) are highly related isoforms often co-expressed with bona fide AR, making functional analysis of one or the other isoform a challenging task. AKR1B/Akr1b members share at least 65% protein identity and the general ability to reduce many redundant substrates such as aldehydes provided from lipid peroxidation, steroids and their by-products, and xenobiotics in vitro. Based on these properties, AKR1B/Akr1b are generally considered as detoxifying enzymes. Considering that divergences should be more informative than similarities to help understanding their physiological functions, we chose to review specific hallmarks of each human/mouse isoforms by focusing on tissue distribution and specific mechanisms of gene regulation. Indeed, although the AR shows ubiquitous expression, AR-like proteins exhibit tissue-specific patterns of expression. We focused on three organs where certain isoforms are enriched, the adrenal gland, enterohepatic, and adipose tissues and tried to connect recent enzymatic and regulation data with endocrine and metabolic functions of these organs. We presented recent mouse models showing unsuspected physiological functions in the regulation of glucido-lipidic metabolism and adipose tissue homeostasis. Beyond the widely accepted idea that AKR1B/Akr1b are detoxification enzymes, these recent reports provide growing evidences that they are able to modify or generate signal molecules. This conceptually shifts this class of enzymes from unenviable status of scavenger to upper class of messengers. PMID:22876234

  8. Aldo-Keto Reductases 1B in Endocrinology and Metabolism.

    PubMed

    Pastel, Emilie; Pointud, Jean-Christophe; Volat, Fanny; Martinez, Antoine; Lefrançois-Martinez, Anne-Marie

    2012-01-01

    The aldose reductase (AR; human AKR1B1/mouse Akr1b3) has been the focus of many research because of its role in diabetic complications. The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme. However, the issue of AR function in non-diabetic condition remains unresolved. AR-like enzymes (AKR1B10, Akr1b7, and Akr1b8) are highly related isoforms often co-expressed with bona fide AR, making functional analysis of one or the other isoform a challenging task. AKR1B/Akr1b members share at least 65% protein identity and the general ability to reduce many redundant substrates such as aldehydes provided from lipid peroxidation, steroids and their by-products, and xenobiotics in vitro. Based on these properties, AKR1B/Akr1b are generally considered as detoxifying enzymes. Considering that divergences should be more informative than similarities to help understanding their physiological functions, we chose to review specific hallmarks of each human/mouse isoforms by focusing on tissue distribution and specific mechanisms of gene regulation. Indeed, although the AR shows ubiquitous expression, AR-like proteins exhibit tissue-specific patterns of expression. We focused on three organs where certain isoforms are enriched, the adrenal gland, enterohepatic, and adipose tissues and tried to connect recent enzymatic and regulation data with endocrine and metabolic functions of these organs. We presented recent mouse models showing unsuspected physiological functions in the regulation of glucido-lipidic metabolism and adipose tissue homeostasis. Beyond the widely accepted idea that AKR1B/Akr1b are detoxification enzymes, these recent reports provide growing evidences that they are able to modify or generate signal molecules. This conceptually shifts this class of enzymes from unenviable status of scavenger to upper class of messengers.

  9. 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

  10. Small molecules as potent protein tyrosine phosphatase 1B (PTP1B) inhibitors documented in patents from 2009 to 2013.

    PubMed

    Wang, Li-Jun; Jiang, Bo; Wu, Ning; Wang, Shuai-Yu; Shi, Da-Yong

    2015-01-01

    Diabetes mellitus, including type 1 and type 2 diabetes mellitus (2-DM) are the main threats to human health in the worldwide. Protein tyrosine phosphatase 1B (PTP1B) is a promising molecular level legitimate therapeutic target in the effective management of 2-DM. For the search of potent PTP1B inhibitors, much investigation has revealed a large number of small-molecule compounds obtained from natural sources or prepared by synthesis/semi-synthesis with various skeletons and promising anti-PTP1B activities in the treatment of 2-DM. Although some reviews on the development of PTP1B inhibitors have been published, they were mainly concentrated on the results reported in journal articles. In this review, we will provide an overview of the developments of the potent PTP1B inhibitors claimed in recent patents during the past five years (2009-2013) with their structural features and biological features, as well as the structure-activity relationships (SARs) and strategies for finding potent and specific PTP1B inhibitors. This paper will provide valuable information for understanding the current anti-PTP1B investigation and developing potent PTP1B inhibitors as treating 2-DM drugs. PMID:25643610

  11. Aldo-Keto Reductases 1B in Adrenal Cortex Physiology.

    PubMed

    Pastel, Emilie; Pointud, Jean-Christophe; Martinez, Antoine; Lefrançois-Martinez, A Marie

    2016-01-01

    Aldose reductase (AKR1B) proteins are monomeric enzymes, belonging to the aldo-keto reductase (AKR) superfamily. They perform oxidoreduction of carbonyl groups from a wide variety of substrates, such as aliphatic and aromatic aldehydes or ketones. Due to the involvement of human aldose reductases in pathologies, such as diabetic complications and cancer, AKR1B subgroup enzymatic properties have been extensively characterized. However, the issue of AKR1B function in non-pathologic conditions remains poorly resolved. Adrenal activities generated large amount of harmful aldehydes from lipid peroxidation and steroidogenesis, including 4-hydroxynonenal (4-HNE) and isocaproaldehyde (4-methylpentanal), which can both be reduced by AKR1B proteins. More recently, some AKR1B isoforms have been shown to be endowed with prostaglandin F synthase (PGFS) activity, suggesting that, in addition to possible scavenger function, they could instigate paracrine signals. Interestingly, the adrenal gland is one of the major sites for human and murine AKR1B expression, suggesting that their detoxifying/signaling activity could be specifically required for the correct handling of adrenal function. Moreover, chronic effects of ACTH result in a coordinated regulation of genes encoding the steroidogenic enzymes and some AKR1B isoforms. This review presents the molecular mechanisms accounting for the adrenal-specific expression of some AKR1B genes. Using data from recent mouse genetic models, we will try to connect their enzymatic properties and regulation with adrenal functions.

  12. Aldo-Keto Reductases 1B in Adrenal Cortex Physiology

    PubMed Central

    Pastel, Emilie; Pointud, Jean-Christophe; Martinez, Antoine; Lefrançois-Martinez, A. Marie

    2016-01-01

    Aldose reductase (AKR1B) proteins are monomeric enzymes, belonging to the aldo-keto reductase (AKR) superfamily. They perform oxidoreduction of carbonyl groups from a wide variety of substrates, such as aliphatic and aromatic aldehydes or ketones. Due to the involvement of human aldose reductases in pathologies, such as diabetic complications and cancer, AKR1B subgroup enzymatic properties have been extensively characterized. However, the issue of AKR1B function in non-pathologic conditions remains poorly resolved. Adrenal activities generated large amount of harmful aldehydes from lipid peroxidation and steroidogenesis, including 4-hydroxynonenal (4-HNE) and isocaproaldehyde (4-methylpentanal), which can both be reduced by AKR1B proteins. More recently, some AKR1B isoforms have been shown to be endowed with prostaglandin F synthase (PGFS) activity, suggesting that, in addition to possible scavenger function, they could instigate paracrine signals. Interestingly, the adrenal gland is one of the major sites for human and murine AKR1B expression, suggesting that their detoxifying/signaling activity could be specifically required for the correct handling of adrenal function. Moreover, chronic effects of ACTH result in a coordinated regulation of genes encoding the steroidogenic enzymes and some AKR1B isoforms. This review presents the molecular mechanisms accounting for the adrenal-specific expression of some AKR1B genes. Using data from recent mouse genetic models, we will try to connect their enzymatic properties and regulation with adrenal functions. PMID:27499746

  13. Aldo-Keto Reductases 1B in Adrenal Cortex Physiology.

    PubMed

    Pastel, Emilie; Pointud, Jean-Christophe; Martinez, Antoine; Lefrançois-Martinez, A Marie

    2016-01-01

    Aldose reductase (AKR1B) proteins are monomeric enzymes, belonging to the aldo-keto reductase (AKR) superfamily. They perform oxidoreduction of carbonyl groups from a wide variety of substrates, such as aliphatic and aromatic aldehydes or ketones. Due to the involvement of human aldose reductases in pathologies, such as diabetic complications and cancer, AKR1B subgroup enzymatic properties have been extensively characterized. However, the issue of AKR1B function in non-pathologic conditions remains poorly resolved. Adrenal activities generated large amount of harmful aldehydes from lipid peroxidation and steroidogenesis, including 4-hydroxynonenal (4-HNE) and isocaproaldehyde (4-methylpentanal), which can both be reduced by AKR1B proteins. More recently, some AKR1B isoforms have been shown to be endowed with prostaglandin F synthase (PGFS) activity, suggesting that, in addition to possible scavenger function, they could instigate paracrine signals. Interestingly, the adrenal gland is one of the major sites for human and murine AKR1B expression, suggesting that their detoxifying/signaling activity could be specifically required for the correct handling of adrenal function. Moreover, chronic effects of ACTH result in a coordinated regulation of genes encoding the steroidogenic enzymes and some AKR1B isoforms. This review presents the molecular mechanisms accounting for the adrenal-specific expression of some AKR1B genes. Using data from recent mouse genetic models, we will try to connect their enzymatic properties and regulation with adrenal functions. PMID:27499746

  14. 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...

  15. 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...

  16. 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...

  17. 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... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18...

  18. 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...

  19. 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...

  20. Organic anion transporter 3- and organic anion transporting polypeptides 1B1- and 1B3-mediated transport of catalposide

    PubMed Central

    Jeong, Hyeon-Uk; Kwon, Mihwa; Lee, Yongnam; Yoo, Ji Seok; Shin, Dae Hee; Song, Im-Sook; Lee, Hye Suk

    2015-01-01

    We investigated the in vitro transport characteristics of catalposide in HEK293 cells overexpressing organic anion transporter 1 (OAT1), OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, organic cation transporter 1 (OCT1), OCT2, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). The transport mechanism of catalposide was investigated in HEK293 and LLC-PK1 cells overexpressing the relevant transporters. The uptake of catalposide was 319-, 13.6-, and 9.3-fold greater in HEK293 cells overexpressing OAT3, OATP1B1, and OATP1B3 transporters, respectively, than in HEK293 control cells. The increased uptake of catalposide via the OAT3, OATP1B1, and OATP1B3 transporters was decreased to basal levels in the presence of representative inhibitors such as probenecid, furosemide, and cimetidine (for OAT3) and cyclosporin A, gemfibrozil, and rifampin (for OATP1B1 and OATP1B3). The concentration-dependent OAT3-mediated uptake of catalposide revealed the following kinetic parameters: Michaelis constant (Km) =41.5 μM, maximum uptake rate (Vmax) =46.2 pmol/minute, and intrinsic clearance (CLint) =1.11 μL/minute. OATP1B1- and OATP1B3-mediated catalposide uptake also showed concentration dependency, with low CLint values of 0.035 and 0.034 μL/minute, respectively. However, the OCT1, OCT2, OAT1, P-gp, and BCRP transporters were apparently not involved in the uptake of catalposide into cells. In addition, catalposide inhibited the transport activities of OAT3, OATP1B1, and OATP1B3 with half-maximal inhibitory concentration values of 83, 200, and 235 μM, respectively. However, catalposide did not significantly inhibit the transport activities of OCT1, OCT2, OAT1, P-gp, or BCRP. In conclusion, OAT3, OATP1B1, and OATP1B3 are major transporters that may regulate the pharmacokinetic properties and may cause herb–drug interactions of catalposide, although their clinical relevance awaits further evaluation. PMID:25653502

  1. Role of 5-hydroxytryptamine 1B (5-HT1B) receptors in the regulation of ethanol intake in rodents

    PubMed Central

    Sari, Youssef

    2012-01-01

    Evidence indicates that the serotonergic system is important in mediating dependence on and craving for alcohol. Among serotonin receptors, 5-hydroxytryptamine 1B (5-HT1B) receptors have been associated with drug abuse including alcohol. In this review, the neurocircuitry involving 5-HT1B receptors in central reward brain regions related to alcohol intake are discussed in detail. Emphasis has been placed on the pharmacological manipulations of 5-HT1B receptor-mediated alcohol intake. Furthermore, 5-HT1B auto- and hetero-receptors regulate alcohol intake through the regulatory mechanism involving release of 5-HT, gamma-aminobutyric acid (GABA), dopamine, and glutamate is evaluated. Thus, interactions between 5-HT1B receptors and these neurotransmitter systems are suggested to modulate alcohol-drinking behavior. This review on the role of 5-HT1B receptors in neurotransmitter release and consequent alcohol intake provides important information about the potential therapeutic role of 5-HT1B receptors for the treatment of alcohol dependence. PMID:23118018

  2. Calpain-catalyzed cleavage and subcellular relocation of protein phosphotyrosine phosphatase 1B (PTP-1B) in human platelets.

    PubMed Central

    Frangioni, J V; Oda, A; Smith, M; Salzman, E W; Neel, B G

    1993-01-01

    The non-transmembrane phosphotyrosine phosphatase 1B (PTP-1B) is an abundant enzyme, normally localized to the cytosolic face of the endoplasmic reticulum via a C-terminal targeting sequence. We have found that agonist-induced platelet activation results in proteolytic cleavage of PTP-1B at a site upstream from this targeting sequence, causing subcellular relocation of its catalytic domain from membranes to the cytosol. PTP-1B cleavage is catalyzed by the calcium-dependent neutral protease calpain and is a general feature of platelet agonist-induced aggregation. Moreover, PTP-1B cleavage correlates with the transition from reversible to irreversible platelet aggregation in platelet-rich plasma. Engagement of gpIIb-IIIa is necessary for inducing PTP-1B cleavage, suggesting that integrins regulate tyrosine phosphatases as well as tyrosine kinases. PTP-1B cleavage is accompanied by a 2-fold stimulation of its enzymatic activity, as measured by immune complex phosphatase assay, and correlates with discrete changes in the pattern of tyrosyl phosphorylation. Cleavage and subcellular relocation of PTP-1B represents a novel mechanism for altering tyrosyl phosphorylation that may have important physiological implications in cell types other than platelets. Images PMID:8223493

  3. 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

    2007-02-01

    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.

  4. Evidence for an age-dependent functional expression of alpha 1D-adrenoceptors in the rat vasculature.

    PubMed

    Ibarra, M; Terrón, J A; López-Guerrero, J J; Villalobos-Molina, R

    1997-03-19

    The role of the alpha 1-adrenoceptor subtypes, and their possible change with maturation, in alpha 1-adrenoceptor-induced pressor responses in the rat has not been established. Thus, the effects of the alpha 1D-, alpha 1A/1D- and alpha 1B/1D-adrenoceptor antagonists, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl) 8-azaspiro (4.5) decane-7,9-dione 2HCl), 5-methyl-urapidil and chloroethylclonidine, respectively, on the pressor responses induced by phenylephrine in 1- and 5-month-old pithed rats were investigated. The pressor responses induced by phenylephrine were competitively antagonized by both BMY 7378 and chloroethylclonidine in 5-month-old, but not in young immature animals; in marked contrast, 5-methylurapidil antagonized with similar potency the phenylephrine-induced pressor responses in animals of both ages. The present pharmacological data suggest that functional expression of alpha 1D-adrenoceptors in the rat resistance vessels increases with age; alpha 1A-, but not alpha 1B- or alpha 1D-adrenoceptors, seem to predominate in immature animals. These findings represent the first evidence that age-related changes in functional alpha 1-adrenoceptor subtypes occur in the systemic vasculature in vivo. PMID:9098690

  5. Enhanced skin carcinogenesis and lack of thymus hyperplasia in transgenic mice expressing human cyclin D1b (CCND1b)

    PubMed Central

    Rojas, Paola; Benavides, Fernando; Blando, Jorge; Perez, Carlos; Cardenas, Kim; Richie, Ellen; Knudsen, Erik S.; Johnson, David G.; Senderowicz, Adrian M.; Rodriguez-Puebla, Marcelo L.; Conti, Claudio J.

    2009-01-01

    Cyclin D1b is an alternative transcript of the cyclin D1 gene (CCND1) expressed in human tumors. Its abundance is regulated by a single base pair polymorphism at the exon 4/intron 4 boundary (nucleotide 870). Epidemiological studies have shown a correlation between the presence of the G870A allele (that favors the splicing for cyclin D1b) with increased risk and less favorable outcome in several forms of cancer. More recently, it has been shown that, unlike cyclin D1a, the alternative transcript D1b by itself has the capacity to transform fibroblasts in vitro. In order to study the oncogenic potential of cyclin D1b, we developed transgenic mice expressing human cyclin D1b under the control of the bovine K5 promoter (K5D1b mice). Seven founders were obtained and none of them presented any significant phenotype or developed spontaneous tumors. Interestingly, K5D1b mice do not develop the fatal thymic hyperplasia, which is characteristic of the cyclin D1a transgenic mice (K5D1a). Susceptibility to skin carcinogenesis was tested in K5D1b mice using two-stage carcinogenesis protocols. In two independent experiments, K5D1b mice developed higher papilloma multiplicity as compared with wild-type littermates. However, when K5D1b mice were crossed with cyclin D1KO mice, the expression of cyclin D1b was unable to rescue the carcinogenesis-resistant phenotype of the cyclin D1 KO mice. To further explore the role of cyclin D1b in mouse models of carcinogenesis we carried out in silico analysis and in vitro experiments to evaluate the existence of a mouse homologous of the human cyclin D1b transcript. We were unable to find any evidence of an alternatively spliced transcript in mouse Ccnd1. These results show that human cyclin D1b has different biological functions than cyclin D1a and confirm its oncogenic properties. PMID:18942117

  6. 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

  7. 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

    2008-03-01

    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.

  8. Identification of Bidentate Salicylic Acid Inhibitors of PTP1B

    PubMed Central

    2015-01-01

    PTP1B is a master regulator in the insulin and leptin metabolic pathways. Hyper-activated PTP1B results in insulin resistance and is viewed as a key factor in the onset of type II diabetes and obesity. Moreover, inhibition of PTP1B expression in cancer cells dramatically inhibits cell growth in vitro and in vivo. Herein, we report the computationally guided optimization of a salicylic acid-based PTP1B inhibitor 6, identifying new and more potent bidentate PTP1B inhibitors, such as 20h, which exhibited a > 4-fold improvement in activity. In CHO-IR cells, 20f, 20h, and 20j suppressed PTP1B activity and restored insulin receptor phosphorylation levels. Notably, 20f, which displayed a 5-fold selectivity for PTP1B over the closely related PTPσ protein, showed no inhibition of PTP-LAR, PRL2 A/S, MKPX, or papain. Finally, 20i and 20j displayed nanomolar inhibition of PTPσ, representing interesting lead compounds for further investigation. PMID:26396684

  9. The role of stat1b in zebrafish hematopoiesis

    PubMed Central

    Song, Hao; Yan, Yi-lin; Titus, Tom; He, Xinjun; Postlethwait, John H.

    2011-01-01

    STAT1 mediates response to interferons and regulates immunity, cell proliferation, apoptosis, and sensitivity of Fanconi Anemia cells to apoptosis after interferon signaling; the roles of STAT1 in embryos, however, are not understood. To explore embryonic functions of STAT1, we investigated stat1b, an unstudied zebrafish co-ortholog of human STAT1. Zebrafish stat1a encodes all five domains of the human STAT1-alpha splice form but, like the human STAT1-beta splice variant, stat1b lacks a complete transactivation domain; thus, two unlinked zebrafish paralogs encode protein forms translated from two splice variants of a single human gene, as expected by subfunctionalization after genome duplication. Phylogenetic and conserved synteny studies showed that stat1b and stat1a arose as duplicates in the teleost genome duplication (TGD) and clarified the evolutionary origin of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 by tandem and genome duplication. RT-PCR revealed maternal expression of stat1a and stat1b. In situ hybridization detected stat1b but not stat1a expression in embryonic hematopoietic tissues. Morpholino knockdown of stat1b, but not stat1a, decreased expression of the myeloid and granulocyte markers spi and mpo and increased expression of the hematopoietic progenitor marker scl, the erythrocyte marker gata1, and hemoglobin. These results suggest that zebrafish Stat1b promotes myeloid development at the expense of erythroid development. PMID:21914475

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

    PubMed

    Kotsampasakou, Eleni; Brenner, Stefan; Jäger, Walter; Ecker, Gerhard F

    2015-12-01

    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

  11. Pharmacokinetic effects of curcumin on docetaxel mediated by OATP1B1, OATP1B3 and CYP450s.

    PubMed

    Sun, Xiaolin; Li, Junxiu; Guo, Chaorui; Xing, Han; Xu, Jie; Wen, Yanli; Qiu, Zhixia; Zhang, Qiuyang; Zheng, Yi; Chen, Xijing; Zhao, Di

    2016-08-01

    Curcumin can synergistically enhance docetaxel's in vitro and in vivo antitumor activity and has been co-administrated with docetaxel in clinical trials. The aim of our study is to investigate the effect of curcumin on the pharmacokinetics of docetaxel and explore its mechanism on OATP1B1, OATP1B3 and human liver microsomes (HLMs). In rats, curcumin increased the docetaxel area under the plasma concentration-time curve (AUC0-8h) and the terminal half-life (t1/2) to 1.86- and 1.55-fold, respectively. Moreover, curcumin decreased the clearance (CL) of docetaxel to 52.1%. Human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1 and OATP1B3 were used to observe the effects of curcumin on OATP1B1 and OATP1B3-mediated uptake of docetaxel. Curcumin exhibited potent inhibition on OATP1B1 and OATP1B3-mediated docetaxel uptake with IC50 values of 3.81 ± 1.19 μM and 33.70 ± 1.22 μM, respectively. The inhibition of curcumin on docetaxel metabolism in HLMs indicated that curcumin can modestly inhibit the metabolism of docetaxel with the IC50 value of 22.70 ± 1.13 μM and Ki value of 24.72 ± 4.24 μM. The preclinical and clinical improved docetaxel's therapeutic efficacy when co-administrated with curcumin may be due to the inhibition of curcumin on OATP1B1, OATP1B3 and HLMs activities. Close attention should be paid when combined treatment with docetaxel and curcumin carried out clinically. PMID:27452633

  12. 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

    2015-03-01

    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.

  13. 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. PMID:25658124

  14. PTP1B: a double agent in metabolism and oncogenesis

    PubMed Central

    Yip, Shu-Chin; Saha, Sayanti; Chernoff, Jonathan

    2010-01-01

    PTP1B, a non-transmembrane protein tyrosine phosphatase that has long been studied as a negative regulator of insulin and leptin signaling, has recently received renewed attention as an unexpected positive factor in tumorigenesis. In this review, we highlight how views of this enzyme have evolved from regarding it as a simple metabolic off-switch to a more complex view of PTP1B as an enzyme that can play both negative and positive roles diverse signaling pathways. These dual characteristics make PTP1B a particularly attractive therapeutic target for diabetes, obesity, and perhaps breast cancer. PMID:20381358

  15. [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.

  16. 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.

  17. Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta.

    PubMed Central

    Weinshank, R L; Zgombick, J M; Macchi, M J; Branchek, T A; Hartig, P R

    1992-01-01

    The serotonin 1D (5-HT1D) receptor is a pharmacologically defined binding site and functional receptor site. Observed variations in the properties of 5-HT1D receptors in different tissues have led to the speculation that multiple receptor proteins with slightly different properties may exist. We report here the cloning, deduced amino acid sequences, pharmacological properties, and second-messenger coupling of a pair of human 5-HT1D receptor genes, which we have designated 5-HT1D alpha and 5-HT1D beta due to their strong similarities in sequence, pharmacological properties, and second-messenger coupling. Both genes are free of introns in their coding regions, are expressed in the human cerebral cortex, and can couple to inhibition of adenylate cyclase activity. The pharmacological binding properties of these two human receptors are very similar, and match closely the pharmacological properties of human, bovine, and guinea pig 5-HT1D sites. Both receptors exhibit high-affinity binding of sumatriptan, a new anti-migraine medication, and thus are candidates for the pharmacological site of action of this drug. Images PMID:1565658

  18. Recombinant saphenous vein 5-HT1B receptors of the rabbit: comparative pharmacology with human 5-HT1B receptors.

    PubMed

    Wurch, T; Palmier, C; Colpaert, F C; Pauwels, P J

    1997-01-01

    1. The rabbit recombinant saphenous vein 5-hydroxytryptamine1B (r 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by measuring adenosine 3':5'-cyclic monophosphate (cycle AMP) formation upon exposure to various 5-HT receptor ligands. The effects of agonists and antagonists were compared with their effects determined previously at the human cloned 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2. Intact C6-glial cells expressing rb HT1B receptors exhibited [3H]-5-carboxamidotryptamine (5-CT) binding sites with a Kd of 0.80 +/- 0.13 nM and a Bmax between 225 to 570 fmol mg-1 protein. The binding affinities of a series of 5-HT receptor ligands determined in a membrane preparation with [3H]-5-CT or [3H]-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(-4 -pyridyl) benzamide (GR 125,743) were similar. With the exception of ketanserin, ligand affinities were comparable to those determined at the clones h 5-HT1B receptor site. 3. rb 5-HT1B receptors were negatively coupled to cyclic AMP formation upon stimulation with 5-HT agonists. Of the several 5-HT agonists tested, 5-CT was the most potent, the potency rank order being: 5-CT > 5-HT > zolmitriptan > naratriptan > rizatriptan > sumatriptan > R (+)-8-(hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The maximal responses of these agonists were similar to those induced by 5-HT. The potency of these agonists showed a positive correlation (r2 = 0.87; P < 0.002) with their potency at the cloned h 5-HT1B receptor subtype. 4. 2'-Methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-e-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935), methiothepin and ketanserin each behaved as silent, competitive antagonists at rb 5HT1B receptors; pKB values were 8.41, 8.32 and 7.05, respectively when naratriptan was used as an agonist. These estimates accorded with their binding affinities and the potencies found on 5-HT and/or sumatriptan

  19. Association of transcription factor gene LMX1B with autism.

    PubMed

    Thanseem, Ismail; Nakamura, Kazuhiko; Anitha, Ayyappan; Suda, Shiro; Yamada, Kazuo; Iwayama, Yoshimi; Toyota, Tomoko; Tsujii, Masatsugu; Iwata, Yasuhide; Suzuki, Katsuaki; Matsuzaki, Hideo; Iwata, Keiko; Sugiyama, Toshiro; Yoshikawa, Takeo; Mori, Norio

    2011-01-01

    Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report.

  20. Association of Transcription Factor Gene LMX1B with Autism

    PubMed Central

    Yamada, Kazuo; Iwayama, Yoshimi; Toyota, Tomoko; Tsujii, Masatsugu; Iwata, Yasuhide; Suzuki, Katsuaki; Matsuzaki, Hideo; Iwata, Keiko; Sugiyama, Toshiro; Yoshikawa, Takeo; Mori, Norio

    2011-01-01

    Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report. PMID:21901133

  1. 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.

  2. UBC9-dependent Association between Calnexin and Protein Tyrosine Phosphatase 1B (PTP1B) at the Endoplasmic Reticulum*

    PubMed Central

    Lee, Dukgyu; Kraus, Allison; Prins, Daniel; Groenendyk, Jody; Aubry, Isabelle; Liu, Wen-Xin; Li, Hao-Dong; Julien, Olivier; Touret, Nicolas; Sykes, Brian D.; Tremblay, Michel L.; Michalak, Marek

    2015-01-01

    Calnexin is a type I integral endoplasmic reticulum (ER) membrane protein, molecular chaperone, and a component of the translocon. We discovered a novel interaction between the calnexin cytoplasmic domain and UBC9, a SUMOylation E2 ligase, which modified the calnexin cytoplasmic domain by the addition of SUMO. We demonstrated that calnexin interaction with the SUMOylation machinery modulates an interaction with protein tyrosine phosphatase 1B (PTP1B), an ER-associated protein tyrosine phosphatase involved in the negative regulation of insulin and leptin signaling. We showed that calnexin and PTP1B form UBC9-dependent complexes, revealing a previously unrecognized contribution of calnexin to the retention of PTP1B at the ER membrane. This work shows that the SUMOylation machinery links two ER proteins from divergent pathways to potentially affect cellular protein quality control and energy metabolism. PMID:25586181

  3. 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.

  4. A review of rizatriptan, a quick and consistent 5-HT1B/1D agonist for the acute treatment of migraine.

    PubMed

    Pascual, Julio

    2004-03-01

    Rizatriptan is a second-generation triptan marketed as 5 and 10 mg tablets and rapidly disintegrating wafer formulations. In > 5000 acute migraine patients enrolled in short-term trials and almost 1800 patients in long-term, open-label trials treating approximately 47000 attacks, rizatriptan was effective and well-tolerated. Controlled head-to-head data and a meta-analysis of 53 randomised, placebo-controlled trials of oral triptans in > 24000 patients have shown that rizatriptan 10 mg offers efficacy advantages over oral sumatriptan 50 and 100 mg and other oral triptans, both in terms of speed of onset of action and consistency. These advantages may reflect its improved pharmacological profile over sumatriptan in terms of higher oral bioavailability and a shorter time to maximum concentration. The wafer formulation offers the convenience of being administered without water. As a result of its superior efficacy profile and generally good tolerability, rizatriptan can be considered as a first-line treatment for acute migraine. PMID:15013934

  5. How efficacious are 5-HT1B/D receptor ligands: an answer from GTP gamma S binding studies with stably transfected C6-glial cell lines.

    PubMed

    Pauwels, P J; Tardif, S; Palmier, C; Wurch, T; Colpaert, F C

    1997-01-01

    The intrinsic activity of a series of 5-hydroxytryptamine (serotonin, 5-HT) receptor ligands was analysed at recombinant h5-HT1B and h5-HT1D receptor sites using a [35S]GTP gamma S binding assay and membrane preparations of stably transfected C6-glial cell lines. Compounds either stimulated or inhibited [35S]GTP gamma S binding to a membrane preparation containing either h5-HT1B or h5-HT1D receptors. The potencies observed for most of the compounds at the h5-HT1B receptor subtype correlated with their potencies measured by inhibition of stimulated cAMP formation on intact cells. Apparent agonist potencies in the [35S]GTP gamma S binding assay to C6-glial/h5-HT1D membranes were, with the exception of 2-[5-[3-(4-methylsulphonylamino)benzyl-1 2,4-oxadiazol-5-yl]-1H-indol-3-yl] ethanamine (L694247), 5- to 13-times lower than in the cAMP assay on intact cells. This suggests that receptor coupling in the h5-HT1D membrane preparation is less efficient than that in the intact cell. It further appeared that 6-times more h5-HT1D than h5-HT1B binding sites were required to attain a similar, maximal (73%), 5-HT-stimulated [35S]GTP gamma S binding response: Hence, the h5-HT1B receptor in C6-glial cell membranes could be more efficiently coupled, even though some compounds more readily displayed intrinsic activity at h5-HT1D receptor sites [e.g. dihydroergotamine and (2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR127935)]. Efficacy differences were apparent for most of the compounds (sumatriptan, zolmitriptan, rizatriptan, N-methyl-3-[pyrrolidin-2(R)-ylmethyl]-1H-indol-5-ylmethyl sulfonamide (CP122638), dihydroergotamine, naratriptan and GR127935) that stimulated [35S]GTP gamma S binding compared to the native agonist 5-HT. The observed maximal responses were different for the h5-HT1B and h5-HT1D receptor subtypes. Few compounds behaved as full agonists: L694247, zolmitriptan and sumatriptan did so at

  6. Ferredoxin 1b (Fdx1b) Is the Essential Mitochondrial Redox Partner for Cortisol Biosynthesis in Zebrafish.

    PubMed

    Griffin, Aliesha; Parajes, Silvia; Weger, Meltem; Zaucker, Andreas; Taylor, Angela E; O'Neil, Donna M; Müller, Ferenc; Krone, Nils

    2016-03-01

    Mitochondrial cytochrome P450 (CYP) enzymes rely on electron transfer from the redox partner ferredoxin 1 (FDX1) for catalytic activity. Key steps in steroidogenesis require mitochondrial CYP enzymes and FDX1. Over 30 ferredoxin mutations have been explored in vitro; however, no spontaneously occurring mutations have been identified in humans leaving the impact of FDX1 on steroidogenesis in the whole organism largely unknown. Zebrafish are an important model to study human steroidogenesis, because they have similar steroid products and endocrine tissues. This study aimed to characterize the influence of ferredoxin on steroidogenic capacity in vivo by using zebrafish. Zebrafish have duplicate ferredoxin paralogs: fdx1 and fdx1b. Although fdx1 was observed throughout development and in most tissues, fdx1b was expressed after development of the zebrafish interrenal gland (counterpart to the mammalian adrenal gland). Additionally, fdx1b was restricted to adult steroidogenic tissues, such as the interrenal, gonads, and brain, suggesting that fdx1b was interacting with steroidogenic CYP enzymes. By using transcription activator-like effector nucleases, we generated fdx1b mutant zebrafish lines. Larvae with genetic disruption of fdx1b were morphologically inconspicuous. However, steroid hormone analysis by liquid chromatography tandem mass spectrometry revealed fdx1b mutants failed to synthesize glucocorticoids. Additionally, these mutants had an up-regulation of the hypothalamus-pituitary-interrenal axis and showed altered dark-light adaptation, suggesting impaired cortisol signaling. Antisense morpholino knockdown confirmed Fdx1b is required for de novo cortisol biosynthesis. In summary, by using zebrafish, we generated a ferredoxin knockout model system, which demonstrates for the first time the impact of mitochondrial redox regulation on glucocorticoid biosynthesis in vivo.

  7. Carnitine Palmitoyltransferase-1b (CPT1b) Deficiency Aggravates Pressure-Overload-Induced Cardiac Hypertrophy due to Lipotoxicity

    PubMed Central

    He, Lan; Kim, Teayoun; Long, Qinqiang; Liu, Jian; Wang, Peiyong; Zhou, Yiqun; Ding, Yishu; Prasain, Jeevan; Wood, Philip A.; Yang, Qinglin

    2012-01-01

    Background Carnitine palmitoyltransferase 1(CPT1) is a rate-limiting step of mitochondrial β-oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT-1 activity by specific CPT-1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby posting concerns on the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 in order to evaluate it as a safe and effective therapeutic approach. Methods and Results Heterozygous CPT1b knockout mice (CPT1b+/−) were subjected to transverse aorta constriction (TAC)-induced pressure-overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by two weeks of transverse aorta constriction (TAC), CPT1b+/− mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b+/− mice exhibited exacerbated cardiac hypertrophy and remodeling compared with that in wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b+/− than in controlled mice. Moreover, the CPT1b+/− heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocytes apoptosis. Conclusions We conclude that CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be applied in the clinical use of CPT-1 inhibitors. PMID:22932257

  8. Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b).

    PubMed

    Kuijpers, Taco W; Maianski, Nikolai A; Tool, Anton T J; Smit, G Peter A; Rake, Jan Peter; Roos, Dirk; Visser, Gepke

    2003-06-15

    Glycogen storage disease type 1b (GSD1b) is a rare autosomal recessive disorder characterized by hypoglycemia, hepatomegaly, and growth retardation, and associated-for unknown reasons- with neutropenia and neutrophil dysfunction. In 5 GSD1b patients in whom nicotin-amide adenine dinucleotide phosphate-oxidase activity and chemotaxis were defective, we found that the majority of circulating granulocytes bound Annexin-V. The neutrophils showed signs of apoptosis with increased caspase activity, condensed nuclei, and perinuclear clustering of mitochondria to which the proapoptotic Bcl-2 member Bax had translocated already. Granulocyte colony-stimulating factor (G-CSF) addition to in vitro cultures did not rescue the GSD1b neutrophils from apoptosis as occurs with G-CSF-treated control neutrophils. Moreover, the 2 GSD1b patients on G-CSF treatment did not show significantly lower levels of apoptotic neutrophils in the bloodstream. Current understanding of neutrophil apoptosis and the accompanying functional demise suggests that GSD1b granulocytes are dysfunctional because they are apoptotic. PMID:12576310

  9. Triptan-induced contractile (5-HT1B receptor) responses in human cerebral and coronary arteries: relationship to clinical effect.

    PubMed

    Edvinsson, Lars; Uddman, Erik; Wackenfors, Angelica; Davenport, Anthony; Longmore, Jenny; Malmsjö, Malin

    2005-09-01

    Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine whether there was any relationship with the maximal plasma concentrations (Cmax; nM) of the drugs achieved following oral administration of clinically relevant doses to man using values reported in the literature. We also examined the expression of 5-HT1B receptors in atherosclerotic and normal coronary arteries. The vasocontractile responses to sumatriptan, rizatriptan or eletriptan were characterized by in vitro pharmacology. The ratio of Cmax/EC50 was calculated. 5-HT1B and 5-HT1D receptors were visualized by immunohistochemical techniques in coronary arteries. Sumatriptan, rizatriptan and eletriptan were powerful vasoconstrictors in cerebral artery. The rank order of agonist potency was eletriptan=rizatriptan=sumatriptan. In the coronary artery, the triptans were weaker vasoconstrictors. The rank order of potency was similar. In cerebral artery the ratio of Cmax/EC50 was not significantly different from unity, indicating a relationship between these two parameters. In general for the coronary artery, the ratios were significantly less than unity, indicating no direct relationship. Immunohistochemistry showed expression of 5-HT1B receptors in the medial layer, but did not reveal any obvious difference in 5-HT1B receptor expression between normal and atherosclerotic coronary arteries. The results support the notion that triptans are selective vasoconstrictors of cerebral arteries over coronary arteries and that there is a relationship between vasoconstrictor potency in cerebral arteries and clinically relevant plasma levels. PMID:15853772

  10. 5-HT1B receptors inhibit glutamate release from primary afferent terminals in rat medullary dorsal horn neurons

    PubMed Central

    Choi, I-S; Cho, J-H; An, C-H; Jung, J-K; Hur, Y-K; Choi, J-K; Jang, I-S

    2012-01-01

    BACKGROUND AND PURPOSE Although 5-HT1B receptors are expressed in trigeminal sensory neurons, it is still not known whether these receptors can modulate nociceptive transmission from primary afferents onto medullary dorsal horn neurons. EXPERIMENTAL APPROACH Primary afferent-evoked EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices using a conventional whole-cell patch clamp technique under a voltage-clamp condition. KEY RESULTS CP93129, a selective 5-HT1B receptor agonist, reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, CP93129 reduced the frequency of spontaneous miniature EPSCs without affecting the current amplitude. The CP93129-induced inhibition of EPSCs was significantly occluded by GR55562, a 5-HT1B/1D receptor antagonist, but not LY310762, a 5-HT1D receptor antagonist. Sumatriptan, an anti-migraine drug, also decreased EPSC amplitude, and this effect was partially blocked by either GR55562 or LY310762. On the other hand, primary afferent-evoked EPSCs were mediated by the Ca2+ influx passing through both presynaptic N-type and P/Q-type Ca2+ channels. The CP93129-induced inhibition of EPSCs was significantly occluded by ω-conotoxin GVIA, an N-type Ca2+ channel blocker. CONCLUSIONS AND IMPLICATIONS The present results suggest that the activation of presynaptic 5-HT1B receptors reduces glutamate release from primary afferent terminals onto medullary dorsal horn neurons, and that 5-HT1B receptors could be, at the very least, a potential target for the treatment of pain from orofacial tissues. LINKED ARTICLE This article is commented on by Connor, pp. 353–355 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01963.x PMID:22462474

  11. 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.

  12. Brady 1D seismic velocity model ambient noise prelim

    DOE Data Explorer

    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.

  13. Endoplasmic Reticulum Glycoprotein Quality Control Regulates CD1d Assembly and CD1d-mediated Antigen Presentation*

    PubMed Central

    Kunte, Amit; Zhang, Wei; Paduraru, Crina; Veerapen, Natacha; Cox, Liam R.; Besra, Gurdyal S.; Cresswell, Peter

    2013-01-01

    The non-classical major histocompatibility complex (MHC) homologue CD1d presents lipid antigens to innate-like lymphocytes called natural-killer T (NKT) cells. These cells, by virtue of their broad cytokine repertoire, shape innate and adaptive immune responses. Here, we have assessed the role of endoplasmic reticulum glycoprotein quality control in CD1d assembly and function, specifically the role of a key component of the quality control machinery, the enzyme UDP glucose glycoprotein glucosyltransferase (UGT1). We observe that in UGT1-deficient cells, CD1d associates prematurely with β2-microglobulin (β2m) and is able to rapidly exit the endoplasmic reticulum. At least some of these CD1d-β2m heterodimers are shorter-lived and can be rescued by provision of a defined exogenous antigen, α-galactosylceramide. Importantly, we show that in UGT1-deficient cells the CD1d-β2m heterodimers have altered antigenicity despite the fact that their cell surface levels are unchanged. We propose that UGT1 serves as a quality control checkpoint during CD1d assembly and further suggest that UGT1-mediated quality control can shape the lipid repertoire of newly synthesized CD1d. The quality control process may play a role in ensuring stability of exported CD1d-β2m complexes, in facilitating presentation of low abundance high affinity antigens, or in preventing deleterious responses to self lipids. PMID:23615906

  14. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1b... various areas because of cattle scabies and has issued the regulations in this part governing the interstate movement of cattle from such areas. It is the policy of the Department to quarantine...

  15. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1b... various areas because of cattle scabies and has issued the regulations in this part governing the interstate movement of cattle from such areas. It is the policy of the Department to quarantine...

  16. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1b... various areas because of cattle scabies and has issued the regulations in this part governing the interstate movement of cattle from such areas. It is the policy of the Department to quarantine...

  17. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1b... various areas because of cattle scabies and has issued the regulations in this part governing the interstate movement of cattle from such areas. It is the policy of the Department to quarantine...

  18. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1b... various areas because of cattle scabies and has issued the regulations in this part governing the interstate movement of cattle from such areas. It is the policy of the Department to quarantine...

  19. 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.

  20. Listeria meningoencephalitis and anti-GQ1b antibody syndrome.

    PubMed

    Vergori, A; Masi, G; Donati, D; Ginanneschi, F; Annunziata, P; Cerase, A; Mencarelli, M; Rossetti, B; De Luca, A; Zanelli, G

    2016-08-01

    We report the first case of Listeria monocytogenes meningoencephalitis associated with anti-GQ1b antibody syndrome in an immunocompetent adult. A prompt diagnosis, made thanks to the multidisciplinary contribution, allowed a combined therapeutic approach leading to final favourable outcome, despite several intercurrent complications. PMID:26825308

  1. 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.

  2. Verruculides A and B, two new protein tyrosine phosphatase 1B inhibitors from an Indonesian ascidian-derived Penicillium verruculosum.

    PubMed

    Yamazaki, Hiroyuki; Nakayama, Wataru; Takahashi, Ohgi; Kirikoshi, Ryota; Izumikawa, Yuta; Iwasaki, Kohei; Toraiwa, Kengo; Ukai, Kazuyo; Rotinsulu, Henki; Wewengkang, Defny S; Sumilat, Deiske A; Mangindaan, Remy E P; Namikoshi, Michio

    2015-08-15

    Two new merosesquiterpenes, verruculides A (1) and B (2), were isolated from a culture broth of the Indonesian ascidian-derived Penicillium verruculosum TPU1311, together with three known congeners, chrodrimanins A (3), B (4), and H (5). The structures of 1 and 2 were assigned on the basis of their spectroscopic data (1D and 2D NMR, HRMS, UV, CD, and IR). Compound 2 had a linear sesquiterpene moiety and was considered to be the derivative of the biosynthetic precursor for 1 and 3-5. Compounds 1, 3, and 5 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 8.4, 8.5, and 14.9 μM, respectively. Compound 2 showed 40% inhibition at 23.1 μM, while 4 was not active at 20.7 μM. PMID:26115570

  3. Verruculides A and B, two new protein tyrosine phosphatase 1B inhibitors from an Indonesian ascidian-derived Penicillium verruculosum.

    PubMed

    Yamazaki, Hiroyuki; Nakayama, Wataru; Takahashi, Ohgi; Kirikoshi, Ryota; Izumikawa, Yuta; Iwasaki, Kohei; Toraiwa, Kengo; Ukai, Kazuyo; Rotinsulu, Henki; Wewengkang, Defny S; Sumilat, Deiske A; Mangindaan, Remy E P; Namikoshi, Michio

    2015-08-15

    Two new merosesquiterpenes, verruculides A (1) and B (2), were isolated from a culture broth of the Indonesian ascidian-derived Penicillium verruculosum TPU1311, together with three known congeners, chrodrimanins A (3), B (4), and H (5). The structures of 1 and 2 were assigned on the basis of their spectroscopic data (1D and 2D NMR, HRMS, UV, CD, and IR). Compound 2 had a linear sesquiterpene moiety and was considered to be the derivative of the biosynthetic precursor for 1 and 3-5. Compounds 1, 3, and 5 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 8.4, 8.5, and 14.9 μM, respectively. Compound 2 showed 40% inhibition at 23.1 μM, while 4 was not active at 20.7 μM.

  4. Wee1B depletion promotes nuclear maturation of canine oocytes.

    PubMed

    Kim, Yu-Gon; Kim, Dong-Hoon; Song, Seok-Hwan; Lee, Kyeong-Lim; Yang, Byoung-Chul; Oh, Jeong Su; Lee, Sang-Ryeul; Kong, Il-Keun

    2015-03-01

    Most mammalian oocytes are arrested at the germinal vesicle stage by activation of Wee1B. Meiotic resumption is regulated by inactivation of Wee1B and activation of cell division cycle 25B. The aim of this study was to determine whether treatment with Wee1B-targeting small interfering RNA (Wee1B-siRNA) promotes nuclear maturation of canine oocytes from germinal vesicle stage to metaphase II (MII) stage. In experiment 1, the percentage of canine oocytes that matured to MII stage was higher (P < 0.05) among oocytes cultured in vitro for 72 hours than among those cultured for 24 and 48 hours (5.4 ± 2.5% vs. 0.0 ± 0.0% and 1.4 ± 1.0%, respectively). Furthermore, the percentage of oocytes that matured to metaphase I (MI) stage was higher (P < 0.05) among oocytes cultured for 48 and 72 hours than among those cultured for 24 hours (14.9 ± 10.0% and 22.4 ± 8.1%, respectively, vs. 5.7 ± 6.0%). In experiment 2, canine oocytes were intracytoplasmically microinjected with Wee1B-siRNA (50 μM) at various culture time points (0, 24, 48, or 72 hours). The nuclear configuration of the exception of oocytes in the 72-hour group was examined after 84 hours of culture. The percentage of oocytes that matured to the MII stage was higher (P < 0.05) among those treated with Wee1B-siRNA at 0 hours than among control oocytes and those injected at 72 hours (18.0 ± 1.7% vs. 2.1 ± 2.8% and 0.0 ± 0.0%, respectively). Moreover, the percentage of oocytes that matured to the MI stage was higher (P < 0.05) among those injected at 0 hours than among control oocytes and those injected at 24 and 72 hours (45.9 ± 6.8% vs. 22.1 ± 3.5%, 22.8 ± 10.0%, and 10.0 ± 4.4%, respectively). In experiment 3, oocytes were intracytoplasmically microinjected with Wee1B-siRNA at 0 hours of IVM and cultured for 0, 24, 48, or 72 hours. Thereafter, maturation-related gene expression was analyzed by quantitative real-time polymerase chain reaction. Messenger RNA

  5. A human serotonin 1D receptor variant (5HT1D beta) encoded by an intronless gene on chromosome 6.

    PubMed Central

    Demchyshyn, L; Sunahara, R K; Miller, K; Teitler, M; Hoffman, B J; Kennedy, J L; Seeman, P; Van Tol, H H; Niznik, H B

    1992-01-01

    An intronless gene encoding a serotonin receptor (5HT1D beta) has been cloned and functionally expressed in mammalian fibroblast cultures. Based on the deduced amino acid sequence, the gene encodes a 390-amino acid protein displaying considerable homology, within putative transmembrane domains (approximately 75% identity) to the canine and human 5HT1D receptors. Membranes prepared from CHO cells stably expressing the receptor bound [3H]serotonin with high affinity (Kd 4 nM) and displayed a pharmacological profile consistent, but not identical, with that of the characterized serotonin 5HT1D receptor. Most notably, metergoline and serotonergic piperazine derivatives, as a group, display 3- to 8-fold lower affinity for the 5HT1D beta receptor than for the 5HT1D receptor, whereas both receptors display similar affinities for tryptamine derivatives, including the antimigraine drug sumatriptan. Northern blot analysis revealed an mRNA of approximately 5.5 kilobases expressed in human and monkey frontal cortex, medulla, striatum, hippocampus and amygdala but not in cerebellum, olfactory tubercle, and pituitary. The 5HT1D beta gene maps to human chromosome 6. The existence of multiple neuronal 5HT1D-like receptors may help account for some of the complexities associated with [3H]serotonin binding patterns in native membranes. Images PMID:1351684

  6. Structural elucidation and NMR assignments of four aromatic lactones from a mangrove endophytic fungus (No. GX4-1B).

    PubMed

    Huang, Hongbo; Li, Qing; Feng, Xiaojun; Chen, Bin; Wang, Jun; Liu, Lan; She, Zhigang; Lin, Yongcheng

    2010-06-01

    Two new aromatic lactones, 6-hydroxy-4-hydroxymethyl-8-methoxy-3- methylisocoumarin (1) and 1,10-dihydroxy-8-methyl-dibenz[b, e]oxepin-6,11-dione (2), together with two known compounds, 1,10-dihydroxy-dibenz[b, e]oxepin-6,11-dione (3) and 3-hydroxymethyl-6,8-dimethoxycoumarin (4), were isolated from a mangrove endophytic fungus (No. GX4-1B) collected from the South China Sea. Their structures were elucidated and the data of (1)H and (13)C NMR were assigned completely by HREIMS, 1D and 2D NMR experiments including HMQC, HMBC and NOESY.

  7. 60. BOILER CHAMBER No. 1, D LOOP STEAM GENERATOR AND ...

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

    60. BOILER CHAMBER No. 1, D LOOP STEAM GENERATOR AND MAIN COOLANT PUMP LOOKING NORTHEAST (LOCATION OOO) - Shippingport Atomic Power Station, On Ohio River, 25 miles Northwest of Pittsburgh, Shippingport, Beaver County, PA

  8. 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. PMID:26902182

  9. 1D Nanostructures: Controlled Fabrication and Energy Applications

    SciTech Connect

    Hu, Michael Z.

    2013-01-01

    Jian Wei, Xuchun Song, Chunli Yang, and Michael Z. Hu, 1D Nanostructures: Controlled Fabrication and Energy Applications, Journal of Nanomaterials, published special issue (http://www.hindawi.com/journals/jnm/si/197254/) (2013).

  10. Involvement of 5-HT1B receptors in triptan-induced contractile responses in guinea-pig isolated iliac artery.

    PubMed

    Jähnichen, S; Radtke, O A; Pertz, H H

    2004-07-01

    Using a series of triptans we characterized in vitro the 5-hydroxytryptamine (5-HT) receptor that mediates the contraction in guinea-pig iliac arteries moderately precontracted by prostaglandin F2alpha (PGF2alpha). Additionally, we investigated by reverse-transcriptase polymerase chain reaction (RT-PCR) which triptan-sensitive receptor is present in this tissue. Frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, and almotriptan contracted guinea-pig iliac arteries with pD2 values of 7.52+/-0.04, 6.72+/-0.03, 6.38+/-0.06, 6.22+/-0.05, 5.86+/-0.05 and 5.26+/-0.04 respectively. For comparison, the pD2 values for 5-HT and 5-carboxamidotryptamine (5-CT) were 7.52+/-0.02 and 7.55+/-0.03 respectively. In contrast to all other triptans tested, the concentration-response curve for eletriptan was biphasic (first phase: 0.01-3 microM, pD2 approximately 6.6; second phase: > or = 10 microM). Contractions to 5-HT, 5-CT, frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, almotriptan, and eletriptan (first phase) were antagonized by the 5-HT1B/1D receptor antagonist GR127935 (10 nM) and the 5-HT1B receptor antagonist SB216641 (10 nM). RT-PCR studies in guinea-pig iliac arteries showed a strong signal for the 5-HT1B receptor while expression of 5-HT1D and 5-HT1F receptors was not detected in any sample. The present results demonstrate that triptan-induced contraction in guinea-pig iliac arteries is mediated by the 5-HT1B receptor. The guinea-pig iliac artery may be used as a convenient in vitro model to study the (cardio)vascular side-effect potential of anti-migraine drugs of the triptan family. PMID:15185063

  11. 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

  12. Effects of chronic paroxetine treatment on dialysate serotonin in 5-HT1B receptor knockout mice.

    PubMed

    Gardier, A M; David, D J; Jego, G; Przybylski, C; Jacquot, C; Durier, S; Gruwez, B; Douvier, E; Beauverie, P; Poisson, N; Hen, R; Bourin, M

    2003-07-01

    The role of serotonin (5-HT)1B receptors in the mechanism of action of selective serotonin re-uptake inhibitors (SSRI) was studied by using intracerebral in vivo microdialysis in conscious, freely moving wild-type and 5-HT1B receptor knockout (KO 5-HT1B) mice in order to compare the effects of chronic administration of paroxetine via osmotic minipumps (1 mg per kg per day for 14 days) on extracellular 5-HT levels ([5-HT]ext) in the medial prefrontal cortex and ventral hippocampus. Basal [5-HT]ext values in the medial prefrontal cortex and ventral hippocampus, approximately 20 h after removing the minipump, were not altered by chronic paroxetine treatment in both genotypes. On day 15, in the ventral hippocampus, an acute paroxetine challenge (1 mg/kg i.p.) induced a larger increase in [5-HT]ext in saline-pretreated mutant than in wild-type mice. This difference between the two genotypes in the effect of the paroxetine challenge persisted following chronic paroxetine treatment. Conversely, in the medial prefrontal cortex, the paroxetine challenge increased [5-HT]ext similarly in saline-pretreated mice of both genotypes. Such a challenge produced a further increase in cortical [5-HT]ext compared with that in saline-pretreated groups of both genotypes, but no differences were found between genotypes following chronic treatment. To avoid the interaction with raphe 5-HT1A autoreceptors, 1 micro m paroxetine was perfused locally through the dialysis probe implanted in the ventral hippocampus; similar increases in hippocampal [5-HT]ext were found in acutely or chronically treated wild-type mice. Systemic administration of the mixed 5-HT1B/1D receptor antagonist GR 127935 (4 mg/kg) in chronically treated wild-type mice potentiated the effect of a paroxetine challenge dose on [5-HT]ext in the ventral hippocampus, whereas systemic administration of the selective 5-HT1A receptor antagonist WAY 100635 did not. By using the zero net flux method of quantitative microdialysis in

  13. COMMIX-1B. 3-D Single-Phase Thermal Hydraulics

    SciTech Connect

    Wildman, D.J.

    1986-01-31

    COMMIX-1B is designed to perform steady-state or transient, single-phase, three-dimensional analysis of fluid flow with heat transfer in a single-component or multicomponent system. The program was developed for the analysis of heat transfer and fluid flow processes in a nuclear reactor system; however, it can easily be applied to non-nuclear systems requiring heat transfer and/or fluid flow analysis. COMMIX-1B solves the conservation equations of mass, momentum, and energy, and transport equations of turbulence parameters and provides detailed local velocity, temperature, and pressure fields for the problem under consideration. It is capable of solving thermal-hydraulic problems involving either a single component, such as a rod bundle, reactor plenum, piping system, heat exchanger, etc., or a multicomponent system that is a combination of these components.

  14. Evaluation of the IRS-1B inflight calibration campaign (1995)

    NASA Astrophysics Data System (ADS)

    Richter, Rudolf; Tischler, Sabine; Muller, A.; Prakash, C. V. S.; Palsule, S. S.; Desai, Y. P.; Berger, Michael

    1997-08-01

    In December 1995 an inflight calibration campaign was conducted in India for the LISS-2 cameras onboard the IRS-1B satellite. For this purpose three test sites were selected where ground reflectance measurements were performed simultaneously with overpasses of the IRS-1B and Landsat-5 satellites. Due to weather conditions, only the data of 8 December 1995 was appropriate for the evaluation of the LISS-2 calibration coefficients. Ground truth data of several reference areas in ICRISAT near Hyderabad was jointly collected by DLR, ISRO, and GFZ using two field spectrometers and a 4-band radiometer. Weather data was recorded at a local meteorological station. The ATCOR2 model, based on the MODTRAN 2 radiative transfer code, was employed to calculate the calibration coefficients for the LISS-2B sensor. The derived inflight calibration coefficients agree within 5 percent with the preflight coefficients. The offset coefficients were not evaluated since no low reflectance target was available at this time.

  15. Vasopressor meets vasodepressor: The AT1-B2 receptor heterodimer.

    PubMed

    Quitterer, Ursula; AbdAlla, Said

    2014-04-01

    The AT1 receptor for the vasopressor angiotensin II is one of the most important drug targets for the treatment of cardiovascular diseases. Sensitization of the AT1 receptor system is a common feature contributing to the pathogenesis of many cardiovascular disorders but underlying mechanisms are not fully understood. More than a decade ago, evidence was provided for control of AT1R activation by heterodimerization with the B2 receptor for the vasodepressor peptide, bradykinin, a physiological counterpart of the vasoconstrictor angiotensin II. AT1-B2 receptor heterodimerization was shown to enhance AT1R-stimulated signaling under pathophysiological conditions such as experimental and human pregnancy hypertension. Notably, AT1R signal sensitization of patients with preeclampsia hypertension was attributed to AT1R-B2R heterodimerization. Vice versa, transgenic mice lacking the AT1-B2 receptor heterodimer due to targeted deletion of the B2R gene showed a significantly reduced AT1R-stimulated vasopressor response compared to transgenic mice with abundant AT1R-B2R heterodimerization. Biophysical methods such as BRET and FRET confirmed those data by demonstrating efficient AT1-B2 receptor heterodimerization in transfected cells and transgenic mice. Recently, a study on AT1R-specific biased agonism directed the focus to the AT1-B2 receptor heterodimer again. The β-arrestin-biased [Sar1,Ile4,Ile8]-angiotensin II promoted not only the recruitment of β-arrestin to the AT1R but also stimulated the down-regulation of the AT1R-associated B2 receptor by co-internalization. Thereby specific targeting of the AT1R-B2R heterodimer became feasible and could open the way to a new class of drugs, which specifically interfere with pathological angiotensin II-AT1 receptor system activation.

  16. Validation of Ozone Monitoring Instrument level 1b data products

    NASA Astrophysics Data System (ADS)

    Dobber, M.; Kleipool, Q.; Dirksen, R.; Levelt, P.; Jaross, G.; Taylor, S.; Kelly, T.; Flynn, L.; Leppelmeier, G.; Rozemeijer, N.

    2008-08-01

    The validation of the collection 2 level 1b radiance and irradiance data measured with the Ozone Monitoring Instrument (OMI) on NASA's Earth Observing System (EOS) Aura satellite is investigated and described. A number of improvements from collection 2 data to collection 3 data are identified and presented. It is shown that with these improvements in the calibration and in the data processing the accuracy of the geophysically calibrated level 1b radiance and irradiance is improved in the collection 3 data. It is shown that the OMI level 1b irradiance product can be reproduced from a high-resolution solar reference spectrum convolved with the OMI spectral slit functions within 3% for the Fraunhofer structure and within 0.5% for the offset. The agreement of the OMI level 1b irradiance data product with other available literature irradiance spectra is within 4%. The viewing angle dependence of the irradiance and the irradiance goniometry are discussed, and improvements in the collection 3 data are described. The in-orbit radiometric degradation since launch is shown to be smaller than 0.5% above 310 nm and increases to about 1.2% at 270 nm. It is shown how the viewing angle dependence of the radiance is improved in the collection 3 data. The calculation of the surface albedo from OMI measurement data is discussed, and first results are presented. The OMI surface albedo values are compared to literature values from the Total Ozone Mapping Spectrometer (TOMS) and the Global Ozone Monitoring Experiment (GOME). Finally, improvements in the spectral and spatial stray light corrections from collection 2 data to collection 3 data are presented and discussed.

  17. SLCO1B1 Polymorphisms and Statin-Induced Myopathy

    PubMed Central

    Stewart, Alison

    2013-01-01

    Statin drugs are highly effective in lowering blood concentrations of LDL-cholesterol, with concomitant reduction in risk of major cardiovascular events. Although statins are generally regarded as safe and well-tolerated, some users develop muscle symptoms that are mostly mild but in rare cases can lead to life-threatening rhabdomyolysis. The SEARCH genome-wide association study, which has been independently replicated, found a significant association between the rs4149056 (c.521T>C) single-nucleotide polymorphism (SNP) in the SLCO1B1 gene, and myopathy in individuals taking 80 mg simvastatin per day, with an odds ratio of 4.5 per rs4149056 C allele. The purpose of this paper is to assemble evidence relating to the analytical validity, clinical validity and clinical utility of using SLCO1B1 rs4149056 genotyping to inform choice and dose of statin treatment, with the aim of minimising statin-induced myopathy and increasing adherence to therapy. Genotyping assays for the rs4149056 SNP appear to be robust and accurate, though direct evidence for the performance of array-based platforms in genotyping individual SNPs was not found. Using data from the SEARCH study, calculated values for the clinical sensitivity, specificity, positive- and negative-predictive values of a test for the C allele to predict definite or incipient myopathy during 5 years of 80 mg/day simvastatin use were 70.4%, 73.7%, 4.1% and 99.4% respectively. There is a need for studies comparing the clinical validity of SLCO1B1 rs4149056 genotyping with risk scores for myopathy based on other factors such as racial background, statin type and dose, gender, body mass index, co-medications and co-morbidities. No direct evidence was found for clinical utility of statin prescription guided by SLCO1B1 genotype. PMID:24459608

  18. 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.

  19. Pharmacophore modeling for protein tyrosine phosphatase 1B inhibitors.

    PubMed

    Bharatham, Kavitha; Bharatham, Nagakumar; Lee, Keun Woo

    2007-05-01

    A three dimensional chemical feature based pharmacophore model was developed for the inhibitors of protein tyrosine phosphatase 1B (PTP1B) using the CATALYST software, which would provide useful knowledge for performing virtual screening to identify new inhibitors targeted toward type II diabetes and obesity. A dataset of 27 inhibitors, with diverse structural properties, and activities ranging from 0.026 to 600 microM, was selected as a training set. Hypol, the most reliable quantitative four featured pharmacophore hypothesis, was generated from a training set composed of compounds with two H-bond acceptors, one hydrophobic aromatic and one ring aromatic features. It has a correlation coefficient, RMSD and cost difference (null cost-total cost) of 0.946, 0.840 and 65.731, respectively. The best hypothesis (Hypol) was validated using four different methods. Firstly, a cross validation was performed by randomizing the data using the Cat-Scramble technique. The results confirmed that the pharmacophore models generated from the training set were valid. Secondly, a test set of 281 molecules was scored, with a correlation of 0.882 obtained between the experimental and predicted activities. Hypol performed well in correctly discriminating the active and inactive molecules. Thirdly, the model was investigated by mapping on two PTP1B inhibitors identified by different pharmaceutical companies. The Hypol model correctly predicted these compounds as being highly active. Finally, docking simulations were performed on few compounds to substantiate the role of the pharmacophore features at the binding site of the protein by analyzing their binding conformations. These multiple validation approaches provided confidence in the utility of this pharmacophore model as a 3D query for virtual screening to retrieve new chemical entities showing potential as potent PTP1B inhibitors.

  20. 1D nanocrystals with precisely controlled dimensions, compositions, and architectures

    NASA Astrophysics Data System (ADS)

    Pang, Xinchang; He, Yanjie; Jung, Jaehan; Lin, Zhiqun

    2016-09-01

    The ability to synthesize a diverse spectrum of one-dimensional (1D) nanocrystals presents an enticing prospect for exploring nanoscale size- and shape-dependent properties. Here we report a general strategy to craft a variety of plain nanorods, core-shell nanorods, and nanotubes with precisely controlled dimensions and compositions by capitalizing on functional bottlebrush-like block copolymers with well-defined structures and narrow molecular weight distributions as nanoreactors. These cylindrical unimolecular nanoreactors enable a high degree of control over the size, shape, architecture, surface chemistry, and properties of 1D nanocrystals. We demonstrate the synthesis of metallic, ferroelectric, upconversion, semiconducting, and thermoelectric 1D nanocrystals, among others, as well as combinations thereof.

  1. The GIRAFFE Archive: 1D and 3D Spectra

    NASA Astrophysics Data System (ADS)

    Royer, F.; Jégouzo, I.; Tajahmady, F.; Normand, J.; Chilingarian, I.

    2013-10-01

    The GIRAFFE Archive (http://giraffe-archive.obspm.fr) contains the reduced spectra observed with the intermediate and high resolution multi-fiber spectrograph installed at VLT/UT2 (ESO). In its multi-object configuration and the different integral field unit configurations, GIRAFFE produces 1D spectra and 3D spectra. We present here the status of the archive and the different functionalities to select and download both 1D and 3D data products, as well as the present content. The two collections are available in the VO: the 1D spectra (summed in the case of integral field observations) and the 3D field observations. These latter products can be explored using the VO Paris Euro3D Client (http://voplus.obspm.fr/ chil/Euro3D).

  2. 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.

  3. 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).

  4. 1D nanocrystals with precisely controlled dimensions, compositions, and architectures.

    PubMed

    Pang, Xinchang; He, Yanjie; Jung, Jaehan; Lin, Zhiqun

    2016-09-16

    The ability to synthesize a diverse spectrum of one-dimensional (1D) nanocrystals presents an enticing prospect for exploring nanoscale size- and shape-dependent properties. Here we report a general strategy to craft a variety of plain nanorods, core-shell nanorods, and nanotubes with precisely controlled dimensions and compositions by capitalizing on functional bottlebrush-like block copolymers with well-defined structures and narrow molecular weight distributions as nanoreactors. These cylindrical unimolecular nanoreactors enable a high degree of control over the size, shape, architecture, surface chemistry, and properties of 1D nanocrystals. We demonstrate the synthesis of metallic, ferroelectric, upconversion, semiconducting, and thermoelectric 1D nanocrystals, among others, as well as combinations thereof. PMID:27634531

  5. 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

  6. 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.

  7. Observation of Dynamical Fermionization in 1D Bose Gases

    NASA Astrophysics Data System (ADS)

    Malvania, Neel; Xia, Lin; Xu, Wei; Wilson, Joshua M.; Zundel, Laura A.; Rigol, Marcos; Weiss, David S.

    2016-05-01

    The momentum distribution of a harmonically trapped 1D Bose gases in the Tonks-Girardeau limit is expected to undergo dynamical fermionization. That is, after the harmonic trap is suddenly turned off, the momentum distribution steadily transforms into that of an ideal Fermi gas in the same initial trap. We measure 1D momentum distributions at variable times after such a quench, and observe the predicted dynamical fermionization. In addition to working in the strong coupling limit, we also perform the experiment with intermediate coupling, where theoretical calculations are more challenging.

  8. Cloning/Characterization of the Canine Organic Anion Transporting Polypeptide 1b4 (Oatp1b4) and Classification of the Canine OATP/SLCO Members

    PubMed Central

    Gui, Chunshan; Hagenbuch, Bruno

    2010-01-01

    The human liver specific organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are involved in the elimination of numerous xenobiotics and drugs. Although dogs are frequently used for toxicologic and pharmacokinetic characterization of novel drugs, nothing is known about their OATP1B1/1B3 ortholog. Therefore, we cloned and characterized the first canine organic anion transporting polypeptide from dog liver, termed Oatp1b4. The isolated Oatp1b4 cDNA comprises 3661 base pairs (bp) with an open reading frame of 2076 bp, encoding a 692-amino acid protein with a molecular mass of ~85 kDa. The Oatp1b4 gene is approximately 61 kb long and has a similar organization as the human OATP1B1 and OATP1B3 with 13 exons identical in length. Northern blot analysis shows that Oatp1b4 is predominantly expressed in the liver. Oatp1b4 mediates sodium-independent transport of typical organic anions including bromosulfophthalein (BSP), [D-penicillamine2,5]enkephalin (DPDPE), estradiol-17β-glucuronide (E17βG), estrone-3-sulfate and taurocholate. In addition, Oatp1b4 transports the OATP1B3-specific substrate cholecystokinin octapeptide (CCK-8). Kinetic studies showed that Oatp1b4-mediated E17βG and estrone-3-sulfate transports were monophasic with Km values of 5 ± 1 μM and 33 ± 4 μM, respectively. In conclusion, the cloned canine Oatp1b4 will provide additional molecular basis to further characterize the species difference of the OATP1B family members. PMID:20079461

  9. 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.

  10. OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy

    PubMed Central

    Teft, W A; Welch, S; Lenehan, J; Parfitt, J; Choi, Y-H; Winquist, E; Kim, R B

    2015-01-01

    Background: Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters. Methods: Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected. Results: SLCO1B1 521C was significantly associated with increased SN-38 exposure (P<0.001), which was additive with UGT1A1*28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2–24C/T (odds ratio (OR)=0.22, 0.06–0.85) and CES1 (rs2244613; OR=0.29, 0.09–0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2–24T/T and UGT1A1*28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS. Conclusions: Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers. PMID:25611302

  11. 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.

  12. 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.

  13. 1D design style implications for mask making and CEBL

    NASA Astrophysics Data System (ADS)

    Smayling, Michael C.

    2013-09-01

    At advanced nodes, CMOS logic is being designed in a highly regular design style because of the resolution limitations of optical lithography equipment. Logic and memory layouts using 1D Gridded Design Rules (GDR) have been demonstrated to nodes beyond 12nm.[1-4] Smaller nodes will require the same regular layout style but with multiple patterning for critical layers. One of the significant advantages of 1D GDR is the ease of splitting layouts into lines and cuts. A lines and cuts approach has been used to achieve good pattern fidelity and process margin to below 12nm.[4] Line scaling with excellent line-edge roughness (LER) has been demonstrated with self-aligned spacer processing.[5] This change in design style has important implications for mask making: • The complexity of the masks will be greatly reduced from what would be required for 2D designs with very complex OPC or inverse lithography corrections. • The number of masks will initially increase, as for conventional multiple patterning. But in the case of 1D design, there are future options for mask count reduction. • The line masks will remain simple, with little or no OPC, at pitches (1x) above 80nm. This provides an excellent opportunity for continual improvement of line CD and LER. The line pattern will be processed through a self-aligned pitch division sequence to divide pitch by 2 or by 4. • The cut masks can be done with "simple OPC" as demonstrated to beyond 12nm.[6] Multiple simple cut masks may be required at advanced nodes. "Coloring" has been demonstrated to below 12nm for two colors and to 8nm for three colors. • Cut/hole masks will eventually be replaced by e-beam direct write using complementary e-beam lithography (CEBL).[7-11] This transition is gated by the availability of multiple column e-beam systems with throughput adequate for high- volume manufacturing. A brief description of 1D and 2D design styles will be presented, followed by examples of 1D layouts. Mask complexity for 1

  14. 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

  15. Microtubule-associated protein 1B (MAP1B)-deficient neurons show structural presynaptic deficiencies in vitro and altered presynaptic physiology.

    PubMed

    Bodaleo, Felipe J; Montenegro-Venegas, Carolina; Henríquez, Daniel R; Court, Felipe A; Gonzalez-Billault, Christian

    2016-01-01

    Microtubule-associated protein 1B (MAP1B) is expressed predominantly during the early stages of development of the nervous system, where it regulates processes such as axonal guidance and elongation. Nevertheless, MAP1B expression in the brain persists in adult stages, where it participates in the regulation of the structure and physiology of dendritic spines in glutamatergic synapses. Moreover, MAP1B expression is also found in presynaptic synaptosomal preparations. In this work, we describe a presynaptic phenotype in mature neurons derived from MAP1B knockout (MAP1B KO) mice. Mature neurons express MAP1B, and its deficiency does not alter the expression levels of a subgroup of other synaptic proteins. MAP1B KO neurons display a decrease in the density of presynaptic and postsynaptic terminals, which involves a reduction in the density of synaptic contacts, and an increased proportion of orphan presynaptic terminals. Accordingly, MAP1B KO neurons present altered synaptic vesicle fusion events, as shown by FM4-64 release assay, and a decrease in the density of both synaptic vesicles and dense core vesicles at presynaptic terminals. Finally, an increased proportion of excitatory immature symmetrical synaptic contacts in MAP1B KO neurons was detected. Altogether these results suggest a novel role for MAP1B in presynaptic structure and physiology regulation in vitro. PMID:27425640

  16. Microtubule-associated protein 1B (MAP1B)-deficient neurons show structural presynaptic deficiencies in vitro and altered presynaptic physiology

    PubMed Central

    Bodaleo, Felipe J.; Montenegro-Venegas, Carolina; Henríquez, Daniel R.; Court, Felipe A.; Gonzalez-Billault, Christian

    2016-01-01

    Microtubule-associated protein 1B (MAP1B) is expressed predominantly during the early stages of development of the nervous system, where it regulates processes such as axonal guidance and elongation. Nevertheless, MAP1B expression in the brain persists in adult stages, where it participates in the regulation of the structure and physiology of dendritic spines in glutamatergic synapses. Moreover, MAP1B expression is also found in presynaptic synaptosomal preparations. In this work, we describe a presynaptic phenotype in mature neurons derived from MAP1B knockout (MAP1B KO) mice. Mature neurons express MAP1B, and its deficiency does not alter the expression levels of a subgroup of other synaptic proteins. MAP1B KO neurons display a decrease in the density of presynaptic and postsynaptic terminals, which involves a reduction in the density of synaptic contacts, and an increased proportion of orphan presynaptic terminals. Accordingly, MAP1B KO neurons present altered synaptic vesicle fusion events, as shown by FM4-64 release assay, and a decrease in the density of both synaptic vesicles and dense core vesicles at presynaptic terminals. Finally, an increased proportion of excitatory immature symmetrical synaptic contacts in MAP1B KO neurons was detected. Altogether these results suggest a novel role for MAP1B in presynaptic structure and physiology regulation in vitro. PMID:27425640

  17. Variation in the ADH1B proximal promoter affects expression.

    PubMed

    Pochareddy, Sirisha; Edenberg, Howard J

    2011-05-30

    The primary pathway of metabolism of dietary alcohol is via its oxidation in liver by alcohol dehydrogenases (ADH). Differences in the ADH enzyme activity or levels of enzyme present could affect the risk for alcoholism. Regulatory variations have been shown to affect the promoter activity and thereby affect the risk for alcoholism. In this study the functional effects of the two SNPs (rs1159918 and rs1229982) in the proximal promoter region of ADH1B that were associated with alcoholism were explored. We examined the effects of five naturally occurring haplotypes on the promoter activity. We observed that a C to A change at rs1229982 increased promoter activity 1.4-fold.

  18. No variations in transit times for Qatar-1 b

    NASA Astrophysics Data System (ADS)

    Maciejewski, G.; Fernández, M.; Aceituno, F. J.; Ohlert, J.; Puchalski, D.; Dimitrov, D.; Seeliger, M.; Kitze, M.; Raetz, St.; Errmann, R.; Gilbert, H.; Pannicke, A.; Schmidt, J.-G.; Neuhäuser, R.

    2015-05-01

    Aims: The transiting hot-Jupiter planet Qatar-1 b exhibits variations in transit times that could be perturbative. A hot Jupiter with a planetary companion on a nearby orbit would constitute an unprecedented planetary configuration, which is important for theories of the formation and evolution of planetary systems. We performed a photometric follow-up campaign to confirm or refute transit timing variations. Methods: We extend the baseline of transit observations by acquiring 18 new transit light curves acquired with 0.6-2.0 m telescopes. These photometric time series, together with data available in the literature, were analyzed in a homogenous way to derive reliable transit parameters and their uncertainties. Results: We show that the dataset of transit times is consistent with a linear ephemeris leaving no hint of any periodic variations with a range of 1 min. We find no compelling evidence of a close-in planetary companion to Qatar-1 b. This finding is in line with a paradigm that hot Jupiters are not components of compact multiplanetary systems. Based on dynamical simulations, we place tighter constraints on the mass of any fictitious nearby planet in the system. Furthermore, new transit light curves allowed us to redetermine system parameters with better precision than reported in previous studies. Our values generally agree with previous determinations. Partly based on (1) data collected with telescopes at the Rozhen National Astronomical Observatory and (2) observations obtained with telescopes of the University Observatory Jena, which is operated by the Astrophysical Institute of the Friedrich-Schiller-University.Tables of light curve data are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/577/A109

  19. 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.

  20. Phase diagram of a bulk 1d lattice Coulomb gas

    NASA Astrophysics Data System (ADS)

    Démery, V.; Monsarrat, R.; Dean, D. S.; Podgornik, R.

    2016-01-01

    The exact solution, via transfer matrix, of the simple one-dimensional lattice Coulomb gas (1d LCG) model can reproduce peculiar features of ionic liquid capacitors, such as overscreening, layering, and camel- and bell-shaped capacitance curves. Using the same transfer matrix method, we now compute the bulk properties of the 1d LCG in the constant voltage ensemble. We unveil a phase diagram with rich structure exhibiting low-density disordered and high-density ordered phases, separated by a first-order phase transition at low temperature; the solid state at full packing can be ordered or not, depending on the temperature. This phase diagram, which is strikingly similar to its three-dimensional counterpart, also sheds light on the behaviour of the confined system.

  1. 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.

  2. Complete Genome Sequence of Classical Swine Fever Virus Strain JSZL, Belonging to a New Subgenotype, 2.1d, Isolated in China in 2014.

    PubMed

    Zhang, Hongliang; Feng, Liping; Liu, Chunxiao; Chen, Jiazeng; Leng, Chaoliang; Bai, Yun; Peng, Jinmei; An, Tongqing; Cai, Xuehui; Yang, Xufu; Tian, Zhijun; Tong, Guangzhi

    2015-01-01

    The complete genome sequence of classic swine fever virus (CSFV) strain JSZL was determined in this study. JSZL was originally isolated from an immune pig farm in Jiangsu Province, China. JSZL is more closely related to subgenotype 2.1b than to 2.1a and 2.1c. Importantly, JSZL was classified into a new subgenotype, 2.1d. PMID:26294620

  3. Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer

    PubMed Central

    Kohnz, Rebecca A.; Mulvihill, Melinda M.; Chang, Jae Won; Hsu, Ku-Lung; Sorrentino, Antonio; Cravatt, Benjamin F.; Bandyopadhyay, Sourav; Goga, Andrei; Nomura, Daniel K.

    2015-01-01

    Targeting dysregulated metabolic pathways is a promising therapeutic strategy for eradicating cancer. Understanding how frequently altered oncogenes regulate metabolic enzyme targets would be useful in identifying both broad-spectrum and targeted metabolic therapies for cancer. Here, we used activity-based protein profiling to identify serine hydrolase activities that were consistently upregulated by various human oncogenes. Through this profiling effort, we found oncogenic regulatory mechanisms for several cancer-relevant serine hydrolases and discovered that platelet activating factor acetylhydrolase 1B2 and 1B3 (PAFAH1B2 and PAFAH1B3) activities were consistently upregulated by several oncogenes, alongside previously discovered cancer-relevant hydrolases fatty acid synthase and monoacylglycerol lipase. While we previously showed that PAFAH1B2 and 1B3 were important in breast cancer our most recent profiling studies have revealed that these enzymes may be dysregulated broadly across many types of cancers. Here, we find that pharmacological blockade of both enzymes impairs cancer pathogenicity across multiple different types of cancer cells, including breast, ovarian, melanoma, and prostate cancer. We also show that pharmacological blockade of PAFAH1B2 and 1B3 cause unique changes in lipid metabolism, including heightened levels of tumor-suppressing lipids. Our results reveal oncogenic regulatory mechanisms of several cancer-relevant serine hydrolases using activity-based protein profiling and we show that PAFAH1B2 and 1B3 are important in maintaining cancer pathogenicity across a wide spectrum of cancer types. PMID:25945974

  4. 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.

  5. Constructing 3D interaction maps from 1D epigenomes

    PubMed Central

    Zhu, Yun; Chen, Zhao; Zhang, Kai; Wang, Mengchi; Medovoy, David; Whitaker, John W.; Ding, Bo; Li, Nan; Zheng, Lina; Wang, Wei

    2016-01-01

    The human genome is tightly packaged into chromatin whose functional output depends on both one-dimensional (1D) local chromatin states and three-dimensional (3D) genome organization. Currently, chromatin modifications and 3D genome organization are measured by distinct assays. An emerging question is whether it is possible to deduce 3D interactions by integrative analysis of 1D epigenomic data and associate 3D contacts to functionality of the interacting loci. Here we present EpiTensor, an algorithm to identify 3D spatial associations within topologically associating domains (TADs) from 1D maps of histone modifications, chromatin accessibility and RNA-seq. We demonstrate that active promoter–promoter, promoter–enhancer and enhancer–enhancer associations identified by EpiTensor are highly concordant with those detected by Hi-C, ChIA-PET and eQTL analyses at 200 bp resolution. Moreover, EpiTensor has identified a set of interaction hotspots, characterized by higher chromatin and transcriptional activity as well as enriched TF and ncRNA binding across diverse cell types, which may be critical for stabilizing the local 3D interactions. PMID:26960733

  6. Constructing 3D interaction maps from 1D epigenomes.

    PubMed

    Zhu, Yun; Chen, Zhao; Zhang, Kai; Wang, Mengchi; Medovoy, David; Whitaker, John W; Ding, Bo; Li, Nan; Zheng, Lina; Wang, Wei

    2016-01-01

    The human genome is tightly packaged into chromatin whose functional output depends on both one-dimensional (1D) local chromatin states and three-dimensional (3D) genome organization. Currently, chromatin modifications and 3D genome organization are measured by distinct assays. An emerging question is whether it is possible to deduce 3D interactions by integrative analysis of 1D epigenomic data and associate 3D contacts to functionality of the interacting loci. Here we present EpiTensor, an algorithm to identify 3D spatial associations within topologically associating domains (TADs) from 1D maps of histone modifications, chromatin accessibility and RNA-seq. We demonstrate that active promoter-promoter, promoter-enhancer and enhancer-enhancer associations identified by EpiTensor are highly concordant with those detected by Hi-C, ChIA-PET and eQTL analyses at 200 bp resolution. Moreover, EpiTensor has identified a set of interaction hotspots, characterized by higher chromatin and transcriptional activity as well as enriched TF and ncRNA binding across diverse cell types, which may be critical for stabilizing the local 3D interactions. PMID:26960733

  7. 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.

  8. Human adenovirus 2 E1B-19K and E1B-53K tumor antigens: antipeptide antibodies targeted to the NH2 and COOH termini.

    PubMed Central

    Green, M; Brackmann, K H; Lucher, L A; Symington, J S; Kramer, T A

    1983-01-01

    The human adenovirus 2 (Ad2) transforming region is located in the left 11.1% of the viral genome and encodes two early transcription units, E1A and E1B. Based on the amino acid sequence deduced from the Ad2 E1B DNA sequence (Gingeras et al., J. Biol. Chem. 257:13475-13491, 1982), we have prepared antibodies against synthetic peptides, 8 to 16 amino acids in length, encoded at the NH2 and COOH termini of the major E1B-19K and E1B-53K tumor antigens. The antipeptide antibodies immunoprecipitated the targeted E1B-19K or E1B-53K tumor antigens from extracts of Ad2-infected cells. The specificity of the peptide competition studies. Antipeptide antibodies directed to the NH2 and COOH termini immunoprecipitated the E1B-19K and E1B-53K tumor antigens from two Ad2-transformed rat cell lines, F17 and F4, providing evidence that identical tumor antigens are synthesized in Ad2-infected and Ad2-transformed cells. These results show that the E1B-19K and E1B-53K T antigens are not processed proteolytically at either the NH2 or COOH terminus. Our data provide strong evidence at the protein level that the E1B-19K and E1B-53K tumor antigens partially overlap in DNA sequence, with the E1B-19K initiating translation at the first ATG at nucleotide 1711 in translation reading frame 1 and the E1B-53K tumor antigen initiating translation at the second ATG at nucleotide 2016 in reading frame 3. This confirms the results of others on the N-terminal amino acid sequence of E1B-19K and theoretical deductions based on the DNA sequence. Our findings prove that the large E1B-53K T antigen initiates translation at the second ATG at nucleotide 2016 and not at equally plausible initiation codons located farther downstream at nucleotides 2202 and 2235. Thus, the E1B-53K T antigen is another example of a protein which initiates translation at an internal ATG rather than at the 5'-proximal ATG. Images PMID:6632083

  9. Development of a Cell-Based High-Throughput Assay to Screen for Inhibitors of Organic Anion Transporting Polypeptides 1B1 and 1B3

    PubMed Central

    Gui, Chunshan; Obaidat, Amanda; Chaguturu, Rathnam; Hagenbuch, Bruno

    2010-01-01

    The two organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are expressed at the sinusoidal membrane of hepatocytes. They have a broad and overlapping substrate specificity and transport many endobiotics and drugs. Specific inhibitors are required to determine the contribution of each OATP to the hepatocellular uptake of common substrates. We have developed a cell-based high-throughput assay to screen chemical libraries in order to identify such inhibitors for OATP1B1 and OATP1B3. We have used OATP1B1- or OATP1B3-expressing Chinese Hamster Ovary cells on 96-well plates and determined uptake of fluorescein-methotrexate (FMTX). We validated the assay with known inhibitors and screened the well characterized Prestwick library of 1120 drugs. Along with several known OATP inhibitors including rifampicin, cyclosporine A and mifepristone we identified some new inhibitors. For inhibitors that seemed to be able to distinguish between OATP1B1- and OATP1B3-mediated FMTX uptake IC50 values were determined. Estropipate (estrone-3-sulfate stabilized with piperazine) was the most selective OATP1B1 inhibitor (IC50 = 0.06 μM vs. 19.3 μM for OATP1B3). Ursolic acid was the most selective OATP1B3 inhibitor (IC50 = 2.3 μM vs. 12.5 μM for OATP1B1). In conclusion, this cell-based assay should allow us to identify even more specific inhibitors by screening larger chemical libraries. PMID:20448812

  10. Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3.

    PubMed

    Gui, Chunshan; Obaidat, Amanda; Chaguturu, Rathnam; Hagenbuch, Bruno

    2010-01-01

    The two organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are expressed at the sinusoidal membrane of hepatocytes. They have a broad and overlapping substrate specificity and transport many endobiotics and drugs. Specific inhibitors are required to determine the contribution of each OATP to the hepatocellular uptake of common substrates. We have developed a cell-based high-throughput assay to screen chemical libraries in order to identify such inhibitors for OATP1B1 and OATP1B3. We have used OATP1B1- or OATP1B3-expressing Chinese Hamster Ovary cells on 96-well plates and determined uptake of fluorescein-methotrexate (FMTX). We validated the assay with known inhibitors and screened the well characterized Prestwick library of 1120 drugs. Along with several known OATP inhibitors including rifampicin, cyclosporine A and mifepristone we identified some new inhibitors. For inhibitors that seemed to be able to distinguish between OATP1B1- and OATP1B3-mediated FMTX uptake IC(50) values were determined. Estropipate (estrone-3-sulfate stabilized with piperazine) was the most selective OATP1B1 inhibitor (IC(50) = 0.06 microM vs. 19.3 microM for OATP1B3). Ursolic acid was the most selective OATP1B3 inhibitor (IC(50) = 2.3 microM vs. 12.5 microM for OATP1B1). In conclusion, this cell-based assay should allow us to identify even more specific inhibitors by screening larger chemical libraries. PMID:20448812

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

    PubMed

    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

  12. 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

  13. 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

  14. Non-linearity in Bayesian 1-D magnetotelluric inversion

    NASA Astrophysics Data System (ADS)

    Guo, Rongwen; Dosso, Stan E.; Liu, Jianxin; Dettmer, Jan; Tong, Xiaozhong

    2011-05-01

    This paper applies a Bayesian approach to examine non-linearity for the 1-D magnetotelluric (MT) inverse problem. In a Bayesian formulation the posterior probability density (PPD), which combines data and prior information, is interpreted in terms of parameter estimates and uncertainties, which requires optimizing and integrating the PPD. Much work on 1-D MT inversion has been based on (approximate) linearized solutions, but more recently fully non-linear (numerical) approaches have been applied. This paper directly compares results of linearized and non-linear uncertainty estimation for 1-D MT inversion; to do so, advanced methods for both approaches are applied. In the non-linear formulation used here, numerical optimization is carried out using an adaptive-hybrid algorithm. Numerical integration applies Metropolis-Hastings sampling, rotated to a principal-component parameter space for efficient sampling of correlated parameters, and employing non-unity sampling temperatures to ensure global sampling. Since appropriate model parametrizations are generally not known a priori, both under- and overparametrized approaches are considered. For underparametrization, the Bayesian information criterion is applied to determine the number of layers consistent with the resolving power of the data. For overparametrization, prior information is included which favours simple structure in a manner similar to regularized inversion. The data variance and/or trade-off parameter regulating data and prior information are treated in several ways, including applying fixed optimal estimates (an empirical Bayesian approach) or including them as hyperparameters in the sampling (hierarchical Bayesian). The latter approach has the benefit of accounting for the uncertainty in the hyperparameters in estimating model parameter uncertainties. Non-linear and linearized inversion results are compared for synthetic test cases and for the measured COPROD1 MT data by considering marginal probability

  15. Pregnancy and pregnancy outcome in hepatitis C type 1b.

    PubMed

    Jabeen, T; Cannon, B; Hogan, J; Crowley, M; Devereux, C; Fanning, L; Kenny-Walsh, E; Shanahan, F; Whelton, M J

    2000-09-01

    A large cohort of rhesus-negative women in Ireland were inadvertently infected with hepatitis C virus following exposure to contaminated anti-D immunoglobulin in 1977-8. This major iatrogenic episode was discovered in 1994. We studied 36 women who had been infected after their first pregnancy, and compared them to an age- and parity-matched control group of rhesus-positive women. The presence of hepatitis C antibody was confirmed in all 36 by enzyme-linked immunosorbent assay and by recombinant immunoblot assay, while 26 (72%) of the cohort were HCV-RNA-positive (type 1b) on PCR testing. In the 20 years post-infection, all members of the study group had at least one pregnancy, and mean parity was 3.5. They had a total of 100 pregnancies and 85 of these went to term. There were four premature births, one being a twin pregnancy, and 11 spontaneous miscarriages. One miscarriage occurred in the pregnancy following HCV infection. There were two neonatal deaths due to severe congenital abnormalities in the PCR-positive women. Of the children born to HCV-RNA positive mothers, only one (2.3%) tested positive for the virus. Significant portal fibrosis on liver biopsy was confined to HCV-RNA-positive mothers apart from one single exception in the antibody-positive HCV-RNA-negative group. Comparison with the control group showed no increase in spontaneous miscarriage rate, and no significant difference in obstetric complications; birth weights were similar for the two groups.

  16. 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.

  17. Viscous behavior in a quasi-1D fractal cluster glass.

    PubMed

    Etzkorn, S J; Hibbs, Wendy; Miller, Joel S; Epstein, A J

    2002-11-11

    The spin glass transition of a quasi-1D organic-based magnet ([MnTPP][TCNE]) is explored using both ac and dc measurements. A scaling analysis of the ac susceptibility shows a spin glass transition near 4 K, with a viscous decay of the thermoremanent magnetization recorded above 4 K. We propose an extension to a fractal cluster model of spin glasses that determines the dimension of the spin clusters (D) ranging from approximately 0.8 to over 1.5 as the glass transition is approached. Long-range dipolar interactions are suggested as the origin of this low value for the apparent lower critical dimension.

  18. Practical variational tomography for critical 1D systems

    NASA Astrophysics Data System (ADS)

    Lee, Jong Yeon; Landon-Cardinal, Olivier

    2015-03-01

    We further investigate a recently introduced efficient quantum state reconstruction procedure targeted to states well-approximated by the multi-scale entanglement renormalization ansatz (MERA). First, we introduce an improved optimization scheme that can be easily generalized for MERA states with larger bond dimension. Second, we provide a detailed analysis of the error propagation and quantify how it affects the distance between the experimental state and the reconstructed state. Third, we explain how to bound this distance using local data, providing an efficient scalable certification method. Fourth, we examine the performance of MERA tomography on the ground states of several 1D critical models.

  19. Structural stability of a 1D compressible viscoelastic fluid model

    NASA Astrophysics Data System (ADS)

    Huo, Xiaokai; Yong, Wen-An

    2016-07-01

    This paper is concerned with a compressible viscoelastic fluid model proposed by Öttinger. Although the model has a convex entropy, the Hessian matrix of the entropy does not symmetrize the system of first-order partial differential equations due to the non-conservative terms in the constitutive equation. We show that the corresponding 1D model is symmetrizable hyperbolic and dissipative and satisfies the Kawashima condition. Based on these, we prove the global existence of smooth solutions near equilibrium and justify the compatibility of the model with the Navier-Stokes equations.

  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. 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.

  2. Coherent thermal conductance of 1-D photonic crystals

    NASA Astrophysics Data System (ADS)

    Tschikin, Maria; Ben-Abdallah, Philippe; Biehs, Svend-Age

    2012-10-01

    We present an exact calculation of coherent thermal conductance in 1-D multilayer photonic crystals using the S-matrix method. In particular, we study the thermal conductance in a bilayer structure of Si/vacuum or Al2O3/vacuum slabs by means of the exact radiative heat flux expression. Based on the results obtained for the Al2O3/vacuum structure we show by comparison with previous works that the material losses and (localized) surface modes supported by the inner layers play a fundamental role and cannot be omitted in the definition of thermal conductance. Our results could have significant implications in the conception of efficient thermal barriers.

  3. Protein tyrosine phosphatase 1B (PTP1B) inhibitors from Morinda citrifolia (Noni) and their insulin mimetic activity.

    PubMed

    Nguyen, Phi-Hung; Yang, Jun-Li; Uddin, Mohammad N; Park, So-Lim; Lim, Seong-Il; Jung, Da-Woon; Williams, Darren R; Oh, Won-Keun

    2013-11-22

    As part of our ongoing search for new antidiabetic agents from medicinal plants, we found that a methanol extract of Morinda citrifolia showed potential stimulatory effects on glucose uptake in 3T3-L1 adipocyte cells. Bioassay-guided fractionation of this active extract yielded two new lignans (1 and 2) and three new neolignans (9, 10, and 14), as well as 10 known compounds (3-8, 11-13, and 15). The absolute configurations of compounds 9, 10, and 14 were determined by ECD spectra analysis. Compounds 3, 6, 7, and 15 showed inhibitory effects on PTP1B enzyme with IC50 values of 21.86 ± 0.48, 15.01 ± 0.20, 16.82 ± 0.42, and 4.12 ± 0.09 μM, respectively. Furthermore, compounds 3, 6, 7, and 15 showed strong stimulatory effects on 2-NBDG uptake in 3T3-L1 adipocyte cells. This study indicated the potential of compounds 3, 6, 7, and 15 as lead molecules for antidiabetic agents.

  4. Isolation of Modulators of the Liver-Specific Organic Anion-Transporting Polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae)

    PubMed Central

    Roth, Megan; Araya, Juan J.; Timmermann, Barbara N.

    2011-01-01

    Organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are liver-specific transporters that mediate the uptake of a broad range of drugs into hepatocytes, including statins, antibiotics, and many anticancer drugs. Compounds that alter transport by one or both of these OATPs could potentially be used to target drugs to hepatocytes or improve the bioavailability of drugs that are cleared by the liver. In this study, we applied a bioassay-guided isolation approach to identify such compounds from the organic extract of Rollinia emarginata Schlecht (Annonaceae). Fractions of the plant extract were screened for effects on OATP1B1- and OATP1B3-mediated transport of the model substrates estradiol-17β-glucuronide and estrone-3-sulfate. We isolated three compounds, ursolic acid, oleanolic acid, and 8-trans-p-coumaroyloxy-α-terpineol, which inhibited estradiol-17β-glucuronide uptake by OATP1B1 but not OATP1B3. In addition, a rare compound, quercetin 3-O-α-l-arabinopyranosyl(1→2) α-l-rhamnopyranoside, was identified that had distinct effects on each OATP. OATP1B1 was strongly inhibited, as was OATP1B3-mediated transport of estradiol-17β-glucuronide. However, OATP1B3-mediated uptake of estrone-3-sulfate was stimulated 4- to 5-fold. Kinetic analysis of this stimulation revealed that the apparent affinity for estrone-3-sulfate was increased (decreased Km), whereas the maximal rate of transport (Vmax) was significantly reduced. These results demonstrate a mechanism through which the hepatic uptake of drug OATP substrates could be stimulated. PMID:21846839

  5. Transport by OATP1B1 and OATP1B3 Enhances the Cytotoxicity of Epigallocatechin 3-O-gallate and Several Quercetin Derivatives⊥

    PubMed Central

    Zhang, Yuchen; Hays, Amanda; Noblett, Alexander; Thapa, Mahendra; Hua, Duy H.; Hagenbuch, Bruno

    2013-01-01

    Organic anion transporting polypeptide (OATP) 1B1 and 1B3 are transporters that are expressed selectively in human hepatocytes under normal conditions. OATP1B3 is also expressed in certain cancers. Flavonoids such as green tea catechins and quercetin glycosides have been shown to modulate the function of some OATPs. In the present study, the extent to which six substituted quercetin derivatives (1 – 6) affected the function of OATP1B1 and OATP1B3 was investigated. Uptake of the radiolabeled model substrates estradiol 17β-glucuronide, estrone 3-sulfate and dehydroepiandrosterone sulfate (DHEAS) was determined in the absence and presence of compounds 1 – 6 using Chinese hamster ovary (CHO) cells stably expressing either OATP1B1 or OATP1B3. Several of compounds 1 – 6 inhibited OATP-mediated uptake of all three model substrates suggesting that they could also be potential substrates. Compound 6 stimulated OATP1B3-mediated estradiol 17β-glucuronide uptake by increasing the apparent affinity of OATP1B3 for its substrate. Cytotoxicity assays demonstrated that epigallocatechin 3-O-gallate (EGCG) and most of compounds 1 – 6 killed preferentially OATP-expressing CHO cells. EGCG, 1 and 3 were the most potent cytotoxic compounds, with EGCG and 3 selectively killing OATP1B3 expressing cells. Given that OATP1B3 is expressed in several cancers, EGCG and some of the quercetin derivatives studied might be promising lead compounds for the development of novel anticancer drugs. PMID:23327877

  6. Nostocyclopeptide-M1: a potent, nontoxic inhibitor of the hepatocyte drug transporters OATP1B3 and OATP1B1.

    PubMed

    Herfindal, Lars; Myhren, Lene; Kleppe, Rune; Krakstad, Camilla; Selheim, Frode; Jokela, Jouni; Sivonen, Kaarina; Døskeland, Stein O

    2011-04-01

    We have isolated a novel cyanobacterial cyclic peptide (nostocyclopeptide M1; Ncp-M1) that blocks the hepatotoxic action of microcystin (MC) and nodularin (Nod). We show here that Ncp-M1 is nontoxic to primary hepatocytes in long-term culture. Ncp-M1 does not affect any known intracellular targets or pathways involved in MC action, like protein phosphatases, CaM-KII, or ROS-dependent cell death effectors. In support of this conclusion Ncp-M1 had no protective effect when microinjected into cells. Rather, the antitoxin effect was solely due to blocked hepatocyte uptake of MC and Nod. The hepatic uptake of MC and Nod is mainly via the closely related organic anion transporters OATP1B1 and OATP1B3, which also mediate hepatic transport of endogenous metabolites and hormones as well as drugs. OATP1B3 is also expressed in some aggressive cancers, where it confers apoptosis resistance. We show that Ncp-M1 inhibits transport through OATP1B3 and OATP1B1 expressed in HEK293 cells. The Ncp-M1 molecule has several nonproteinogenic amino acids and an imino bond, which hamper its synthesis. Moreover, a cyclic all L-amino acid heptapeptide analogue of Ncp-M1 also inhibits the OATP1B1/1B3 transporters, and with higher OATP1B3 preference than Ncp-M1 itself. The nontoxic Ncp-M1 and its synthetic cyclic peptide analogues thus provide new tools to probe the role of OATB1B1/1B3 mediated drug and metabolite transport in liver and cancer cells. They can also serve as scaffolds to design new, exopeptidase resistant OATP1B3-specific modulators.

  7. Isolation of modulators of the liver-specific organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae).

    PubMed

    Roth, Megan; Araya, Juan J; Timmermann, Barbara N; Hagenbuch, Bruno

    2011-11-01

    Organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are liver-specific transporters that mediate the uptake of a broad range of drugs into hepatocytes, including statins, antibiotics, and many anticancer drugs. Compounds that alter transport by one or both of these OATPs could potentially be used to target drugs to hepatocytes or improve the bioavailability of drugs that are cleared by the liver. In this study, we applied a bioassay-guided isolation approach to identify such compounds from the organic extract of Rollinia emarginata Schlecht (Annonaceae). Fractions of the plant extract were screened for effects on OATP1B1- and OATP1B3-mediated transport of the model substrates estradiol-17β-glucuronide and estrone-3-sulfate. We isolated three compounds, ursolic acid, oleanolic acid, and 8-trans-p-coumaroyloxy-α-terpineol, which inhibited estradiol-17β-glucuronide uptake by OATP1B1 but not OATP1B3. In addition, a rare compound, quercetin 3-O-α-l-arabinopyranosyl(1→2) α-L-rhamnopyranoside, was identified that had distinct effects on each OATP. OATP1B1 was strongly inhibited, as was OATP1B3-mediated transport of estradiol-17β-glucuronide. However, OATP1B3-mediated uptake of estrone-3-sulfate was stimulated 4- to 5-fold. Kinetic analysis of this stimulation revealed that the apparent affinity for estrone-3-sulfate was increased (decreased K(m)), whereas the maximal rate of transport (V(max)) was significantly reduced. These results demonstrate a mechanism through which the hepatic uptake of drug OATP substrates could be stimulated.

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

    PubMed

    Ribeiro, Carlos Alberto S; Pupo, André S

    2015-03-01

    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. PMID:25617795

  9. Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo.

    PubMed

    Zabolotny, Janice M; Kim, Young-Bum; Welsh, Laura A; Kershaw, Erin E; Neel, Benjamin G; Kahn, Barbara B

    2008-05-23

    Protein-tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin and leptin sensitivity. PTP1B overexpression in adipose tissue and skeletal muscle of humans and rodents may contribute to insulin resistance and obesity. The mechanisms mediating PTP1B overexpression in obese and diabetic states have been unclear. We find that adipose tissue inflammation and the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) regulate PTP1B expression in vivo. High fat feeding of mice increased PTP1B expression 1.5- to 7-fold in adipose tissue, liver, skeletal muscle, and arcuate nucleus of hypothalamus. PTP1B overexpression in high fat-fed mice coincided with increased adipose tissue expression of the macrophage marker CD68 and TNFalpha, which is implicated in causing obesity-induced insulin resistance. TNFalpha increased PTP1B mRNA and protein levels by 2- to 5-fold in a dose- and time-dependent manner in adipocyte and hepatocyte cell lines. TNFalpha administration in mice increased PTP1B mRNA 1.4- to 4-fold in adipose tissue, liver, skeletal muscle, and hypothalamic arcuate nucleus and PTP1B protein 2-fold in liver. Actinomycin D treatment blocked, and high dose salicylate treatment inhibited by 80%, TNFalpha-induced PTP1B expression in adipocyte cell lines, suggesting TNFalpha may induce PTP1B transcription via nuclear factor kappaB (NFkappaB) activation. Chromatin immunoprecipitation from adipocyte cell lines and liver of mice demonstrated TNFalpha-induced recruitment of NFkappaB subunit p65 to the PTP1B promoter in vitro and in vivo. In mice with diet-induced obesity, TNFalpha deficiency also partly blocked PTP1B overexpression in adipose tissue. Our data suggest that PTP1B overexpression in multiple tissues in obesity is regulated by inflammation and that PTP1B may be a target of anti-inflammatory therapies. PMID:18281274

  10. Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel

    PubMed Central

    de Graan, Anne-Joy M.; Lancaster, Cynthia S.; Obaidat, Amanda; Hagenbuch, Bruno; Elens, Laure; Friberg, Lena E.; de Bruijn, Peter; Hu, Shuiying; Gibson, Alice A.; Bruun, Gitte H.; Corydon, Thomas J.; Mikkelsen, Torben S.; Walker, Aisha L.; Du, Guoqing; Loos, Walter J.; van Schaik, Ron H. N.; Baker, Sharyn D.; Mathijssen, Ron H. J.; Sparreboom, Alex

    2012-01-01

    Purpose Docetaxel is extensively metabolized by CYP3A4 in the liver, but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3, and (ii) that inherited genetic defects in this process may impair systemic drug elimination. Methods Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wildtype), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wildtype and Oatp1b2-knockout mice, as well as in 141 white patients with multiple variant transporter genotypes. Results Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2, but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P=0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced-function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P>0.05). Conclusions The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that extreme caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3. PMID:22711709

  11. A simple quasi-1D model of Fibonacci anyons

    NASA Astrophysics Data System (ADS)

    Aasen, David; Mong, Roger; Clarke, David; Alicea, Jason; Fendley, Paul

    2015-03-01

    There exists various ways of understanding the topological properties of Ising anyons--from simple free-fermion toy models to formal topological quantum field theory. For other types of anyons simple toy models rarely exist; their properties have to be obtained using formal self-consistency relations. We explore a family of gapped 1D local bosonic models that in a certain limit become trivial to solve and provide an intuitive picture for Fibonacci anyons. One can interpret this model as a quasi-1D wire that forms the building block of a 2D topological phase with Fibonacci anyons. With this interpretation all topological properties of the Fibonacci anyons become manifest including ground state degeneracy and braid relations. We conjecture that the structure of the model is protected by an emergent symmetry analogous to fermion parity. 1) NSF Grant DMR-1341822 2) Institute for Quantum Information and Matter, an NSF physics frontier center with support from the Moore Foundation. 3) NSERC-PGSD.

  12. A 1D analysis of two high order MOC methods

    SciTech Connect

    Everson, M. S.; Forget, B.

    2012-07-01

    The work presented here provides two different methods for evaluating angular fluxes along long characteristics. One is based off a projection of the 1D transport equation onto a complete set of Legendre polynomials, while the other uses the 1D integral transport equation to evaluate the angular flux values at specific points along each track passing through a cell. The Moment Long Characteristic (M-LC) method is shown to provide 2(P+1) spatial convergence and significant gains in accuracy with the addition of only a few spatial degrees of freedom. The M-LC method, though, is shown to be ill-conditioned at very high order and for optically thin geometries. The Point Long Characteristic (P-LC) method, while less accurate, significantly improves stability to problems with optically thin cells. The P-LC method is also more flexible, allowing for extra angular flux evaluations along a given track to give a more accurate representation of the shape along each track. This is at the expense of increasing the degrees of freedom of the system, though, and requires an increase in memory storage. This work concludes that both may be used simultaneously within the same geometry to provide the best mix of accuracy and stability possible. (authors)

  13. 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.

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

    PubMed

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

    2016-02-01

    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.

  15. 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

  16. 77 FR 3284 - Comment Request for Information Collection for the H-1B Technical Skills Training (H-1B) and the...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-23

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

    PubMed

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

    2016-02-01

    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

  18. Histone Demethylase Jumonji AT-rich Interactive Domain 1B (JARID1B) Controls Mammary Gland Development by Regulating Key Developmental and Lineage Specification Genes*

    PubMed Central

    Zou, Mike Ran; Cao, Jian; Liu, Zongzhi; Huh, Sung Jin; Polyak, Kornelia; Yan, Qin

    2014-01-01

    The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b−/− mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b−/− strains, the majority of these Jarid1b−/− mice were viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy. These Jarid1b−/− mice exhibited decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreased serum estrogen level and reduced mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminished the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor α. Mechanistically, JARID1B was required for GATA3 recruitment to the Foxa1 promoter to activate Foxa1 expression. These results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms. PMID:24802759

  19. 77 FR 53912 - Agency Information Collection Activities; Submission for OMB Review; Comment Request; H-1B...

    Federal Register 2010, 2011, 2012, 2013, 2014

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    ... the Federal Register on January 23, 2012 (77 FR 3284). Interested parties are encouraged to send...; H-1B Technical Skills Training Grants and H-1B Jobs and Innovation Accelerator Challenge Grants... Training Grants and H-1B Jobs and Innovation Accelerator Challenge Grants,'' to the Office of...

  20. 18 CFR 1b.17 - Appearance and practice before the Commission.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

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    Code of Federal Regulations, 2013 CFR

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    ... 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...

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    Code of Federal Regulations, 2011 CFR

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  10. 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. PMID:15486049

  11. 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

  12. 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

  13. 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

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

    PubMed

    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

  15. NACA Aircraft on Lakebed - D-558-2, X-1B, and X-1E

    NASA Technical Reports Server (NTRS)

    1955-01-01

    of increased capacity, and a thinner high-speed wing. The X-1E was used to obtain in-flight data at twice the speed of sound, with particular emphasis placed on investigating the improvements achieved with the high-speed wing. These wings, made by Stanley Aircraft, were only 3-3/8-inches thick at the root and had 343 gauges installed in them to measure structural loads and aerodynamic heating. The X-1E used its rocket engine to power it up to a speed of 1,471 miles per hour (Mach 2.24) and to an altitude of 73,000 feet. Like the X-1 it was air-launched. The X-1 aircraft were almost 31 feet long and had a wingspan of 28 feet. The X-1 was built of conventional aluminum stressed-skin construction to extremely high structural standards. The X-1E was also 31 feet long but had a wingspan of only 22 feet, 10 inches. It was powered by a Reaction Motors, Inc., XLR-8-RM-5, four-chamber rocket engine. As did all X-1 rocket engines, the LR-8-RM-5 engine did not have throttle capability, but instead, depended on ignition of any one chamber or group of chambers to vary speed. The X-1A, X-1B, and the X-1D were growth versions of the X-1. They were almost five feet longer, almost 2,500 pounds heavier and had conventional canopies. The X-1A and X-1B were modified to have ejection seats. Their mission was to continue the X-1 studies at higher speeds and altitudes. The X-1A began this research after the X-1D was destroyed in an explosion on a captive flight before it made any research flights. On December 12, 1953, Major Charles Yeager flew the X-1A up to a speed of 1,612 miles per hour (almost two-and-a-half times the speed of sound). Then on August 26, 1954, Major Arthur Murray took the X-1A up to an altitude of 90,440 feet. Those two performances were the records for the X-1 program. Later the X-1A was also destroyed after being jettisoned from the carrier aircraft because of an explosion. The X-1B was fitted with 300 thermocouples for exploratory aerodynamic heating tests. It also

  16. 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.

  17. 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.

  18. 1D-transport properties of single superconducting lead nanowires

    NASA Astrophysics Data System (ADS)

    Michotte, S.; Mátéfi-Tempfli, S.; Piraux, L.

    2003-09-01

    We report on the transport properties of single superconducting lead nanowires grown by an electrodeposition technique, embedded in a nanoporous track-etched polymer membrane. The nanowires are granular, have uniform diameter of ∼40 nm and a very large aspect ratio (∼500). The diameter of the nanowire is small enough to ensure a 1D superconducting regime in a wide temperature range below Tc. The non-zero resistance in the superconducting state and its variation caused by fluctuations of the superconducting order parameter were measured versus temperature, magnetic field, and applied DC current (or voltage). The current induced breakdowns in the V- I characteristics may be explained by the formation of phase slip centers. Moreover, DC voltage driven measurements reveal the existence of a new S-shape behavior near the formation of these phase slip centers.

  19. Microlens Masses from 1-D Parallaxes and Heliocentric Proper Motions

    NASA Astrophysics Data System (ADS)

    Gould, Andrew

    2014-12-01

    One-dimensional (1-D) microlens parallaxes can be combined with heliocentric lens-source relative proper motion measurements to derive the lens mass and distance, as suggested by Ghosh et al. (2004). Here I present the first mathematical anlysis of this procedure, which I show can be represented as a quadratic equation. Hence, it is formally subject to a two-fold degeneracy. I show that this degeneracy can be broken in many cases using the relatively crude 2-D parallax information that is often available for microlensing events. I also develop an explicit formula for the region of parameter space where it is more difficult to break this degeneracy. Although no mass/distance measurements have yet been made using this technique, it is likely to become quite common over the next decade.

  20. Quadratic Finite Element Method for 1D Deterministic Transport

    SciTech Connect

    Tolar, Jr., D R; Ferguson, J M

    2004-01-06

    In the discrete ordinates, or SN, numerical solution of the transport equation, both the spatial ({und r}) and angular ({und {Omega}}) dependences on the angular flux {psi}{und r},{und {Omega}}are modeled discretely. While significant effort has been devoted toward improving the spatial discretization of the angular flux, we focus on improving the angular discretization of {psi}{und r},{und {Omega}}. Specifically, we employ a Petrov-Galerkin quadratic finite element approximation for the differencing of the angular variable ({mu}) in developing the one-dimensional (1D) spherical geometry S{sub N} equations. We develop an algorithm that shows faster convergence with angular resolution than conventional S{sub N} algorithms.

  1. 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.

  2. Connected components of irreducible maps and 1D quantum phases

    NASA Astrophysics Data System (ADS)

    Szehr, Oleg; Wolf, Michael M.

    2016-08-01

    We investigate elementary topological properties of sets of completely positive (CP) maps that arise in quantum Perron-Frobenius theory. We prove that the set of primitive CP maps of fixed Kraus rank is path-connected and we provide a complete classification of the connected components of irreducible CP maps at given Kraus rank and fixed peripheral spectrum in terms of a multiplicity index. These findings are then applied to analyse 1D quantum phases by studying equivalence classes of translational invariant matrix product states that correspond to the connected components of the respective CP maps. Our results extend the previously obtained picture in that they do not require blocking of physical sites, they lead to analytic paths, and they allow us to decompose into ergodic components and to study the breaking of translational symmetry.

  3. Glycolipid antigen processing for presentation by CD1d molecules.

    PubMed

    Prigozy, T I; Naidenko, O; Qasba, P; Elewaut, D; Brossay, L; Khurana, A; Natori, T; Koezuka, Y; Kulkarni, A; Kronenberg, M

    2001-01-26

    The requirement for processing glycolipid antigens in T cell recognition was examined with mouse CD1d-mediated responses to glycosphingolipids (GSLs). Although some disaccharide GSL antigens can be recognized without processing, the responses to three other antigens, including the disaccharide GSL Gal(alpha1-->2)GalCer (Gal, galactose; GalCer, galactosylceramide), required removal of the terminal sugars to permit interaction with the T cell receptor. A lysosomal enzyme, alpha-galactosidase A, was responsible for the processing of Gal(alpha1-->2)GalCer to generate the antigenic monosaccharide epitope. These data demonstrate a carbohydrate antigen processing system analogous to that used for peptides and an ability of T cells to recognize processed fragments of complex glycolipids.

  4. 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. PMID:26058865

  5. The potential of transferrin-pendant-type polyethyleneglycol liposomes encapsulating decahydrodecaborate-{sup 1}B (GB-10) as {sup 1}B-carriers for boron neutron capture therapy

    SciTech Connect

    Masunaga, Shin-ichiro . E-mail: smasuna@rri.kyoto-u.ac.jp; Kasaoka, Satoshi; Maruyama, Kazuo; Nigg, David; Sakurai, Yoshinori; Nagata, Kenji; Suzuki, Minoru; Kinashi, Yuko; Maruhashi, Akira; Ono, Koji

    2006-12-01

    Purpose: To evaluate GB-10-encapsulating transferrin (TF)-pendant-type polyethyleneglycol (PEG) liposomes as tumor-targeting {sup 1}B-carriers for boron neutron capture therapy. Methods and Materials: A free mercaptoundecahydrododecaborate-{sup 1}B (BSH) or decahydrodecaborate-{sup 1}B (GB-10) solution, bare liposomes, PEG liposomes, or TF-PEG liposomes were injected into SCC VII tumor-bearing mice, and {sup 1}B concentrations in the tumors and normal tissues were measured by {gamma}-ray spectrometry. Meanwhile, tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all intratumor proliferating cells, then injected with these {sup 1}B-carriers containing BSH or GB-10 in the same manner. Right after thermal neutron irradiation, the response of quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The frequency in the total tumor cells was determined from the BrdU nontreated tumors. Results: Transferrin-PEG liposomes showed a prolonged retention in blood circulation, low uptake by reticuloendothelial system, and the most enhanced accumulation of {sup 1}B in solid tumors. In general, the enhancing effects were significantly greater in total cells than Q cells. In both cells, the enhancing effects of GB-10-containing {sup 1}B-carriers were significantly greater than BSH-containing {sup 1}B-carriers, whether loaded in free solution or liposomes. In both cells, whether BSH or GB-10 was employed, the greatest enhancing effect was observed with TF-PEG liposomes followed in decreasing order by PEG liposomes, bare liposomes, and free BSH or GB-10 solution. In Q cells, the decrease was remarkable between PEG and bare liposomes. Conclusions: In terms of biodistribution characteristics and tumor cell-killing effect as a whole, including Q cells, GB-10 TF-PEG liposomes were regarded as promising {sup 1}B-carriers.

  6. Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice.

    PubMed

    Bettaieb, Ahmed; Koike, Shinichiro; Chahed, Samah; Bachaalany, Santana; Griffey, Stephen; Sastre, Juan; Haj, Fawaz G

    2016-08-01

    Acute pancreatitis (AP) is a common and devastating gastrointestinal disorder that causes significant morbidity. The disease starts as local inflammation in the pancreas that may progress to systemic inflammation and complications. Protein tyrosine phosphatase 1B (PTP1B) is implicated in inflammatory signaling, but its significance in AP remains unclear. To investigate whether PTP1B may have a role in AP, we used pancreas PTP1B knockout (panc-PTP1B KO) mice and determined the effects of pancreatic PTP1B deficiency on cerulein- and arginine-induced acute pancreatitis. We report that PTP1B protein expression was increased in the early phase of AP in mice and rats. In addition, histological analyses of pancreas samples revealed enhanced features of AP in cerulein-treated panc-PTP1B KO mice compared with controls. Moreover, cerulein- and arginine-induced serum amylase and lipase were significantly higher in panc-PTP1B KO mice compared with controls. Similarly, pancreatic mRNA and serum concentrations of the inflammatory cytokines IL-1B, IL-6, and tumor necrosis factor-α were increased in panc-PTP1B KO mice compared with controls. Furthermore, panc-PTP1B KO mice exhibited enhanced cerulein- and arginine-induced NF-κB inflammatory response accompanied with increased mitogen-activated protein kinases activation and elevated endoplasmic reticulum stress. Notably, these effects were recapitulated in acinar cells treated with a pharmacological inhibitor of PTP1B. These findings reveal a novel role for pancreatic PTP1B in cerulein- and arginine-induced acute pancreatitis. PMID:27461362

  7. Overexpression of OATP1B3 confers apoptotic resistance in colon cancer

    PubMed Central

    Lee, Wooin; Belkhiri, Abbes; Lockhart, A. Craig; Merchant, Nipun; Glaeser, Hartmut; Harris, Elizabeth I.; Washington, M. Kay; Brunt, Elizabeth M.; Zaika, Alex; Kim, Richard B.; El-Rifai, Wael

    2008-01-01

    Organic anion transporting polypeptide 1B3 (OATP1B3, SLCO1B3) is normally expressed in hepatocytes. In this study, we demonstrated frequent overexpression of OATP1B3 in colorectal adenocarcinomas. Quantitative RT-PCR analysis of 17 colon tumors indicated tumoral overexpression of OATP1B3 by ~100 fold, compared to 20 normal colon samples (p<0.0001). Using immunohistochemistry on a tissue microarray containing 93 evaluable colon tumor specimens, we detected immunostaining of OATP1B3 in 75 colon adenocarcinomas (81%) and no immunostaining in normal samples. To determine the functional effects of OATP1B3 expression on drug-induced apoptosis, we used camptothecin and oxaliplatin on a panel of colorectal cancer cell lines stably overexpressing OATP1B3. The results indicated that OATP1B3 overexpression enhanced cell survival in RKO, HCT-8 and HCT116p53+/+ cells that harbor wildtype p53 but not in Caco-2 and HCT116p53-/- cells that lack p53, compared to the respective empty vector controls (p<0.01). The TUNEL assay confirmed that HCT116p53+/+ cells overexpressing OATP1B3 had significantly lower apoptotic levels compared to empty vector control (P<0.001). The overexpression of OATP1B3 reduced the transcriptional activity of p53, with subsequent reductions in transcript and protein levels of its downstream transcription targets (P21WAF1 and PUMA). Overexpression of a point mutation (G583E) variant of OATP1B3 lacking transport activity did not confer an antiapoptotic effect or affect p53 transcriptional activity, suggesting that the antiapoptotic effect of OATP1B3 may be associated with its transport activity. Taken together, our results suggest that OATP1B3 overexpression in colorectal cancer cells may provide a survival advantage by altering p53-dependent pathways. PMID:19074900

  8. Essential Roles for ARID1B in Dendritic Arborization and Spine Morphology of Developing Pyramidal Neurons

    PubMed Central

    Ka, Minhan; Chopra, Divyan A.; Dravid, Shashank M.

    2016-01-01

    De novo truncating mutations in ARID1B, a chromatin-remodeling gene, cause Coffin–Siris syndrome, a developmental disorder characterized by intellectual disability and speech impairment; however, how the genetic elimination leads to cognitive dysfunction remains unknown. Thus, we investigated the neural functions of ARID1B during brain development. Here, we show that ARID1B regulates dendritic differentiation in the developing mouse brain. We knocked down ARID1B expression in mouse pyramidal neurons using in utero gene delivery methodologies. ARID1B knockdown suppressed dendritic arborization of cortical and hippocampal pyramidal neurons in mice. The abnormal development of dendrites accompanied a decrease in dendritic outgrowth into layer I. Furthermore, knockdown of ARID1B resulted in aberrant dendritic spines and synaptic transmission. Finally, ARID1B deficiency led to altered expression of c-Fos and Arc, and overexpression of these factors rescued abnormal differentiation induced by ARID1B knockdown. Our results demonstrate a novel role for ARID1B in neuronal differentiation and provide new insights into the origin of cognitive dysfunction associated with developmental intellectual disability. SIGNIFICANCE STATEMENT Haploinsufficiency of ARID1B, a component of chromatin remodeling complex, causes intellectual disability. However, the role of ARID1B in brain development is unknown. Here, we demonstrate that ARID1B is required for neuronal differentiation in the developing brain, such as in dendritic arborization and synapse formation. Our findings suggest that ARID1B plays a critical role in the establishment of cognitive circuitry by regulating dendritic complexity. Thus, ARID1B deficiency may cause intellectual disability via abnormal brain wiring induced by the defective differentiation of cortical neurons. PMID:26937011

  9. Basal and 3-methylcholanthrene-induced expression of cytochrome P450 1A, 1B and 1C genes in the Brazilian guppy, Poecilia vivipara.

    PubMed

    Dorrington, Tarquin; Zanette, Juliano; Zacchi, Flávia L; Stegeman, John J; Bainy, Afonso C D

    2012-11-15

    In fish there are four cytochrome P450 (CYP1) subfamilies: CYP1A, CYP1B, CYP1C, and CYP1D. Here we cloned Poecilia vivipara CYP1A, with an inferred amino acid sequence 91% identical to CYP1A from the killifish Fundulus heteroclitus, another member of the Cypriniformes, and an important model in ecotoxicology. In addition, we examined the expression of CYP1A, CYP1B1, and CYP1C1 by qPCR in liver, gill, and intestine of adult P. vivipara injected with 3-methylcholanthrene (3-MC) or held in clean water (control group) for 24h. All three tissues examined showed basal expression of the three CYP1 genes. CYP1A was most strongly expressed in the liver, while CYP1B1, and CYP1C1 were most strongly expressed in the gill and intestine respectively. 3-MC induced CYP1A, CYP1B1, and CYP1C1 significantly (20-120-fold) in the three organs, consistent with the regulation of CYP1A, CYP1B1 and CYP1C1 via the aryl hydrocarbon receptor. Validation of CYP1 gene biomarkers in fish collected from a contaminated urban mangrove environment was confirmed with significant induction of CYP1A and CYP1C1 in gills (10-15-fold) and CYP1B1 in liver (23-fold), relative to fish from a control site. The responsiveness of these CYP1 genes indicates P. vivipara is suitable as a model for environmental toxicology studies and environmental assessment in Brazil.

  10. 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.

  11. 5-HT1B Autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex.

    PubMed

    Malagié, I; Trillat, A C; Bourin, M; Jacquot, C; Hen, R; Gardier, A M

    2001-02-01

    We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 1B receptor subtype in mediating the effects of selective serotonin re-uptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg, but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiated the effect of a single administration of paroxetine on extracellular 5-HT levels more in the ventral hippocampus than in the frontal cortex. These data suggest that 5-HT1B autoreceptors limit the effects of SSRIs on dialysate 5-HT levels at serotonergic nerve terminals.

  12. Functional expression of novel human and murine AKR1B genes

    PubMed Central

    Salabei, Joshua K.; Li, Xiao-Ping; Petrash, J. Mark; Bhatnagar, Aruni; Barski, Oleg A.

    2011-01-01

    The Aldo Keto Reductases (AKRs) are a superfamily of enzymes that catalyze the reduction of biogenic and xenobiotic aldehydes and ketones. AKR1B family has 2 known members in humans and 3 in rodents. Two novel gene loci, hereafter referred to as AKR1B15 in human and Akr1b16 in mouse have been predicted to exist within the AKR1B clusters. AKR1B15 displays 91% and 67% sequence identity with human genes AKR1B10 and AKR1B1, respectively while Akr1b16 shares 82–84% identity with murine Akr1b8 and Akr1b7. We tested the hypothesis that AKR1B15 and Akr1b16 genes are expressed as functional proteins in human and murine tissues, respectively. Using whole tissue mRNA, we were able to clone the full-length open reading frames for AKR1B15 from human eye and testes, and Akr1b16 from murine spleen, demonstrating that these genes are transcriptionally active. The corresponding cDNAs were cloned into pET28a and pIRES-hrGFP-1α vectors for bacterial and mammalian expression respectively. Both genes were expressed as 36 kDA proteins found in the insoluble fraction of bacterial cell lysate. These proteins, expressed in bacteria showed no enzymatic activity. However, lysates from COS-7 cells transfected with AKR1B15 showed a 4.8-fold (with p-nitrobenzaldehyde) and 3.3-fold (with DL-glyceraldehyde) increase in enzyme activity compared with untransfected COS-7 cells. The Akr1b16 transcript was shown to be ubiquitously expressed in murine tissues. Highest levels of transcript were found in heart, spleen, and lung. From these observations we conclude that the predicted AKR1B15 and 1b16 genes are expressed in several murine and human tissues. Further studies are required to elucidate their physiological roles. PMID:21276782

  13. Microtubule and Cell Contact Dependency of ER-bound PTP1B Localization in Growth Cones

    PubMed Central

    Fuentes, Federico

    2009-01-01

    PTP1B is an ER-bound protein tyrosine phosphatase implied in the regulation of cell adhesion. Here we investigated mechanisms involved in the positioning and dynamics of PTP1B in axonal growth cones and evaluated the role of this enzyme in axons. In growth cones, PTP1B consistently localizes in the central domain, and occasionally at the peripheral region and filopodia. Live imaging of GFP-PTP1B reveals dynamic excursions of fingerlike processes within the peripheral region and filopodia. PTP1B and GFP-PTP1B colocalize with ER markers and coalign with microtubules at the peripheral region and redistribute to the base of the growth cone after treatment with nocodazole, a condition that is reversible. Growth cone contact with cellular targets is accompanied by invasion of PTP1B and stable microtubules in the peripheral region aligned with the contact axis. Functional impairment of PTP1B causes retardation of axon elongation, as well as reduction of growth cone filopodia lifetime and Src activity. Our results highlight the role of microtubules and cell contacts in the positioning of ER-bound PTP1B to the peripheral region of growth cones, which may be required for the positive role of PTP1B in axon elongation, filopodia stabilization, and Src activity. PMID:19158394

  14. 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.

  15. Arabidopsis HEAT SHOCK TRANSCRIPTION FACTORA1b overexpression enhances water productivity, resistance to drought, and infection.

    PubMed

    Bechtold, Ulrike; Albihlal, Waleed S; Lawson, Tracy; Fryer, Michael J; Sparrow, Penelope A C; Richard, François; Persad, Ramona; Bowden, Laura; Hickman, Richard; Martin, Cathie; Beynon, Jim L; Buchanan-Wollaston, Vicky; Baker, Neil R; Morison, James I L; Schöffl, Friedrich; Ott, Sascha; Mullineaux, Philip M

    2013-08-01

    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.

  16. Frequent amplification of PTP1B is associated with poor survival of gastric cancer patients.

    PubMed

    Wang, Na; She, Junjun; Liu, Wei; Shi, Jing; Yang, Qi; Shi, Bingyin; Hou, Peng

    2015-01-01

    The protein tyrosine phosphatase 1B (PTP1B), a non-transmembrane protein tyrosine phosphatase, has been implicated in gastric pathogenesis. Several lines of recent evidences have shown that PTP1B is highly amplified in breast and prostate cancers. The aim of this study was to investigate PTP1B amplification in gastric cancer and its association with poor prognosis of gastric cancer patients, and further determine the role of PTP1B in gastric tumorigenesis. Our data demonstrated that PTP1B was significantly up-regulated in gastric cancer tissues as compared with matched normal gastric tissues by using quantitative RT-PCR (qRT-PCR) assay. In addition, copy number analysis showed that PTP1B was amplified in 68/131 (51.9%) gastric cancer cases, whereas no amplification was found in the control subjects. Notably, PTP1B amplification was positively associated with its protein expression, and was significantly related to poor survival of gastric cancer patients. Knocking down PTP1B expression in gastric cancer cells significantly inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrested and apoptosis. Mechanically, PTP1B promotes gastric cancer cell proliferation, survival and invasiveness through modulating Src-related signaling pathways, such as Src/Ras/MAPK and Src/phosphatidylinositol-3-kinase (PI3K)/Akt pathways. Collectively, our data demonstrated frequent overexpression and amplification PTP1B in gastric cancer, and further determined the oncogenic role of PTP1B in gastric carcinogenesis. Importantly, PTP1B amplification predicts poor survival of gastric cancer patients. PMID:25590580

  17. Arabidopsis HEAT SHOCK TRANSCRIPTION FACTORA1b overexpression enhances water productivity, resistance to drought, and infection.

    PubMed

    Bechtold, Ulrike; Albihlal, Waleed S; Lawson, Tracy; Fryer, Michael J; Sparrow, Penelope A C; Richard, François; Persad, Ramona; Bowden, Laura; Hickman, Richard; Martin, Cathie; Beynon, Jim L; Buchanan-Wollaston, Vicky; Baker, Neil R; Morison, James I L; Schöffl, Friedrich; Ott, Sascha; Mullineaux, Philip M

    2013-08-01

    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

  18. 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, 2011 CFR

    2011-04-01

    ... (Public Law 106-95) and the regulations issued thereunder, 20 CFR part 655, subparts L and M. (3) E-3... U.S.C. 1101(a)(15)(H)(i)(b1)), under the U.S.-Chile and U.S.-Singapore Free Trade Agreements as long... condition application is for an “E-3 Australia,” “H-1B1 Chile,” or “H-1B1 Singapore” nonimmigrant....

  19. 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

    ... (Public Law 106-95) and the regulations issued thereunder, 20 CFR part 655, subparts L and M. (3) E-3... U.S.C. 1101(a)(15)(H)(i)(b1)), under the U.S.-Chile and U.S.-Singapore Free Trade Agreements as long... condition application is for an “E-3 Australia,” “H-1B1 Chile,” or “H-1B1 Singapore” nonimmigrant....

  20. 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, 2012 CFR

    2012-04-01

    ... (Public Law 106-95) and the regulations issued thereunder, 20 CFR part 655, subparts L and M. (3) E-3... U.S.C. 1101(a)(15)(H)(i)(b1)), under the U.S.-Chile and U.S.-Singapore Free Trade Agreements as long... condition application is for an “E-3 Australia,” “H-1B1 Chile,” or “H-1B1 Singapore” nonimmigrant....

  1. 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, 2013 CFR

    2013-04-01

    ... (Public Law 106-95) and the regulations issued thereunder, 20 CFR part 655, subparts L and M. (3) E-3... U.S.C. 1101(a)(15)(H)(i)(b1)), under the U.S.-Chile and U.S.-Singapore Free Trade Agreements as long... condition application is for an “E-3 Australia,” “H-1B1 Chile,” or “H-1B1 Singapore” nonimmigrant....

  2. 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, 2014 CFR

    2014-04-01

    ... (Public Law 106-95) and the regulations issued thereunder, 20 CFR part 655, subparts L and M. (3) E-3... U.S.C. 1101(a)(15)(H)(i)(b1)), under the U.S.-Chile and U.S.-Singapore Free Trade Agreements as long... condition application is for an “E-3 Australia,” “H-1B1 Chile,” or “H-1B1 Singapore” nonimmigrant....

  3. Characterization of ursodeoxycholic and norursodeoxycholic acid as substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and NTCP.

    PubMed

    König, Jörg; Klatt, Sabine; Dilger, Karin; Fromm, Martin F

    2012-08-01

    Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid (norUDCA) is currently tested in clinical trials for future treatment of primary sclerosing cholangitis because of beneficial effects in cholestatic Mdr2 knock-out mice. Uptake of UDCA and norUDCA into hepatocytes is believed to be a prerequisite for subsequent metabolism and therapeutic action. However, the molecular determinants of hepatocellular uptake of UDCA and norUDCA are poorly understood. We therefore investigated whether UDCA and norUDCA are substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and Na(+) -taurocholate co-transporting polypeptide (NTCP), which are localized in the basolateral membrane of hepatocytes. Uptake of [(3) H]UDCA and [(14) C]norUDCA into Human embryonic kidney (HEK) cells stably expressing OATP1B1, OATP1B3, OATP2B1 or NTCP was investigated and compared with uptake into vector control cells. Uptake ratios were calculated by dividing uptake into transporter-transfected cells by uptake into respective control cells. Uptake ratios of OATP1B1-, OATP1B3- and OATP2B1-mediated UDCA and norUDCA uptake were at maximum 1.23 and 1.49, respectively. Uptake of UDCA was significantly higher into HEK-NTCP cells only at the lowest tested concentration (1 μM, p < 0.001) compared with the control cells with an uptake ratio of 1.34-fold. NorUDCA was not significantly transported by NTCP. The low uptake rates suggest that OATP1B1, OATP1B3, OATP2B1 and NTCP are not relevant for hepatocellular uptake and effects of UDCA and norUDCA in human beings.

  4. Role of dual specificity tyrosine-phosphorylation-regulated kinase 1B (Dyrk1B) in S-phase entry of HPV E7 expressing cells from quiescence

    PubMed Central

    Zhou, Na; Yuan, Shoudao; Wang, Rongchun; Zhang, Weifang; Chen, Jason J.

    2015-01-01

    The high-risk human papillomavirus (HPV) is the causative agent for cervical cancer. The HPV E7 oncogene promotes S-phase entry from quiescent state in the presence of elevated cell cycle inhibitor p27Kip1, a function that may contribute to carcinogenesis. However, the mechanism by which HPV E7 induces quiescent cells to entry into S-phase is not fully understood. Interestingly, we found that Dyrk1B, a dual-specificity kinase and negative regulator of cell proliferation in quiescent cells, was upregulated in E7 expressing cells. Surprisingly and in contrast to what was previously reported, Dyrk1B played a positive role in S-phase entry of quiescent HPV E7 expressing cells. Mechanistically, Dyrk1B contributed to p27 phosphorylation (at serine 10 and threonine 198), which was important for the proliferation of HPV E7 expressing cells. Moreover, Dyrk1B up-regulated HPV E7. Taken together, our studies uncovered a novel function of Dyrk1B in high-risk HPV E7-mediated cell proliferation. Dyrk1B may serve as a target for therapy in HPV-associated cancers. PMID:26307683

  5. 1D X-ray Beam Compressing Monochromators

    SciTech Connect

    Korytar, D.; Dobrocka, E.; Konopka, P.; Zaprazny, Z.; Ferrari, C.; Mikulik, P.; Vagovic, P.; Ac, V.; Erko, A.; Abrosimov, N.

    2010-04-06

    A total beam compression of 5 and 10 corresponding to the asymmetry angles of 9 deg. and 12 deg. is achieved with V-5 and V-10 monochromators, respectively, in standard single crystal pure germanium (220) X-ray beam compressing (V-shaped) monochromators for CuKalpha{sub 1} radiation. A higher 1D compression of X-ray beam is possible using larger angles of asymmetry, however it is achieved at the expense of the total intensity, which is decreased due to the refraction effect. To increase the monochromator intensity, several ways are considered both theoretically and experimentally. Linearly graded germanium rich Ge{sub x}Si{sub (1-x)} single crystal was used to prepare a V-21 single crystal monochromator with 15 deg. asymmetry angles (compression factor of 21). Its temperature gradient version is discussed for CuKalpha{sub 1} radiation. X-ray diffraction measurements on the graded GeSi monochromator showed more than 3-times higher intensity at the output compared with that of a pure Ge monochromator.

  6. 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.

  7. 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.

  8. Control and imaging of O(1D2) precession

    NASA Astrophysics Data System (ADS)

    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 O2 at 157 nm provides a clean source of fast-moving O(1D2) 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.

  9. Diagnostic nerve ultrasound in Charcot-Marie-Tooth disease type 1B.

    PubMed

    Cartwright, Michael S; Brown, Martin E; Eulitt, Patrick; Walker, Francis O; Lawson, Victoria H; Caress, James B

    2009-07-01

    Ultrasound is emerging as a useful tool for evaluation of neuromuscular conditions, because it can provide high-resolution anatomic information to complement electrodiagnostic data. There have been few studies in which ultrasound was used to assess the peripheral nerves of individuals with Charcot-Marie-Tooth (CMT) disease and none involving CMT type 1B. In this study we compared nerve cross-sectional area in individuals from a single large family with CMT 1B with normal, healthy controls. We also assessed for cranial nerve enlargement in those with CMT 1B with cranial neuropathies compared to those with CMT 1B without cranial neuropathies. Individuals with CMT 1B have significantly larger median and vagus nerves than healthy controls, but no difference was seen in cranial nerve size between those with versus those without cranial neuropathies. This is the first study to characterize the ultrasonographic findings in the peripheral nerves of individuals with CMT 1B.

  10. Absolute rate constant determinations for the deactivation of O/1D/ by time resolved decay of O/1D/ yields O/3P/ emission

    NASA Technical Reports Server (NTRS)

    Davidson, J. A.; Sadowski, C. M.; Schiff, H. I.; Howard, C. J.; Schmeltekopf, A. L.; Jennings, D. A.; Streit, G. E.

    1976-01-01

    Absolute rate constants for the deactivation of O(1D) atoms by some atmospheric gases have been determined by observing the time-resolved emission of O(1D) at 630 nm. O(1D) atoms were produced by the dissociation of ozone via repetitive laser pulses at 266 nm. Absolute rate constants for the relaxation of O(1D) at 298 K are reported for N2, O2, CO2, O3, H2, D2, CH4, HCl, NH3, H2O, N2O, and Ne. The results obtained are compared with previous relative and absolute measurements reported in the literature.

  11. Zebrafish cdx1b regulates expression of downstream factors of Nodal signaling during early endoderm formation.

    PubMed

    Cheng, Pei-Yi; Lin, Chia-Chi; Wu, Chun-Shiu; Lu, Yu-Fen; Lin, Che Yi; Chung, Chih-Ching; Chu, Cheng-Ying; Huang, Chang-Jen; Tsai, Chun-Yen; Korzh, Svetlana; Wu, Jen-Leih; Hwang, Sheng-Ping L

    2008-03-01

    We identified a zebrafish caudal-related homeobox (cdx1b) gene, which shares syntenic conservation with both human and mouse Cdx1. Zebrafish cdx1b transcripts are maternally deposited. cdx1b is uniformly expressed in both epiblast and hypoblast cells from late gastrulation to the 1-2s stages and can be identified in the retinas, brain and somites during 18-22 hpf stages. After 28 hours of development, cdx1b is exclusively expressed in the developing intestine. Both antisense morpholino oligonucleotide-mediated knockdown and overexpression experiments were conducted to analyze cdx1b function. Hypoplastic development of the liver and pancreas and intestinal abnormalities were observed in 96 hpf cdx1b morphants. In 85% epiboly cdx1b morphants, twofold decreases in the respective numbers of gata5-, cas-, foxa2- and sox17-expressing endodermal precursors were identified. Furthermore, ectopic cdx1b expression caused substantial increases in the respective numbers of gata5-, cas-, foxa2- and sox17-expressing endodermal precursors and altered their distribution patterns in 85% epiboly injected embryos. Conserved Cdx1-binding motifs were identified in both gata5 and foxa2 genes by interspecific sequence comparisons. Cdx1b can bind to the Cdx1-binding motif located in intron 1 of the foxa2 gene based on an electrophoretic mobility shift assay. Co-injection of either zebrafish or mouse foxa2 mRNA with the cdx1b MO rescued the expression domains of ceruloplasmin in the liver of 53 hpf injected embryos. These results indicate that zebrafish cdx1b regulates foxa2 expression and may also modulate gata5 expression, thus affecting early endoderm formation. This study underscores a novel role of zebrafish cdx1b in the development of different digestive organs compared with its mammalian homologs. PMID:18234726

  12. Effects of oxytocin on serotonin 1B agonist-induced autism-like behavior in mice.

    PubMed

    Lawson, Sarah K; Gray, Andrew C; Woehrle, Nancy S

    2016-11-01

    Social impairments in autism remain poorly understood and without approved pharmacotherapies. Novel animals models are needed to elucidate mechanisms and evaluate novel treatments for the social deficits in autism. Recently, serotonin 1B receptor (5-HT1B) agonist challenge in mice was shown to induce autism-like behaviors including perseveration, reduced prepulse inhibition, and delayed alternation deficits. However, the effects of 5-HT1B agonists on autism-related social behaviors in mice remain unknown. Here, we examine the effects of 5-HT1B agonist challenge on sociability and preference for social novelty in mice. We also examine the effects of 5-HT1B agonist treatment on average rearing duration, a putative rodent measure of non-selective attention. Non-selective attention is an associated feature of autism that is also not well understood. We show that 5-HT1B receptor activation reduces sociability, preference for social novelty, and rearing in mice. In addition, we examine the ability of oxytocin, an off-label treatment for the social impairments in autism, to reverse 5-HT1B agonist-induced social and attention deficits in mice. We show that oxytocin restores social novelty preference in mice treated with a 5-HT1B agonist. We also show that oxytocin attenuates 5-HT1B agonist-induced sociability and rearing deficits in mice. Our results suggest that 5-HT1B agonist challenge provides a useful pharmacological mouse model for aspects of autism, and implicate 5-HT1B in autism social and attention deficits. Moreover, our findings suggest that oxytocin may treat the social deficits in autism through a mechanism involving 5-HT1B.

  13. The pathogenic mechanism of dysbindin-1B toxic aggregation: BLOC-1 and intercellular vesicle trafficking.

    PubMed

    Yang, Wei; Zhu, Chunyan; Shen, Yan; Xu, Qi

    2016-10-01

    DTNBP1, which encodes dysbindin-1, is associated with cognitive impairment. Genetic evidence indicates that the C allele of rs117610176 leads to an increase in DTNBP-1b mRNA splicing in patients with paranoid schizophrenia. In addition, dysbindin-1B, rather than dysbindin-1A/C, exhibits a tendency toward toxic aggregation. In postmortem brains, dysbindin-1B not only aggregates with itself, it also co-aggregates with proteins that interact with it. However, the pathogenic mechanism underlying dysbindin-1B toxic aggregation remains unknown. In the brain, dysbindin-1 is primarily found as a subunit of biogenesis of lysosome-related organelles complex 1 (BLOC-1), which plays a role in intracellular vesicle trafficking. Therefore, we hypothesized that dysbindin-1B might impair the cognitive function of schizophrenia patients by co-aggregating with BLOC-1 subunits and disturbing the function of BLOC-1. In this study, we investigated the dominant-negative effect of dysbindin-1B on the BLOC-1 complex. We found that in multiple brain areas in Dys1B(+/+) mice, the expression levels of soluble functional BLOC-1 subunits were decreased. Meanwhile, BLOC-1 subunits co-aggregated with dysbindin-1B-myc. Functional studies in primary cortical neurons further revealed the malfunction of BLOC-1 in intercellular vesicle trafficking in Dys1B(+/+) mice. In addition, we used the Morris water maze task to investigate the effects of dysbindin-1B aggregation on cognition. The results demonstrated that Dys1B(+/+) mice exhibited spatial learning and memory deficits, which were accompanied by the shrinkage of apical and basal dendritic branches and the loss of dendritic spines in hippocampal CA1 neurons, as demonstrated by Golgi staining. Taken together, the results of the present study suggest that dysbindin-1B toxic aggregation might impair cognition through a dominant-negative effect on BLOC-1.

  14. In vivo and in vitro CYP1B mRNA expression in channel catfish.

    PubMed

    Willett, Kristine L; Ganesan, Shobana; Patel, Monali; Metzger, Christine; Quiniou, Sylvie; Waldbieser, Geoff; Scheffler, Brian

    2006-07-01

    Our goal was to study the induction of CYP1B mRNA expression in channel catfish (Ictalurus punctatus). CYP1B belongs to the cytochrome P450 superfamily of genes, is involved in the oxidation of endogenous and exogenous compounds, and could potentially be a useful biomarker in fish for exposure to AhR ligands. The full-length catfish CYP1B cDNA is 2417 nt to the polyA tail and encodes a putative protein of 536 amino acids. It has 67% amino acid similarity to carp and zebrafish CYP1B and 68% similarity to carp CYP1B2. Male channel catfish were collected from three Mississippi Delta sites: Lake Roebuck, Itta Bena; Bee Lake, Thornton; and Sunflower River, Indianola. Total RNA was isolated from wild-caught catfish gill, blood, gonad and liver tissues. Quantitative real-time reverse transcriptase PCR was used to determine relative induction of CYP1B in wild catfish compared to laboratory control and BaP-exposed catfish (20mg/kg i.p. after 4 days). BaP exposure significantly induced CYP1B message in blood, gonad, and liver of laboratory catfish. In these same tissues of wild catfish from sites with relatively low sediment contaminants, CYP1B message was not statistically increased relative to laboratory control catfish. CYP1B transcript abundance was higher in gills compared to other tissues in both laboratory and wild catfish. When primary cultured gill cells were treated with increasing concentrations of BaP, TCDD, and PCBs 77, 126 and 169, CYP1B mRNA was induced more than 10-fold while PCB153 and 4,4'DDT did not cause significant CYP1B induction. Our results suggest that catfish CYP1B is induced by the classic AhR ligands. PMID:16697458

  15. Role of transmembrane domain 10 for the function of organic anion transporting polypeptide 1B1

    PubMed Central

    Gui, Chunshan; Hagenbuch, Bruno

    2009-01-01

    The liver-specific organic anion transporting polypeptides OATP1B1 and OATP1B3 are highly homologous and share numerous substrates. However, at low concentrations OATP1B1 shows substrate selectivity for estrone-3-sulfate. In this study, we investigated the molecular mechanism for this substrate selectivity of OATP1B1 by constructing OATP1B1/1B3 chimeric transporters and by site-directed mutagenesis. Functional studies of chimeras showed that transmembrane domain 10 is critical for the function of OATP1B1. We further identified four amino acid residues, namely L545, F546, L550, and S554 in TM10, whose simultaneous mutation caused almost complete loss of OATP1B1-mediated estrone-3-sulfate transport. Comparison of the kinetics of estrone-3-sulfate transport confirmed a biphasic pattern for OATP1B1, but showed a monophasic pattern for the quadruple mutant L545S/F546L/L550T/S554T. This mutant also showed reduced transport for other OATP1B1 substrates such as bromosulfophthalein and [d-penicillamine2,5]enkephalin. Helical wheel analysis and molecular modeling suggest that L545 is facing the substrate translocation pathway, whereas F546, L550, and S554 are located inside the protein. These results indicate that L545 might contribute to OATP1B1 function by interacting with substrates, whereas F546, L550, and S554 seem important for protein structure. In conclusion, our results show that TM10 is critical for the function of OATP1B1. PMID:19760661

  16. 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

  17. Characterization of the C-terminal ER membrane anchor of PTP1B

    SciTech Connect

    Anderie, Ines Schulz, Irene; Schmid, Andreas

    2007-09-10

    The tyrosine phosphatase PTP1B is an important regulator of cell function. In living cells PTP1B activity is restricted to the vicinity of the endoplasmic reticulum (ER) by post-translational C-terminal attachment of PTP1B to the ER membrane network. In our study we investigated the membrane anchor of PTP1B by use of EGFP fusion proteins. We demonstrate that the membrane anchor of PTP1B cannot be narrowed down to a unique amino acid sequence with a defined start and stop point but rather is moveable within several amino acids. Removal of up to seven amino acids from the C-terminus, as well as exchange of single amino acids in the putative transmembrane sequence did not influence subcellular localization of PTP1B. With the method of bimolecular fluorescence complementation we could demonstrate dimerization of PTP1B in vivo. Homodimerization was, in contrast to other tail-anchored proteins, not dependent on the membrane anchor. Our data demonstrate that the C-terminal membrane anchor of PTP1B is formed by a combination of a single stretch transmembrane domain (TMD) followed by a tail. TMD and tail length are variable and there are no sequence-specific features. Our data for PTP1B are consistent with a concept that explains the ER membrane anchor of tail-anchored proteins as a physicochemical structure.

  18. Plectin isoform 1b mediates mitochondrion-intermediate filament network linkage and controls organelle shape.

    PubMed

    Winter, Lilli; Abrahamsberg, Christina; Wiche, Gerhard

    2008-06-16

    Plectin is a versatile intermediate filament (IF)-bound cytolinker protein with a variety of differentially spliced isoforms accounting for its multiple functions. One particular isoform, plectin 1b (P1b), remains associated with mitochondria after biochemical fractionation of fibroblasts and cells expressing exogenous P1b. Here, we determined that P1b is inserted into the outer mitochondrial membrane with the exon 1b-encoded N-terminal sequence serving as a mitochondrial targeting and anchoring signal. To study P1b-related mitochondrial functions, we generated mice that selectively lack this isoform but express all others. In primary fibroblasts and myoblasts derived from these mice, we observe a substantial elongation of mitochondrial networks, whereas other mitochondrial properties remain largely unaffected. Normal morphology of mitochondria could be restored by isoform-specific overexpression of P1b in P1b-deficient as well as plectin-null cells. We propose a model where P1b both forms a mitochondrial signaling platform and affects organelle shape and network formation by tethering mitochondria to IFs.

  19. Evidence against dopamine D1/D2 receptor heteromers

    PubMed Central

    Frederick, Aliya L.; Yano, Hideaki; Trifilieff, Pierre; Vishwasrao, Harshad D.; Biezonski, Dominik; Mészáros, József; Sibley, David R.; Kellendonk, Christoph; Sonntag, Kai C.; Graham, Devon L.; Colbran, Roger J.; Stanwood, Gregg D.; Javitch, Jonathan A.

    2014-01-01

    Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer (BRET), ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq knockout mice, as well as in knock-in mice expressing a mutant Ala286-CaMKIIα, that cannot autophosphorylate to become active. Moreover, we found that in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1–D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies. PMID:25560761

  20. Dynamical functions of a 1D correlated quantum liquid

    NASA Astrophysics Data System (ADS)

    Carmelo, J. M. P.; Bozi, D.; Penc, K.

    2008-10-01

    The dynamical correlation functions in one-dimensional electronic systems show power-law behaviour at low energies and momenta close to integer multiples of the charge and spin Fermi momenta. These systems are usually referred to as Tomonaga-Luttinger liquids. However, near well defined lines of the (k,ω) plane the power-law behaviour extends beyond the low-energy cases mentioned above, and also appears at higher energies, leading to singular features in the photoemission spectra and other dynamical correlation functions. The general spectral-function expressions derived in this paper were used in recent theoretical studies of the finite-energy singular features in photoemission of the organic compound tetrathiafulvalene-tetracyanoquinodimethane (TTF-TCNQ) metallic phase. They are based on a so-called pseudofermion dynamical theory (PDT), which allows us to systematically enumerate and describe the excitations in the Hubbard model starting from the Bethe ansatz, as well as to calculate the charge and spin object phase shifts appearing as exponents of the power laws. In particular, we concentrate on the spin-density m\\rightarrow 0 limit and on effects in the vicinity of the singular border lines, as well as close to half filling. Our studies take into account spectral contributions from types of microscopic processes that do not occur for finite values of the spin density. In addition, the specific processes involved in the spectral features of TTF-TCNQ are studied. Our results are useful for the further understanding of the unusual spectral properties observed in low-dimensional organic metals and also provide expressions for the one- and two-atom spectral functions of a correlated quantum system of ultracold fermionic atoms in a 1D optical lattice with on-site two-atom repulsion.

  1. Synthesis, characterization, and physical properties of 1D nanostructures

    NASA Astrophysics Data System (ADS)

    Marley, Peter Mchael

    The roster of materials exhibiting metal---insulator transitions with sharply discontinuous switching of electrical conductivity close to room temperature remains rather sparse despite the fundamental interest in the electronic instabilities manifested in such materials and the plethora of potential technological applications, ranging from frequency-agile metamaterials to electrochromic coatings and Mott field-effect transistors. Vanadium oxide bronzes with the general formula MxV2O 5, provide a wealth of compositions and frameworks where strong electron correlation can be systematically (albeit thus far only empirically) tuned. Charge fluctuations along the quasi-1D frameworks of MxV 2O5 bronzes have evinced much recent interest owing to the manifestation of colossal metal---insulator transitions and superconductivity. We start with a general review on the phase transitions, both electronic and structural, of vanadium oxide bronzes in Chapter 1. In Chapter 2, we demonstrate an unprecedented reversible transformation between double-layered (delta) and tunnel (beta) quasi-1D geometries for nanowires of a divalent vanadium bronze CaxV2O5 (x ˜0.23) upon annealing-induced dehydration and hydrothermally-induced hydration. Such a facile hydration/dehydration-induced interconversion between two prominent quasi-1D structures (accompanied by a change in charge ordering motifs) has not been observed in the bulk and is posited to result from the ease of propagation of crystallographic slip processes across the confined nanowire widths for the delta→beta conversion and the facile diffusion of water molecules within the tunnel geometries for the beta→delta reversion. We demonstrate in Chapter 3 unprecedented pronounced metal-insulator transitions induced by application of a voltage for nanowires of a vanadium oxide bronze with intercalated divalent cations, beta-PbxV 2O5 (x ˜0.33). The induction of the phase transition through application of an electric field at room

  2. Synthesis, characterization, and physical properties of 1D nanostructures

    NASA Astrophysics Data System (ADS)

    Marley, Peter Mchael

    The roster of materials exhibiting metal---insulator transitions with sharply discontinuous switching of electrical conductivity close to room temperature remains rather sparse despite the fundamental interest in the electronic instabilities manifested in such materials and the plethora of potential technological applications, ranging from frequency-agile metamaterials to electrochromic coatings and Mott field-effect transistors. Vanadium oxide bronzes with the general formula MxV2O 5, provide a wealth of compositions and frameworks where strong electron correlation can be systematically (albeit thus far only empirically) tuned. Charge fluctuations along the quasi-1D frameworks of MxV 2O5 bronzes have evinced much recent interest owing to the manifestation of colossal metal---insulator transitions and superconductivity. We start with a general review on the phase transitions, both electronic and structural, of vanadium oxide bronzes in Chapter 1. In Chapter 2, we demonstrate an unprecedented reversible transformation between double-layered (delta) and tunnel (beta) quasi-1D geometries for nanowires of a divalent vanadium bronze CaxV2O5 (x ˜0.23) upon annealing-induced dehydration and hydrothermally-induced hydration. Such a facile hydration/dehydration-induced interconversion between two prominent quasi-1D structures (accompanied by a change in charge ordering motifs) has not been observed in the bulk and is posited to result from the ease of propagation of crystallographic slip processes across the confined nanowire widths for the delta→beta conversion and the facile diffusion of water molecules within the tunnel geometries for the beta→delta reversion. We demonstrate in Chapter 3 unprecedented pronounced metal-insulator transitions induced by application of a voltage for nanowires of a vanadium oxide bronze with intercalated divalent cations, beta-PbxV 2O5 (x ˜0.33). The induction of the phase transition through application of an electric field at room

  3. NACA Aircraft on Lakebed - D-558-2, X-1B, and X-1E

    NASA Technical Reports Server (NTRS)

    1955-01-01

    of increased capacity, and a thinner high-speed wing. The X-1E was used to obtain in-flight data at twice the speed of sound, with particular emphasis placed on investigating the improvements achieved with the high-speed wing. These wings, made by Stanley Aircraft, were only 3-3/8-inches thick at the root and had 343 gauges installed in them to measure structural loads and aerodynamic heating. The X-1E used its rocket engine to power it up to a speed of 1,471 miles per hour (Mach 2.24) and to an altitude of 73,000 feet. Like the X-1 it was air-launched. The X-1 aircraft were almost 31 feet long and had a wingspan of 28 feet. The X-1 was built of conventional aluminum stressed-skin construction to extremely high structural standards. The X-1E was also 31 feet long but had a wingspan of only 22 feet, 10 inches. It was powered by a Reaction Motors, Inc., XLR-8-RM-5, four-chamber rocket engine. As did all X-1 rocket engines, the LR-8-RM-5 engine did not have throttle capability, but instead, depended on ignition of any one chamber or group of chambers to vary speed. The X-1A, X-1B, and the X-1D were growth versions of the X-1. They were almost five feet longer, almost 2,500 pounds heavier and had conventional canopies. The X-1A and X-1B were modified to have ejection seats. Their mission was to continue the X-1 studies at higher speeds and altitudes. The X-1A began this research after the X-1D was destroyed in an explosion on a captive flight before it made any research flights. On December 12, 1953, Major Charles Yeager flew the X-1A up to a speed of 1,612 miles per hour (almost two-and-a-half times the speed of sound). Then on August 26, 1954, Major Arthur Murray took the X-1A up to an altitude of 90,440 feet. Those two performances were the records for the X-1 program. Later the X-1A was also destroyed after being jettisoned from the carrier aircraft because of an explosion. The X-1B was fitted with 300 thermocouples for exploratory aerodynamic heating tests. It also

  4. 78 FR 5210 - Open Government Initiative: Implementation of the iCERT Labor Certification Registry for the H-1B...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-24

    ... Certification Registry for the H-1B, H-1B1, E-3, H-2A, H-2B and Permanent Labor Certification Employment-Based... to the general public appropriately redacted copies of H-1B, H-1B1, E-3, H-2A, H-2B and permanent... a labor certification or, in the case of an H-1B, H-1B1, or E-3 visa, a labor condition...

  5. 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.

  6. 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

  7. Beyond Oncolytics: E1B55K-Deleted Adenovirus as a Vaccine Delivery Vector.

    PubMed

    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

  8. Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel

    PubMed Central

    Nieuweboer, Annemieke J.M.; Hu, Shuiying; Hagenbuch, Bruno; Moghaddam-Helmantel, Inge Ghobadi; Gibson, Alice A.; de Bruijn, Peter; Mathijssen, Ron H. J.; Sparreboom, Alex

    2014-01-01

    Purpose Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters prior to metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically-important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Experimental Design Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent Oatp1b2. Pharmacokinetic studies were done in wildtype and Oatp1b2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Results Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and Oatp1b2, and these transport processes were strongly reduced in the presence of clinically-relevant concentrations of PS80 and CrEL. In the absence of solubilizers, deficiency of Oatp1b2 in mice was associated with a significantly decreased taxane clearance due to a liver distribution defect (P<0.00001), but these kinetic changes were masked in the presence of PS80 or CrEL (P>0.05). Conclusions Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes, and that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. PMID:24755470

  9. No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery

    PubMed Central

    Bouchelet, Isabelle; Case, Bruce; Olivier, André; Hamel, Edith

    2000-01-01

    Using subtype-selective 5-HT1 receptor agonists and/or the 5-HT1 receptor antagonist GR127935, we characterized in vitro the 5-HT receptor that mediates the contraction of human and bovine cerebral arteries. Further, we investigated which sumatriptan-sensitive receptors are present in human coronary artery by reverse-transcriptase polymerase chain reaction (RT–PCR). Agonists with affinity at the 5-HT1B receptor, such as sumatriptan, alniditan and/or IS-159, elicited dose-dependent contraction in both human and bovine cerebral arteries. They behaved as full agonists at the sumatriptan-sensitive 5-HT1 receptors in both species. In contrast, PNU-109291 and LY344864, selective agonists at 5-HT1D and 5-HT1F receptors, respectively, were devoid of any significant vasocontractile activity in cerebral arteries, or did not affect the sumatriptan-induced vasocontraction. The rank order of agonist potency was similar in both species and could be summarized as 5-HT=alniditan>sumatriptan=IS-159>>>PNU-109291=LY344864. In bovine cerebral arteries, the 5-HT1 receptor antagonist GR127935 dose-dependently inhibited the vasoconstrictions elicited by both 5-HT and sumatriptan, with respective pA2 values of 8.0 and 8.6. RT–PCR studies in human coronary arteries showed a strong signal for the 5-HT1B receptor while message for the 5-HT1F receptor was weak and less frequently detected. Expression of 5-HT1D receptor mRNA was not detected in any sample. The present results demonstrate that the triptan-induced contraction in brain vessels is mediated exclusively by the 5-HT1B receptor, which is also present in a majority of human coronary arteries. These results suggest that selective 5-HT1D and 5-HT1F receptor agonists might represent new antimigraine drugs devoid of cerebro- and cardiovascular effects. PMID:10711348

  10. 1-D Tremor Streaks: Implications for a Streak Source Model

    NASA Astrophysics Data System (ADS)

    Houston, H.; Ghosh, A.; Vidale, J. E.

    2009-12-01

    Recent observations of non-volcanic tremor in Cascadia and Japan show “streaks” of tremor moving up and down dip in a convergence-parallel direction at “driving velocities” (i.e., 30 to 120 km/hr). Streak lengths of 30 to 40 km are occasionally observed. We explore the implications of these observations for a source model and spectrum of tremor. Key elements involve the extreme geometry and slow “rupture velocity” implied by the streaks. The source spectrum of tremor and other ETS seismic radiation exhibits a spectral falloff roughly as the inverse of frequency (1/f) in contrast to that of earthquakes, which follow a spectral falloff of 1/f squared above a corner frequency. Nevertheless, several observations suggest that the deformation that generates tremor is shear slip in the plate convergence direction. A fundamental question, then, has been what slip source could produce such an observed 1/f falloff over a wide frequency range. We propose a kinematic model, consistent with the 1-D geometry of the tremor streaks, in which fault displacement and width are strongly limited and rupture growth occurs only along fault length, which is oriented in a convergence-parallel direction (up or down dip). This is a version of the well-known Haskell model in which the durations of the two boxcars are very different. A 1/f spectral falloff holds between the corner frequencies associated with the two durations. Thus, the frequency range of the observed 1/f spectral falloff of tremor provides constraints on the durations of the boxcars. Further constraints involve the maximum likely displacement in an ETS event, the rupture velocities of the streaks, and the moment release rate. The narrow streak geometry implies fairly high strain and stress drops, in contrast to the low overall stress drops inferred from tidal modulation of tremor and the low strain across the entire ETS region. The observation of tremor streaks migrating at 10's of km/hour, in conjunction with the

  11. Human CD1d knock-in mouse model demonstrates potent antitumor potential of human CD1d-restricted invariant natural killer T cells

    PubMed Central

    Wen, Xiangshu; Rao, Ping; Carreño, Leandro J.; Kim, Seil; Lawrenczyk, Agnieszka; Porcelli, Steven A.; Cresswell, Peter; Yuan, Weiming

    2013-01-01

    Despite a high degree of conservation, subtle but important differences exist between the CD1d antigen presentation pathways of humans and mice. These differences may account for the minimal success of natural killer T (NKT) cell-based antitumor therapies in human clinical trials, which contrast strongly with the powerful antitumor effects in conventional mouse models. To develop an accurate model for in vivo human CD1d (hCD1d) antigen presentation, we have generated a hCD1d knock-in (hCD1d-KI) mouse. In these mice, hCD1d is expressed in a native tissue distribution pattern and supports NKT cell development. Reduced numbers of invariant NKT (iNKT) cells were observed, but at an abundance comparable to that in most normal humans. These iNKT cells predominantly expressed mouse Vβ8, the homolog of human Vβ11, and phenotypically resembled human iNKT cells in their reduced expression of CD4. Importantly, iNKT cells in hCD1d knock-in mice exert a potent antitumor function in a melanoma challenge model. Our results show that replacement of mCD1d by hCD1d can select a population of functional iNKT cells closely resembling human iNKT cells. These hCD1d knock-in mice will allow more accurate in vivo modeling of human iNKT cell responses and will facilitate the preclinical assessment of iNKT cell-targeted antitumor therapies. PMID:23382238

  12. 12 CFR 329.102 - Deposits described in § 329.1(b)(3).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 4 2011-01-01 2011-01-01 false Deposits described in § 329.1(b)(3). 329.102 Section 329.102 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY INTEREST ON DEPOSITS § 329.102 Deposits described in § 329.1(b)(3). This interpretive...

  13. 12 CFR 329.102 - Deposits described in § 329.1(b)(3).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Deposits described in § 329.1(b)(3). 329.102 Section 329.102 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY INTEREST ON DEPOSITS § 329.102 Deposits described in § 329.1(b)(3). This interpretive...

  14. The phosphate exporter xpr1b is required for differentiation of tissue-resident macrophages

    PubMed Central

    Meireles, Ana M.; Shiau, Celia E.; Guenther, Catherine; Sidik, Harwin; Kingsley, David M.; Talbot, William S.

    2014-01-01

    Summary Phosphate concentration is tightly regulated at the cellular and organismal levels. The first metazoan phosphate exporter, XPR1, was recently identified, but its in vivo function remains unknown. In a genetic screen, we identified a mutation in a zebrafish ortholog of human XPR1, xpr1b. xpr1b mutants lack microglia, the specialized macrophages that reside in the brain, and also displayed an osteopetrotic phenotype characteristic of defects in osteoclast function. Transgenic expression studies indicated that xpr1b acts autonomously in developing macrophages. xpr1b mutants displayed no gross developmental defects that may arise from phosphate imbalance. We constructed a targeted mutation of xpr1a, a duplicate of xpr1b in the zebrafish genome, to determine if Xpr1a and Xpr1b have redundant functions. Single mutants for xpr1a were viable, and double mutants for xpr1b;xpr1a were similar to xpr1b single mutants. Our genetic analysis reveals a specific role for the phosphate exporter Xpr1 in differentiation of tissue macrophages. PMID:25220463

  15. 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

  16. 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

  17. 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...

  18. Interleukin 1B variant -1473G/C (rs1143623) influences triglyceride and interleukin 6 metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Interleukin 1b (IL1B or IL-1ß), is a key modulator of the immune response which exerts its functions mainly via interleukin 6 (IL6) regulation. Fatty meals cause transient hypertriglyceridemia and are considered to be proinflammatory, but the extent of these responses shows high interindividual susc...

  19. Extending the Impact of RAC1b Overexpression to Follicular Thyroid Carcinomas.

    PubMed

    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

  20. 76 FR 56637 - Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-14

    ... Policies and Procedures (44 FR 11034, February 26, 1979), (3) Will not affect intrastate aviation in Alaska... Model IO-720-A1B Reciprocating Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final... model IO-720-A1B Lycoming Engines reciprocating engines. This AD requires a crankshaft inspection...

  1. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes1

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 13 2013-10-01 2013-10-01 false Discard and Disposition Codes1 1b Table 1b to Part 679 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND... Confiscation or seized 63 Deadloss (crab only) 79 Overage 62 Retained for future sale 87 Tagged IFQ...

  2. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes1

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 11 2011-10-01 2011-10-01 false Discard and Disposition Codes1 1b Table 1b to Part 679 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND... Confiscation or seized 63 Deadloss (crab only) 79 Overage 62 Retained for future sale 87 Tagged IFQ...

  3. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes1

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 13 2014-10-01 2014-10-01 false Discard and Disposition Codes1 1b Table 1b to Part 679 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND... Confiscation or seized 63 Deadloss (crab only) 79 Overage 62 Retained for future sale 87 Tagged IFQ...

  4. 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 to Part 679 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND... overage type in comment). 62 Tagged Fish (Exempt from IFQ). 64 Whole fish/bait, not sold. Used as bait...

  5. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes1

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 13 2012-10-01 2012-10-01 false Discard and Disposition Codes1 1b Table 1b to Part 679 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND... Confiscation or seized 63 Deadloss (crab only) 79 Overage 62 Retained for future sale 87 Tagged IFQ...

  6. 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 §...

  7. 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 §...

  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 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...

  10. 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 §...

  11. 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 §...

  12. 18 CFR 2.1b - Availability in contested cases of information acquired by staff 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 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...

  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. 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

    2015-08-01

    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.

  15. 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 §...

  16. PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180/Rac1 pathway

    PubMed Central

    Wang, Yuan; Yan, Feng; Ye, Qing; Wu, Xiao; Jiang, Fan

    2016-01-01

    Promoting endothelial cell (EC) migration is important not only for therapeutic angiogenesis, but also for accelerating re-endothelialization after vessel injury. Several recent studies have shown that inhibition of protein tyrosine phosphatase 1B (PTP1B) may promote EC migration and angiogenesis by enhancing the vascular endothelial growth factor receptor-2 (VEGFR2) signalling. In the present study, we demonstrated that PTP1B inhibitor could promote EC adhesion, spreading and migration, which were abolished by the inhibitor of Rac1 but not RhoA GTPase. PTP1B inhibitor significantly increased phosphorylation of p130Cas, and the interactions among p130Cas, Crk and DOCK180; whereas the phosphorylation levels of focal adhesion kinase, Src, paxillin, or Vav2 were unchanged. Gene silencing of DOCK180, but not Vav2, abrogated the effects of PTP1B inhibitor on EC motility. The effects of PTP1B inhibitor on EC motility and p130Cas/DOCK180 activation persisted in the presence of the VEGFR2 antagonist. In conclusion, we suggest that stimulation of the DOCK180 pathway represents an alternative mechanism of PTP1B inhibitor-stimulated EC motility, which does not require concomitant VEGFR2 activation as a prerequisite. Therefore, PTP1B inhibitor may be a useful therapeutic strategy for promoting EC migration in cardiovascular patients in which the VEGF/VEGFR functions are compromised. PMID:27052191

  17. The vasopressin 1b receptor and the neural regulation of social behavior

    PubMed Central

    Stevenson, Erica L.; Caldwell, Heather K.

    2011-01-01

    To date, much of the work in rodents implicating vasopressin (Avp) in the regulation of social behavior has focused on its action via the Avp 1a receptor (Avpr1a). However, there is mounting evidence that the Avp 1b receptor (Avpr1b) also plays a significant role in Avp's modulation of social behavior. The Avpr1b is heavily expressed on the anterior pituitary cortiocotrophs where it acts as an important modulator of the endocrine stress response. In the brain, the Avpr1b is prominent in the CA2 region of the hippocampus, but can also be found in areas such as the paraventicular nucleus of the hypothalamus and the olfactory bulb. Studies that have employed genetic knockouts or pharmacological manipulation of the Avpr1b point to the importance of central Avpr1b in the modulation of social behavior. However, there continues to be a knowledge gap in our understanding of where in the brain this is occurring, as well as how and if the central actions of Avp acting via the Avpr1b interact with the stress axis. In this review we focus on the genetic and pharmacological studies that have implicated the Avpr1b in the neural regulation of social behaviors, including social forms of aggressive behavior, social memory, and social motivation. PMID:22178035

  18. 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.

  19. Analyzing the role of AP-1B in polarized sorting from recycling endosomes in epithelial cells.

    PubMed

    Fölsch, Heike

    2015-01-01

    Epithelial cells polarize their plasma membrane into apical and basolateral domains where the apical membrane faces the luminal side of an organ and the basolateral membrane is in contact with neighboring cells and the basement membrane. To maintain this polarity, newly synthesized and internalized cargos must be sorted to their correct target domain. Over the last ten years, recycling endosomes have emerged as an important sorting station at which proteins destined for the apical membrane are segregated from those destined for the basolateral membrane. Essential for basolateral sorting from recycling endosomes is the tissue-specific adaptor complex AP-1B. This chapter describes experimental protocols to analyze the AP-1B function in epithelial cells including the analysis of protein sorting in LLC-PK1 cells lines, immunoprecipitation of cargo proteins after chemical crosslinking to AP-1B, and radioactive pulse-chase experiments in MDCK cells depleted of the AP-1B subunit μ1B.

  20. Endoplasmic reticulum stress and the on site function of resident PTP1B.

    PubMed

    Popov, Doina

    2012-06-15

    Growing evidence links the stress at the endoplasmic reticulum (ER) to pathologies such as diabetes mellitus, obesity, liver, heart, renal and neurodegenerative diseases, endothelial dysfunction, atherosclerosis, and cancer. Therefore, identification of molecular pathways beyond ER stress and their appropriate modulation might alleviate the stress, and direct toward novel tools to fight this disturbance. An interesting resident of the ER membrane is protein tyrosine phosphatase 1B (PTP1B), an enzyme that negatively regulates insulin and leptin signaling, contributing to insulin and leptin resistance. Recently, new functions of PTP1B have been established linked to ER stress response. This review evaluates the novel data on ER stressors, discusses the mechanisms beyond PTP1B function in the ER stress response, and emphasizes the potential therapeutic exploitation of PTP1B to relieve ER stress. PMID:22609202

  1. Identification of novel functional Organic Anion-transporting Polypeptide 1B3 (OATP1B3) polymorphisms and assessment of substrate specificity

    PubMed Central

    Schwarz, Ute I.; Meyer zu Schwabedissen, Henriette E.; Tirona, Rommel G.; Suzuki, Atsuko; Leake, Brenda F.; Mokrab, Younes; Mizuguchi, Kenji; Ho, Richard H.; Kim, Richard B.

    2011-01-01

    Objective The uptake carrier Organic Anion-transporting Polypeptide 1B3 (OATP1B3, gene SLCO1B3) is involved in the hepatic clearance of xenobiotics including statins, taxanes and mycophenolic acid. We thought to assess the SLCO1B3 coding region for yet unidentified polymorphisms, and to analyze their functional relevance. Methods We used DNA of ethnically diverse subjects for polymerase chain reaction (PCR), and determined polymorphisms by sequencing or temperature-dependent capillary electrophoresis. We then created variant OATP1B3 expression plasmids by site-directed mutagenesis, which were transiently expressed and functionally characterized in HeLa cells using radiolabeled substrates. Results We identified six non-synonymous polymorphisms including novel variants 439A>G (Thr147Ala), 767G>C (Gly256Ala), 1559A>C (His520Pro) and 1679T>C (Val560Ala). Allelic frequencies occurred ethnicity-dependent, with the latter observed only in African Americans (3.6%). After expression in HeLa cells, variants His520Pro, Val560Ala, and Met233Ile or Met233Ile_Ser112Ala haplotype demonstrated decreased uptake activity compared to wildtype for cholecystokinin-8 (CCK8) and rosuvastatin, but not atorvastatin. Kinetic CCK8 analysis revealed reduced Vmax without altering Km. His520Pro and Val560Ala exhibited decreased total and plasma membrane protein expression. Val560 mapped onto a structural model of OATP1B3 revealed this is a key region for substrate–transporter interaction. His520 resides in a predicted extracellular region thought to be critical to the pH-dependent component of OATP1B3 activity. Loss of activity at pH 7.4 and 8.0 relative to pH 6.5 was significantly greater for the Pro520 variant. Conclusion OATP1B3 polymorphisms that result in altered expression, substrate specificity, and pH-dependent activity may be of potential relevance to hepatic clearance of substrate drugs in vivo. PMID:21278621

  2. Proteasome-mediated degradation antagonizes critical levels of the apoptosis-inducing C1D protein

    PubMed Central

    Rothbarth, Karsten; Stammer, Hermann; Werner, Dieter

    2002-01-01

    The C1D gene is expressed in a broad spectrum of mammalian cells and tissues but its product induces apoptotic cell death when exceeding a critical level. Critical levels are achieved in a fraction of cells by transient transfection with EGFP-tagged C1D expression constructs. However, transfected cells expressing sub-critical levels of C1D(EGFP) escape apoptotic cell death by activation of a proteasome-mediated rescue mechanism. Inhibition of the proteasome-dependent degradation of the C1D(EGFP) protein results in a parallel increase of the intracellular C1D level and in the fraction of apoptotic cells. PMID:12379155

  3. Vasopressin 1b receptor knock-out impairs memory for temporal order.

    PubMed

    DeVito, Loren M; Konigsberg, Rachael; Lykken, Christine; Sauvage, Magdalena; Young, W Scott; Eichenbaum, Howard

    2009-03-01

    Mice lacking a functional vasopressin 1b receptor (Avpr1b) display decreased levels of aggression and social memory. Here, we used Avpr1b-knock-out (Avpr1b(-/-)) mice to examine whether an abnormality of this receptor results in specific cognitive deficits in the domain of hippocampal function. Avpr1b(-/-) mice were deficient in sociability and in detecting social novelty, extending previous findings of impairment in social recognition in these mutants. Avpr1b(-/-) mice could recognize previously explored objects and remember where they were experienced, but they were impaired in remembering the temporal order of presentation of those objects. Consistent with this finding, Avpr1b(-/-) mice were also impaired on an object-odor paired associate task that involved a temporal discontiguity between the associated elements. Finally, Avpr1b(-/-) mice performed normally in learning a set of overlapping odor discriminations and could infer relationships among odors that were only indirectly associated (i.e., transitive inference), indicating intact relational memory. The Avpr1b is expressed at much higher levels than any other part of the brain in the pyramidal cells of hippocampal CA2 area, a subfield of the hippocampus that has physiological and genetic properties that distinguish it from subfields CA1 and CA3. The combined results suggest that the Avpr1b, perhaps in CA2, may play a highly specific role in social behavior and episodic memory. Because schizophrenia and bipolar disorder are associated with a unique pathology in CA2 and impairments in both social behavior and episodic memory, this animal model could provide insights into the etiology of these disorders.

  4. 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

  5. Grid Cell Responses in 1D Environments Assessed as Slices through a 2D Lattice.

    PubMed

    Yoon, KiJung; Lewallen, Sam; Kinkhabwala, Amina A; Tank, David W; Fiete, Ila R

    2016-03-01

    Grid cells, defined by their striking periodic spatial responses in open 2D arenas, appear to respond differently on 1D tracks: the multiple response fields are not periodically arranged, peak amplitudes vary across fields, and the mean spacing between fields is larger than in 2D environments. We ask whether such 1D responses are consistent with the system's 2D dynamics. Combining analytical and numerical methods, we show that the 1D responses of grid cells with stable 1D fields are consistent with a linear slice through a 2D triangular lattice. Further, the 1D responses of comodular cells are well described by parallel slices, and the offsets in the starting points of the 1D slices can predict the measured 2D relative spatial phase between the cells. From these results, we conclude that the 2D dynamics of these cells is preserved in 1D, suggesting a common computation during both types of navigation behavior. PMID:26898777

  6. Prophylactic effects of asiaticoside-based standardized extract of Centella asiatica (L.) Urban leaves on experimental migraine: Involvement of 5HT1A/1B receptors.

    PubMed

    Bobade, Vijeta; Bodhankar, Subhash L; Aswar, Urmila; Vishwaraman, Mohan; Thakurdesai, Prasad

    2015-04-01

    The present study aimed at evaluation of prophylactic efficacy and possible mechanisms of asiaticoside (AS) based standardized extract of Centella asiatica (L.) Urban leaves (INDCA) in animal models of migraine. The effects of oral and intranasal (i.n.) pretreatment of INDCA (acute and 7-days subacute) were evaluated against nitroglycerine (NTG, 10 mg·kg(-1), i.p.) and bradykinin (BK, 10 μg, intra-arterial) induced hyperalgesia in rats. Tail flick latencies (from 0 to 240 min) post-NTG treatment and the number of vocalizations post-BK treatment were recorded as a measure of hyperalgesia. Separate groups of rats for negative (Normal) and positive (sumatriptan, 42 mg·kg(-1), s.c.) controls were included. The interaction of INDCA with selective 5-HT1A, 5-HT1B, and 5-HT1D receptor antagonists (NAN-190, Isamoltane hemifumarate, and BRL-15572 respectively) against NTG-induced hyperalgesia was also evaluated. Acute and sub-acute pre-treatment of INDCA [10 and 30 mg·kg(-1) (oral) and 100 μg/rat (i.n.) showed significant anti-nociception activity, and reversal of the NTG-induced hyperalgesia and brain 5-HT concentration decline. Oral pre-treatment with INDCA (30 mg·kg(-1), 7 d) showed significant reduction in the number of vocalization. The anti-nociceptive effects of INDCA were blocked by 5-HT1A and 5-HT1B but not 5-HT1D receptor antagonists. In conclusion, INDCA demonstrated promising anti-nociceptive effects in animal models of migraine, probably through 5-HT1A/1B medicated action.

  7. Imidazo[2,1-b]benzothiazoles. II. Synthesis and antiinflammatory activity of some imidazo[2,1-b]benzothiazoles.

    PubMed

    El-Shorbagi, A N; Sakai, S; el-Gendy, M A; Omar, N; Farag, H H

    1989-11-01

    3-[2-[p-(Un)substituted phenyl]imidazo [2,1-b]benzothiazol-3- yl]propionic acid derivatives (2a--e) were prepared via the interaction of the corresponding 2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazoles (1a--e) with acrylic acid in the presence of acetic anhydride and acetic acid. Esterification of 2a--e produced methyl esters (3a--e). Upon the interaction of 3a with m-chloroperbenzoic acid, the S-dioxide (4a) was obtained. Compound 5a was prepared from 4a by alkaline hydrolysis. Vilsmeier formylation for 1a--e produced novel [2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol-3- yl]formaldehyde derivatives (6a--e). Derivatives 6a--e reacted with ethyl bromoacetate to give ethyl 3-hydroxy-3-[2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol- 3-yl]propionate esters (7a--e). Compound dl-7a was resolved with l-(+)-tartaric acid. Compounds 2a--e showed weak or no activity in the carrageein-induced paw edema assay. Compound 4a significantly inhibited the leakage of pontamine-sky blue dye into the peritoneal cavity of mice, in the capillary permeability inhibition assay. Compound 5a inhibited the writhing by 62% in the acetic acid-induced writhing assay.

  8. 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). PMID:19430804

  9. Interaction between 5-HT(1A) and 5-HT(1B) receptors: effects of 8-OH-DPAT-induced hypothermia in 5-HT(1B) receptor knockout mice.

    PubMed

    Gardier, A M; Gruwez, B; Trillat, A C; Jacquot, C; Hen, R; Bourin, M

    2001-06-15

    To test for adaptive compensatory changes that may have occurred in the functional activity of somatodendritic 5-HT(1A) receptors during the development of constitutive "knockout" mice lacking the 5-HT(1B) receptor subtype (5-HT(1B) -/- KO), we assayed for decrease in body temperature induced by an acute subcutaneous injection of the 5-HT(1A) receptor agonist, 8-hydroxy 2(di-n-propyl(amino)tetralin (8-OH-DPAT), either alone or in the presence of a selective 5-HT(1A) receptor antagonist, N-[4-(2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide (WAY 100635). We compared dose-response curves, time course study, calculated ED(50) values (potency), maximal response to 8-OH-DPAT (efficacy) as well as measurements of the dose-dependent blockade of this response by WAY 100635 between wild-type controls and mutant mice. We found a higher efficacy of 8-OH-DPAT-induced hypothermia in 5-HT(1B) -/- KO compared to wild-type mice suggesting that an adaptive thermoregulatory process involving the functional activity of somatodendritic 5-HT(1A) receptors is altered in mutant mice lacking 5-HT(1B) receptors.

  10. 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).

  11. 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.

  12. Zinc Resistance Mechanisms of P1B-type ATPases in Sinorhizobium meliloti CCNWSX0020

    PubMed Central

    Lu, Mingmei; Li, Zhefei; Liang, Jianqiang; Wei, Yibing; Rensing, Christopher; Wei, Gehong

    2016-01-01

    The Sinorhizobium meliloti (S. meliloti) strain CCNWSX0020 displayed tolerance to high levels exposures of multiple metals and growth promotion of legume plants grown in metal-contaminated soil. However, the mechanism of metal-resistant strain remains unknown. We used five P1B-ATPases deletions by designating as ∆copA1b, ∆fixI1, ∆copA3, ∆zntA and ∆nia, respectively to investigate the role of P1B-ATPases in heavy metal resistance of S. meliloti. The ∆copA1b and ∆zntA mutants were sensitive to zinc (Zn), cadmium (Cd) and lead (Pb) in different degree, whereas the other mutants had no significant influence on the metal resistance. Moreover, the expression of zntA was induced by Zn, Cd and Pb whereas copA1b was induced by copper (Cu) and silver (Ag). This two deletions could led to the increased intracellular concentrations of Zn, Pb and Cd, but not of Cu. Complementation of ∆copA1b and ∆zntA mutants showed a restoration of tolerance to Zn, Cd and Pb to a certain extent. Taken together, the results suggest an important role of copA1b and zntA in Zn homeostasis and Cd and Pb detoxification in S. meliloti CCNWSX0020. PMID:27378600

  13. In vitro effects of cinnamic acid derivatives on protein tyrosine phosphatase 1B.

    PubMed

    Adisakwattana, Sirichai; Pongsuwan, Jirawan; Wungcharoen, Chompunut; Yibchok-anun, Sirintorn

    2013-10-01

    Protein Tyrosine Phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling pathways. Finding selective PTP1B inhibitors from natural sources has been widely recognized as a potential drug target for the treatment of diabetes mellitus and obesity. In the present study, we evaluated the inhibitory activity of cinnamic acid derivatives against PTP1B in vitro. Among 14 cinnamic acid derivatives and related compounds, the most potent inhibitor PTP1Bs were o-hydroxycinnamic acid and p-hydroxycinnamic acid, which had IC50 values of 137.67 ± 13.37 and 181.60 ± 9.34 µM, respectively. The kinetics analysis revealed that PTP1B was inhibited by o-hydroxycinnamic acid and p-hydroxycinnamic acid in a non-competitive manner. o-Hydroxycinnamic acid (25 μM) and p-hydroxycinnamic acid (25 μM), in combination with sodium orthovanadate (0.0125 μM), demonstrated a synergistic effect to inhibit PTP1B activity. In conclusion, the findings provide a new insight into naturally occurring PTP1B inhibitors that could be useful for treatment of diabetes and obesity.

  14. Polycomb group targeting through different binding partners of RING1B C-terminal domain.

    PubMed

    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

    2010-08-11

    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.

  15. 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

  16. Zinc Resistance Mechanisms of P1B-type ATPases in Sinorhizobium meliloti CCNWSX0020.

    PubMed

    Lu, Mingmei; Li, Zhefei; Liang, Jianqiang; Wei, Yibing; Rensing, Christopher; Wei, Gehong

    2016-01-01

    The Sinorhizobium meliloti (S. meliloti) strain CCNWSX0020 displayed tolerance to high levels exposures of multiple metals and growth promotion of legume plants grown in metal-contaminated soil. However, the mechanism of metal-resistant strain remains unknown. We used five P1B-ATPases deletions by designating as ∆copA1b, ∆fixI1, ∆copA3, ∆zntA and ∆nia, respectively to investigate the role of P1B-ATPases in heavy metal resistance of S. meliloti. The ∆copA1b and ∆zntA mutants were sensitive to zinc (Zn), cadmium (Cd) and lead (Pb) in different degree, whereas the other mutants had no significant influence on the metal resistance. Moreover, the expression of zntA was induced by Zn, Cd and Pb whereas copA1b was induced by copper (Cu) and silver (Ag). This two deletions could led to the increased intracellular concentrations of Zn, Pb and Cd, but not of Cu. Complementation of ∆copA1b and ∆zntA mutants showed a restoration of tolerance to Zn, Cd and Pb to a certain extent. Taken together, the results suggest an important role of copA1b and zntA in Zn homeostasis and Cd and Pb detoxification in S. meliloti CCNWSX0020. PMID:27378600

  17. Intranuclear location of the adenovirus type 5 E1B 55-kilodalton protein.

    PubMed Central

    Smiley, J K; Young, M A; Flint, S J

    1990-01-01

    The intracellular location of the adenovirus type 5 E1B 55-kilodalton (kDa) protein, particularly the question of whether it is associated with nuclear pore complexes, was examined. Fractionation of adenovirus type 5-infected HeLa cell nuclei by an established procedure (N. Dwyer and G. Blobel, J. Cell. Biol. 70:581-591, 1976) yielded one population of E1B 55-kDa protein molecules released by digestion of nuclei with RNase A and a second population recovered in the pore complex-lamina fraction. Free and E1B 55-kDa protein-bound forms of the E4 34-kDa protein (P. Sarnow, C. A. Sullivan, and A. J. Levine, Virology 120:387-394, 1982) were largely recovered in the pore complex-lamina fraction. Nevertheless, the association of E1B 55-kDa protein molecules with this nuclear envelope fraction did not depend on interaction of the E1B 55-kDa protein with the E4 34-kDa protein. Comparison of the immunofluorescence patterns observed with antibodies recognizing the E1B 55-kDa protein or cellular pore complex proteins and of the behavior of these viral and cellular proteins during in situ fractionation suggests that the E1B 55-kDa protein does not become intimately or stably associated with pore complexes in adenovirus-infected cells. Images PMID:2143545

  18. 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. PMID:26529431

  19. Dachsous1b cadherin regulates actin and microtubule cytoskeleton during early zebrafish embryogenesis

    PubMed Central

    Li-Villarreal, Nanbing; Forbes, Meredyth M.; Loza, Andrew J.; Chen, Jiakun; Ma, Taylur; Helde, Kathryn; Moens, Cecilia B.; Shin, Jimann; Sawada, Atsushi; Hindes, Anna E.; Dubrulle, Julien; Schier, Alexander F.; Longmore, Gregory D.; Marlow, Florence L.; Solnica-Krezel, Lilianna

    2015-01-01

    Dachsous (Dchs), an atypical cadherin, is an evolutionarily conserved regulator of planar cell polarity, tissue size and cell adhesion. In humans, DCHS1 mutations cause pleiotropic Van Maldergem syndrome. Here, we report that mutations in zebrafish dchs1b and dchs2 disrupt several aspects of embryogenesis, including gastrulation. Unexpectedly, maternal zygotic (MZ) dchs1b mutants show defects in the earliest developmental stage, egg activation, including abnormal cortical granule exocytosis (CGE), cytoplasmic segregation, cleavages and maternal mRNA translocation, in transcriptionally quiescent embryos. Later, MZdchs1b mutants exhibit altered dorsal organizer and mesendodermal gene expression, due to impaired dorsal determinant transport and Nodal signaling. Mechanistically, MZdchs1b phenotypes can be explained in part by defective actin or microtubule networks, which appear bundled in mutants. Accordingly, disruption of actin cytoskeleton in wild-type embryos phenocopied MZdchs1b mutant defects in cytoplasmic segregation and CGE, whereas interfering with microtubules in wild-type embryos impaired dorsal organizer and mesodermal gene expression without perceptible earlier phenotypes. Moreover, the bundled microtubule phenotype was partially rescued by expressing either full-length Dchs1b or its intracellular domain, suggesting that Dchs1b affects microtubules and some developmental processes independent of its known ligand Fat. Our results indicate novel roles for vertebrate Dchs in actin and microtubule cytoskeleton regulation in the unanticipated context of the single-celled embryo. PMID:26160902

  20. The arginine vasopressin V1b receptor gene and prosociality: Mediation role of emotional empathy.

    PubMed

    Wu, Nan; Shang, Siyuan; Su, Yanjie

    2015-09-01

    The vasopressin V1b receptor (AVPR1B) gene has been shown to be closely associated with bipolar disorder and depression. However, whether it relates to positive social outcomes, such as empathy and prosocial behavior, remains unknown. This study explored the possible role of the AVPR1B gene rs28373064 in empathy and prosociality. A total of 256 men, who were genetically unrelated, non-clinical ethnic Han Chinese college students, participated in the study. Prosociality was tested by measuring the prosocial tendencies of cognitive and emotional empathy using the Interpersonal Reactivity Index (IRI). The single nucleotide polymorphism (SNP), rs28373064, was genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results suggest that the AVPR1B gene rs28373064 is linked to emotional empathy and prosociality. The mediation analysis indicated that the effect of the AVPR1B gene on prosociality might be mediated by emotional empathy. This study demonstrated the link between the AVPR1B gene and prosociality and provided evidence that emotional empathy might mediate the relation between the AVPR1B gene and prosociality.

  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. 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

  3. Pathogenesis-Related Protein 1b1 (PR1b1) Is a Major Tomato Fruit Protein Responsive to Chilling Temperature and Upregulated in High Polyamine Transgenic Genotypes.

    PubMed

    Goyal, Ravinder K; 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 of

  4. Pathogenesis-Related Protein 1b1 (PR1b1) Is a Major Tomato Fruit Protein Responsive to Chilling Temperature and Upregulated in High Polyamine Transgenic Genotypes.

    PubMed

    Goyal, Ravinder K; 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 of

  5. 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

  6. Human serotonin1B receptor expression in Sf9 cells: phosphorylation, palmitoylation, and adenylyl cyclase inhibition.

    PubMed

    Ng, G Y; George, S R; Zastawny, R L; Caron, M; Bouvier, M; Dennis, M; O'Dowd, B F

    1993-11-01

    Analysis of the primary protein structure of the human serotonin1B (5-HT1B) receptor reveals consensus sites for phosphorylation and a putative site for palmitoylation. To investigate these posttranslational modifications, we have expressed a c-myc epitope-tagged 5-HT1B (m5-HT1B) receptor in Sf9 cells. This strategy enabled receptors to be detected by immunoblot analysis and purified by immunoprecipitation using a monoclonal antibody, 9E10, specific for the c-myc epitope. Agonist radioligand [3H]5-HT binding studies showed that the expressed 5-HT1B and m5-HT1B receptors displayed the characteristic pharmacological profile of the neuronal 5-HT1B receptor. The expressed receptors displayed both high- and low-affinity states for [3H]5-HT, suggesting that the receptors were coupled to endogenous G-proteins. Indeed, agonist binding to the high-affinity receptor state was regulated in the presence of GTP gamma S, Gpp(NH)p, and pertussis toxin. [32P]ADP-ribosylation experiments identified a major approximately 41-kDa ADP-ribosylated protein present in Sf9 membranes that comigrated with partially purified bovine brain Gi alpha/G(o) alpha subunits. Measurements of adenylyl cyclase activity in membranes from cells expressing m5-HT1B receptors showed that serotonergic agonists mediated the inhibition of adenylyl cyclase activity with a rank order of potency comparable to their affinity constants. Immunoblot analysis of membranes prepared from cells expressing m5-HT1B receptors and photoaffinity labeling of the immunoprecipitated material revealed photolabeled species at approximately 95 and at approximately 42 kDa.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. 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

  8. Contrasting signaling pathways of alpha1A- and alpha1B-adrenergic receptor subtype activation of phosphatidylinositol 3-kinase and Ras in transfected NIH3T3 cells.

    PubMed

    Hu, Z W; Shi, X Y; Lin, R Z; Hoffman, B B

    1999-01-01

    Activation of protein kinases is an important intermediate step in signaling pathways of many G protein-coupled receptors including alpha1-adrenergic receptors. The present study was designed to investigate the capacity of the three cloned subtypes of human alpha1-receptors, namely, alpha1A, alpha1B and alpha1D to activate phosphatidylinositol 3-kinase (PI 3-kinase) and p21ras in transfected NIH3T3 cells. Norepinephrine activated PI 3-kinase in cells expressing human alpha1A and alpha1B via pertussis toxin-insensitive G proteins; alpha1D-receptors did not detectably activate this kinase. Transient transfection of NIH 3T3 cells with the alpha-subunit of the G protein transducin (alpha(t)) a scavenger of betagamma-subunits released from activated G proteins, inhibited alpha1B-receptor but not alpha1A-receptor-stimulated PI 3-kinase activity. Stimulation of both alpha1A- and alpha1B-receptors activated p21ras and stimulated guanine nucleotide exchange on Ras protein. Overexpression of a dominant negative mutant of p21ras attenuated alpha1B-receptor but not alpha1A-receptor activation of PI 3-kinase. Overexpression of a dominant negative mutant of PI 3-kinase attenuated alpha1A- but not alpha1B-receptor-stimulated mitogen-activated protein kinase activity. These results demonstrate the capacity for heterologous signaling of the alpha1-adrenergic receptor subtypes in promoting cellular responses in NIH3T3 cells.

  9. Insulin Receptor Substrate 2 (IRS2)-Deficient Mice Show Sensorineural Hearing Loss That Is Delayed by Concomitant Protein Tyrosine Phosphatase 1B (PTP1B) Loss of Function

    PubMed Central

    Murillo-Cuesta, Silvia; Camarero, Guadalupe; González-Rodríguez, Águeda; de la Rosa, Lourdes Rodríguez; Burks, Deborah J; Avendaño, Carlos; Valverde, Ángela M; Varela-Nieto, Isabel

    2012-01-01

    The insulin receptor substrate (IRS) proteins are key mediators of insulin and insulinlike growth factor 1 (IGF-1) signaling. Protein tyrosine phosphatase (PTP)-1B dephosphorylates and inactivates both insulin and IGF-1 receptors. IRS2-deficient mice present altered hepatic insulin signaling and β-cell failure and develop type 2–like diabetes. In addition, IRS2 deficiency leads to developmental defects in the nervous system. IGF1 gene mutations cause syndromic sensorineural hearing loss in humans and mice. However, the involvement of IRS2 and PTP1B, two IGF-1 downstream signaling mediators, in hearing onset and loss has not been studied. Our objective was to study the hearing function and cochlear morphology of Irs2-null mice and the impact of PTP1B deficiency. We have studied the auditory brainstem responses and the cochlear morphology of systemic Irs2−/−Ptpn1+/+, Irs2+/+Ptpn1−/−and Irs2−/−Ptpn1−/− mice at different postnatal ages. The results indicated that Irs2−/−Ptpn1+/+ mice present a profound congenital sensorineural deafness before the onset of diabetes and altered cochlear morphology with hypoinnervation of the cochlear ganglion and aberrant stria vascularis, compared with wild-type mice. Simultaneous PTP1B deficiency in Irs2−/−Ptpn1−/− mice delays the onset of deafness. We show for the first time that IRS2 is essential for hearing and that PTP1B inhibition may be useful for treating deafness associated with hyperglycemia and type 2 diabetes. PMID:22160220

  10. Serotonin 1B Receptor Gene (HTR1B) Methylation as a Risk Factor for Callous-Unemotional Traits in Antisocial Boys

    PubMed Central

    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. PMID:25993020

  11. Interferon β-1b and glatiramer acetate effects on permanent black hole evolution

    PubMed Central

    Rocca, M.A.; Camesasca, F.; Cook, S.; O'Connor, P.; Arnason, B.G.W.; Kappos, L.; Goodin, D.; Jeffery, D.; Hartung, H.-P.; Comi, G.; Wolinsky, J.S.; Bogumil, T.; Pohl, C.; Beckmann, K.; Sandbrink, R.; Croze, E.; Brown, C.; DeSimone, T.M.; Arnold, D.L.; Cutter, G.; Knappertz, V.

    2011-01-01

    Objective: To compare interferon β-1b (IFNβ-1b) and glatiramer acetate (GA) on new lesion (NL) (gadolinium-enhancing, new T2) evolution into permanent black holes (PBH)—a marker of irreversible tissue damage—in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: BEYOND was a large, phase III, clinical trial comparing IFNβ-1b 250 μg, IFNβ-1b 500 μg, and GA (2:2:1). Patient scans were reexamined post hoc for PBH in a rater-blinded manner. Two predefined coprimary endpoints compared IFNβ-1b 250 μg with GA: first, number of PBH per patient at year 2 evolving from year 1 NL, then proportion of year 1 NL evolving into PBH at year 2. IFNβ-1b 500 μg and GA were compared in an exploratory fashion. Results: Approximately 90% (1,957/2,244) of patients had NL at year 1 with follow-up at year 2. Mean numbers of PBH per patient at year 2 evolving from year 1 NL were lower for IFNβ-1b 250 μg than GA (0.30 vs 0.43; p = 0.0451). The proportion of NL evolving into PBH was similar (IFNβ-1b 250 μg vs GA: 21.6% vs 23.5%; p > 0.20). For IFNβ-1b 500 μg, both the mean PBH number per patient at year 2 evolving from year 1 NL (0.26 vs 0.43; p = 0.0037) and proportion of NL evolving into PBH (16.3% vs 23.5%; p = 0.0409) were lower relative to GA. Conclusion: IFNβ-1b affected PBH development to a similar or better extent than GA. IFNβ-1b favorably influences an MRI outcome indicative of permanent tissue destruction in the brains of patients with multiple sclerosis. Classification of evidence: This study provides Class III evidence that IFNβ-1b is associated with a reduction in MRI PBH formation and evolution compared with GA between years 1 and 2 of treatment. PMID:21464426

  12. 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

  13. 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.

  14. Dark Matter and neutrino masses from global U(1) B - L symmetry breaking

    NASA Astrophysics Data System (ADS)

    Lindner, Manfred; Schmidt, Daniel; Schwetz, Thomas

    2011-11-01

    We present a scenario where neutrino masses and Dark Matter are related due to a global U(1) B - L symmetry. Specifically we consider neutrino mass generation via the Zee-Babu two-loop mechanism, augmented by a scalar singlet whose VEV breaks the global U(1) B - L symmetry. In order to obtain a Dark Matter candidate we introduce two Standard Model singlet fermions. They form a Dirac particle and are stable because of a remnant Z2 symmetry. Hence, in this model the stability of Dark Matter follows from the global U(1) B - L symmetry. We discuss the Dark Matter phenomenology of the model, and compare it to similar models based on gauged U(1) B - L. We argue that in contrast to the gauged versions, the model based on the global symmetry does not suffer from severe constraints from Z‧ searches.

  15. 3. Building 1B, oblique of south and east elevations with ...

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

    3. Building 1B, oblique of south and east elevations with southwest corner of Building 4 on right. View looking NNW. - John & James Dobson Carpet Mill (West Parcel), The Tower, 4041-4055 Ridge Avenue, Philadelphia, Philadelphia County, PA

  16. 2. Building 1 west elevation, showing Building 1B (tower) and ...

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

    2. Building 1 west elevation, showing Building 1B (tower) and stack associated with Building 3. View looking SE. - John & James Dobson Carpet Mill (West Parcel), Building No. 1, 4041-4055 Ridge Avenue, Philadelphia, Philadelphia County, PA

  17. 3. Building 5 north elevation. Building 1B (tower) on right. ...

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

    3. Building 5 north elevation. Building 1B (tower) on right. View looking south. - John & James Dobson Carpet Mill (West Parcel), Building No. 5, 4041-4055 Ridge Avenue, Philadelphia, Philadelphia County, PA

  18. Current perspectives on interferon Beta-1b for the treatment of multiple sclerosis.

    PubMed

    Marziniak, Martin; Meuth, Sven

    2014-09-01

    Interferon (IFN) beta-1b was the first disease-modifying therapy to be approved for the treatment of multiple sclerosis (MS), and over 21 years of follow-up data demonstrate its efficacy and long-term safety profile. Following recent regulatory approvals in the USA and European Union, IFN beta-1b is now one of the seven disease-modifying therapies [intramuscular IFN beta-1a; subcutaneous (SC) IFN beta-1a; IFN beta-1b SC; glatiramer acetate SC; oral dimethyl fumarate; oral teriflunomide; and intravenous alemtuzumab] indicated for first-line use in relapsing-remitting MS. Here we review the clinical trial and follow-up data for IFN beta-1b and discuss factors that clinicians may consider when selecting this treatment, both at first line in early MS, and later in the disease course. PMID:25182864

  19. Molecular epidemiology of Salmonella enteritidis phage type 1b and 6a isolates in Portugal.

    PubMed Central

    Soares, A. R.; Machado, J.

    2003-01-01

    Salmonella enterica serotype Enteritidis is an important serovar comprising 76 % of Salmonella isolates in Portugal in 2001. For better understand the epidemiology of salmonellosis, a total of 47 isolates of S. Enteritidis phage type (PT) 1b and 6a were analysed by pulsed-field gel electrophoresis (PFGE) and genomic DNA was subjected to macro restriction with XbaI. For PT 1b isolates, only three different patterns were observed, and PT6a showed a total of 10 digestion patterns. Curiously, the main pattern among PT1b isolates seams quite similar to main pattern of PT6a isolates, but when the two patterns were analysed with Bionumerics, we observed that they exhibited some differences. It was concluded that, in 2001, there was one predominant pattern for PT1b and PT6a and, possibly, we were in presence of clonal strains that exists all over the country. PMID:12948358

  20. Expression of CD1d protein in human testis showing normal and abnormal spermatogenesis.

    PubMed

    Adly, Mohamed A; Abdelwahed Hussein, Mahmoud-Rezk

    2011-05-01

    CD1d is a member of CD1 family of transmembrane glycoproteins, which represent antigen-presenting molecules. Immunofluorescent staining methods were utilized to examine expression pattern of CD1d in human testicular specimens. In testis showing normal spermatogenesis, a strong CD1d cytoplasmic expression was seen the Sertoli cells, spermatogonia, and Leydig cells. A moderate expression was observed in the spermatocytes. In testes showing maturation arrest, CD1d expression was strong in the Sertoli cells and weak in spermatogonia and spermatocytes compared to testis with normal spermatogenesis. In Sertoli cell only syndrome, CD1d expression was strong in the Sertoli and Leydig cells. This preliminary study displayed testicular infertility-related changes in CD1d expression. The ultrastructural changes associated with with normal and abnormal spermatogenesis are open for further investigations.

  1. Hydroxysteroid sulfotransferase 2B1b expression and localization in normal human brain

    PubMed Central

    Salman, Emily D.; Faye-Petersen, Ona; Falany, Charles N.

    2012-01-01

    Steroid sulfonation in the human brain has not been well characterized. The major sulfotransferase (SULT) isoforms that conjugate steroids in humans are SULT1E1, SULT2A1, and SULT2B1b. SULT2B1b catalyzes the sulfonation of 3β-hydroxysteroids, including neurosteroids dehydroepiandrosterone and pregnenolone, as well as cholesterol and several hydroxycholesterols. SULT2B1b mRNA and protein expression were detected in adult and fetal human brain sections, whereas neither mRNA, nor protein expression were identified for SULT1E1 or SULT2A1. Using immunohistochemical analysis, SULT2B1b expression was detected in neurons and oligodendrocytes in adult brain and in epithelial tissues in 28-week-old fetal brain. Sulfonation of cholesterol, oxysterols, and neurosteroids in the brain is apparently catalyzed by SULT2B1b since expression of neither SULT2A1 nor SULT1E1 was detected in human brain sections. SULT2B1b mRNA and protein were also detected in human U373-MG glioblastoma cells. Both mRNA and protein expression of liver X receptor (LXR)-β, but not LXR-α, were detected in U373-MG cells, and LXR-β activation resulted in a decrease in SULT2B1b protein expression. Since hydroxycholesterols are important physiological LXR activators, this suggests a role for regulation of sterol metabolism by LXR and SULT2B1b. Therefore, elucidating key enzymes in the metabolism of cholesterol and neurosteroids could help define the properties of steroid conjugation in the human brain. PMID:24683427

  2. 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.

  3. Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis

    PubMed Central

    Cuff, Justin; Salari, Keyan; Clarke, Nicole; Esheba, Ghada E.; Forster, Andrew D.; Huang, Stephanie; West, Robert B.; Higgins, John P.; Longacre, Teri A.; Pollack, Jonathan R.

    2013-01-01

    Clear cell carcinoma (CCC) is a histologically distinct carcinoma subtype that arises in several organ systems and is marked by cytoplasmic clearing, attributed to abundant intracellular glycogen. Previously, transcription factor hepatocyte nuclear factor 1-beta (HNF1B) was identified as a biomarker of ovarian CCC. Here, we set out to explore more broadly the relation between HNF1B and carcinomas with clear cell histology. HNF1B expression, evaluated by immunohistochemistry, was significantly associated with clear cell histology across diverse gynecologic and renal carcinomas (P<0.001), as was hypomethylation of the HNF1B promoter (P<0.001). From microarray analysis, an empirically-derived HNF1B signature was significantly enriched for computationally-predicted targets (with HNF1 binding sites) (P<0.03), as well as genes associated with glycogen metabolism, including glucose-6-phophatase, and strikingly the blood clotting cascade, including fibrinogen, prothrombin and factor XIII. Enrichment of the clotting cascade was also evident in microarray data from ovarian CCC versus other histotypes (P<0.01), and HNF1B-associated prothrombin expression was verified by immunohistochemistry (P = 0.015). Finally, among gynecologic carcinomas with cytoplasmic clearing, HNF1B immunostaining was linked to a 3.0-fold increased risk of clinically-significant venous thrombosis (P = 0.043), and with a 2.3-fold increased risk (P = 0.011) in a combined gynecologic and renal carcinoma cohort. Our results define HNF1B as a broad marker of clear cell phenotype, and support a mechanistic link to glycogen accumulation and thrombosis, possibly reflecting (for gynecologic CCC) derivation from secretory endometrium. Our findings also implicate a novel mechanism of tumor-associated thrombosis (a major cause of cancer mortality), based on the direct production of clotting factors by cancer cells. PMID:24040285

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. SMC1B is present in mammalian somatic cells and interacts with mitotic cohesin proteins.

    PubMed

    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.

  9. Potential role for kv3.1b channels as oxygen sensors.

    PubMed

    Osipenko, O N; Tate, R J; Gurney, A M

    2000-03-17

    Hypoxia inhibits voltage-gated K channels in pulmonary artery smooth muscle (PASM). This is thought to contribute to hypoxic pulmonary vasoconstriction by promoting membrane depolarization, Ca(2+) influx, and contraction. Several of the K-channel subtypes identified in pulmonary artery have been implicated in the response to hypoxia, but contradictory evidence clouds the identity of the oxygen-sensing channels. Using patch-clamp techniques, this study investigated the effect of hypoxia on recombinant Kv1 channels previously identified in pulmonary artery (Kv1.1, Kv1.2, and Kv1.5) and Kv3.1b, which has similar kinetic and pharmacological properties to native oxygen-sensitive currents. Hypoxia failed to inhibit any Kv1 channel, but it inhibited Kv3.1b channels expressed in L929 cells, as shown by a reduction of whole-cell current and single-channel activity, without affecting unitary conductance. Inhibition was retained in excised membrane patches, suggesting a membrane-delimited mechanism. Using reverse transcription-polymerase chain reaction and immunocytochemistry, Kv3.1b expression was demonstrated in PASM cells. Moreover, hypoxia inhibited a K(+) current in rabbit PASM cells in the presence of charybdotoxin and capsaicin, which preserve Kv3.1b while blocking most other Kv channels, but not in the presence of millimolar tetraethylammonium ions, which abolish Kv3.1b current. Kv3.1b channels may therefore contribute to oxygen sensing in pulmonary artery.

  10. Jarid1b targets genes regulating development and is involved in neural differentiation

    PubMed Central

    Schmitz, Sandra U; Albert, Mareike; Malatesta, Martina; Morey, Lluis; Johansen, Jens V; Bak, Mads; Tommerup, Niels; Abarrategui, Iratxe; Helin, Kristian

    2011-01-01

    H3K4 methylation is associated with active transcription and in combination with H3K27me3 thought to keep genes regulating development in a poised state. The contribution of enzymes regulating trimethylation of lysine 4 at histone 3 (H3K4me3) levels to embryonic stem cell (ESC) self-renewal and differentiation is just starting to emerge. Here, we show that the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) is dispensable for ESC self-renewal, but essential for ESC differentiation along the neural lineage. By genome-wide location analysis, we demonstrate that Jarid1b localizes predominantly to transcription start sites of genes encoding developmental regulators, of which more than half are also bound by Polycomb group proteins. Virtually all Jarid1b target genes are associated with H3K4me3 and depletion of Jarid1b in ESCs leads to a global increase of H3K4me3 levels. During neural differentiation, Jarid1b-depleted ESCs fail to efficiently silence lineage-inappropriate genes, specifically stem and germ cell genes. Our results delineate an essential role for Jarid1b-mediated transcriptional control during ESC differentiation. PMID:22020125

  11. 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

  12. Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling

    PubMed Central

    Fazzari, Pietro; Snellinx, An; Sabanov, Victor; Ahmed, Tariq; Serneels, Lutgarde; Gartner, Annette; Shariati, S Ali M; Balschun, Detlef; De Strooper, Bart

    2014-01-01

    Neuregulin 1 (NRG1) and the γ-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the Aph1b-γ-secretase is selectively involved in Nrg1 intracellular signalling. We found that Aph1b-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that Aph1b is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that Nrg1 intracellular signalling promotes dendritic spine formation downstream of Aph1b-γ-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of Aph1b-γ-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia. DOI: http://dx.doi.org/10.7554/eLife.02196.001 PMID:24891237

  13. Identification of a hemerythrin-like domain in a P1B-type transport ATPase†

    PubMed Central

    Traverso, Matthew E.; Subramanian, Poorna; Davydov, Roman; Hoffman, Brian M.; Stemmler, Timothy L.; Rosenzweig, Amy C.

    2010-01-01

    The P1B-type ATPases couple the energy of ATP hydrolysis to metal ion translocation across cell membranes. Important for prokaryotic metal resistance and essential metal distribution in eukaryotes, P1B-ATPases are divided into subclasses on the basis of their metal substrate specificities. Sequence analysis of putative P1B-5-ATPases, for which the substrate has not been identified, led to the discovery of a C-terminal soluble domain homologous to hemerythrin (Hr) proteins and domains. The Hr domain from the Acidothermus cellulolyticus P1B-5-ATPase was cloned, expressed, and purified (P1B-5-Hr). P1B-5-Hr binds two iron ions per monomer and adopts a predominantly helical fold. Optical absorption features of the iron-loaded and azide-treated protein are consistent with features observed for other Hr proteins. Autooxidation to the met form is very rapid, as reported for other prokaryotic Hr domains. The presence of a diiron center was confirmed by electron paramagnetic resonance (EPR) and X-ray absorption spectroscopic (XAS) data. The occurrence of a Hr-like domain in a P-type ATPase is unprecedented and suggests new regulatory mechanisms as well as an expanded function for Hr proteins in biology. PMID:20672819

  14. 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.

  15. 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.

  16. Aryl morpholino triazenes inhibit cytochrome P450 1A1 and 1B1.

    PubMed

    Lee, Daniel; Perez, Pedro; Jackson, William; Chin, Taylor; Galbreath, Michael; Fronczek, Frank R; Isovitsch, Ralph; Iimoto, Devin S

    2016-07-15

    Many cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1) inhibitors, such as resveratrol, have planar, hydrophobic, aromatic rings in their structure and exhibit anti-cancer activity. Aryl morpholino triazenes have similar structural features and in addition contain a triazene unit consisting of three consecutive, conjugated nitrogen atoms. Several aryl morpholino triazenes, including 4-[(E)-2-(3,4,5-trimethoxyphenyl)diazenyl]-morpholine (2), were prepared from a reaction involving morpholine and a diazonium ion produced from different aniline derivatives, such as 3,4,5-trimethoxyaniline. The aryl morpholino triazenes were then screened at 100μM for their ability to inhibit CYP1A1 and CYP1B1 using ethoxyresorufin as the substrate. Triazenes that inhibited the enzymes to less than 80% of the uninhibited enzyme activity were assayed to determine their IC50 value. Compound 2 was the only triazene to inhibit both CYP1A1 and CYP1B1 to the same degree as resveratrol with IC50 values of 10μM and 18μM, respectively. Compounds 3 and 6 selectively inhibited CYP1B1 over CYP1A1 with IC values of 2μM and 7μM, respectively. Thus, aryl morpholino triazenes are a new class of compounds that can inhibit CYP1A1 and CYP1B1 and potentially prevent cancer. PMID:27265259

  17. Uroplakin 1b is critical in urinary tract development and urothelial differentiation and homeostasis.

    PubMed

    Carpenter, Ashley R; Becknell, M Brian; Ching, Christina B; Cuaresma, Edward J; Chen, Xi; Hains, David S; McHugh, Kirk M

    2016-03-01

    Proper development and maintenance of urothelium is critical to its function. Uroplakins are expressed in developing and mature urothelium where they establish plaques associated with the permeability barrier. Their precise functional role in development and disease is unknown. Here, we disrupted Upk1b in vivo where its loss resulted in urothelial plaque disruption in the bladder and kidney. Upk1b(RFP/RFP) bladder urothelium appeared dysplastic with expansion of the progenitor cell markers, Krt14 and Krt5, increased Shh expression, and loss of terminal differentiation markers Krt20 and uroplakins. Upk1b(RFP/RFP) renal urothelium became stratified with altered cellular composition. Upk1b(RFP/RFP) mice developed age-dependent progressive hydronephrosis. Interestingly, 16% of Upk1b(RFP/RFP) mice possessed unilateral duplex kidneys. Our study expands the role of uroplakins, mechanistically links plaque formation to urinary tract development and function, and provides a tantalizing connection between congenital anomalies of the kidney and urinary tract along with functional deficits observed in a variety of urinary tract diseases. Thus, kidney and bladder urothelium are regionally distinct and remain highly plastic, capable of expansion through tissue-specific progenitor populations. Furthermore, Upk1b plays a previously unknown role in early kidney development representing a novel genetic target for congenital anomalies of the kidney and urinary tract. PMID:26880456

  18. 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.

  19. [OATP1B1 in drug-drug interactions between traditional Chinese medicine Danshensu and rosuvastatin].

    PubMed

    Wen, Jin-hua; Wei, Xiao-hua; Cheng, Xiao-hua; Zuo, Rong; Peng, Hong-wei; Lü, Yan-ni; Zhou, Jian; Zheng, Xue-lian; Cai, Jun; Xiong, Yu-qing; Cao, Li

    2016-01-01

    The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 μmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) μmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 μmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence. PMID:27405165

  20. 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.; 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