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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. 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

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

    PubMed

    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. PMID:25088042

  4. Genetic variation in aldo-keto reductase 1D1 (AKR1D1) affects the expression and activity of multiple cytochrome P450s.

    PubMed

    Chaudhry, Amarjit S; Thirumaran, Ranjit K; Yasuda, Kazuto; Yang, Xia; Fan, Yiping; Strom, Stephen C; Schuetz, Erin G

    2013-08-01

    Human liver gene regulatory (Bayesian) network analysis was previously used to identify a cytochrome P450 (P450) gene subnetwork with Aldo-keto reductase 1D1 (AKR1D1) as a key regulatory driver of this subnetwork. This study assessed the biologic importance of AKR1D1 [a key enzyme in the synthesis of bile acids, ligand activators of farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), known transcriptional regulators of P450s] to hepatic P450 expression. Overexpression of AKR1D1 in primary human hepatocytes led to increased expression of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6. Conversely, AKR1D1 knockdown decreased expression of these P450s. We resequenced AKR1D1 from 98 donor livers and identified a 3'-untranslated region (UTR) (rs1872930) single nucleotide polymorphism (SNP) significantly associated with higher AKR1D1 mRNA expression. AKR1D1 3'-UTR-luciferase reporter studies showed that the variant allele resulted in higher luciferase activity, suggesting that the SNP increases AKR1D1 mRNA stability and/or translation efficiency. Consistent with AKR1D1's putative role as a driver of the P450 subnetwork, the AKR1D1 3'-UTR SNP was significantly associated with increased hepatic mRNA expression of multiple P450s (CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6) and CYP3A4, CYP2C8, CYP2C19, and CYP2B6 activities. After adjusting for multiple testing, the association remained significant for AKR1D1, CYP2C9, and CYP2C8 mRNA expression and CYP2C8 activity. These results provide new insights into the variation in expression and activity of P450s that can account for interindividual differences in drug metabolism/efficacy and adverse drug events. In conclusion, we provide the first experimental evidence supporting a role for AKR1D1 as a key genetic regulator of the P450 network. PMID:23704699

  5. Comparative effects of nodularin and microcystin-LR in zebrafish: 1. Uptake by organic anion transporting polypeptide Oatp1d1 (Slco1d1).

    PubMed

    Faltermann, Susanne; Prétôt, René; Pernthaler, Jakob; Fent, Karl

    2016-02-01

    Microcystin-LR (MC-LR) and nodularin are hepatotoxins produced by several cyanobacterial species. Their toxicity is based on active cellular uptake and subsequent inhibition of protein phosphatases PP1/2A, leading to hyperphosphorylation and cell death. To date, uptake of MC-LR and nodularin in fish is poorly understood. Here, we investigated the role of the organic anion transporting polypeptide Oatp1d1 in zebrafish (drOatp1d1, Slco1d1) in cellular uptake in zebrafish. We stably transfected CHO and HEK293 cell lines expressing drOatp1d1. In both transfectants, uptake of MC-LR and nodularin was demonstrated by competitive inhibition of uptake with fluorescent substrate lucifer yellow. Direct uptake of MC-LR was demonstrated by immunostaining, and indirectly by the high cytotoxicity in stable transfectants. By means of a synthesized fluorescent labeled MC-LR derivative, direct uptake was further confirmed in HEK293 cells expressing drOatp1d1. Additionally, uptake and toxicity was investigated in the permanent zebrafish liver cell line ZFL. These cells had only a low relative abundance of drOatp1d1, drOatp2b1 and drOatp1f transcripts, which correlated with the lack of MC-LR induced cytotoxicity and transcriptional changes of genes indicative of endoplasmic reticulum stress, a known effect of this toxin. Our study demonstrates that drOatp1d1 functions as an uptake transporter for both MC-LR and nodularin in zebrafish. PMID:26769064

  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. 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.

  8. Substrate specificity and inhibitor analyses of human steroid 5β-reductase (AKR1D1)

    PubMed Central

    Chen, Mo; Drury, Jason E.; Penning, Trevor M.

    2011-01-01

    Human steroid 5β-reductase (Aldo-keto Reductase 1D1) catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of Δ4-ketosteroids to yield an A/B cis-ring junction. This cis-configuration is crucial for bile acid biosynthesis and plays important roles in steroid metabolism. The biochemical properties of the enzyme have not been thoroughly studied and conflicting data have been reported, partially due to the lack of highly homogeneous protein. In the present study, we systematically determined the substrate specificity of homogeneous human recombinant AKR1D1 using C18, C19, C21, and C27 Δ4-ketosteroids and assessed the pH-rate dependence of the enzyme. Our results show that AKR1D1 proficiently reduced all the steroids tested at physiological pH, indicating AKR1D1 is the only enzyme necessary for all the 5β-steroid metabolite present in humans. Substrate inhibition was observed with C18 to C21 steroids provided that the side-chain at C17 was unsubstituted. This structure activity relationship can be explained by the existence of a small alternative substrate binding pocket revealed by the AKR1D1 crystal structure. Non-steroidal anti-inflammatory drugs which are potent inhibitors of the related AKR1C enzymes do not inhibit AKR1D1 by contrast chenodeoxycholate and ursodeoxycholate were found to be potent non-competitive inhibitors suggesting that bile-acids may regulate their own synthesis at the level of AKR1D1 inhibition. PMID:21255593

  9. 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

  10. 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...

  11. 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...

  12. Investigation of Associations between NR1D1, RORA and RORB Genes and Bipolar Disorder

    PubMed Central

    Lai, Yin-Chieh; Kao, Chung-Feng; Lu, Mong-Liang; Chen, Hsi-Chung; Chen, Po-Yu; Chen, Chien-Hsiun; Shen, Winston W.; Wu, Jer-Yuarn; Lu, Ru-Band; Kuo, Po-Hsiu

    2015-01-01

    Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10−6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0

  13. Regulatory mode shift of Tbc1d1 is required for acquisition of insulin-responsive GLUT4-trafficking activity

    PubMed Central

    Hatakeyama, Hiroyasu; Kanzaki, Makoto

    2013-01-01

    Tbc1d1 is key to skeletal muscle GLUT4 regulation. By using GLUT4 nanometry combined with a cell-based reconstitution model, we uncover a shift in the regulatory mode of Tbc1d1 by showing that Tbc1d1 temporally acquires insulin responsiveness, which triggers GLUT4 trafficking only after an exercise-mimetic stimulus such as aminoimidazole carboxamide ribonucleotide (AICAR) pretreatment. The functional acquisition of insulin responsiveness requires Ser-237 phosphorylation and an intact phosphotyrosine-binding (PTB) 1 domain. Mutations in PTB1, including R125W (a natural mutant), thus result in complete loss of insulin-responsiveness acquisition, whereas AICAR-responsive GLUT4-liberation activity remains intact. Thus our data provide novel insights into temporal acquisition/memorization of Tbc1d1 insulin responsiveness, relying on the PTB1 domain, possibly a key factor in the beneficial effects of exercise on muscle insulin potency. PMID:23325788

  14. Identification of the minimum pharmacophore of lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1D1.

    PubMed

    Singh, Jaspal; Shukla, Satya Prakash; Desai, Tanvi J; Udugamasooriya, D Gomika

    2016-09-15

    We previously reported a unique peptide-peptoid hybrid, PPS1 that specifically recognizes lipid-phosphatidylserine (PS) and a few other negatively charged phospholipids, but not neutral phospholipids, on the cell membrane. The dimeric version of PPS1, i.e., PPS1D1 triggers strong cancer cell cytotoxicity and has been validated in lung cancer models both in vitro and in vivo. Given that PS and other negatively charged phospholipids are abundant in almost all tumor microenvironments, PPS1D1 is an attractive drug lead that can be developed into a globally applicable anti-cancer agent. Therefore, it is extremely important to identify the minimum pharmacophore of PPS1D1. In this study, we have synthesized alanine/sarcosine derivatives as well as truncated derivatives of PPS1D1. We performed ELISA-like competitive binding assay to evaluate the PS-recognition potential and standard MTS cell viability assay on HCC4017 lung cancer cells to validate the cell cytotoxicity effects of these derivatives. Our studies indicate that positively charged residues at the second and third positions, as well as four hydrophobic residues at the fifth through eighth positions, are imperative for the binding and activity of PPS1D1. Methionine at the first position was not essential, whereas the positively charged Nlys at the fourth position was minimally needed, as two derivatives that were synthesized replacing this residue were almost as active as PPS1D1. PMID:27485601

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Cytochrome P450 1D1: A novel CYP1A-related gene that is not transcriptionally activated by PCB126 or TCDD

    PubMed Central

    Goldstone, J. V.; Jönsson, M. E.; Behrendt, L.; Woodin, B. R.; Jenny, M. J.; Nelson, D. R.; Stegeman, J. J.

    2009-01-01

    Enzymes in the cytochrome P450 1 family oxidize many common environmental toxicants. We identified a new CYP1, termed CYP1D1, in zebrafish. Phylogenetically, CYP1D1 is paralogous to CYP1A and the two share 45% amino acid identity and similar gene structure. In adult zebrafish, CYP1D1 is most highly expressed in liver and is relatively highly expressed in brain. CYP1D1 transcript levels were higher at 9 hours post-fertilization than at later developmental times. Treatment of zebrafish with potent aryl hydrocarbon receptor (AHR) agonists (3,3′,4,4′,5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin) did not induce CYP1D1 transcript expression. Morpholino oligonucleotide knockdown of AHR2, which mediates induction of other CYP1s, did not affect CYP1D1 expression. Zebrafish CYP1D1 heterologously expressed in yeast exhibited ethoxyresorufin- and methoxyresorufin-O-dealkylase activities. Antibodies against a CYP1D1 peptide specifically detected a single electrophoretically-resolved protein band in zebrafish liver microsomes, distinct from CYP1A. CYP1D1 in zebrafish is a CYP1A-like gene that could have metabolic functions targeting endogenous compounds. PMID:19103147

  20. 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.... The MCAI describes the unsafe condition as: During production of Arriel 1 and Arriel 2 Power...

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

    PubMed

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

    2016-08-01

    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

  2. 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

  3. 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

  4. NMRmix: A Tool for the Optimization of Compound Mixtures in 1D (1)H NMR Ligand Affinity Screens.

    PubMed

    Stark, Jaime L; Eghbalnia, Hamid R; Lee, Woonghee; Westler, William M; Markley, John L

    2016-04-01

    NMR ligand affinity screening is a powerful technique that is routinely used in drug discovery or functional genomics to directly detect protein-ligand binding events. Binding events can be identified by monitoring differences in the 1D (1)H NMR spectrum of a compound with and without protein. Although a single NMR spectrum can be collected within a short period (2-10 min per sample), one-by-one screening of a protein against a library of hundreds or thousands of compounds requires a large amount of spectrometer time and a large quantity of protein. Therefore, compounds are usually evaluated in mixtures ranging in size from 3 to 20 compounds to improve the efficiency of these screens in both time and material. Ideally, the NMR signals from individual compounds in the mixture should not overlap so that spectral changes can be associated with a particular compound. We have developed a software tool, NMRmix, to assist in creating ideal mixtures from a large panel of compounds with known chemical shifts. Input to NMRmix consists of an (1)H NMR peak list for each compound, a user-defined overlap threshold, and additional user-defined parameters if default settings are not used. NMRmix utilizes a simulated annealing algorithm to optimize the composition of the mixtures to minimize spectral peak overlaps so that each compound in the mixture is represented by a maximum number of nonoverlapping chemical shifts. A built-in graphical user interface simplifies data import and visual evaluation of the results. PMID:26965640

  5. NMRmix: A Tool for the Optimization of Compound Mixtures in 1D 1H NMR Ligand Affinity Screens

    PubMed Central

    2016-01-01

    NMR ligand affinity screening is a powerful technique that is routinely used in drug discovery or functional genomics to directly detect protein–ligand binding events. Binding events can be identified by monitoring differences in the 1D 1H NMR spectrum of a compound with and without protein. Although a single NMR spectrum can be collected within a short period (2—10 min per sample), one-by-one screening of a protein against a library of hundreds or thousands of compounds requires a large amount of spectrometer time and a large quantity of protein. Therefore, compounds are usually evaluated in mixtures ranging in size from 3 to 20 compounds to improve the efficiency of these screens in both time and material. Ideally, the NMR signals from individual compounds in the mixture should not overlap so that spectral changes can be associated with a particular compound. We have developed a software tool, NMRmix, to assist in creating ideal mixtures from a large panel of compounds with known chemical shifts. Input to NMRmix consists of an 1H NMR peak list for each compound, a user-defined overlap threshold, and additional user-defined parameters if default settings are not used. NMRmix utilizes a simulated annealing algorithm to optimize the composition of the mixtures to minimize spectral peak overlaps so that each compound in the mixture is represented by a maximum number of nonoverlapping chemical shifts. A built-in graphical user interface simplifies data import and visual evaluation of the results. PMID:26965640

  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. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic

    PubMed Central

    Sakamoto, Kei; Holman, Geoffrey D.

    2008-01-01

    Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation. PMID:18477703

  8. Automated structure verification based on a combination of 1D (1)H NMR and 2D (1)H - (13)C HSQC spectra.

    PubMed

    Golotvin, Sergey S; Vodopianov, Eugene; Pol, Rostislav; Lefebvre, Brent A; Williams, Antony J; Rutkowske, Randy D; Spitzer, Timothy D

    2007-10-01

    A method for structure validation based on the simultaneous analysis of a 1D (1)H NMR and 2D (1)H - (13)C single-bond correlation spectrum such as HSQC or HMQC is presented here. When compared with the validation of a structure by a 1D (1)H NMR spectrum alone, the advantage of including a 2D HSQC spectrum in structure validation is that it adds not only the information of (13)C shifts, but also which proton shifts they are directly coupled to, and an indication of which methylene protons are diastereotopic. The lack of corresponding peaks in the 2D spectrum that appear in the 1D (1)H spectrum, also gives a clear picture of which protons are attached to heteroatoms. For all these benefits, combined NMR verification was expected and found by all metrics to be superior to validation by 1D (1)H NMR alone. Using multiple real-life data sets of chemical structures and the corresponding 1D and 2D data, it was possible to unambiguously identify at least 90% of the correct structures. As part of this test, challenging incorrect structures, mostly regioisomers, were also matched with each spectrum set. For these incorrect structures, the false positive rate was observed as low as 6%. PMID:17694570

  9. 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.

  10. 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

  11. 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.

  12. Modifier Genes as Therapeutics: The Nuclear Hormone Receptor Rev Erb Alpha (Nr1d1) Rescues Nr2e3 Associated Retinal Disease

    PubMed Central

    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. PMID:24498227

  13. 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.

  14. 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

  15. 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

  16. 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...

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

    PubMed

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

    2014-12-21

    Hierarchically ordered ZnO nanorods (NRs) decorated nanoporous-layer-covered TiO2 nanotube array (ZnO NRs/NP-TNTAs) nanocomposites have been prepared by an efficient, two-step anodization route combined with an electrochemical deposition strategy, by which monodispersed one-dimensional (1D) ZnO NRs were uniformly grown on the framework of NP-TNTAs. The crystal phases, morphologies, optical properties, photocatalytic as well as photoelectrocatalytic performances of the well-defined ZnO NRs/NP-TNTAs heterostructures were systematically explored to clarify the structure-property correlation. It was found that the ZnO NRs/NP-TNTAs heterostructure exhibits significantly enhanced photocatalytic and photoelectrocatalytic performances, along with favorable photostability toward degradation of organic pollutants under UV light irradiation, as compared to the single component counterparts. The remarkably enhanced photoactivity of ZnO NRs/NP-TNTAs heterostructure is ascribed to the intimate interfacial integration between ZnO NRs and NP-TNTAs substrate imparted by the unique spatially branched hierarchical structure, thereby contributing to the efficient transfer and separation of photogenerated electron-hole charge carriers. Moreover, the specific active species during the photocatalytic process was unambiguously determined and photocatalytic mechanism was tentatively presented. It is anticipated that our work could provide new insights for the construction of various hierarchical 1D-1D hybrid nanocomposites for extensive photocatalytic applications. PMID:25363649

  18. 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.

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

    SciTech Connect

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

    2013-06-01

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

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

    PubMed

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

    2014-10-01

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

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

    PubMed Central

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

    2015-01-01

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

  2. 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

  3. 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

  4. Reaction of nitrilimines with 2-substituted aza-heterocycles. Synthesis of pyrrolo[1,2-a]pyridine and pyrimido[2,1-d]1,2,3,5- tetrazine.

    PubMed

    Awadallah, Adel M; Zahra, Jalal A

    2008-01-01

    The reaction of nitrilimine 6a with ethyl pyridine-2-acetate (7) gave the corresponding pyrrolo[1,2-a]pyridine 8, while the reaction of 6b containing an ester moiety afforded the acyclic adduct 9. The reaction of 6a with 2-aminopyrimidine (10) gave the novel unexpected pyrimido[2,1-d]1,2,3,5-tetrazine 11. Acyclic adducts 16 and 17 were obtained from the reaction of 6b with 2-cyanomethylbenzimidazole (14) and 2-aminobenzimidazole (15), respectively. PMID:18259139

  5. 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

  6. 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

    ...) that were published in the Federal Register on Friday, December 18, 2009 (74 FR 67053) providing... Sections 368(a)(1)(D) and 354(b)(1)(B); Correction AGENCY: Internal Revenue Service (IRS), Treasury... final regulations (TD 9475) contain an error that may prove to be misleading and is in need...

  7. 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

  8. 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

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

    PubMed

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

    2015-08-15

    Plectin, a versatile 500-kDa cytolinker protein, is essential for muscle fiber integrity and function. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is characterized by severe skin blistering and progressive muscular dystrophy. Besides displaying pathological desmin-positive protein aggregates and degenerative changes in the myofibrillar apparatus, skeletal muscle specimens of EBS-MD patients and plectin-deficient mice are characterized by massive mitochondrial alterations. In this study, we demonstrate that structural and functional alterations of mitochondria are a primary aftermath of plectin deficiency in muscle, contributing to myofiber degeneration. We found that in skeletal muscle of conditional plectin knockout mice (MCK-Cre/cKO), mitochondrial content was reduced, and mitochondria were aggregated in sarcoplasmic and subsarcolemmal regions and were no longer associated with Z-disks. Additionally, decreased mitochondrial citrate synthase activity, respiratory function and altered adenosine diphosphate kinetics were characteristic of plectin-deficient muscles. To analyze a mechanistic link between plectin deficiency and mitochondrial alterations, we comparatively assessed mitochondrial morphology and function in whole muscle and teased muscle fibers of wild-type, MCK-Cre/cKO and plectin isoform-specific knockout mice that were lacking just one isoform (either P1b or P1d) while expressing all others. Monitoring morphological alterations of mitochondria, an isoform P1b-specific phenotype affecting the mitochondrial fusion-fission machinery and manifesting with upregulated mitochondrial fusion-associated protein mitofusin-2 could be identified. Our results show that the depletion of distinct plectin isoforms affects mitochondrial network organization and function in different ways. PMID:26019234

  10. 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. PMID:21271688

  11. 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

  12. 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

  13. 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

  14. 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

    ...This document describes a correction to final regulations (TD 9475) that were published on Friday, December 18, 2009 (74 FR 67053). The regulations provide guidance regarding the qualification of certain transactions as reorganizations described in section 368(a)(1)(D) where no stock and/or securities of the acquiring corporation is issued and distributed in the transaction. This document also......

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

    PubMed

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

    2016-06-15

    Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15nmol) or valerenic acid (1nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01-0.1nmol); (ii) SB-699551 (selective 5-HT5A; up to 10nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1-1nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1-1nmol). Likewise, antinociception by intraplantar ergotamine (15nmol) and valerenic acid (10nmol) was: (i) partially blocked by methiothepin (1nmol), SB-699551 (10nmol) or SB-224289 (1nmol); and (ii) abolished by BRL-15572 (1nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain. PMID:27068146

  16. Inhibition of trigeminal neurones after intravenous administration of naratriptan through an action at 5-hydroxy-tryptamine (5-HT1B/1D) receptors

    PubMed Central

    Goadsby, Peter J; Knight, Yolande

    1997-01-01

    The observation that 5-hydroxytryptamine (5-HT) is effective in treating acute attacks of migraine when administered intravenously resulted in a research effort that led to the discovery of the 5-HT1B/1D receptor agonist sumatriptan. Clinical experience has shown sumatriptan to be an effective treatment with some limitations, such as relatively poor bioavailability, which naratriptan was developed to address. Increasing bioavailability has been achieved with greater lipophilicity and thus the potential for greater activity in the central nervous system. In this study the increased access to central sites has been exploited in an attempt to characterize the pharmacology of those central receptors with the newer tools available. Trigeminovascular activation was examined in the model of superior sagittal sinus stimulation. Cats were anaesthetized with α-chloralose (60 mg kg−1, intraperitoneal), paralyzed (gallamine 6 mg kg−1, intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation (250 μs pulses, 0.3 Hz, 100 V) by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.69±0.1 at a latency of 9.2±0.2 ms. Intravenous (i.v.) administration of naratriptan at clinically relevant doses (30 and 100 μg kg−1), inhibited neuronal activity in trigeminal neurones of the C2 dorsal horn, reducing probability of firing without affecting latency. The effect of naratriptan could be reversed by administration of the selective 5-HT1B/1D receptor antagonist GR127935 (100 μg kg−1, i.v.). These data establish that naratriptan acts on central trigeminal neurones since sagittal sinus stimulation activates axons within the tentorial

  17. 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

  18. Full-length genomes of 16 hepatitis C virus genotype 1 isolates representing subtypes 1c, 1d, 1e, 1g, 1h, 1i, 1j and 1k, and two new subtypes 1m and 1n, and four unclassified variants reveal ancestral relationships among subtypes.

    PubMed

    Lu, Ling; Li, Chunhua; Xu, Yan; Murphy, Donald G

    2014-07-01

    We characterized the full-length genomes of 16 distinct hepatitis C virus genotype 1 (HCV-1) isolates. Among them, four represented the first full-length genomes for subtypes 1d (QC103), 1i (QC181), 1j (QC329) and 1k (QC82), and another four corresponded to subtypes 1c (QC165), 1g (QC78), 1h (QC156) and 1e (QC172). Both QC196 and QC87 were assigned into a new subtype 1m, and QC113 and QC74 into another new subtype 1n. The remaining four (QC60, QC316, QC152 and QC180) did not classify among the established subtypes and corresponded to four new lineages. Subtypes 1j, 1k, 1m, 1n and the unclassified isolate QC60 were identified in Haitian immigrants. In the updated HCV nomenclature of 2005, a total of 12 subtypes of HCV-1 were designated. Including the data from the present study, all but subtype 1f now have their full-length genomes defined. Further analysis of partial NS5B sequences available in GenBank denoted a total of 21 unclassified lineages, indicating the taxonomic complexity of HCV-1. Among them, six have had their full-length genomes characterized. Based on the available full-length genome sequences, a timescale phylogenetic tree was reconstructed which estimated important time points in the evolution of HCV-1. It revealed that subtype 1a diverged from its nearest relatives 135 years ago and subtype 1b diverged from its nearest relatives 112 years ago. When subtypes 1a, 1j, 1k, 1m, 1n and six close relatives (all but one from Haitian immigrants) were considered as a whole, the divergence time was 176 years ago. This diversification was concurrent with the time period when the transatlantic slave trade was active. When taking all the HCV-1 isolates as a single lineage, the divergence time was 326 years ago. This analysis suggested the existence of a recent common ancestor for subtype 1a and the Haitian variants; a co-origin for subtypes 1b, 1i and 1d was also implied. PMID:24718832

  19. 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

  20. 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

  1. 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

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

    PubMed Central

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

    1998-01-01

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

  3. 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

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

    PubMed Central

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

    1998-01-01

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

  5. Characterization of a ( sub 3 H)-5-hydroxtyryptamine binding site in rabbit caudate nucleus that differs from the 5-HT sub 1A , 5-HT sub 1B , 5-HT sub 1C and 5-HT sub 1D subtypes

    SciTech Connect

    Xiong, Wencheng; Nelson, D.L. )

    1989-01-01

    ({sup 3}H)5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). ({sup 3}H)5-HT labeled both 5-HT{sub 1A} and 5-HT{sub 1C} recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific ({sup 3}H)5-HT binding. Saturation experiments of ({sup 3}H)5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT{sub 1A} and 5-HT{sub 1C} sites revealed that non-5-HT{sub 1A}/non-5-HT{sub 1C} sites represented about 60% of the total 5-HT{sub 1} sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profile of the non-5-HT{sub 1A}/non-5-HT{sub 1C} sites (designated 5-HT{sub 1R}) also differed from that of 5-HT{sub 1B} and 5-HT{sub 2} sites, but was similar to that of the 5-HT{sub 1D} site. However, significant differences existed between the 5-HT{sub 1D} and 5-HT{sub 1B} sites for their K{sub i} values for spiperone, spirilene, metergoline, and methiothepin. The study of modulatory agents also showed differences between the 5-HT{sub 1R} and 5-HT{sub 1D} sites. In addition, calcium enhanced the effects of GTP on the 5-HT{sub 1R} sites, whereas calcium inhibited the GTP effect on the 5-HT{sub 1D} sites.

  6. 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. PMID:26477316

  7. Pharmacological evidence that 5-HT1A/1B/1D, α2-adrenoceptors and D2-like receptors mediate ergotamine-induced inhibition of the vasopressor sympathetic outflow in pithed rats.

    PubMed

    Villamil-Hernández, Ma Trinidad; Alcántara-Vázquez, Oscar; Sánchez-López, Araceli; Gutiérrez-Lara, Erika J; Centurión, David

    2014-10-01

    The sympathetic nervous system that innervates the peripheral circulation is regulated by several mechanisms/receptors. It has been reported that prejunctional 5-HT1A, 5-HT1B, 5-HT1D, D2-like receptors and α2-adrenoceptors mediate the inhibition of the vasopressor sympathetic outflow in pithed rats. In addition, ergotamine, an antimigraine drug, displays affinity at the above receptors and may explain some of its adverse/therapeutic effects. Thus, the aims of this study were to investigate in pithed rats: (i) whether ergotamine produces inhibition of the vasopressor sympathetic outflow; and (ii) the major receptors involved in this effect. For this purpose, male Wistar pithed rats were pre-treated with gallamine (25 mg/kg; i.v.) and desipramine (50 µg/kg) and prepared to stimulate the vasopressor sympathetic outflow (T7-T9; 0.03-3 Hz) or to receive i.v. bolus of exogenous noradrenaline (0.03-3 µg/kg). I.v. continuous infusions of ergotamine (1 and 1.8 μg/kgmin) dose-dependently inhibited the vasopressor responses to sympathetic stimulation but not those to exogenous noradrenaline. The sympatho-inhibition elicited by 1.8 μg/kg min ergotamine was (i) unaffected by saline (1 ml/kg); (ii) partially antagonised by WAY 100635 (5-HT1A; 30 μg/kg) and rauwolscine (α2-adrenoceptor; 300 μg/kg), and (iii) dose-dependently blocked by GR 127935 (5-HT1B/1D; 100 and 300 μg/kg) or raclopride (D2-like; 300 and 1000 μg/kg), The above doses of antagonists did not modify per se the sympathetically-induced vasopressor responses. The above results suggest that ergotamine induces inhibition of the vasopressor sympathetic outflow by activation of prejunctional 5-HT1A, 5-HT1B/1D, α2-adrenoceptors and D2-like receptors in pithed rats. PMID:24975101

  8. Effect of peptides corresponding to extracellular domains of serotonin 1B/1D receptors and melanocortin 3 and 4 receptors on hormonal regulation of adenylate cyclase in rat brain.

    PubMed

    Shpakova, E A; Derkach, K V; Shpakov, A O

    2014-03-01

    The ligand-recognizing part of G protein-coupled receptors consists of their extracellular loops and N-terminal domain. Identification of these sites is essential for receptor mapping and for the development and testing of new hormone system regulators. The peptides corresponding by their structure to extracellular loop 2 of serotonin 1B/1D receptor (peptide 1), extracellular loop 3 of melanocortin 3 receptor (peptide 2), and N-terminal domain of melanocortin 4 (peptide 3) were synthesized by the solid-phase method. In synaptosomal membranes isolated from rat brain, peptide 1 (10(-5)-10(-4) M) attenuated the effects of 5-nonyloxytryptamine (selective agonist of serotonin 1B/1D receptor) and to a lesser extent serotonin and 5-methoxy-N,N-dimethyltryptamine acting on all the subtypes of serotonin receptor 1. Peptide 2 (10(-5)-10(-4) M) significantly reduced the adenylate cyclase-stimulating effect of γ-melanocyte-stimulating hormone (agonist of melanocortin receptor 3), but had no effect on the adenylate cyclase effect of THIQ (agonist melanocortin receptor 4). Peptide 3 reduced the adenylate cyclase-stimulating effects of THIQ and α-melanocyte-stimulating hormone (non-selective agonist of melanocortin receptors 3 and 4), but did not modulate the effect of γ-melanocyte-stimulating hormone. The effect of peptide 3 was weaker: it was observed at peptide 3 concentration of 10(-4) M. Peptides 1-3 did no change the adenylate cyclase-modulating effects of hormones acting through non-homologous receptors. Thus, the synthesized peptides specifically inhibited the regulatory effects of hormones acting through homologous receptors. This suggests that the corresponding extracellular domains are involved in ligand recognition and binding and determine functional activity of the receptor. PMID:24770752

  9. Cyclin K and cyclin D1b are oncogenic in myeloma cells

    PubMed Central

    2010-01-01

    Background Aberrant expression of cyclin D1 is a common feature in multiple myeloma (MM) and always associated with mantle cell lymphoma (MCL). CCND1 gene is alternatively spliced to produce two cyclin D1 mRNA isoforms which are translated in two proteins: cyclin D1a and cyclin D1b. Both isoforms are present in MM cell lines and primary cells but their relative role in the tumorigenic process is still elusive. Results To test the tumorigenic potential of cyclin D1b in vivo, we generated cell clones derived from the non-CCND1 expressing MM LP-1 cell line, synthesizing either cyclin D1b or cyclin K, a structural homolog and viral oncogenic form of cyclin D1a. Immunocompromised mice injected s.c. with LP-1K or LP-1D1b cells develop tumors at the site of injection. Genome-wide analysis of LP-1-derived cells indicated that several cellular processes were altered by cyclin D1b and/or cyclin K expression such as cell metabolism, signal transduction, regulation of transcription and translation. Importantly, cyclin K and cyclin D1b have no major action on cell cycle or apoptosis regulatory genes. Moreover, they impact differently cell functions. Cyclin K-expressing cells have lost their migration properties and display enhanced clonogenic capacities. Cyclin D1b promotes tumorigenesis through the stimulation of angiogenesis. Conclusions Our study indicates that cyclin D1b participates into MM pathogenesis via previously unrevealed actions. PMID:20459741

  10. 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...

  11. 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.

  12. 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

  13. Allelic frequencies for the HLA-DQA1, D1S80, HUMTHO1, HUMTPOX, HUMCSF1PO and HUMVWA loci in Cantabria (middle north Spain).

    PubMed

    Sánchez-Molina, I; Calvet, R

    2000-01-01

    Allele frequencies for six DNA polymorphisms have been studied in a population sample from Cantabria (middle north Spain) using the polymerase chain reaction. The HLA-DQA1 locus was analyzed by the reverse dot-blot technique and the other five by polyacrylamide gel electrophoresis followed by silver staining. Six alleles were found for HLA-DQA1. 15 alleles for D1S80, 6 alleles for HUMTHO1 and HUMCSF1PO, 7 for HUMTPOX and 8 alleles for HUMVWA. The 21 repeat allele in HUMVWA had not previously been reported in a Spanish population. The genotype distributions met Hardy-Weinberg expectations for all the systems and some statistical parameters of forensic interest were calculated. Comparisons with other populations revealed significant differences for HLA-DQA1, HUMVWA and HUMTHO1, with interracial differences being more pronounced than between Spanish populations. The HUMVWA system showed the highest forensic efficiency of the six polymorphisms studied. PMID:10641932

  14. 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.

  15. Interferon Gamma-1b Injection

    MedlinePlus

    Interferon gamma-1b injection is used to reduce the frequency and severity of serious infections in people ... with severe, malignant osteopetrosis (an inherited bone disease). Interferon gamma-1b is in a class of medications ...

  16. 5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats.

    PubMed

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

    2015-09-01

    Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3±1.0, 43.7±2.7 and 66.7±4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125-0.1μg/kg each) or l-694,247 (5-HT1D agonist; 0.0125μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K(+) channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release. PMID:26003124

  17. Functional characterization of 5-HT1D autoreceptors on the modulation of 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex.

    PubMed Central

    el Mansari, M.; Blier, P.

    1996-01-01

    1. The aims of the present study were (i) to characterize further the pharmacology of 5-HT1D autoreceptors modulating 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex; (ii) to determine whether 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones; (iii) to determine whether 5-HT1D autoreceptors are coupled to G proteins; and (iv) to assess their sensitivity following long-term 5-HT reuptake blockade and inhibition of type-A monoamine oxidase. 2. In mesencephalic raphe, hippocampus and frontal cortex slices, the 5-HT1D/1B receptor agonist, sumatriptan and the 5-HT1 receptor agonist, 5-methoxytryptamine (5-MeOT) but not the 5-HT1B receptor agonist, CP93129, inhibited electrically the evoked release of [3H]-5-HT in a concentration-dependent manner. This effect was antagonized by the 5-HT1D/1B receptor antagonist GR127935 in the three structures, but not by the 5-HT1A receptor antagonist, (+)-WAY100635 in mesencephalic raphe slices. These results confirm the presence of functional 5-HT1D autoreceptors controlling 5-HT release within the mesencephalic raphe as well as in terminal regions. 3. The inhibitory effect of sumatriptan on K(+)-evoked release of [3H]-5-HT was not reduced by the addition of the Na+ channel blocker, tetrodotoxin to the superfusion medium, suggesting that these 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones and may be considered autoreceptors. 4. The in vitro treatment with the alkylating agent N-ethylmaleimide (NEM) was used to determine whether these 5-HT1D autoreceptors are coupled to G proteins. The inhibitory effect of sumatriptan on electrically evoked release of [3H]-5-HT was attenuated in NEM-pretreated slices from mesencephalic raphe, hippocampus and frontal cortex, indicating that the 5-HT1D autoreceptors activated by sumatriptan are coupled to G proteins in these three structures. Taken together with our previous results, this suggests that, in addition to the 5

  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. α1B-Adrenergic receptor signaling controls circadian expression of Tnfrsf11b by regulating clock genes in osteoblasts

    PubMed Central

    Hirai, Takao; Tanaka, Kenjiro; Togari, Akifumi

    2015-01-01

    ABSTRACT Circadian clocks are endogenous and biological oscillations that occur with a period of <24 h. In mammals, the central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN) and is linked to peripheral tissues through neural and hormonal signals. In the present study, we investigated the physiological function of the molecular clock on bone remodeling. The results of loss-of-function and gain-of-function experiments both indicated that the rhythmic expression of Tnfrsf11b, which encodes osteoprotegerin (OPG), was regulated by Bmal1 in MC3T3-E1 cells. We also showed that REV-ERBα negatively regulated Tnfrsf11b as well as Bmal1 in MC3T3-E1 cells. We systematically investigated the relationship between the sympathetic nervous system and the circadian clock in osteoblasts. The administration of phenylephrine, a nonspecific α1-adrenergic receptor (AR) agonist, stimulated the expression of Tnfrsf11b, whereas the genetic ablation of α1B-AR signaling led to the alteration of Tnfrsf11b expression concomitant with Bmal1 and Per2 in bone. Thus, this study demonstrated that the circadian regulation of Tnfrsf11b was regulated by the clock genes encoding REV-ERBα (Nr1d1) and Bmal1 (Bmal1, also known as Arntl), which are components of the core loop of the circadian clock in osteoblasts. PMID:26453621

  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 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

  3. 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

  4. 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....

  5. 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,...

  6. 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...

  7. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  8. 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....

  9. 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)...

  10. 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...

  11. 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...

  12. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 1 2012-01-01 2012-01-01 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 the various USDA agencies shall be planned, developed, and implemented so as to achieve the goals...

  13. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 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 the various USDA agencies shall be planned, developed, and implemented so as to achieve the goals...

  14. 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 the various USDA agencies shall be planned, developed, and implemented so as to achieve the goals...

  15. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 1 2014-01-01 2014-01-01 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 the various USDA agencies shall be planned, developed, and implemented so as to achieve the goals...

  16. 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. (a) The following are categories of activities which have been determined not to have a significant individual or cumulative effect on the...

  17. 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 the various USDA agencies shall be planned, developed, and implemented so as to achieve the goals and to follow the procedures declared by...

  18. Processing TES Level-1B Data

    NASA Technical Reports Server (NTRS)

    DeBaca, Richard C.; Sarkissian, Edwin; Madatyan, Mariyetta; Shepard, Douglas; Gluck, Scott; Apolinski, Mark; McDuffie, James; Tremblay, Dennis

    2006-01-01

    TES L1B Subsystem is a computer program that performs several functions for the Tropospheric Emission Spectrometer (TES). The term "L1B" (an abbreviation of "level 1B"), refers to data, specific to the TES, on radiometric calibrated spectral radiances and their corresponding noise equivalent spectral radiances (NESRs), plus ancillary geolocation, quality, and engineering data. The functions performed by TES L1B Subsystem include shear analysis, monitoring of signal levels, detection of ice build-up, and phase correction and radiometric and spectral calibration of TES target data. Also, the program computes NESRs for target spectra, writes scientific TES level-1B data to hierarchical- data-format (HDF) files for public distribution, computes brightness temperatures, and quantifies interpixel signal variability for the purpose of first-order cloud and heterogeneous land screening by the level-2 software summarized in the immediately following article. This program uses an in-house-developed algorithm, called "NUSRT," to correct instrument line-shape factors.

  19. 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...) that were published in the Federal Register on Friday, December 18, 2009 (74 FR 67053) providing... Internal Revenue Service 26 CFR Part 1 RIN 1545-BF83 Corporate Reorganizations; Distributions...

  20. Clinical pharmacokinetics of almotriptan, a serotonin 5-HT(1B/1D) receptor agonist for the treatment of migraine.

    PubMed

    McEnroe, Janet D; Fleishaker, Joseph C

    2005-01-01

    The pharmacokinetics of almotriptan are linear over a range of oral doses up to 200mg in healthy volunteers. The compound has a half-life of approximately 3 hours. Almotriptan is well absorbed after oral administration and the mean absolute bioavailability is 69.1%. Maximal plasma concentrations are achieved between 1.5 and 4 hours after dose administration; however, within 1 hour after administration, plasma concentrations are approximately 68% of the value at 3 hours after administration. Food does not significantly affect almotriptan absorption. Almotriptan is not highly protein bound and is extensively distributed in the body. Approximately 50% of an almotriptan dose is excreted unchanged in the urine; this is the predominant single mechanism of elimination. Renal clearance is mediated, in part, through active tubular secretion, while the balance of the almotriptan dose is metabolised to inactive compounds. The predominant route of metabolism is via monoamine oxidase-A, and cytochrome P450 (CYP) mediated oxidation (via CYP3A4 and CYP2D6) occurs to a minor extent. Almotriptan clearance is moderately reduced in elderly subjects, but the magnitude of this effect does not warrant a dose reduction. Sex has no significant effect on almotriptan pharmacokinetics. Almotriptan pharmacokinetic parameters do not differ between adolescents and adults, and absorption is not affected during a migraine attack. As expected, renal dysfunction results in reduced clearance of almotriptan. Patients with moderate-to-severe renal dysfunction should use the lowest dose of almotriptan and the total daily dose should not exceed 12.5 mg. Similar dosage recommendations are valid for patients with hepatic impairment, based on the clearance mechanisms for almotriptan. Drug-drug interaction studies were conducted between almotriptan and the following compounds: fluoxetine, moclobemide, propranolol, verapamil and ketoconazole. No significant pharmacokinetic or pharmacodynamic interactions with almotriptan were observed for fluoxetine or propranolol. Almotriptan clearance was reduced, to a modest degree, by moclobemide and verapamil, which was consistent with the contribution of monoamine oxidase-A and CYP3A4 to the metabolic clearance of almotriptan. Although ketoconazole has a greater effect on almotriptan clearance than verapamil, no dosage adjustment is required when almotriptan is given with these drugs. PMID:15762767

  1. Gene profiling of growth factor independence 1B gene (Gfi-1B) in leukemic cells.

    PubMed

    Koldehoff, Michael; Zakrzewski, Johannes L; Klein-Hitpass, Ludger; Beelen, Dietrich W; Elmaagacli, Ahmet H

    2008-01-01

    To investigate the molecular effects of growth factor independence 1B (Gfi-1B), a transcription factor essential for the development of hematopoietic cells and differentiation of erythroid and megakaryocytic lineages, the naturally Gfi-1B overexpressing cell line K562 was cultured in the presence of Gfi-1B target-specific small interfering RNA (siRNA). SiRNA treatment significantly knocked down Gfi-1B expression with an efficiency of nearly 90%. Analysis of the siRNA silencing protocol by colony-forming units ensured that it was not cytotoxic. Samples from Gfi-1B overexpressing cells and cells with knocked-down Gfi-1B were analyzed by oligonucleotide microarray technology and based upon rigorous statistical analysis of the data; relevant genes were chosen for confirmation by reserve transcriptase-polymerase chain reaction, including MYC/MYCBP and CDKN1A. Interestingly, transcripts within components of the signalling cascade of immune cells (PLD1, LAMP1, HSP90, IL6ST), of the tyrosine kinase pathway (TPR, RAC3) and of the transcription factors (RAC3, CEP290, JEM-1, ATR, MYC, SMC3, RARA, RBBP6) were found to be differentially expressed in Gfi-1B overexpressing cells compared to controls. Individual genes such as ZDHHC17, DMXL1, ZNF292 were found to be upregulated in Gfi-1B overexpressing cells. In addition, down-regulated transcripts showed cell signaling transcripts for several chemokine gene members including GNAL, CXCL5, GNL3L, GPR65, TMEM30, BCL11B and transcription factors (GTF2H3, ATXN3). In conclusion, several essential cell signalling factors, as well as transcriptional and post-translational regulation genes were differentially expressed in cells that overexpressed Gfi-1B compared to control cells with knocked-down Gfi-1B. Our data indicate that Gfi-1B signalling is important for commitment and maturation of hematopoietic cell populations. PMID:18224412

  2. Experimental Reproduction of Type 1B Chondrules

    NASA Technical Reports Server (NTRS)

    Lofgren, G. E.; Le, L.

    2002-01-01

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

  3. Aldo-keto Reductase 1B15 (AKR1B15)

    PubMed Central

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

    2015-01-01

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

  4. Vought F4U-1D Corsair

    NASA Technical Reports Server (NTRS)

    1945-01-01

    Vought F4U-1D Corsair: In February and March of 1945 this Corsair was examined in the NACA's 30 x 60 Full Scale Tunnel at Langley Field. The F4U-1D has rockets mounted on its wings for this test. After installation and during testing, the wings would be lowered to their flight position.

  5. 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.

  6. Regulation of CD1d expression by murine tumor cells: escape from immunosurveillance or alternate target molecules?

    PubMed

    Fiedler, Tim; Walter, Wolfgang; Reichert, Torsten E; Maeurer, Markus J

    2002-03-20

    alpha beta+ TCR T cells recognize peptide fragments displayed by MHC-class I or -class II molecules. Recently, additional mechanisms of antigen recognition by T cells have been identified, including CD1-mediated presentation of nonpeptide antigens. Only a limited number of CD1 antigens is retained in the mouse, i.e., the group II CD1 antigens, which are split into CD1D1 and CD1d2. Several T cell subsets have been shown to interact with murine CD1 antigens, including NK cells or "natural T cells" with the invariant V alpha 14 J alpha 281 TCR chain. Even if TAP defects may prevent classical endogenous antigen presentation in tumor cell lines, antigen presentation via CD1 is still functional. Therefore, CD1-mediated recognition of transformed cells by NK cells or "natural T cells" may represent an alternative way for immune surveillance. CD1 cell surface expression in murine tumor cell lines of different histology, including the B cell lymphoma A20, macrophage cell lines J774 and P388D1, mastocytoma P815, thymoma EL-4, melanoma B16, colon adenocarcinoma MC-38 and renal carcinoma Renca is regulated by Th1- (IFN-gamma), Th2- (IL-4, IL-10 and vIL-10) or GM-CSF (Th1/Th2) cytokines, depending on the tumor histology. In order to distinguish between CD1D1 and CD1d2 molecules, we examined differential expression of these CD1 isoforms by ratio RT-PCR: A20, EL-4, P815 and MC-38 cells exclusively express CD1D1 transcripts but not CD1D2 mRNA independent of cytokine treatment. Decreased CD1d expression leads to reduced immune recognition of CD1d+ tumor cells by freshly isolated NK1.1(+) effector cells as defined by cytolysis and IFN-gamma release. Thus, modulation of CD1 expression on tumor cells by cytokines may be advantageous to drive cellular anti-tumor antigen directed immune responses directed against TAP-independent, non-classical MHC restricting molecules. PMID:11920590

  7. 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.

  8. 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.

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

    Atmospheric Science Data Center

    2013-04-01

    ... Mode L1B2 data processing. Added ProductVersion Attribute to metadata of all products. New ancillary files: ... and AN data, as well as Band-to-Band transform fix. ROI Image Matching improvements to blunder detection algorithm and to Image Coordinate Correction. New ancillary files: ...

  10. 1D ferrimagnetism in homometallic chains

    NASA Astrophysics Data System (ADS)

    Coronado, E.; Gómez-García, C. J.; Borrás-Almenar, J. J.

    1990-05-01

    The magnetic properties of the cobalt zigzag chain Co(bpy)(NCS)2 (bpy=2,2'-bipyridine) are discussed on the basis of an Ising-chain model that takes into account alternating Landé factors. It is emphasized, for the first time, that a homometallic chain containing only one type of site can give rise to a 1D ferrimagneticlike behavior.

  11. 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.

  12. 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. PMID:25529606

  13. Preparation of 1D nanostructures using biomolecules

    NASA Astrophysics Data System (ADS)

    Pruneanu, Stela; Olenic, Liliana; Barbu Tudoran, Lucian; Kacso, Irina; Farha Al-Said, Said A.; Hassanien, Reda; Houlton, Andrew; Horrocks, Benjamin R.

    2009-08-01

    In this paper we have shown that one-dimensional (1D) particle arrays can be obtained using biomolecules, like DNA or amino-acids. Nano-arrays of silver and gold were prepared in a single-step synthesis, by exploiting the binding abilities of λ-DNA and L-Arginine. The morphology and optical properties of these nanostructures were investigated using AFM, TEM and UV-Vis absorption spectroscopy.

  14. 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.

  15. Coalescence phenomena in 1D silver nanostructures

    NASA Astrophysics Data System (ADS)

    Gutiérrez-Wing, C.; Pérez-Alvarez, M.; Mondragón-Galicia, G.; Arenas-Alatorre, J.; Gutiérrez-Wing, M. T.; Henk, M. C.; Negulescu, I. I.; Rusch, K. A.

    2009-07-01

    Different coalescence processes on 1D silver nanostructures synthesized by a PVP assisted reaction in ethylene glycol at 160 °C were studied experimentally and theoretically. Analysis by TEM and HRTEM shows different defects found on the body of these materials, suggesting that they were induced by previous coalescence processes in the synthesis stage. TEM observations showed that irradiation with the electron beam eliminates the boundaries formed near the edges of the structures, suggesting that this process can be carried out by the application of other means of energy (i.e. thermal). These results were also confirmed by theoretical calculations by Monte Carlo simulations using a Sutton-Chen potential. A theoretical study by molecular dynamics simulation of the different coalescence processes on 1D silver nanostructures is presented, showing a surface energy driven sequence followed to form the final coalesced structure. Calculations were made at 1000-1300 K, which is near the melting temperature of silver (1234 K). Based on these results, it is proposed that 1D nanostructures can grow through a secondary mechanism based on coalescence, without losing their dimensionality.

  16. 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...

  17. 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...

  18. 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...

  19. 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  1. 18 CFR 1b.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...

  2. 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....

  3. 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....

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  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. The Alpha-1D Is the Predominant Alpha-1-Adrenergic Receptor Subtype in Human Epicardial Coronary Arteries

    PubMed Central

    Jensen, Brian C.; Swigart, Philip M.; Laden, Marie-Eve; DeMarco, Teresa; Hoopes, Charles; Simpson, Paul C.

    2009-01-01

    Objectives The goal was to identify alpha-1-adrenergic receptor (α1-AR) subtypes in human coronary arteries. Background The α1-ARs regulate human coronary blood flow. α1-ARs exist as three molecular subtypes, α1A, α1B, and α1D, and the α1D subtype mediates coronary vasoconstriction in the mouse. However, the α1A is thought to be the only subtype in human coronary arteries. Methods We obtained human epicardial coronary arteries and left ventricular (LV) myocardium from 19 transplant recipients and 6 unused donors (age 19–70 years; 68% male; 32% with coronary artery disease). We cultured coronary rings and human coronary smooth muscle cells. We assayed α1- and β-AR subtype mRNAs by quantitative real-time reverse transcription PCR; and subtype proteins, by radioligand binding and ERK activation. Results The α1D subtype was 85% of total coronary α1-AR mRNA and 75% of total α1-AR protein, and α1D stimulation activated ERK. In contrast, the α1D was low in LV myocardium. Total coronary α1-AR levels were one-third of β-ARs, which were 99% the β2 subtype. Conclusions The α1D subtype is predominant and functional in human epicardial coronary arteries, whereas the α1A and α1B are present at very low levels. This distribution is similar to the mouse, where myocardial α1A and α1B-ARs mediate beneficial functional responses, and coronary α1Ds mediate vasoconstriction. Thus, α1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of non-selective α1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial α1A and/or α1B-AR signaling without causing coronary vasoconstriction. PMID:19761933

  14. Do mutations in SCN1B cause Dravet syndrome?

    PubMed

    Kim, Young Ok; Dibbens, Leanne; Marini, Carla; Suls, Arvid; Chemaly, Nicole; Mei, Davide; McMahon, Jacinta M; Iona, Xenia; Berkovic, Samuel F; De Jonghe, Peter; Guerrini, Renzo; Nabbout, Rima; Scheffer, Ingrid E

    2013-01-01

    A homozygous SCN1B mutation was previously identified in a patient with early onset epileptic encephalopathy (EOEE) described as Dravet syndrome (DS) despite a more severe phenotype than DS. We investigated whether SCN1B mutations are a common cause of DS. Patients with DS who did not have a SCN1A sequencing mutation or copy number variation were studied. Genomic DNA was Sanger sequenced for mutations in the 6 exons of SCN1B. In 54 patients with DS recruited from four centres, no SCN1B mutations were identified. SCN1B mutation is not a common cause of DS. PMID:23182416

  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. Social dominance in male vasopressin 1b receptor knockout mice.

    PubMed

    Caldwell, Heather K; Dike, Obianuju E; Stevenson, Erica L; Storck, Kathryn; Young, W Scott

    2010-07-01

    We have previously reported that mice with a targeted disruption of their vasopressin 1b receptor gene, Avpr1b, have mild impairments in social recognition and reduced aggression. The reductions in aggression are limited to social forms of aggression, i.e., maternal and inter-male aggression, while predatory aggression remains unaffected. To further clarify the role of the Avpr1b in the regulation of social behavior we first examined anxiety-like and depression-like behaviors in Avpr1b knockout (Avpr1b -/-) mice. We then went on to test the ability of Avpr1b -/- mice to form dominance hierarchies. No major differences were found between Avpr1b -/- and wildtype mice in anxiety-like behaviors, as measured using an elevated plus maze and an open field test, or depression-like behaviors, as measured using a forced swim test. In the social dominance study we found that Avpr1b -/- mice are able to form dominance hierarchies, though in early hierarchy formation dominant Avpr1b -/- mice display significantly more mounting behavior on Day 1 of testing compared to wildtype controls. Further, non-socially dominant Avpr1b -/- mice spend less time engaged in attack behavior than wildtype controls. These findings suggest that while Avpr1b -/- mice may be able to form dominance hierarchies they appear to employ alternate strategies. PMID:20298692

  17. 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

  18. 1-D EQUILIBRIUM DISCRETE DIFFUSION MONTE CARLO

    SciTech Connect

    T. EVANS; ET AL

    2000-08-01

    We present a new hybrid Monte Carlo method for 1-D equilibrium diffusion problems in which the radiation field coexists with matter in local thermodynamic equilibrium. This method, the Equilibrium Discrete Diffusion Monte Carlo (EqDDMC) method, combines Monte Carlo particles with spatially discrete diffusion solutions. We verify the EqDDMC method with computational results from three slab problems. The EqDDMC method represents an incremental step toward applying this hybrid methodology to non-equilibrium diffusion, where it could be simultaneously coupled to Monte Carlo transport.

  19. Positional identification of RT1-B (HLA-DQ) as susceptibility locus for autoimmune arthritis.

    PubMed

    Haag, Sabrina; Tuncel, Jonatan; Thordardottir, Soley; Mason, Daniel E; Yau, Anthony C Y; Dobritzsch, Doreen; Bäcklund, Johan; Peters, Eric C; Holmdahl, Rikard

    2015-03-15

    Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA. PMID:25672758

  20. 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.

  1. New Hippolide Derivatives with Protein Tyrosine Phosphatase 1B Inhibitory Activity from the Marine Sponge Hippospongia lachne

    PubMed Central

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

    2014-01-01

    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. PMID:25007159

  2. 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.

  3. 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

  4. 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. PMID:18079022

  5. MAN1B1 Deficiency: An Unexpected CDG-II

    PubMed Central

    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

  6. 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.

  7. [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

  8. 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

  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. 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

  11. 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... person, such person shall have the right to appear on the record; and in addition to the rights...

  12. 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... person, such person shall have the right to appear on the record; and in addition to the rights...

  13. 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... person, such person shall have the right to appear on the record; and in addition to the rights...

  14. 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... person, such person shall have the right to appear on the record; and in addition to the rights...

  15. ALDH1B1 links alcohol consumption and diabetes.

    PubMed

    Singh, Surendra; Chen, Ying; Matsumoto, Akiko; Orlicky, David J; Dong, Hongbin; Thompson, David C; Vasiliou, Vasilis

    2015-08-01

    Aldehyde dehydrogenase 1B1 (ALDH1B1) is a mitochondrial enzyme sharing 65% and 72% sequence identity with ALDH1A1 and ALDH2 proteins, respectively. Compared to the latter two ALDH isozymes, little is known about the physiological functions of ALDH1B1. Studies in humans indicate that ALDH1B1 may be associated with alcohol sensitivity and stem cells. Our recent in vitro studies using human ALDH1B1 showed that it metabolizes acetaldehyde and retinaldehyde. To investigate the in vivo role of ALDH1B1, we generated and characterized a global Aldh1b1 knockout mouse line. These knockout (KO) mice are fertile and show overtly good health. However, ethanol pharmacokinetic analysis revealed ∼40% increase in blood acetaldehyde levels in KO mice. Interestingly, the KO mice exhibited higher fasting blood glucose levels. Collectively, we show for the first time the functional in vivo role of ALDH1B1 in acetaldehyde metabolism and in maintaining glucose homeostasis. This mouse model is a valuable tool to investigate the mechanism by which alcohol may promote the development of diabetes. PMID:26086111

  16. 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... confidential treatment. Any person compelled to produce documents in an investigation may claim that some...

  17. 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... confidential treatment. Any person compelled to produce documents in an investigation may claim that some...

  18. 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... confidential treatment. Any person compelled to produce documents in an investigation may claim that some...

  19. 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... confidential treatment. Any person compelled to produce documents in an investigation may claim that some...

  20. 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... confidential treatment. Any person compelled to produce documents in an investigation may claim that some...

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

    PubMed

    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 (K m) =41.5 μM, maximum uptake rate (V max) =46.2 pmol/minute, and intrinsic clearance (CL int) =1.11 μL/minute. OATP1B1- and OATP1B3-mediated catalposide uptake also showed concentration dependency, with low CL int 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

  2. 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

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

    PubMed

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

    2016-08-01

    We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Cε, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 hyperalgesia. The prolongation of PGE2 hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming. PMID:27075428

  4. 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

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

    PubMed

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

    2016-08-01

    Artemisia roxburghiana is used in traditional medicine for treating various diseases including diabetes. The present study was designed to evaluate the antidiabetic potential of active constituents by using protein tyrosine phosphatase 1B (PTP1B) as a validated target for management of diabetes. Various compounds were isolated as active principles from the crude methanolic extract of aerial parts of A. roxburghiana. All compounds were screened for PTP1B inhibitory activity. Molecular docking simulations were performed to investigate the mechanism behind PTP1B inhibition of the isolated compound and positive control, ursolic acid. Betulinic acid, betulin and taraxeryl acetate were the active PTP1B principles with IC50 values 3.49 ± 0.02, 4.17 ± 0.03 and 87.52 ± 0.03 µM, respectively. Molecular docking studies showed significant molecular interactions of the triterpene inhibitors with Gly220, Cys215, Gly218 and Asp48 inside the active site of PTP1B. The antidiabetic activity of A. roxburghiana could be attributed due to PTP1B inhibition by its triterpene constituents, betulin, betulinic acid and taraxeryl acetate. Computational insights of this study revealed that the C-3 and C-17 positions of the compounds needs extensive optimization for the development of new lead compounds. PMID:26118418

  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. Identification of Bidentate Salicylic Acid Inhibitors of PTP1B.

    PubMed

    Haftchenary, Sina; Jouk, Andriana O; Aubry, Isabelle; Lewis, Andrew M; Landry, Melissa; Ball, Daniel P; Shouksmith, Andrew E; Collins, Catherine V; Tremblay, Michel L; Gunning, Patrick T

    2015-09-10

    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

  8. MISR Level 1B2 Terrain Data (MI1B2T_V2)

    NASA Technical Reports Server (NTRS)

    Diner, David J. (Principal Investigator)

    The MISR instrument consists of nine pushbroom cameras which measure radiance in four spectral bands. Global coverage is achieved in nine days. The cameras are arranged with one camera pointing toward the nadir, four cameras pointing forward and four cameras pointing aftward. It takes 7 minutes for all nine cameras to view the same surface location. The view angles relative to the surface reference ellipsoid, are 0, 26.1, 45.6, 60.0, and 70.5 degrees. The spectral band shapes are nominally gaussian, centered at 443, 555, 670, and 865 nm. The Terrain data are re-projected to the terrain altitude. In this product, surface data from all cameras will appear in the same geographic location. Thus, this product is the primary input to Level 2 aerosol/surface processing, which requires co-registration of the L1B2 imagery at the surface. Clouds will still be displaced due to their elevation above the surface, but this time with respect to the terrain rather than the ellipsoid. (The mountain location T is now assigned the geographic location at T, and the Cloud at F appears at the geographic location T.) In Level 2 aerosol/surface processing, algorithms are applied to screen out the clouds. Terrain data only exist for MISR blocks containing some land. [Location=GLOBAL LAND] [Temporal_Coverage: Start_Date=2000-02-24; Stop_Date=] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=563.2 km (cross-track); Longitude_Resolution=140.8 km (along-track).; Temporal_Resolution=about 15 orbits/day; Temporal_Resolution_Range=about 15 orbits/day].

  9. 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

  10. The COBRA-1B irradiation experiment in EBR-II

    SciTech Connect

    Tsai, H.; Hins, A.G.; Strain, R.V.; Smith, D.L.

    1994-09-01

    The objective of the forthcoming COBRA-1B experiment in EBR-II is to evaluate the effects of fast neutron irradiation on the physical and mechanical properties of candidate fusion structural materials. Of special interest in this experiment will be ITER-relevant temperature and exposure for the test specimens. Approximately 50% of the irradiation test volume will be devoted to vanadium-alloy specimens. Design of the COBRA-1B irradiation experiment began in this reporting period and is in progress. The target reactor insertion date for COBRA-1B is September 1994. Technical and programmatic feasibility approval for the experiment has been granted by EBR-II Operations.

  11. 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.

  12. 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

  13. Understanding 1D Electrostatic Dust Levitation

    NASA Astrophysics Data System (ADS)

    Hartzell, C. M.; Scheeres, D. J.

    2011-12-01

    Electrostatically-dominated dust motion has been hypothesized since the Lunar Horizon Glow was observed by the Surveyor spacecraft. The hypothesized occurence of this phenomenon was naturally extended to asteroids due to their small gravities. Additionally, it has been suggested that the dust ponds observed on Eros by the NEAR mission may be created by electrostatically-dominated dust transport. Previous attempts to numerically model dust motion on the Moon and Eros have been stymied by poorly understood dust launching mechanisms. As a result, the initial velocity and charge of dust particles used in numerical simulations may or may not have any relevance to the actual conditions occurring in situ. It has been seen that properly tuned initial states (velocity and charge) result in dust particles levitating above the surface in both 1D and 2D simulations. Levitation is of interest to planetary scientists since it provides a way to quickly redistribute the surface dust particles over a body. However, there is currently no method to predict whether or not a certain initial state will result in levitation. We have developed a method to provide constraints on the initial states that result in levitation as a function of dust particle size and central body gravity. Additionally, our method can be applied to several models of the plasma sheath. Thus, we limit the guesswork involved in determining which initial conditions result in levitation. We provide a more detailed understanding of levitation phenomena couched in terms of the commonly recognized spring-mass system. This method of understanding dust motion removes the dependency on the launching mechanism, which remains fraught with controversy. Once a feasible dust launching mechanism is identified (be it micrometeoroid bombardment or electrostatic lofting), our method will allow the community to quickly ascertain if dust levitation will occur in situ or if it is simply a numerical artifact. In addition to

  14. Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver.

    PubMed

    Thomson, Margaret M S; Hines, Ronald N; Schuetz, Erin G; Meibohm, Bernd

    2016-07-01

    Determining appropriate pharmacotherapy in young children can be challenging due to uncertainties in the development of drug disposition pathways. With knowledge of the ontogeny of drug-metabolizing enzymes and an emerging focus on drug transporters, the developmental pattern of the uptake transporters organic anion transporting polypeptide (OATP) 1B1 and 1B3 was assessed by relative protein quantification using Western blotting in 80 human pediatric liver specimens covering an age range from 9 days to 12 years. OATP1B3 exhibited high expression at birth, which declined over the first months of life, and then increased again in the preadolescent period. In comparison with children 6-12 years of age, the relative protein expression of highly glycosylated (total) OATP1B3 was 235% (357%) in children <3 months of age, 33% (64%) in the age group from 3 months to 2 years, and 50% (59%) in children 2-6 years of age. The fraction of highly glycosylated to total OATP1B3 increased with age, indicating ontogenic processes not only at the transcriptional level but also at the post-translational level. Similar to OATP1B3, OATP1B1 showed high interindividual variability in relative protein expression but no statistically significant difference among the studied age groups. PMID:27098745

  15. MISR Level 1B1 Radiance Data (MI1B1_V2)

    NASA Technical Reports Server (NTRS)

    Diner, David J. (Principal Investigator)

    summary, the Level 1B1 Product contains the Data Numbers (DNs) radiometrically-scaled to radiances with no geometric resampling. [Temporal_Coverage: Start_Date=2000-02-24; Stop_Date=] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=1.1 km; Longitude_Resolution=1.1 km; Temporal_Resolution=about 15 orbits/day; Temporal_Resolution_Range=about 15 orbits/day].

  16. CX3CR1(+) B Cells Show Immune Suppressor Properties*

    PubMed Central

    Wu, Zhiqiang

    2014-01-01

    The immune regulatory functions of B cells are not fully understood yet. The present study aims to characterize a subtype of B cells that expresses CX3CR1. In this study, peripheral blood samples were collected from patients with food allergies and healthy subjects. Peripheral B cells were analyzed by flow cytometry. T cell proliferation was assessed by carboxyfluorescein succinimidyl ester dilution assay. The results showed that the CX3CR1+ B cells were detected in the peripheral blood samples of healthy subjects and were significantly less in patients with food allergies. CX3CR1+ B cells expressed high levels of TGF-β and integrin αvβ6. CX3CR1+ B cells could efficiently suppress other effector CD4+ T cell activation. We conclude that human peripheral CX3CR1+ B cells have immune suppressor properties. PMID:24970890

  17. 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

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

    PubMed

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

    2014-06-01

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

  19. Novel chromenedione derivatives displaying inhibition of protein tyrosine phosphatase 1B (PTP1B) from Flemingia philippinensis.

    PubMed

    Wang, Yan; Yuk, Heung Joo; Kim, Jeong Yoon; Kim, Dae Wook; Song, Yeong Hun; Tan, Xue Fei; Curtis-Long, Marcus J; Park, Ki Hun

    2016-01-15

    Protein tyrosine phosphatase 1B (PTP1B) is an important target to treat obesity and diabetes due to its key roles in insulin and leptin signaling. The MeOH extracts of the root bark of Flemingia philippinensis yielded eight inhibitory molecules (1-8) capable of targeting PTP1B. Three of them were identified to be novel compounds, philippin A (1), philippin B (2), and philippin C (3) which have a rare 3-phenylpropanoyl chromenedione skeleton. The other compounds (4-8) were known prenylated isoflavones. All compounds (1-8) inhibited PTP1B in a dose dependent manner with IC50s ranging between 2.4 and 29.4μM. The most potent compound emerged to be prenylated isoflavone 5 (IC50=2.4μM). In kinetic studies, chromenedione derivatives (1-3) emerged to be reversible, competitive inhibitors, whereas prenylated isoflavones (5-8) were noncompetitive inhibitors. PMID:26704263

  20. 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

  1. 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

  2. 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. PMID:26650568

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. Oncolytic Replication of E1b-Deleted Adenoviruses

    PubMed Central

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

    2015-01-01

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

  11. Oncolytic Replication of E1b-Deleted Adenoviruses.

    PubMed

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

    2015-11-01

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

  12. The α1B/D-adrenoceptor knockout mouse permits isolation of the vascular α1A-adrenoceptor and elucidates its relationship to the other subtypes

    PubMed Central

    Methven, L; McBride, M; Wallace, GA; McGrath, JC

    2009-01-01

    Background and purpose: Mesenteric and carotid arteries from the α1B/D-adrenoceptor knockout (α1B/D-KO) were employed to isolate α1A-adrenoceptor pharmacology and location and to reveal these features in the wild-type (WT) mouse. Experimental approach: Functional pharmacology by wire myography and receptor localization by confocal microscopy, using the fluorescent α1-adrenoceptor ligand BODIPY FL-Prazosin (QAPB), on mesenteric (an ‘α1A-adrenoceptor’ tissue) and carotid (an ‘α1D-adrenoceptor’ tissue) arteries. Key results: α1B/D-KO mesenteric arteries showed straightforward α1A-adrenoceptor agonist/antagonist pharmacology. WT had complex pharmacology with α1A- and α1D-adrenoceptor components. α1B/D-KO had a larger α1A-adrenoceptor response suggesting compensatory up-regulation: no increase in fluorescent ligand binding suggests up-regulation of signalling. α1B/D-KO carotid arteries had low efficacy α1A-adrenoceptor responses. WT had complex pharmacology consistent with co-activation of all three subtypes. Fluorescent binding had straightforward α1A-adrenoceptor characteristics in both arteries of α1B/D-KO. Fluorescent binding varied between cells in relative intracellular and surface distribution. Total fluorescence was reduced in the α1B/D-KO due to fewer smooth muscle cells showing fluorescent binding. WT binding was greater and sensitive to α1A- and α1D-adrenoceptor antagonists. Conclusions and implications: The straightforward pharmacology and fluorescent binding in the α1B/D-KO was used to interpret the properties of the α1A-adrenoceptor in the WT. Reduced total fluorescence in α1B/D-KO arteries, despite a clear difference in the functionally dominant subtype, indicates that measurement of receptor protein is unlikely to correlate with function. Fewer cells bound QAPB in the α1B/D-KO suggesting different cellular phenotypes of α1A-adrenoceptor exist. The α1B/D-KO provides robust assays for the α1A-adrenoceptor and takes us

  13. 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.

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. 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... COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to submit statements. Any person may, at any time during the course of an investigation, submit documents,...

  20. PTP1B: mediating ROS signaling to silence genes

    PubMed Central

    Boivin, Benoit; Tonks, Nicholas K.

    2015-01-01

    Numerous studies have shown that normal cells often respond to the activation of oncogenes by undergoing reactive oxygen species-dependent induction of senescence. Here, we discuss our recent publication identifying protein tyrosine phosphatase PTP1B as an important redox-controlled checkpoint for senescence downstream of oncogenic RAS.

  1. AIRS Level 1b Algorithm Theoretical Basis Document

    NASA Technical Reports Server (NTRS)

    Aumann, H.; Gregorich, D.; Gaiser, S.; Hagan, D.; Pagano, T.; Ting, D.

    2000-01-01

    The level 1b Algorithm Theoretical Basis Document (ATBD) describes the theoretical bases of the algorithms used to convert the raw detector output (data numbers) from the Atmospheric Infrared Sounder (AIRS), the Advanced Microwave Sounding Unit (AMSU) and Humidity Sounder Brazil (HSB) to physical radiance units and, in the case of AIRS, perform in-orbit spectral calibrations.

  2. Leukocyte transcellular diapedesis: Rap1b is in control

    PubMed Central

    Filippi, Marie-Dominique

    2015-01-01

    The neutrophil transmigration across the blood endothelial cell barrier represents the prerequisite step of innate inflammation. It is well known that neutrophils cross the endothelial barrier by transmigrating at the endothelial cell junction (‘paracellular’). However, in vivo and in vitro evidence have clearly demonstrated occurrence of an alternate mode of migration directly through the endothelial cell body (‘transcellular’). Despite our knowledge on mechanisms of transendothelial migration, it remains unclear which factors determine distinct modes of migration. We recently found that the Ras-like Rap1b GTPase limits neutrophil transcellular migration. Rap1b restrains transcellular migration by suppressing Akt-driven invasive protrusions while leaving the paracellular route unaffected. Furthermore, Rap1b limits neutrophil tissue infiltration in mice and prevents hyper susceptibility to endotoxin shock. These findings uncover a novel role for Rap1b in neutrophil migration and inflammation. Importantly, they offer emerging evidences that paracellular and transcellular migration of neutrophils are regulated by separate mechanisms. Here, we discuss the mechanisms of neutrophil transmigration and their clinical importance for vascular integrity and innate inflammation. PMID:26451346

  3. 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.

  4. 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

  5. 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.

  6. 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... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and...

  7. 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... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and...

  8. 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... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and...

  9. 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

  10. Dolphin: a tool for automatic targeted metabolite profiling using 1D and 2D (1)H-NMR data.

    PubMed

    Gómez, Josep; Brezmes, Jesús; Mallol, Roger; Rodríguez, Miguel A; Vinaixa, Maria; Salek, Reza M; Correig, Xavier; Cañellas, Nicolau

    2014-12-01

    One of the main challenges in nuclear magnetic resonance (NMR) metabolomics is to obtain valuable metabolic information from large datasets of raw NMR spectra in a high throughput, automatic, and reproducible way. To date, established software packages used to match and quantify metabolites in NMR spectra remain mostly manually operated, leading to low resolution results and subject to inconsistencies not attributable to the NMR technique itself. Here, we introduce a new software package, called Dolphin, able to automatically quantify a set of target metabolites in multiple sample measurements using an approach based on 1D and 2D NMR techniques to overcome the inherent limitations of 1D (1)H-NMR spectra in metabolomics. Dolphin takes advantage of the 2D J-resolved NMR spectroscopy signal dispersion to avoid inconsistencies in signal position detection, enhancing the reliability and confidence in metabolite matching. Furthermore, in order to improve accuracy in quantification, Dolphin uses 2D NMR spectra to obtain additional information on all neighboring signals surrounding the target metabolite. We have compared the targeted profiling results of Dolphin, recorded from standard biological mixtures, with those of two well established approaches in NMR metabolomics. Overall, Dolphin produced more accurate results with the added advantage of being a fully automated and high throughput processing package. PMID:25370160

  11. 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

  12. Phosphorylation and desensitization of alpha1d-adrenergic receptors.

    PubMed Central

    García-Sáinz, J A; Vázquez-Cuevas, F G; Romero-Avila, M T

    2001-01-01

    In rat-1 fibroblasts stably expressing rat alpha(1d)-adrenoceptors, noradrenaline and PMA markedly decreased alpha(1d)-adrenoceptor function (noradrenaline-elicited increases in calcium in whole cells and [(35)S]guanosine 5'-[gamma-thio]triphosphate binding in membranes), suggesting homologous and heterologous desensitizations. Photoaffinity labelling, Western blotting and immunoprecipitation identified alpha(1d)-adrenoceptors as a broad band of 70-80 kDa. alpha(1d)-Adrenoceptors were phosphorylated in the basal state and noradrenaline and PMA increased it. The effect of noradrenaline was concentration-dependent (EC(50) 75 nM), rapid (maximum at 1 min) and transient. Phorbol ester-induced phosphorylation was concentration-dependent (EC(50) 25 nM), slightly slower (maximum at 5 min) and stable for at least 60 min. Inhibitors of protein kinase C decreased the effect of phorbol esters but not that of noradrenaline. Evidence of cross-talk of alpha(1d)-adrenoceptors with receptors endogenously expressed in rat-1 fibroblasts was given by the ability of endothelin, lysophosphatidic acid and bradykinin to induce alpha(1d)-adrenoceptor phosphorylation. In summary, it is shown for the first time here that alpha(1d)-adrenoceptors are phosphoproteins and that receptor phosphorylation is increased by the natural ligand, noradrenaline, by direct activation of protein kinase C and via cross-talk with other receptors endogenously expressed in rat-1 fibroblasts. Receptor phosphorylation has functional repercussions. PMID:11171057

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

    PubMed

    Tautz, Lutz

    2015-08-01

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

  14. 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.

  15. 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. PMID:17615669

  16. Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

    PubMed Central

    Lancaster, Cynthia S.; Finkelstein, David; Ware, Russell E.; Sparreboom, Alex

    2013-01-01

    Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b−/−) mice, hydroxyurea PK was analyzed in vivo by measuring [14C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled 14CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b−/− mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h−1·ml−1, respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b−/− mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b−/− mice, respectively) correlating with a decrease in exhaled 14CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK. PMID:23986199

  17. 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.

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

    SciTech Connect

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

    2010-08-20

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

  19. 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

  20. 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).

  1. 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

  2. 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

  3. Polar discontinuities and 1D interfaces in monolayered materials

    NASA Astrophysics Data System (ADS)

    Martinez-Gordillo, Rafael; Pruneda, Miguel

    2015-12-01

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

  4. 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.

  5. 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

  6. 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.

  7. Probing 1D super-strongly correlated dipolar quantum gases

    NASA Astrophysics Data System (ADS)

    Citro, R.; de Palo, S.; Orignac, E.; Pedri, P.; Chiofalo, M.-L.

    2009-04-01

    One-dimensional (1D) dipolar quantum gases are characterized by a very special condition where super-strong correlations occur to significantly affect the static and dynamical low-energy behavior. This behavior is accurately described by the Luttinger Liquid theory with parameter K < 1. Dipolar Bose gases are routinely studied in laboratory with Chromium atoms. On the other hand, 1D realizations with molecular quantum gases can be at reach of current experimental expertises, allowing to explore such extreme quantum degenerate conditions which are the bottom line for designing technological devices. Aim of the present contribution is to focus on the possible probes expected to signal the reach of Luttinger-Liquid behavior in 1D dipolar gases.

  8. 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.

  9. 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).

  10. Nanodamage and Nanofailure of 1d Zno Nanomaterials and Nanodevices

    NASA Astrophysics Data System (ADS)

    Li, Peifeng; Yang, Ya; Huang, Yunhua; Zhang, Yue

    2012-08-01

    One-dimensional (1D) ZnO nanomaterials include nanowires, nanobelts, and nanorods etc. The extensive applied fields and excellent properties of 1D ZnO nanomaterials can meet the requests of the electronic and electromechanical devices for "smaller, faster and colder", and would be applied in new energy convention, environmental protection, information science and technology, biomedical, security and defense fields. While micro porous, etching pits nanodamage and brittle fracture, dissolving, functional failure nanofailure phenomena of 1D ZnO nanomaterials and nanodevices are observed in some practical working environments like illumination, currents or electric fields, external forces, and some chemical gases or solvents. The more important thing is to discuss the mechanism and reduce or prohibit their generation.

  11. Resonant indirect exchange in 1D semiconductor nanostructures

    NASA Astrophysics Data System (ADS)

    Rozhansky, I. V.; Krainov, I. V.; Averkiev, N. S.; Lähderanta, E.

    2015-06-01

    We consider resonant indirect exchange interaction between magnetic centers in 1D nanostructures. The magnetic centers are assumed to be coupled to the 1D conducting channel by the quantum tunneling which can be of resonant character. The indirect exchange between the centers is mediated by the free carriers of the channel. The two cases of quadratic and linear energy dispersion of the 1D free carriers are considered. The former case is attributed to conventional semiconductor (InGaAs based to be concrete) nanowires or nanowhiskers, while the latter case is associated with carbon nanotubes with magnetic adatoms. We demonstrate that whenever the energy of a bound state at the magnetic center lies within the continuum energy spectra of the delocalized carriers in the channel the indirect exchange is strongly enhanced due to effective tunnel hybridization of the bound states with the continuum.

  12. 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 ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES OF THE EXCLUSIVE ECONOMIC ZONE OFF ALASKA Pt. 679, Table 1b Table 1b to Part...

  13. 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 ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES OF THE EXCLUSIVE ECONOMIC ZONE OFF ALASKA Pt. 679, Table 1b Table 1b to Part...

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  15. 40 CFR Table 1b to Subpart Dddd of... - Add-on Control Systems Compliance Options

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  16. 40 CFR Table 1b to Subpart Dddd of... - Add-on Control Systems Compliance Options

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  17. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  18. 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.

  19. 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

  20. 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

  1. Photometric observation of the transiting exoplanet WASP-1b

    NASA Astrophysics Data System (ADS)

    Wang, Xiao-bin; Collier Cameron, Andrew; Gu, Sheng-hong; Zhang, Li-yun

    2008-05-01

    The extra-solar planet WASP-1b, discovered by SuperWASP consortium in 2006, was observed through R filter using the 1-meter telescope with CCD camera at Yunnan Observatory on November 11, 2006. The systematic errors in photometric data were reduced by means of Tamuz et al. (2005) and Collier Cameron et al. (2006)'s algorithms. In order to estimate the parameters of the system, the MCMC (Markov Chain Monte Carlo) analysis is applied to fit the observed light curve. The following parameters of the system are derived: Rp=1.44RJ, Mp=0.88MJ, R*=1.52R, a=0.0396AU. The new parameters of the planet imply its low density, which agrees to the previous results.

  2. Serotonin type-1D receptor stimulation of A-type K(+) channel decreases membrane excitability through the protein kinase A- and B-Raf-dependent p38 MAPK pathways in mouse trigeminal ganglion neurons.

    PubMed

    Zhao, Xianyang; Zhang, Yuan; Qin, Wenjuan; Cao, Junping; Zhang, Yi; Ni, Jianqiang; Sun, Yangang; Jiang, Xinghong; Tao, Jin

    2016-08-01

    Although recent studies have implicated serotonin 5-HT1B/D receptors in the nociceptive sensitivity of primary afferent neurons, the underlying molecular and cellular mechanisms remain unclear. In this study, we identified a novel functional role of the 5-HT1D receptor subtype in regulating A-type potassium (K(+)) currents (IA) as well as membrane excitability in small trigeminal ganglion (TG) neurons. We found that the selective activation of 5-HT1D, rather than 5-HT1B, receptors reversibly increased IA, while the sustained delayed rectifier K(+) current was unaffected. The 5-HT1D-mediated IA increase was associated with a depolarizing shift in the voltage dependence of inactivation. Blocking G-protein signaling with pertussis toxin or by intracellular application of a selective antibody raised against Gαo or Gβ abolished the 5-HT1D effect on IA. Inhibition of protein kinase A (PKA), but not of phosphatidylinositol 3-kinase or protein kinase C, abolished the 5-HT1D-mediated IA increase. Analysis of phospho-p38 (p-p38) revealed that activation of 5-HT1D, but not 5-HT1B, receptors significantly activated p38, while p-ERK and p-JNK were unaffected. The p38 MAPK inhibitor SB203580, but not its inactive analogue SB202474, and inhibition of B-Raf blocked the 5-HT1D-mediated IA response. Functionally, we observed a significantly decreased action potential firing rate induced by the 5-HT1D receptors; pretreatment with 4-aminopyridine abolished this effect. Taken together, these results suggest that the activation of 5-HT1D receptors selectively enhanced IA via the Gβγ of the Go-protein, PKA, and the sequential B-Raf-dependent p38 MAPK signaling cascade. This 5-HT1D receptor effect may contribute to neuronal hypoexcitability in small TG neurons. PMID:27156838

  3. Optical properties of LEDs with patterned 1D photonic crystal

    NASA Astrophysics Data System (ADS)

    Hronec, P.; Kuzma, A.; Å kriniarová, J.; Kováč, J.; Benčurová, A.; Haščík, Å.; Nemec, P.

    2015-08-01

    In this paper we focus on the application of the one-dimensional photonic crystal (1D PhC) structures on the top of Al0.295Ga0.705As/GaAs multi-quantum well light emitting diode (MQW LED). 1D PhC structures with periods of 600 nm, 700 nm, 800 nm, and 900 nm were fabricated by the E-Beam Direct Write (EBDW) Lithography. Effect of 1D PhC period on the light extraction enhancement was studied. 1D PhC LED radiation profiles were obtained from Near Surface Light Emission Images (NSLEI). Measurements showed the strongest light extraction enhancement using 800 nm period of PhC. Investigation of PhC LED radiation profiles showed strong light decoupling when light reaches PhC structure. Achieved LEE was from 22.6% for 600 nm PhC LED to 47.0% for 800 nm PhC LED. LED with PhC structure at its surface was simulated by FDTD simulation method under excitation of appropriate launch field.

  4. NEW FEATURES OF HYDRUS-1D, VERSION 3.0

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper briefly summarizes new features in version 3.0 of HYDRUS-1D, released in May 2005, as compared to version 2.1. The new features are a) new approaches to simulate preferential and nonequilibrium water flow and solute transport, b) a new hysteresis module that avoids the effects of pumpin...

  5. A 1D wavelet filtering for ultrasound images despeckling

    NASA Astrophysics Data System (ADS)

    Dahdouh, Sonia; Dubois, Mathieu; Frenoux, Emmanuelle; Osorio, Angel

    2010-03-01

    Ultrasound images appearance is characterized by speckle, shadows, signal dropout and low contrast which make them really difficult to process and leads to a very poor signal to noise ratio. Therefore, for main imaging applications, a denoising step is necessary to apply successfully medical imaging algorithms on such images. However, due to speckle statistics, denoising and enhancing edges on these images without inducing additional blurring is a real challenging problem on which usual filters often fail. To deal with such problems, a large number of papers are working on B-mode images considering that the noise is purely multiplicative. Making such an assertion could be misleading, because of internal pre-processing such as log compression which are done in the ultrasound device. To address those questions, we designed a novel filtering method based on 1D Radiofrequency signal. Indeed, since B-mode images are initially composed of 1D signals and since the log compression made by ultrasound devices modifies noise statistics, we decided to filter directly the 1D Radiofrequency signal envelope before log compression and image reconstitution, in order to conserve as much information as possible. A bi-orthogonal wavelet transform is applied to the log transform of each signal and an adaptive 1D split and merge like algorithm is used to denoise wavelet coefficients. Experiments were carried out on synthetic data sets simulated with Field II simulator and results show that our filter outperforms classical speckle filtering methods like Lee, non-linear means or SRAD filters.

  6. 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.

  7. 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

  8. Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

    PubMed Central

    Ji, Shaonin; You, Yun; Kerner, Janos; Hoppel, Charles L.; Schoeb, Trenton R.; Chick, Wallace S.H.; Hamm, Doug A.; Sharer, J. Daniel; Wood, Philip A.

    2008-01-01

    Carnitine palmitoyltransferase-1 (CPT-1) catalyzes the rate-limiting step of mitochondrial β-oxidation of long chain fatty acids (LCFA), the most abundant fatty acids in mammalian membranes and in energy metabolism. Human deficiency of the muscle isoform CPT-1b is poorly understood. In the current study, embryos with a homozygous knockout of Cpt-1b were lost before embryonic day 9.5 − 11.5. Also, while there were normal percentages of CPT-1b+/−pups born from both male and female CPT-1b+/− mice crossed with wild-type mates, the number of CPT-1b+/− pups from CPT-1b+/− breeding pairs was under-represented (63% of the expected number). Northern blot analysis demonstrated ∼50% Cpt-1b mRNA expression in brown adipose tissue (BAT), heart and skeletal muscles in the CPT-1b+/− male mice. Consistent with tissue-specific expression of Cpt-1b mRNA in muscle but not liver, CPT-1+/− mice had ∼60% CPT-1 activity in skeletal muscle and no change in total liver CPT-1 activity. CPT-1b+/− mice had normal fasting blood glucose concentration. Consistent with expression of CPT-1b in BAT and muscle, ∼7% CPT-1b+/− mice (n=30) developed fatal hypothermia following a 3 hr cold challenge, while none of the CPT-1b+/+ mice (n=30) did. With a prolonged cold challenge (6 hr), significantly more CPT-1b+/− mice developed fatal hypothermia (52% CPT-1b+/− mice vs. 21% CPT-1b+/+ mice), with increased frequency in females of both genotypes (67% female vs. 38% male CPT-1b+/− mice, and 33% female vs. 8% male CPT-1b+/+ mice). Therefore, lethality of homozygous CPT-1b deficiency in the mice is consistent with paucity of human cases. PMID:18023382

  9. Xpbx1b and Xmeis1b play a collaborative role in hindbrain and neural crest gene expression in Xenopus embryos

    PubMed Central

    Maeda, Ryu; Ishimura, Akihiko; Mood, Kathleen; Park, Eui Kyun; Buchberg, Arthur M.; Daar, Ira O.

    2002-01-01

    Pbx1 is a homeodomain protein that functions in complexes with other homeodomain-containing proteins to regulate gene expression during embryogenesis and oncogenesis. Pbx proteins bind DNA cooperatively as heterodimers or higher order complexes with Meis family members and Hox proteins and are believed to specify cell identity during development. Here, we present evidence that Pbx1, in partnership with Meis1b, can regulate posterior neural markers and neural crest marker genes during Xenopus development. A Xenopus homolog of the Pbx1b homeodomain protein was isolated and shown to be expressed throughout embryogenesis. Xpbx1b expression overlaps with Xmeis1 in several areas, including the lateral neural folds, caudal branchial arch, hindbrain, and optic cup. When ectopically expressed, Xpbx1b can synergize with Xmeis1b to promote posterior neural and neural crest gene expression in ectodermal explants. Further, a physical interaction between these two homeodomain proteins is necessary for induction of these genes in embryonic tissue. In addition, coexpression of Xmeis1b and Xpbx1b leads to a prominent shift in the localization of Xmeis1b from the cytoplasm to the nucleus, suggesting that nuclear transport or retention of Xmeis1b may depend upon Xpbx1b. Finally, expression of a mutant construct in which Xpbx1b protein is fused to the repressor domain from Drosophila Engrailed inhibits posterior neural and neural crest gene expression. These data indicate that Xpbx1b and its partner, Xmeis1b, function in a transcriptional activation complex during hindbrain and neural crest development. PMID:11960001

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

    PubMed

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

    2012-08-01

    A methanol extract of the leaves of Syzygium polyanthum (Wight) Walp. afforded four new acylbenzene derivatives (1-4) together with seven known compounds (5-11). The structures of 1-11 were elucidated by extensive spectroscopic methods and comparison with the literature data. The new compounds 1-3 and a known compound, campest-4-en-3-one (10), exhibited a significant protein tyrosine phosphatase 1B inhibitory activity with IC₅₀ values of 13.1 ± 0.1, 5.77 ± 0.15, 4.01 ± 0.26, and 10.4 ± 0.5 µM, respectively. The inhibitory potency of the new compounds 2 and 3 was comparable to that of a positive control RK-682 (IC₅₀, 5.51 ± 0.04 µM). PMID:22763740

  11. Attenuated Stress Response to Acute Restraint and Forced Swimming Stress in Arginine Vasopressin 1b Receptor Subtype (Avpr1b) Receptor Knockout Mice and Wild-Type Mice Treated with a Novel Avpr1b Receptor Antagonist

    PubMed Central

    Roper, J A; Craighead, M; O’Carroll, A-M; Lolait, S J

    2010-01-01

    Arginine vasopressin (AVP) synthesised in the parvocellular region of the hypothalamic paraventricular nucleus and released into the pituitary portal vessels acts on the 1b receptor subtype (Avpr1b) present in anterior pituitary corticotrophs to modulate the release of adrenocorticotrophic hormone (ACTH). Corticotrophin-releasing hormone is considered the major drive behind ACTH release; however, its action is augmented synergistically by AVP. To determine the extent of vasopressinergic influence in the hypothalamic-pituitary-adrenal axis response to restraint and forced swimming stress, we compared the stress hormone levels [plasma ACTH in both stressors and corticosterone (CORT) in restraint stress only] following acute stress in mutant Avpr1b knockout (KO) mice compared to their wild-type controls following the administration of a novel Avpr1b antagonist. Restraint and forced swimming stress-induced increases in plasma ACTH were significantly diminished in mice lacking a functional Avpr1b and in wild-type mice that had been pre-treated with Avpr1b antagonist. A corresponding decrease in plasma CORT levels was also observed in acute restraint-stressed knockout male mice, and in Avpr1b-antagonist-treated male wild-type mice. By contrast, plasma CORT levels were not reduced in acutely restraint-stressed female knockout animals, or in female wild-type animals pre-treated with Avpr1b antagonist. These results demonstrate that pharmacological antagonism or inactivation of Avpr1b causes a reduction in the hypothalamic-pituitary-adrenal (HPA) axis response, particularly ACTH, to acute restraint and forced swimming stress, and show that Avpr1b knockout mice constitute a model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors. PMID:20846299

  12. 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

  13. 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

  14. 5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice.

    PubMed

    Evrard, A; Laporte, A M; Chastanet, M; Hen, R; Hamon, M; Adrien, J

    1999-11-01

    The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5-HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5 spikes/s. Intravenous administration of the 5-HT reuptake inhibitor citalopram or the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the mutants were less sensitive than wild-type animals to citalopram (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (specifically labelled by [3H]citalopram) in 5-HT1B-/- mice. In wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively, P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of 5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control through 5-HT1A

  15. Paresev 1-B in flight with tow cable

    NASA Technical Reports Server (NTRS)

    1964-01-01

    The Paresev 1-B tested the concept of a paraglider, designed to enable a Gemini capsule to fly to a controlled ground landing. This would remove the need to make an ocean splashdown at the end of a spaceflight. Once the paraglider was deployed, the Gemini crew could use it to steer toward a touchdown point and to land on three retractable skids. Because the paraglider represented an unproved technology, approval was given to build a simple test vehicle to try out the concept. The paraglider research vehicle, or Paresev, was built of steel tubing, with a fabric paraglider. The Paresev was unpowered, so it had to be towed aloft either by ground vehicles or aircraft, such as a biplane or a light aircraft. The Paresev was a demanding aircraft to fly. Milt Thompson said that he found it more difficult to handle than the later lifting bodies. Due to technical and cost problems, the Gemini spacecraft never used the paraglider, and all missions made ocean splashdowns.

  16. Serotonin 1B Receptor Imaging in Alcohol Dependence

    PubMed Central

    Hu, Jian; Henry, Shannan; Gallezot, Jean-Dominique; Ropchan, Jim; Neumaier, John F.; Potenza, Marc N.; Sinha, Rajita; Krystal, John H.; Huang, Yiyun; Ding, Yu-Shin; Carson, Richard E.; Neumeister, Alexander

    2010-01-01

    Background Although animal models suggest that alcohol dependence (AD) is associated with elevations in the number of serotonin-1B receptors (5HT1BR), 5HT1BR levels have not been investigated in people with AD. The selective 5HT1BR antagonist radioligand, [11C]P943, permits in vivo assessment of central 5HT1BR binding potential (BPND) using positron emission tomography (PET). Because of its central role in AD, we were particularly interested in ventral striatal 5HT1BR BPND values. Methods Twelve medication-free, recently abstinent (at least 4 weeks) patients with AD (mean age 35.2±10.1 years, 5 women) and 12 healthy control subjects (HC) (mean age 30.6±9.2 years, 5 women) completed [11C]P943 PET on a high resolution research tomograph (HRRT). Individual MRI scans were collected to exclude individuals with anatomical abnormalities and for co-registration. Imaging data were analyzed using a multilinear reference tissue model. Results Ventral striatal 5-HT1BR BPND values (2.01±0.57 and 1.55±0.09, 29% between-group difference, p=.006) were increased in AD compared to HC subjects. No influence of demographic or clinical variables or amount of injected radiotracer was observed. Conclusions This study provides the first evidence that AD in humans, like in rodent models, is associated with increased levels of ventral striatal 5HT1BRs. PMID:20172504

  17. 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.

  18. A Bayesian Algorithm for Reading 1D Barcodes

    PubMed Central

    Tekin, Ender; Coughlan, James

    2010-01-01

    The 1D barcode is a ubiquitous labeling technology, with symbologies such as UPC used to label approximately 99% of all packaged goods in the US. It would be very convenient for consumers to be able to read these barcodes using portable cameras (e.g. mobile phones), but the limited quality and resolution of images taken by these cameras often make it difficult to read the barcodes accurately. We propose a Bayesian framework for reading 1D barcodes that models the shape and appearance of barcodes, allowing for geometric distortions and image noise, and exploiting the redundant information contained in the parity digit. An important feature of our framework is that it doesn’t require that every barcode edge be detected in the image. Experiments on a publicly available dataset of barcode images explore the range of images that are readable, and comparisons with two commercial readers demonstrate the superior performance of our algorithm. PMID:20428491

  19. Waves in a 1D electrorheological dusty plasma lattice

    NASA Astrophysics Data System (ADS)

    Rosenberg, M.

    2015-08-01

    The behavior of waves in a one-dimensional (1D) dusty plasma lattice where the dust interacts via Yukawa and electric dipole interactions is discussed theoretically. This study is motivated by recent reports on electrorheological dusty plasmas (e.g. Ivlev et al. 2008 Phys. Rev. Lett. 100, 095003) where the dipole interaction arises due to an external uniaxial AC electric field that distorts the Debye sphere surrounding each grain. Application to possible dusty plasma experimental parameters is discussed.

  20. Nonreciprocity of edge modes in 1D magnonic crystal

    NASA Astrophysics Data System (ADS)

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

    2015-03-01

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

  1. A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro".

    PubMed

    Colciago, Alessandra; Mornati, Ornella; Ferri, Nicola; Castelnovo, Luca Franco; Fumagalli, Laura; Bolchi, Cristiano; Pallavicini, Marco; Valoti, Ermanno; Negri-Cesi, Paola

    2016-01-01

    The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype. PMID:26621245

  2. 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

  3. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2013-06-01

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

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

    PubMed Central

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

    2013-01-01

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

  7. 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

  8. 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

  9. Inhibition of human acid-sensing ion channel 1b by zinc

    PubMed Central

    Jiang, Qian; Zha, Xiang-Ming; Chu, Xiang-Ping

    2012-01-01

    Acid-sensing ion channel 1b (ASIC1b) is expressed in peripheral sensory neurons and has been implicated in nociception. Understanding the modulation of ASIC1b will provide important insight into how ASIC1b contributes to pain sensation. In our previous study, we showed that zinc, an important modulator of pain sensation, reduces rat ASIC1b current. However, rat ASIC1b shows several important differences from its recently identified human homolog. Most noticeably, human ASIC1b (hASIC1b) has a sustained component, which may play a role in persistent pain. Therefore, we tested here the hypothesis that zinc modulates the current properties of hASIC1b. Bath application of zinc suppressed the peak amplitude of hASIC1b currents, with a half-maximum inhibitory concentration of 37 μM. However, zinc did not affect the sustained component of hASIC1b currents. The effect of zinc was independent of pH-dependent activation, steady-state desensitization, and extracellular Ca2+, suggesting noncompetitive mechanisms. Further, we found that extracellular site(s) of the hASIC1b subunit is important for the effect of zinc. Mutating cysteine 196, but not cysteine 309, in the extracellular domain of the hASIC1b abolished the zinc inhibition. These results suggest that, through modulating cysteine196, zinc may have a modulatory role in acute pain. PMID:22837807

  10. 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

  11. 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.

  12. 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. PMID:24224843

  13. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes1

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... ALASKA Pt. 679, Table 1b Table 1b to Part 679—Discard and Disposition Codes1 Description Code... salmon or Pacific halibut, otherwise required to be discarded, that is donated to charity under a...

  14. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes1

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... ALASKA Pt. 679, Table 1b Table 1b to Part 679—Discard and Disposition Codes1 Description Code... salmon or Pacific halibut, otherwise required to be discarded, that is donated to charity under a...

  15. 20 CFR 655.705 - What Federal agencies are involved in the H-1B and H-1B1 programs, and what are the...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... CFR 214.2(h)(4)(iii)(B)(2), which specifies the employer will comply with the terms of the LCA for the... Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and as Fashion Models, and Requirements for Employers Seeking To Employ Nonimmigrants on H-1b1 and E-3 Visas in Specialty...

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

    PubMed

    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

  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 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

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false What Federal agencies are involved in the H-1B and H-1B1 programs, and what are the responsibilities of those agencies and of employers? 655.705 Section 655.705 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR TEMPORARY EMPLOYMENT OF FOREIGN WORKERS IN THE...

  20. 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

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

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-04

    ... 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  4. 49 CFR 178.358-4 - Construction of Specification 21PF-1B overpacks.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Construction of Specification 21PF-1B overpacks... Construction of Specification 21PF-1B overpacks. (a) Each Specification 21PF-1 overpack for which construction...-1B must be of stainless steel as shown on the drawings referred to in paragraph (a) of this section....

  5. 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

  6. 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

  7. 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

  8. Spatial coherence of polaritons in a 1D channel

    SciTech Connect

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

    2013-01-15

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

  9. 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.

  10. Phthalocyanine based 1D nanowires for device applications

    NASA Astrophysics Data System (ADS)

    Saini, Rajan; Mahajan, Aman; Bedi, R. K.

    2012-06-01

    1D nanowires (NWs) of Cu (II) 1,4,8,11,15,18,22,25-octabutoxy-29H,31H-Phthalocyanine (CuPc(OBu)8) molecule have been grown on different substrates by cost effective solution processing technique. The density of NWs is found to be strongly dependent on the concentration of solution. The possible formation mechanism of these structures is π-π interaction between phthalocyanine molecules. The improved conductivity of these NWs as compared to spin coated film indicates their potential for molecular device applications.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. Blood flow quantification using 1D CFD parameter identification

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  16. Validation of 3D/1D Analysis of ICRF Antennas

    NASA Astrophysics Data System (ADS)

    Milanesio, D.; Lancellotti, V.; Kyrytsya, V.; Maggiora, R.; Vecchi, G.; Parisot, A.; Wukitch, S. J.

    2004-11-01

    An innovative tool has been realized for the 3D/1D simulation of Ion Cyclotron Radio Frequency (ICRF), i.e. accounting for antennas in a realistic 3D geometry and with an accurate 1D plasma model. The approach to the problem is based on an integral-equation formulation for the self-consistent evaluation of the current distribution on the conductors. The environment has been subdivided in two coupled region: the plasma region and the vacuum region. The two problems are linked by means of electromagnetic current distribution on the aperture between the two regions. The plasma enters the formalism via a surface impedance matrix for this reason any plasma model can be used. The source term directly models the TEM mode of the coax feeding the antenna and the current in the coax is determined self-consistently, giving the input impedance/admittance of the antenna itself. The suite, called TOPICA, has been used in the design of various ICRF antennas and also for the performance prediction of the ALCATOR C-MOD D and E antenna. An extensive set of comparisons between measured and simulated antenna parameters during ALCATOR C-MOD operation will be presented.

  17. 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.

  18. Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor.

    PubMed

    Sun, Jin-Peng; Fedorov, Alexander A; Lee, Seung-Yub; Guo, Xiao-Ling; Shen, Kui; Lawrence, David S; Almo, Steven C; Zhang, Zhong-Yin

    2003-04-01

    Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket. PMID:12547827

  19. 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

  20. 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.

  1. 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

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

    PubMed Central

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

    2015-01-01

    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 24 h. 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. PMID:22940225

  3. 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

  4. 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

  5. Magnetic behavior of some 1D Cu chains

    NASA Astrophysics Data System (ADS)

    Willett, Roger D.; Gomez-García, Carlos J.; Ghosh, Ashutosh

    2004-05-01

    The magnetic properties of three 1D copper(II) salts are reported. The compound Cu(14ane)Cu(N 3) 4 contains alternating site chains with weak FM coupling with J/k=0.635 K . Magnetization studies are reported on Cu(TIM)CuCl 4, an alternating site, alternating FM/AFM exchange system with J FM/k=29.7 K and J AFM/k=-8.66 K. (HPy) 2Cu 3Cl 8.2H 2O contains FM chains composed of alternating Cu 2Cl 62- dimers and CuCl 2(H 2O) 2 monomers, with intradimer coupling J 1/k=17.35 K and dimer-monomer coupling J 2/k=1.93 K .

  6. 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.

  7. Electron Energy Levels in the 1D-2D Transition

    NASA Astrophysics Data System (ADS)

    Pepper, Michael; Sanjeev, Kumar; Thomas, Kalarikad; Creeth, Graham; English, David; Ritchie, David; Griffiths, Jonathan; Farrer, Ian; Jones, Geraint

    Using GaAs-AlGaAs heterostructures we have investigated the behaviour of electron energy levels with relaxation of the potential confining a 2D electron gas into a 1D configuration. In the ballistic regime of transport, when the conductance shows quantized plateaux, different types of behaviour are found according to the spins of interacting levels, whether a magnetic field is applied and lifting of the momentum degeneracy with a source-drain voltage. We have observed both crossing and anti-crossing of levels and have investigated the manner in which they can be mutually converted. In the presence of a magnetic field levels can cross and lock together as the confinement is altered in a way which is characteristic of parallel channels. The overall behaviour is discussed in terms of electron interactions and the wavefunction flexibility allowed by the increasing two dimensionality of the electron distribution as the confinement is weakened. Work supported by UK EPSRC.

  8. Directed enzymatic activation of 1-D DNA tiles.

    PubMed

    Garg, Sudhanshu; Chandran, Harish; Gopalkrishnan, Nikhil; LaBean, Thomas H; Reif, John

    2015-02-24

    The tile assembly model is a Turing universal model of self-assembly where a set of square shaped tiles with programmable sticky sides undergo coordinated self-assembly to form arbitrary shapes, thereby computing arbitrary functions. Activatable tiles are a theoretical extension to the Tile assembly model that enhances its robustness by protecting the sticky sides of tiles until a tile is partially incorporated into a growing assembly. In this article, we experimentally demonstrate a simplified version of the Activatable tile assembly model. In particular, we demonstrate the simultaneous assembly of protected DNA tiles where a set of inert tiles are activated via a DNA polymerase to undergo linear assembly. We then demonstrate stepwise activated assembly where a set of inert tiles are activated sequentially one after another as a result of attachment to a growing 1-D assembly. We hope that these results will pave the way for more sophisticated demonstrations of activated assemblies. PMID:25625898

  9. Robust recognition of 1D barcodes using Hough transform

    NASA Astrophysics Data System (ADS)

    Dwinell, John; Bian, Peng; Bian, Long Xiang

    2012-01-01

    In this paper we present an algorithm for the recognition of 1D barcodes using the Hough transform, which is highly robust regarding the typical degraded image. The algorithm addresses various typical image distortions, such as inhomogeneous illumination, reflections, damaged barcode or blurriness etc. Other problems arise from recognizing low quality printing (low contrast or poor ink receptivity). Traditional approaches are unable to provide a fast solution for handling such complex and mixed noise factors. A multi-level method offers a better approach to best manage competing constraints of complex noise and fast decode. At the lowest level, images are processed in gray scale. At the middle level, the image is transformed into the Hough domain. At the top level, global results, including missing information, is processed within a global context including domain heuristics as well as OCR. The three levels work closely together by passing information up and down between levels.

  10. 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.

  11. MX chains: 1-D analog of CuO planes

    SciTech Connect

    Gammel, J.T.; Batistic, I.; Bishop, A.R.; Loh, E.Y. Jr.; Marianer, S.

    1989-01-01

    We study a two-band Peierls-Hubbard model for halogen-bridged mixed-valence transition metal linear chain complexes (MX chains). We include electron-electron correlations (both Hubbard and PPP-like expressions) using several techniques including calculations in the zero-hopping limit, exact diagonalization of small systems, mean field approximation, and a Gutzwiller-like Ansatz for quantum phonons. The adiabatic optical absorption and phonon spectra for both photo-excited and doping induced defects (kinks, polarons, bipolarons, and excitons) are discussed. A long period phase which occurs even at commensurate filling for certain parameter values may be related to twinning. The effect of including the electron-phonon in addition to the electron-electron interaction on the polaron/bipolaron (pairing) competition is especially interesting when this class of compounds is viewed as a 1-D analog of high-temperature superconductors. 6 refs., 4 figs.

  12. 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.

  13. Detection of Genes Regulated by Lmx1b During Limb Dorsalization

    PubMed Central

    Feenstra, Jennifer M.; Kanaya, Kohei; Pira, Charmaine U; Hoffman, Sarah E.; Eppey, Richard J.; Oberg, Kerby C.

    2012-01-01

    Lmx1b is a homeodomain transcription factor that regulates dorsal identity during limb development. Lmx1b knockout (KO) mice develop distal ventral-ventral limbs. Although induction of Lmx1b is linked to Wnt7a expression in the dorsal limb ectoderm, the downstream targets of Lmx1b that accomplish limb dorsalization are unknown. To identify genes targeted by Lmx1b, we compared gene arrays from Lmx1b KO and wildtype mouse limbs during limb dorsalization, i.e., 11.5, 12.5, and 13.5 days post coitum. We identified 54 target genes differentially expressed in all three stages. Several skeletal targets, including Emx2, Matrilin1 and Matrilin4, demonstrated a loss of scapular expression in the Lmx1b KO mice, supporting a role for Lmx1b in scapula development. Furthermore, the relative abundance of extracellular matrix-related soft tissue targets regulated by Lmx1b, such as collagens and proteoglycans, suggests a mechanism which includes changes in the extracellular matrix composition to accomplish limb dorsalization. Our study provides the most comprehensive characterization of genes regulated by Lmx1b during limb development to-date and provides targets for further investigation. PMID:22417325

  14. Detection of genes regulated by Lmx1b during limb dorsalization.

    PubMed

    Feenstra, Jennifer M; Kanaya, Kohei; Pira, Charmaine U; Hoffman, Sarah E; Eppey, Richard J; Oberg, Kerby C

    2012-05-01

    Lmx1b is a homeodomain transcription factor that regulates dorsal identity during limb development. Lmx1b knockout (KO) mice develop distal ventral-ventral limbs. Although induction of Lmx1b is linked to Wnt7a expression in the dorsal limb ectoderm, the downstream targets of Lmx1b that accomplish limb dorsalization are unknown. To identify genes targeted by Lmx1b, we compared gene arrays from Lmx1b KO and wild type mouse limbs during limb dorsalization, i.e., 11.5, 12.5, and 13.5 days post coitum. We identified 54 target genes that were differentially expressed in all three stages. Several skeletal targets, including Emx2, Matrilin1 and Matrilin4, demonstrated a loss of scapular expression in the Lmx1b KO mice, supporting a role for Lmx1b in scapula development. Furthermore, the relative abundance of extracellular matrix-related soft tissue targets regulated by Lmx1b, such as collagens and proteoglycans, suggests a mechanism that includes changes in the extracellular matrix composition to accomplish limb dorsalization. Our study provides the most comprehensive characterization of genes regulated by Lmx1b during limb development to-date and provides targets for further investigation. PMID:22417325

  15. Recurrent CDKN1B (p27) mutations in hairy cell leukemia.

    PubMed

    Dietrich, Sascha; Hüllein, Jennifer; Lee, Stanley Chun-Wei; Hutter, Barbara; Gonzalez, David; Jayne, Sandrine; Dyer, Martin J S; Oleś, Małgorzata; Else, Monica; Liu, Xiyang; Słabicki, Mikołaj; Wu, Bian; Troussard, Xavier; Dürig, Jan; Andrulis, Mindaugas; Dearden, Claire; von Kalle, Christof; Granzow, Martin; Jauch, Anna; Fröhling, Stefan; Huber, Wolfgang; Meggendorfer, Manja; Haferlach, Torsten; Ho, Anthony D; Richter, Daniela; Brors, Benedikt; Glimm, Hanno; Matutes, Estella; Abdel Wahab, Omar; Zenz, Thorsten

    2015-08-20

    Hairy cell leukemia (HCL) is marked by near 100% mutational frequency of BRAFV600E mutations. Recurrent cooperating genetic events that may contribute to HCL pathogenesis or affect the clinical course of HCL are currently not described. Therefore, we performed whole exome sequencing to explore the mutational landscape of purine analog refractory HCL. In addition to the disease-defining BRAFV600E mutations, we identified mutations in EZH2, ARID1A, and recurrent inactivating mutations of the cell cycle inhibitor CDKN1B (p27). Targeted deep sequencing of CDKN1B in a larger cohort of HCL patients identify deleterious CDKN1B mutations in 16% of patients with HCL (n = 13 of 81). In 11 of 13 patients the CDKN1B mutation was clonal, implying an early role of CDKN1B mutations in the pathogenesis of HCL. CDKN1B mutations were not found to impact clinical characteristics or outcome in this cohort. These data identify HCL as having the highest frequency of CDKN1B mutations among cancers and identify CDNK1B as the second most common mutated gene in HCL. Moreover, given the known function of CDNK1B, these data suggest a novel role for alterations in regulation of cell cycle and senescence in HCL with CDKN1B mutations. PMID:26065650

  16. Consequence of the tumor-associated conversion to cyclin D1b

    PubMed Central

    Augello, Michael A; Berman-Booty, Lisa D; Carr, Richard; Yoshida, Akihiro; Dean, Jeffry L; Schiewer, Matthew J; Feng, Felix Y; Tomlins, Scott A; Gao, Erhe; Koch, Walter J; Benovic, Jeffrey L; Diehl, John Alan; Knudsen, Karen E

    2015-01-01

    Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b-driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre-clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant. PMID:25787974

  17. PLU-1/JARID1B overexpression predicts proliferation properties in head and neck squamous cell carcinoma.

    PubMed

    Cui, Zhibin; Song, Liwei; Hou, Zhaoyuan; Han, Yifan; Hu, Yuhua; Wu, Yadi; Chen, Wantao; Mao, Li

    2015-05-01

    PLU-1/JARID1B (jumonji AT rich interactive domain 1B) is one of the testis cancer antigens and functions as a histone demethylase in the regulation of various human types of cancers. However, its functions in head and neck squamous cell carcinoma (HNSCC) are rarely reported. The aim of the present study was to examine PLU-1/JARID1B expression levels in HNSCCs and to investigate its role in cancer cell proliferation. In the present study, we found that PLU-1/JARID1B mRNA was upregulated in all tested HNSCC cell lines. Immunohistochemical staining showed that PLU-1/JARID1B protein expression was detected in 87.8% (87/99) of the HNSCC cases. A positive association was observed between high PLU-1/JARID1B expression and higher Ki-67 labeling in the HNSCC samples (Pearson r=0.6514, P=0.0003). Stable PLU-1/JARID1B knockdown by PLU-1-shRNAs in the HNSCC cell lines suppressed cell growth both in the in vitro and in vivo studies. Moreover, PLU-1/JARID1B knockdown resulted in G1 arrest and early apoptosis by suppressing Bcl-2 family members in the HNSCCs. These data indicate that PLU-1/JARID1B is overexpressed in HNSCCs and is associated with tumor proliferation and apoptosis. Therefore, PLU-1/JARID1B represents a candidate proliferation biomarker for HNSCC diagnosis and treatment. PMID:25777981

  18. Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult β cells.

    PubMed

    van Arensbergen, Joris; García-Hurtado, Javier; Maestro, Miguel Angel; Correa-Tapia, Miguel; Rutter, Guy A; Vidal, Miguel; Ferrer, Jorge

    2013-01-01

    Polycomb-mediated gene repression is essential for embryonic development, yet its precise role in lineage-specific programming is poorly understood. Here we inactivated Ring1b, encoding a polycomb-repressive complex 1 subunit, in pancreatic multipotent progenitors (Ring1b(progKO)). This caused transcriptional derepression of a subset of direct Ring1b target genes in differentiated pancreatic islet cells. Unexpectedly, Ring1b inactivation in differentiated islet β cells (Ring1b(βKO)) did not cause derepression, even after multiple rounds of cell division, suggesting a role for Ring1b in the establishment but not the maintenance of repression. Consistent with this notion, derepression in Ring1b(progKO) islets occurred preferentially in genes that were targeted de novo by Ring1b during pancreas development. The results support a model in which Ring1b bookmarks its target genes during embryonic development, and these genes are maintained in a repressed state through Ring1b-independent mechanisms in terminally differentiated cells. This work provides novel insights into how epigenetic mechanisms contribute to shaping the transcriptional identity of differentiated lineages. PMID:23271347

  19. Cytochrome P450 1B1: An Unexpected Modulator of Liver Fatty Acid Homeostasis

    PubMed Central

    Larsen, Michele Campaigne; Bushkofsky, Justin R.; Gorman, Tyler; Adhami, Vaqar; Mukhtar, Hasan; Wang, Suqing; Reeder, Scott B.; Sheibani, Nader; Jefcoate, Colin R.

    2015-01-01

    Cytochrome P450 1b1 (Cyp1b1) expression is absent in mouse hepatocytes, but present in liver endothelia and activated stellate cells. Increased expression during adipogenesis suggests a role of Cyp1b1 metabolism in fatty acid homeostasis. Wild-type C57BL/6j (WT) and Cyp1b1-null (Cyp1b1-ko) mice were provided low or high fat diets (LFD and HFD, respectively). Cyp1b1-deletion suppressed HFD-induced obesity, improved glucose tolerance and prevented liver steatosis. Suppression of lipid droplets in sinusoidal hepatocytes, concomitant with enhanced glycogen granules, was a consistent feature of Cyp1b1-ko mice. Cyp1b1 deletion altered the in vivo expression of 560 liver genes, including suppression of PPARγ, stearoyl CoA desaturase 1 (Scd1) and many genes stimulated by PPARα, each consistent with this switch in energy storage mechanism. Ligand activation of PPARα in Cyp1b1-ko mice by WY-14643 was, nevertheless, effective. Seventeen gene changes in Cyp1b1-ko mice correspond to mouse transgenic expression that attenuated diet-induced diabetes. The absence of Cyp1b1 in mouse hepatocytes indicates participation in energy homeostasis through extra-hepatocyte signaling. Extensive sexual dimorphism in hepatic gene expression suggests a developmental impact of estrogen metabolism by Cyp1b1. Suppression of Scd1 and increased leptin turnover support enhanced leptin participation from the hypothalamus. Cyp1b1-mediated effects on vascular cells may underlie these changes. PMID:25703193

  20. RPRD1B promotes tumor growth by accelerating the cell cycle in endometrial cancer.

    PubMed

    Wang, Yuan; Qiu, Haifeng; Hu, Weixu; Li, Shaoru; Yu, Jinjin

    2014-03-01

    RPRD1B, the regulation of nuclear pre-mRNA domain containing 1B gene, functions as a cell cycle manipulator and has been found overexpressed in a small panel of endometrial cancer types. In the present study, we investigated the roles of RPRD1B in endometrial cancer using various in vitro and in vivo experiments. According to our results, RPRD1B mRNA was significantly upregulated in endometrial cancer tissues (P=0.0012). RPRD1B overexpression was correlated with tumor stage (P=0.0004), histology type (P=0.0146) and depth of myometrial invasion (P=0.024). In vitro, RPRD1B promoted cellular proliferation (P=0.032 for MTT assay and P=0.018 for colony formation assay), and accelerated the cell cycle (P=0.007) by upregulating cyclin D1, CDK4 and CDK6, while knockdown of RPRD1B suppressed cellular proliferation (P=0.02 for MTT assay and P=0.031 for colony formation assay), and led to G1 phase arrest (P=0.025) through downregulating cyclin D1, CDK4 and CDK6. Consistently, in the nude mice model, RPRD1B overexpression significantly accelerated the tumor xenograft growth (P=0.0012), accompanied by elevated Ki-67 and cyclin D1. In addition, we demonstrated that downregulating RPRD1B could sensitize Ishikawa cells to Raloxifene (P=0.01). In summary, we demonstrated that RPRD1B was frequently overexpressed in human endometrial cancer. Both in vitro and in vivo, over-abundant RPRD1B could promote tumor growth and accelerate cellular cell cycle. In addition, knockdown of RPRD1B also increased cell sensitivity to Raloxifene, making RPRD1B a potent therapeutic target for endometrial cancer, particularly in patients with resistance to the selective ER modulators. PMID:24452636

  1. 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

  2. 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

  3. Ganglioside GQ1b induces dopamine release through the activation of Pyk2.

    PubMed

    Zhang, Zhao; Chu, Shi-Feng; Mou, Zheng; Gao, Yan; Wang, Zhen-Zhen; Wei, Gui-Ning; Chen, Nai-Hong

    2016-03-01

    Growing evidence indicates that GQ1b, one of the gangliosides members, contributes to synaptic transmission and synapse formation. Previous studies have shown that GQ1b could enhance depolarization induced neurotransmitter release, while the role of GQ1b in asynchronous release is still largely unknown. Here in our result, we found low concentration of GQ1b, but not GT1b or GD1b (which were generated from GQ1b by plasma membrane-associated sialidases), evoked asynchronous dopamine (DA) release from both clonal rat pheochromocytoma PC12 cells and rat striatal slices significantly. The release peaked at 2min after GQ1b exposure, and lasted for more than 6min. This effect was caused by the enhancement of intracellular Ca(2+) and the activation of Pyk2. Inhibition of Pyk2 by PF-431396 (a dual inhibitor of Pyk2 and FAK) or Pyk2 siRNA abolished DA release induced by GQ1b. Moreover, Pyk2 Y402, but not other tyrosine site, was phosphorylated at the peaking time. The mutant of Pyk2 Y402 (Pyk2-Y402F) was built to confirm the essential role of Y402 activation. Further studies revealed that activated Pyk2 stimulated ERK1/2 and p-38, while only the ERK1/2 activation was indispensable for GQ1b induced DA release, which interacted with Synapsin I directly and led to its phosphorylation, then depolymerization of F-actin, thus contributed to DA release. In conclusion, low concentration of GQ1b is able to enhance asynchronous DA release through Pyk2/ERK/Synapsin I/actin pathway. Our findings provide new insights into the role of GQ1b in neuronal communication, and implicate the potential application of GQ1b in neurological disorders. PMID:26704905

  4. LMX1B is Essential for the Maintenance of Differentiated Podocytes in Adult Kidneys

    PubMed Central

    Burghardt, Tillmann; Kastner, Jürgen; Suleiman, Hani; Rivera-Milla, Eric; Stepanova, Natalya; Lottaz, Claudio; Kubitza, Marion; Böger, Carsten A.; Schmidt, Sarah; Gorski, Mathias; de Vries, Uwe; Schmidt, Helga; Hertting, Irmgard; Kopp, Jeffrey; Rascle, Anne; Moser, Markus; Heid, Iris M.; Warth, Richard; Spang, Rainer; Wegener, Joachim; Mierke, Claudia T.; Englert, Christoph

    2013-01-01

    Mutations of the LMX1B gene cause nail–patella syndrome, a rare autosomal-dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes. PMID:23990680

  5. A 1-D morphodynamic model of postglacial valley incision

    NASA Astrophysics Data System (ADS)

    Tunnicliffe, Jon F.; Church, Michael

    2015-11-01

    Chilliwack River is typical of many Cordilleran valley river systems that have undergone dramatic Holocene degradation of valley fills that built up over the course of Pleistocene glaciation. Downstream controls on base level, mainly blockage of valleys by glaciers, led to aggradation of significant glaciofluvial and glaciolacustrine valley fills and fan deposits, subsequently incised by fluvial action. Models of such large-scale, long-term degradation present a number of important challenges since the evolution of model parameters, such as the rate of bedload transport and grain size characteristics, are governed by the nature of the deposit. Sediment sampling in the Chilliwack Valley reveals a complex sequence of very coarse to fine textural modes. We present a 1-D numerical morphodynamic model for the river-floodplain system tailored to conditions in the valley. The model is adapted to dynamically adjust channel width to optimize sediment transporting capacity and to integrate relict valley fill material as the channel incises through valley deposits. Sensitivity to model parameters is studied using four principal criteria: profile concavity, rate of downstream grain size fining, bed surface sand content, and the timescale to equilibrium. Model results indicate that rates of abrasion and coarsening of the grain size distributions exert the strongest controls on all of the interrelated model performance criteria. While there are a number of difficulties in satisfying all model criteria simultaneously, results indicate that 1-D models of valley bottom sedimentary systems can provide a suitable framework for integrating results from sediment budget studies and chronologies of sediment evacuation established from dating.

  6. Impact of Atmospheric and Oceanic De-aliasing Level-1B (AOD1B) products on precise orbits of altimetry satellites and altimetry results

    NASA Astrophysics Data System (ADS)

    Rudenko, Sergei; Dettmering, Denise; Esselborn, Saskia; Fagiolini, Elisa; Schöne, Tilo

    2016-03-01

    We have extended backwards from 2001 to 1979 the current release 05 (RL05) of the Gravity Recovery and Climate Experiment (GRACE) Atmospheric and Oceanic De-aliasing Level-1B (AOD1B) product and studied the impact of this and a previous release 04 (RL04) of the AOD1B product on precise orbits of five altimetry satellites (ERS-1, ERS-2, TOPEX/Poseidon, Envisat and Jason-1) for the time span 1991-2012, as compared to the case when no AOD1B product is used. We have found that using AOD1B RL05 product reduces root mean square (RMS) fits of satellite laser ranging (SLR) observations by about 1.0-6.4 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by about 1.3-12.0, 0.3-10.0 and 2.0-10.0 per cent, respectively, for various satellites tested, as compared to the case without AOD1B product. Using AOD1B RL05 product instead of RL04 one reduces SLR RMS fits by 0.1-0.7 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by 0.1-0.6, 0.1-1.3 and 0.2-1.2 per cent, respectively, for the satellite orbits tested. The multi-mission crossover analysis shows that the application of an AOD1B product reduces the scatter of radial errors by 0.4-2.8 per cent for the satellite missions studied. At the regions with the most pronounced changes the use of the AOD1B products improves the consistency between the sea level as measured by the TOPEX and ERS-2 missions and by the Jason-1 and Envisat missions by 5 to 10 per cent (globally by about 2 per cent). The results of our study show that extended AOD1B RL05 product performs better than the AOD1B RL04 and improves orbits of altimetry satellites and consistency of sea level products.

  7. 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....

  8. Impaired Intestinal Calcium Absorption in Protein 4.1R-deficient Mice Due to Altered Expression of Plasma Membrane Calcium ATPase 1b (PMCA1b)*

    PubMed Central

    Liu, Congrong; Weng, Haibao; Chen, Lixiang; Yang, Shaomin; Wang, Hua; Debnath, Gargi; Guo, Xinhua; Wu, Liancheng; Mohandas, Narla; An, Xiuli

    2013-01-01

    Protein 4.1R was first identified in the erythrocyte membrane skeleton. It is now known that the protein is expressed in a variety of epithelial cell lines and in the epithelia of many tissues, including the small intestine. However, the physiological function of 4.1R in the epithelial cells of the small intestine has not so far been explored. Here, we show that 4.1R knock-out mice exhibited a significantly impaired small intestinal calcium absorption that resulted in secondary hyperparathyroidism as evidenced by increased serum 1,25-(OH)2-vitamin D3 and parathyroid hormone levels, decreased serum calcium levels, hyperplasia of the parathyroid, and demineralization of the bones. 4.1R is located on the basolateral membrane of enterocytes, where it co-localizes with PMCA1b (plasma membrane calcium ATPase 1b). Expression of PMCA1b in enterocytes was decreased in 4.1−/− mice. 4.1R directly associated with PMCA1b, and the association involved the membrane-binding domain of 4.1R and the second intracellular loop and C terminus of PMCA1b. Our findings have enabled us to define a functional role for 4.1R in small intestinal calcium absorption through regulation of membrane expression of PMCA1b. PMID:23460639

  9. Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis.

    PubMed

    Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

    2016-01-01

    Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing. PMID:27217144

  10. 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

  11. Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis

    PubMed Central

    Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

    2016-01-01

    Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39–45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing. PMID:27217144

  12. The design strategy of selective PTP1B inhibitors over TCPTP.

    PubMed

    Li, XiangQian; Wang, LiJun; Shi, DaYong

    2016-08-15

    Protein tyrosine phosphatase 1B (PTP1B) has already been well studied as a highly validated therapeutic target for diabetes and obesity. However, the lack of selectivity limited further studies and clinical applications of PTP1B inhibitors, especially over T-cell protein tyrosine phosphatase (TCPTP). In this review, we enumerate the published specific inhibitors of PTP1B, discuss the structure-activity relationships by analysis of their X-ray structures or docking results, and summarize the characteristic of selectivity related residues and groups. Furthermore, the design strategy of selective PTP1B inhibitors over TCPTP is also proposed. We hope our work could provide an effective way to gain specific PTP1B inhibitors. PMID:27353889

  13. 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. PMID:27439030

  14. 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. PMID:27421225

  15. LincRNA-p21 acts as a mediator of ING1b-induced apoptosis

    PubMed Central

    Tran, U M; Rajarajacholan, U; Soh, J; Kim, T-s; Thalappilly, S; Sensen, C W; Riabowol, K

    2015-01-01

    ING1b is a tumor suppressor that affects transcription, cell cycle control and apoptosis. ING1b is deregulated in disease, and its activity is closely linked to that of p53. In addition to regulating protein-coding genes, we found that ING1b also influences the expression of large intergenic non-coding RNAs (lincRNAs). In particular, lincRNA-p21 was significantly induced after DNA-damage stress or by ING1b overexpression. Furthermore, lincRNA-p21 expression in response to DNA damage was significantly attenuated in cells lacking ING1b. LincRNA-p21 is also a target of p53 and can trigger apoptosis in mouse cell models. We found that this function of lincRNA-p21 is conserved in human cell models. Moreover, ING1b and p53 could function independently to influence lincRNA-p21 expression. However, their effects become more additive under conditions of stress. In particular, ING1b regulates lincRNA-p21 levels by binding to its promoter and is required for induction of lincRNA-p21 by p53. The ability of ING1b to cause apoptosis is also impaired in the absence of lincRNA-p21. Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21. Our findings suggest that ING1b induces lincRNA-p21 expression independently of histone 3 lysine 4 trimethylation mark recognition and that lincRNA-p21 functions downstream of ING1b. Thus, regulation at the level of lincRNA-p21 may represent the point at which ING1b and p53 pathways converge to induce apoptosis under specific stress conditions. PMID:25741593

  16. Loss of the histone chaperone ASF1B reduces female reproductive capacity in mice.

    PubMed

    Messiaen, S; Guiard, J; Aigueperse, C; Fliniaux, I; Tourpin, S; Barroca, V; Allemand, I; Fouchet, P; Livera, G; Vernet, M

    2016-05-01

    Anti-silencing function 1 (ASF1) is an evolutionarily conserved histone H3-H4 chaperone involved in the assembly/disassembly of nucleosome and histone modification. Two paralogous genes, Asf1a and Asf1b, exist in the mouse genome. Asf1a is ubiquitously expressed and its loss causes embryonic lethality. Conversely, Asf1b expression is more restricted and has been less studied. To determine the in vivo function of Asf1b, we generated a Asf1b-deficient mouse line (Asf1b(GT(ROSA-βgeo)437)) in which expression of the lacZ reporter gene is driven by the Asf1b promoter. Analysis of β-galactosidase activity at early embryonic stages indicated a correlation between Asf1b expression and cell differentiation potential. In the gonads of both male and female, Asf1b expression was specifically detected in the germ cell lineage with a peak expression correlated with meiosis. The viability of Asf1b-null mice suggests that Asf1b is dispensable for mouse development. However, these mice showed reduced reproductive capacity compared with wild-type controls. We present evidence that the timing of meiotic entry and the subsequent gonad development are affected more severely in Asf1b-null female mice than in male mice. In female mice, in addition to subfertility related to altered gamete formation, variable defects compromising the development and/or survival of their offspring were also observed. Altogether, our data indicate the importance of Asf1b expression at the time of meiotic entry, suggesting that chromatin modifications may play a central role in this process. PMID:26850882

  17. Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding

    PubMed Central

    Kim, Teayoun; Moore, John F; Sharer, Jon D; Yang, Kevin; Wood, Philip A; Yang, Qinglin

    2014-01-01

    Background Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria. Treatments with CPT1 inhibitors protect against insulin resistance in short-term preclinical animal studies. We recently reported that mice with muscle isoform CPT1b deficiency demonstrated improved insulin sensitivity when fed a High Fat-Diet (HFD) for up to 5 months. In this follow up study, we further investigated whether the insulin sensitizing effects of partial CPT1b deficiency could be maintained under a prolonged HFD feeding condition. Methods We investigated the effects of CPT1b deficiency on HFD-induced insulin resistance using heterozygous CPT1b deficient (Cpt1b+/−) mice compared with Wild Type (WT) mice fed a HFD for a prolonged period of time (7 months). We assessed insulin sensitivity using hyperinsulinemic-euglycemic clamps. We also examined body composition, skeletal muscle lipid profile, and changes in the insulin signaling pathways of skeletal muscle, liver, and adipose tissue. Results We found that Cpt1b+/− mice became severely insulin resistant after 7 months of HFD feeding. Cpt1b+/− mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake. While Cpt1b+/− mice maintained a slower weight gain with less fat mass than WT mice, accumulation of lipid intermediates became evident in the muscle of Cpt1b+/− but not WT mice after 7 months of HFD feeding. Insulin signaling was impaired in the Cpt1b+/− as compared to the WT muscles. Conclusion Partial CPT1b deficiency, mimicking CPT1b inhibition, may lead to impaired insulin signaling and insulin sensitivity under a prolonged HFD feeding condition. Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy. PMID:25580367

  18. 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

  19. The Mechanism of Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

    PubMed Central

    Lu, Shaoyong; Huang, Wenkang; Geng, Lv; Shen, Qiancheng; Zhang, Jian

    2014-01-01

    As the prototypical member of the PTP family, protein tyrosine phosphatase 1B (PTP1B) is an attractive target for therapeutic interventions in type 2 diabetes. The extremely conserved catalytic site of PTP1B renders the design of selective PTP1B inhibitors intractable. Although discovered allosteric inhibitors containing a benzofuran sulfonamide scaffold offer fascinating opportunities to overcome selectivity issues, the allosteric inhibitory mechanism of PTP1B has remained elusive. Here, molecular dynamics (MD) simulations, coupled with a dynamic weighted community analysis, were performed to unveil the potential allosteric signal propagation pathway from the allosteric site to the catalytic site in PTP1B. This result revealed that the allosteric inhibitor compound-3 induces a conformational rearrangement in helix α7, disrupting the triangular interaction among helix α7, helix α3, and loop11. Helix α7 then produces a force, pulling helix α3 outward, and promotes Ser190 to interact with Tyr176. As a result, the deviation of Tyr176 abrogates the hydrophobic interactions with Trp179 and leads to the downward movement of the WPD loop, which forms an H-bond between Asp181 and Glu115. The formation of this H-bond constrains the WPD loop to its open conformation and thus inactivates PTP1B. The discovery of this allosteric mechanism provides an overall view of the regulation of PTP1B, which is an important insight for the design of potent allosteric PTP1B inhibitors. PMID:24831294

  20. 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.

  1. 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

  2. Distinctive role of vasohibin-1A and its splicing variant vasohibin-1B in tumor angiogenesis.

    PubMed

    Horie, S; Suzuki, Y; Kobayashi, M; Kadonosono, T; Kondoh, S; Kodama, T; Sato, Y

    2016-05-01

    Vasohibin-1 (VASH1) was isolated as a negative-feedback regulator of angiogenesis expressed in endothelial cells (ECs). There are two transcripts of VASH1, that is, the full-length VASH1A consisting of seven exons and the splicing variant VASH1B consisting of four exons. Here, we compared the effects of VASH1A and VASH1B on tumor angiogenesis. When ECs were transfected with VASH1A or VASH1B cDNAs, VASH1B transfectants, but not VASH1A ones, induced autophagic cell death of ECs. With sonoporation, the VASH1A or VASH1B gene were transfected specifically in ECs of tumor vessels in mice. Both VASH1A and VASH1B decreased tumor vessel density and inhibited tumor growth. VASH1A normalized the remaining tumor vessels, increased their rate of perfusion, decreased tumor hypoxia and enhanced the efficacy of anticancer chemotherapy, whereas VASH1B pruned tumor vessels without causing normalization, increased tumor hypoxia and tumor necrosis and did not enhance the efficacy of anticancer chemotherapy. The alternate transfection of mice with the VASH1A and VASH1B gene showed the highest effects on antitumor activity and normalization of tumor vessels. Our present findings on VASH1A and VASH1B should provide an innovative approach that would improve the efficacy of antiangiogenic cancer therapy by balancing vascular normalization and pruning. PMID:27080222

  3. The ING1b tumor suppressor facilitates nucleotide excision repair by promoting chromatin accessibility to XPA

    SciTech Connect

    Kuo, Wei-Hung W.; Wang Yemin; Wong, Ronald P.C.; Campos, Eric I.; Li Gang . E-mail: gangli@interchange.ubc.ca

    2007-05-01

    ING1b is the most studied ING family protein and perhaps the most ubiquitously and abundantly expressed. This protein is involved in the regulation of various biological functions ranging from senescence, cell cycle arrest, apoptosis, to DNA repair. ING1b is upregulated by UV irradiation and enhances the removal of bulky nucleic acid photoproducts. In this study, we provide evidence that ING1b mediates nucleotide excision repair by facilitating the access to damaged nucleosomal DNA. We demonstrate that ING1b is not recruited to UV-induced DNA lesions but enhances nucleotide excision repair only in XPC-proficient cells, implying an essential role in early steps of the 'access, repair, restore' model. We also find that ING1b alters histone acetylation dynamics upon exposure to UV radiation and induces chromatin relaxation in microccocal nuclease digestion assay, revealing that ING1b may allow better access to nucleotide excision repair machinery. More importantly, ING1b associates with chromatin in a UV-inducible manner and facilitates DNA access to nucleotide excision repair factor XPA. Furthermore, depletion of the endogenous ING1b results to the sensitization of cells at S-phase to UV irradiation. Taken together, these observations establish a role of ING1b acting as a chromatin accessibility factor for DNA damage recognition proteins upon genotoxic injury.

  4. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.

    PubMed

    Schubert, Julian; Siekierska, Aleksandra; Langlois, Mélanie; May, Patrick; Huneau, Clément; Becker, Felicitas; Muhle, Hiltrud; Suls, Arvid; Lemke, Johannes R; de Kovel, Carolien G F; Thiele, Holger; Konrad, Kathryn; Kawalia, Amit; Toliat, Mohammad R; Sander, Thomas; Rüschendorf, Franz; Caliebe, Almuth; Nagel, Inga; Kohl, Bernard; Kecskés, Angela; Jacmin, Maxime; Hardies, Katia; Weckhuysen, Sarah; Riesch, Erik; Dorn, Thomas; Brilstra, Eva H; Baulac, Stephanie; Møller, Rikke S; Hjalgrim, Helle; Koeleman, Bobby P C; Jurkat-Rott, Karin; Lehman-Horn, Frank; Roach, Jared C; Glusman, Gustavo; Hood, Leroy; Galas, David J; Martin, Benoit; de Witte, Peter A M; Biskup, Saskia; De Jonghe, Peter; Helbig, Ingo; Balling, Rudi; Nürnberg, Peter; Crawford, Alexander D; Esguerra, Camila V; Weber, Yvonne G; Lerche, Holger

    2014-12-01

    Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes. PMID:25362483

  5. Yersinia pestis Requires Host Rab1b for Survival in Macrophages.

    PubMed

    Connor, Michael G; Pulsifer, Amanda R; Price, Christopher T; Abu Kwaik, Yousef; Lawrenz, Matthew B

    2015-10-01

    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

  6. 3D/1D Analysis of ICRF Antennas

    NASA Astrophysics Data System (ADS)

    Maggiora, Riccardo; Lancellotti, Vito; Vecchi, Giuseppe

    2003-10-01

    An innovative tool has been realized for the 3D/1D simulation of Ion Cyclotron Radio Frequency (ICRF), i.e. accounting for antennas in a realistic 3D geometry and with an accurate 1D plasma model. The approach to the problem is based on an integral-equation formulation for the self-consistent evaluation of the current distribution on the conductors. The environment has been subdivided in two coupled region: the plasma region and the vacuum region. The two problems are linked by means of a magnetic current (electric field) distribution on the aperture between the two regions. In the vacuum region all the calculations are executed in the spatial domain while in the plasma region an extraction in the spectral domain of some integrals is employed that permits to significantly reduce the integration support and to obtain a high numerical efficiency leading to the practical possibility of using a large number of sub-domain (rectangular or triangular) basis functions on each solid conductor of the system. The plasma enters the formalism of the plasma region via a surface impedance matrix; for this reason any plasma model can be used; at present the FELICE code has been adopted, that affords density and temperature profiles, and FLR effects. The source term directly models the TEM mode of the coax feeding the antenna and the current in the coax is determined self-consistently, giving the input impedance/admittance of the antenna itself. Calculation of field distributions (both magnetic and electric), useful for sheath considerations, is included. This tool has been implemented in a suite, called TOPICA, that is modular and applicable to ICRF antenna structures of arbitrary shape. This new simulation tool can assist during the detailed design phase and for this reason can be considered a "Virtual Prototyping Laboratory" (VPL). The TOPICA suite has been tested against assessed codes and against measurements and data of mock-ups and existing antennas. The VPL is being used in

  7. Utility of a novel Oatp1b2 knockout mouse model for evaluating the role of Oatp1b2 in the hepatic uptake of model compounds.

    PubMed

    Chen, Cuiping; Stock, Jeffery L; Liu, Xingrong; Shi, Jilin; Van Deusen, Jeffrey W; DiMattia, Debra A; Dullea, Robert G; de Morais, Sonia M

    2008-09-01

    We generated the organic anion transporting polypeptide (Oatp) 1b2 knockout (KO) mouse model and assessed its utility to study hepatic uptake using model compounds: cerivastatin, lovastatin acid, pravastatin, simvastatin acid, rifampicin, and rifamycin SV. A selective panel of liver cytochromes P450 (P450s) (Cyp3a11, Cyp3a13, Cyp3a16, Cyp2c29, and Cyp2c39) and transporters [Oatp1b2, Oatp1a1, Oatp1a4, Oatp1a5; organic anion transporter (Oat) 1, Oat2, Oat3; multidrug resistance gene 1 (Mdr1) a, Mdr1b; bile salt export pump, multidrug resistance associated protein (Mrp) 2, Mrp3; breast cancer resistance protein] were measured by reverse transcription-polymerase chain reaction in both KO and wild-type (WT) male mice. Male KO and WT mice received each model compound s.c. at 3 mg/kg. Blood and liver samples were obtained at 0, 0.5, and 2 h postdose and analyzed using liquid chromatography/tandem mass spectrometry. Liver/plasma concentration ratio (K(p,liver)) was calculated. Student's t test was used to compare the mRNA and K(p,liver) between the KO and WT mice. A similar mRNA expression was observed between the KO and WT for the selected P450s and transporters except for Oatp1b2, for which the level was negligible in the KO but prominent in the WT mice with P < 0.0001. The in vivo results showed a differential effect of Oatp1b2 on hepatic uptake of the model compounds, indicating that Oatp1b2 plays a more significant role in the hepatobiliary disposition of rifampicin and lovastatin than the other compounds tested. This study suggests the Oatp1b2 mouse as a useful in vivo tool to understand drug targeting and disposition in the liver. PMID:18556442

  8. Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms exacerbate bladder cancer risk associated with alcohol drinking: gene-environment interaction.

    PubMed

    Masaoka, Hiroyuki; Ito, Hidemi; Soga, Norihito; Hosono, Satoyo; Oze, Isao; Watanabe, Miki; Tanaka, Hideo; Yokomizo, Akira; Hayashi, Norio; Eto, Masatoshi; Matsuo, Keitaro

    2016-06-01

    Although a range of chemical exposures (cigarette smoking and occupational exposure) are recognized risk factors for the development of bladder cancer (BCa), many epidemiological studies have demonstrated that alcohol drinking is not associated with BCa risk. Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms impact the accumulation of acetaldehyde, resulting in an increased risk of various cancers. To date, however, no studies evaluating the association between BCa risk and alcohol drinking have considered these polymorphisms. Here, we conducted a matched case-control study to investigate whether ALDH2 and ADH1B polymorphisms influence BCa risk associated with alcohol drinking. Cases were 74 BCa patients and controls were 740 first-visit outpatients without cancer at Aichi Cancer Center Hospital between January 2001 and December 2005. Odds ratio (OR), 95% confidence interval (CI) and gene-environment interaction were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results showed that ALDH2 Glu/Lys was associated with a significantly increased risk of BCa compared with Glu/Glu (OR 2.03, 95% CI 1.14-3.62, P = 0.017). In contrast, ALDH2 Glu/Lys showed no increase in risk among the stratum of never drinkers compared with Glu/Glu, indicating a gene-environment interaction. ADH1B His/Arg had an OR of 1.98 (1.20-3.24, P = 0.007) compared with His/His. ADH1B Arg+ showed a similar OR and 95% CI. Individuals with ALDH2 Glu/Lys and ADH1B Arg+ had the highest risk of BCa compared with ALDH2 Glu/Glu and ADH1B His/His [OR 4.00 (1.81-8.87), P = 0.001]. PMID:26992901

  9. 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...

  10. 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.

  11. 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.

  12. Spectral functions of 1D Peierls and Mott insulators

    NASA Astrophysics Data System (ADS)

    Voit, Johannes

    1998-03-01

    We construct the spectral function of the Luther-Emery model which describes one-dimensional Peierls and Mott insulators with a spin resp. charge gap, using symmetries and known limits and equivalences to other models. For the Peierls insulator, we find a true singularity with interaction dependent exponents on the gapped spin dispersion and a finite maximum depending on the magnitude of the spin gap, on a charge dispersion shifted by Δ_σ, as well as strong shadow bands with the same functional form as the main bands. For 1D Mott insulators, one or two singularities with universal inverse-square-root singularities are found depending on whether the charge velocity is larger or smaller than the spin velocity. The shadow band has a single singularity on the renormalized charge dispersion. These results could apply to the description of photoemission experiments in systems like K_0.3 Mo O_3, TTF-TCNQ, or Sr Cu O_2.

  13. 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.

  14. Graphs on uniform points in [0,1]d

    NASA Astrophysics Data System (ADS)

    Appel, Martin J. B.; Russo, Ralph P.; Yang, King J.

    1995-06-01

    Statistical problems in pattern or structure recognition for a random multidimensional point set may be addressed by variations on the random graph model of Erdos and Renyui. The imposition of graph structure with a variable edge criterion on a large random point set allows a search for signature quantities or behavior under the given distributional hypothesis. The work is motivated by the question of how to make statistical inferences from sensed mine field data. This article describes recent results obtained in the following special cases. On independent random points U1,...,Un distributed uniformly on [0,1]d, a random graph Gn(x) is constructed in which two distinct such points are joined by an edge if the l(infinity )-distance between them is at most some prescribed value 0 = 2.

  15. 1-D Modeling of Massive Particle Injection (MPI) in Tokamaks

    NASA Astrophysics Data System (ADS)

    Wu, W.; Parks, P. B.; Izzo, V. A.

    2008-11-01

    A 1-D Fast Current Quench (FCQ) model is developed to study current evolution and runaway electron suppression under massive density increase. The model consists of coupled toroidal electric field and energy equations, and it is solved numerically for DIII-D and ITER operating conditions. Simulation results suggest that fast shutdown by D2 liquid jet/pellet injection is in principle achievable for the desired plasma cooling time (˜15 ms for DIII-D and ˜50 ms for ITER) under ˜150x or higher densification. The current density and pressure profile are practically unaltered during the initial phase of jet propagation when dilution cooling dominates. With subsequent radiation cooling, the densified discharge enters the strongly collisional regime where Pfirsch-Schluter thermal diffusion can inhibit current contraction on the magnetic axis. Often the 1/1 kink instability, addressed by Kadomtsev's magnetic reconnection model, can be prevented. Our results are compared with NIMROD simulations in which the plasma is suddenly densified by ˜100x and experiences instantaneous dilution cooling, allowing for use of actual (lower) Lundquist numbers.

  16. 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

  17. Effective-range signatures in quasi-1D matter waves: sound velocity and solitons

    NASA Astrophysics Data System (ADS)

    Sgarlata, F.; Mazzarella, G.; Salasnich, L.

    2015-06-01

    We investigate ultracold and dilute bosonic atoms under strong transverse harmonic confinement using a 1D modified Gross-Pitaevskii equation (1D MGPE), which accounts for the energy dependence of the two-body scattering amplitude within an effective-range expansion. We study sound waves and solitons of the quasi-1D system, comparing the 1D MGPE results with the 1D GPE ones. We find that when the finite-size nature of the interaction is taken into account, the speed of sound and the density profiles of both dark and bright solitons show relevant quantitative changes with respect to predictions given by the standard 1D GPE.

  18. 5-HT1B receptor modulation of the serotonin transporter in vivo: studies using KO mice.

    PubMed

    Montañez, Sylvia; Munn, Jaclyn L; Owens, W Anthony; Horton, Rebecca E; Daws, Lynette C

    2014-07-01

    The serotonin transporter (SERT) controls the strength and duration of serotonergic neurotransmission by the high-affinity uptake of serotonin (5-HT) from extracellular fluid. SERT is a key target for many psychotherapeutic and abused drugs, therefore understanding how SERT activity and expression are regulated is of fundamental importance. A growing literature suggests that SERT activity is under regulatory control of the 5-HT1B autoreceptor. The present studies made use of mice with a constitutive reduction (5-HT1B+/-) or knockout of 5-HT1B receptors (5-HT1B-/-), as well as mice with a constitutive knockout of SERT (SERT-/-) to further explore the relationship between SERT activity and 5-HT1B receptor expression. High-speed chronoamperometry was used to measure clearance of 5-HT from CA3 region of hippocampus in vivo. Serotonin clearance rate, over a range of 5-HT concentrations, did not differ among 5-HT1B receptor genotypes, nor did [(3)H]cyanoimipramine binding to SERT in this brain region, suggesting that SERT activity is not affected by constitutive reduction or loss of 5-HT1B receptors; alternatively, it might be that other transport mechanisms for 5-HT compensate for loss of 5-HT1B receptors. Consistent with previous reports, we found that the 5-HT1B receptor antagonist, cyanopindolol, inhibited 5-HT clearance in wild-type mice. However, this effect of cyanopindolol was lost in 5-HT1B-/- mice and diminished in 5-HT1B+/- mice, indicating that the 5-HT1B receptor is necessary for cyanopindolol to inhibit 5-HT clearance. Likewise, cyanopindolol was without effect on 5-HT clearance in SERT-/- mice, demonstrating a requirement for the presence of both SERT and 5-HT1B receptors in order for cyanopindolol to inhibit 5-HT clearance in CA3 region of hippocampus. Our findings are consistent with SERT being under the regulatory control of 5-HT1B autoreceptors. Future studies to identify signaling pathways involved may help elucidate novel therapeutic targets for the

  19. 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

  20. Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

    PubMed Central

    De Vas, Matias G.; Kopp, Janel L.; Heliot, Claire; Sander, Maike; Cereghini, Silvia; Haumaitre, Cécile

    2015-01-01

    Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3+ endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5. PMID:25715395

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

    PubMed Central

    Thomas, Michael A.; Nyanhete, Tinashe; Tuero, Iskra; Venzon, David; Robert-Guroff, Marjorie

    2016-01-01

    Type 5 human adenoviruses (Ad5) deleted of genes encoding the early region 1B 55-kDa (E1B55K) protein including Onyx-015 (dl1520) and H101 are best known for their oncolytic potential. As a vaccine vector the E1B55K deletion may allow for the insertion of a transgene nearly 1,000 base pairs larger than now possible. This has the potential of extending the application for which the vectors are clinically known. However, the immune priming ability of E1B55K-deleted vectors is unknown, undermining our ability to gauge their usefulness in vaccine applications. For this reason, we created an E1B55K-deleted Ad5 vector expressing full-length single chain HIVBaLgp120 attached to a flexible linker and the first two domains of rhesus CD4 (rhFLSC) in exchange for the E3 region. In cell-based experiments the E1B55K-deleted vector promoted higher levels of innate immune signals including chemokines, cytokines, and the NKG2D ligands MIC A/B compared to an E1B55K wild-type vector expressing the same immunogen. Based on these results we evaluated the immune priming ability of the E1B55K-deleted vector in mice. The E1B55K-deleted vector promoted similar levels of Ad5-, HIVgp120, and rhFLSC-specific cellular and humoral immune responses as the E1B55K wild-type vector. In pre-clinical HIV-vaccine studies the wild-type vector has been employed as part of a very effective prime-boost strategy. This study demonstrates that E1B55K-deleted adenoviruses may serve as effective vaccine delivery vectors. PMID:27391605

  2. 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 POLICY AND INTERPRETATIONS Statements of...

  3. Myelin protein zero gene mutated in Charcot-Marie-Tooth type 1B patients

    SciTech Connect

    Su, Ying; Li, Lanying; Lepercq, J.; Lebo, R.V. ); Brooks, D.G.; Ravetch, J.V. ); Trofatter, J.A. )

    1993-11-15

    The autosomal dominant of Charcot-Marie-Tooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMT1B in one large CMT1B family. The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate. The same MPZ locus cosegregates with the CMT1B disease gene in a second CMT1B family [total multipoint logarithm of odds (lod) = 11.4 at [theta] = 0.00] with a splice junction mutation. Both mutations occur in MPZ protein regions otherwise conserved identically in human, rat, and cow since these species diverged 100 million years ago. MPZ protein, expressed exclusively in myelinated peripheral nerve Schwann cells, constitutes >50% of myelin protein. These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination.

  4. 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 §...

  5. 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 §...

  6. 18 CFR 1b.13 - Powers of persons conducting formal investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Powers of persons conducting formal investigations. 1b.13 Section 1b.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS §...

  7. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations.

    PubMed

    Scheffer, Ingrid E; Harkin, Louise A; Grinton, Bronwyn E; Dibbens, Leanne M; Turner, Samantha J; Zielinski, Marta A; Xu, Ruwei; Jackson, Graeme; Adams, Judith; Connellan, Mary; Petrou, Steven; Wellard, R Mark; Briellmann, Regula S; Wallace, Robyn H; Mulley, John C; Berkovic, Samuel F

    2007-01-01

    SCN1B, the gene encoding the sodium channel beta 1 subunit, was the first gene identified for generalized epilepsy with febrile seizures plus (GEFS+). Only three families have been published with SCN1B mutations. Here, we present four new families with SCN1B mutations and characterize the associated phenotypes. Analysis of SCN1B was performed on 402 individuals with various epilepsy syndromes. Four probands with missense mutations were identified. Detailed electroclinical phenotyping was performed on all available affected family members including quantitative MR imaging in those with temporal lobe epilepsy (TLE). Two new families with the original C121W SCN1B mutation were identified; novel mutations R85C and R85H were each found in one family. The following phenotypes occurred in the six families with SCN1B missense mutations: 22 febrile seizures, 20 febrile seizures plus, five TLE, three other GEFS+ phenotypes, two unclassified and ten unaffected individuals. All individuals with confirmed TLE had the C121W mutation; two underwent temporal lobectomy (one with hippocampal sclerosis and one without) and both are seizure free. We confirm the role of SCN1B in GEFS+ and show that the GEFS+ spectrum may include TLE alone. TLE with an SCN1B mutation is not a contraindication to epilepsy surgery. PMID:17020904

  8. Selective binding modes and allosteric inhibitory effects of lupane triterpenes on protein tyrosine phosphatase 1B.

    PubMed

    Jin, Tiantian; Yu, Haibo; Huang, Xu-Feng

    2016-01-01

    Protein Tyrosine Phosphatase 1B (PTP1B) has been recognized as a promising therapeutic target for treating obesity, diabetes, and certain cancers for over a decade. Previous drug design has focused on inhibitors targeting the active site of PTP1B. However, this has not been successful because the active site is positively charged and conserved among the protein tyrosine phosphatases. Therefore, it is important to develop PTP1B inhibitors with alternative inhibitory strategies. Using computational studies including molecular docking, molecular dynamics simulations, and binding free energy calculations, we found that lupane triterpenes selectively inhibited PTP1B by targeting its more hydrophobic and less conserved allosteric site. These findings were verified using two enzymatic assays. Furthermore, the cell culture studies showed that lupeol and betulinic acid inhibited the PTP1B activity stimulated by TNFα in neurons. Our study indicates that lupane triterpenes are selective PTP1B allosteric inhibitors with significant potential for treating those diseases with elevated PTP1B activity. PMID:26865097

  9. 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

  10. 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

  11. Molecular cloning and expression analysis of Fem1b from oriental river prawn Macrobrachium nipponense.

    PubMed

    Rahman, N M A; Fu, H; Qiao, H; Jin, S; Bai, H; Zhang, W; Jiang, F W; Liang, G; Sun, S; Gong, Y; Jiang, F F; Xiong, Y; Wu, Y

    2016-01-01

    Feminization-1 homolog b (Fem1b) is one of the genes essential for male development and play central roles in sex determination of Caenorhabditis elegans. In this study, we cloned and characterized the full-length Fem1b cDNA from the freshwater prawn Macrobrachium nipponense (MnFem1b) in different tissues and at different developmental stages. Real-time quantitative reverse polymerase chain reaction (RT-qPCR) showed that the MnFem1b gene was expressed in all investigated tissues, with the highest expression level found in the testes. The results revealed that the MnFem1b gene might play roles in aspects of development of the male prawn phenotype. The RT-qPCR also revealed that MnFem1b mRNA expression was significantly increased at 10 days after metamorphosis. The expression levels in all investigated tissues showed a certain degree of sexually dimorphism, the expression levels in males were significantly higher than those in females (P < 0.05). Notably, the highest expression of MnFem1b was found in the testes. The expression of MnFem1b in different tissues indicates that it plays multiple biological functions in M. nipponense. PMID:27323097

  12. 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

  13. 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. PMID:26214522

  14. Selective binding modes and allosteric inhibitory effects of lupane triterpenes on protein tyrosine phosphatase 1B

    PubMed Central

    Jin, Tiantian; Yu, Haibo; Huang, Xu-Feng

    2016-01-01

    Protein Tyrosine Phosphatase 1B (PTP1B) has been recognized as a promising therapeutic target for treating obesity, diabetes, and certain cancers for over a decade. Previous drug design has focused on inhibitors targeting the active site of PTP1B. However, this has not been successful because the active site is positively charged and conserved among the protein tyrosine phosphatases. Therefore, it is important to develop PTP1B inhibitors with alternative inhibitory strategies. Using computational studies including molecular docking, molecular dynamics simulations, and binding free energy calculations, we found that lupane triterpenes selectively inhibited PTP1B by targeting its more hydrophobic and less conserved allosteric site. These findings were verified using two enzymatic assays. Furthermore, the cell culture studies showed that lupeol and betulinic acid inhibited the PTP1B activity stimulated by TNFα in neurons. Our study indicates that lupane triterpenes are selective PTP1B allosteric inhibitors with significant potential for treating those diseases with elevated PTP1B activity. PMID:26865097

  15. 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

  16. 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...

  17. 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...

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

    PubMed

    Stevenson, Erica L; Caldwell, Heather K

    2012-03-01

    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 paraventricular 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. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID:22178035

  19. High fat diet deviates PtC-specific B1 B cell phagocytosis in obese mice

    PubMed Central

    Vo, Hung; Chiu, Joanna; Allaimo, Danielle; Mao, Changchuin; Wang, Yaqi; Gong, Yuefei; Ow, Hooisweng; Porter, Tyrone; Zhong, Xuemei

    2014-01-01

    Phagocytosis had been attributed predominantly to “professional” phagocytes such as macrophages, which play critical roles in adipose tissue inflammation. However, recently, macrophage-like phagocytic activity has been reported in B1 B lymphocytes. Intrigued by the long-established correlation between high fat diet (HFD)-induced obesity and immune dysfunction, we investigated how HFD affects B1 B cell phagocytosis. A significant number of B1 B cells recognize phosphatidylcholine (PtC), a common phospholipid component of cell membrane. We report here that unlike macrophages, B1 B cells have a unique PtC-specific phagocytic function. In the presence of both PtC-coated and non-PtC control fluorescent nano-particles, B1 B cells from healthy lean mice selectively engulfed PtC-coated beads, whereas B1 B cells from HFD-fed obese mice non-discriminately phagocytosed both PtC-coated and control beads. Morphologically, B1 B cells from obese mice resembled macrophages, displaying enlarged cytosol and engulfed more beads. Our study suggests for the first time that HFD can affect B1 B cell phagocytosis, substantiating the link of HFD-induced obesity and immune deviation. PMID:25866632

  20. Crystal structure of bovine CD1b3 with endogenously bound ligands1,2

    PubMed Central

    Girardi, Enrico; Wang, Jing; Mac, Thien-Thi; Versluis, Cees; Bhowruth, Veemal; Besra, Gurdyal; Heck, Albert JR; Van Rhijn, Ildiko; Zajonc, Dirk M.

    2010-01-01

    The CD1 family of antigen-presenting molecules is able to display lipids to T cells by binding them within a hydrophobic groove connected to the protein surface. In particular, the CD1b isotype is capable of binding ligands with greatly varying alkyl chain lengths through a complex network of interconnected hydrophobic pockets. Interestingly, mycobacterial lipids, such as glucose monomycolate (GMM) exclusively bind to CD1b. We determined the crystal structure of one of the three expressed bovine CD1b proteins, CD1b3, in complex with endogenous ligands, identified by mass spectrometry as a mixture of phosphatidylcholine and phosphatidylethanolamine, and analyzed the ability of the protein to bind glycolipids in vitro. The structure reveals a complex binding groove architecture, similar to the human ortholog but with consequential differences. Intriguingly, in bovine CD1b3 only the A’, C’ and F’ pockets are present while the T’ pocket previously described in human CD1b is closed. This different pocket conformation could affect the ability of boCD1b3 to recognize lipids with long acyl chains such as GMM. However, even in the absence of a T’ tunnel, bovine CD1b3 is able to bind mycolates from Rhodococcus ruber in vitro. PMID:20519644

  1. Synthesis and properties of a few 1-D cobaltous fumarates

    SciTech Connect

    Bora, Sanchay J.; Das, Birinchi K.

    2012-08-15

    Metal fumarates are often studied in the context of metal organic framework solids. Preparation, structure and properties of three cobalt(II) fumarates, viz. [Co(fum)(H{sub 2}O){sub 4}]{center_dot}H{sub 2}O 1, [Co(fum)(py){sub 2}(H{sub 2}O){sub 2}] 2, and [Co(fum)(4-CNpy){sub 2}(H{sub 2}O){sub 2}] 3 (fum=fumarate, py=pyridine, 4-CNpy=4-cyanopyridine) are described. All three are chain polymers involving bridging fumarato ligands between each pair of octahedral Co(II) centres, but while the first one is zigzag in structure, the latter two are linear. Indexed powder X-ray diffraction patterns, solid state electronic spectra and magnetic properties of the species are reported. Thermal decomposition behaviour of the compounds suggests that they may be suitable as precursors to make Co{sub 3}O{sub 4} via pyrolysis below 600 Degree-Sign C. - Graphical abstract: Structure and properties of three chain-polymeric cobalt(II) fumarates are described. Highlights: Black-Right-Pointing-Pointer Three fumarate bridged 1-D coordination polymers of cobalt(II) are reported. Black-Right-Pointing-Pointer While Co(II) fumarate pentahydrate is zigzag, the species having both pyridine and water as co-ligands are linear in structure. Black-Right-Pointing-Pointer Prominent lines in the powder X-ray diffraction patterns have been indexed. Black-Right-Pointing-Pointer Thermal decomposition of the species yields Co{sub 3}O{sub 4} as the final product.

  2. 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.

  3. 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

  4. A new general 1-D vadose zone flow solution method

    NASA Astrophysics Data System (ADS)

    Ogden, Fred L.; Lai, Wencong; Steinke, Robert C.; Zhu, Jianting; Talbot, Cary A.; Wilson, John L.

    2015-06-01

    We have developed an alternative to the one-dimensional partial differential equation (PDE) attributed to Richards (1931) that describes unsaturated porous media flow in homogeneous soil layers. Our solution is a set of three ordinary differential equations (ODEs) derived from unsaturated flux and mass conservation principles. We used a hodograph transformation, the Method of Lines, and a finite water-content discretization to produce ODEs that accurately simulate infiltration, falling slugs, and groundwater table dynamic effects on vadose zone fluxes. This formulation, which we refer to as "finite water-content", simulates sharp fronts and is guaranteed to conserve mass using a finite-volume solution. Our ODE solution method is explicitly integrable, does not require iterations and therefore has no convergence limits and is computationally efficient. The method accepts boundary fluxes including arbitrary precipitation, bare soil evaporation, and evapotranspiration. The method can simulate heterogeneous soils using layers. Results are presented in terms of fluxes and water content profiles. Comparing our method against analytical solutions, laboratory data, and the Hydrus-1D solver, we find that predictive performance of our finite water-content ODE method is comparable to or in some cases exceeds that of the solution of Richards' equation, with or without a shallow water table. The presented ODE method is transformative in that it offers accuracy comparable to the Richards (1931) PDE numerical solution, without the numerical complexity, in a form that is robust, continuous, and suitable for use in large watershed and land-atmosphere simulation models, including regional-scale models of coupled climate and hydrology.

  5. 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

  6. 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

  7. JARID1B is a luminal lineage-driving oncogene in breast cancer

    PubMed Central

    Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege G.; Takagi, Shinji; Peluffo, Guillermo; Vaske, Charles; Zhao, Xi; Vollan, Hans Kristian Moen; Maruyama, Reo; Ekram, Muhammad B.; Sun, Hanfei; Kim, Jee Hyun; Carver, Kristopher; Zucca, Mattia; Feng, Jianxing; Almendro, Vanessa; Bessarabova, Marina; Rueda, Oscar M.; Nikolsky, Yuri; Caldas, Carlos; Liu, X. Shirley; Polyak, Kornelia

    2014-01-01

    SUMMARY Recurrent mutations in histone modifying enzymes imply key roles in tumorigenesis yet their functional relevance is largely unknown. Here we show that JARID1B, encoding a histone H3 lysine 4 (H3K4) demethylase, is frequently amplified and overexpressed in luminal breast tumors and a somatic mutation in a basal-like breast cancer results in the gain of unique chromatin binding and luminal expression and splicing patterns. Downregulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGFβ pathway inhibitors. Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. High luminal JARID1B activity is associated with poor outcome in patients with hormone receptor positive breast tumors. PMID:24937458

  8. AKR1B7 Is Induced by the Farnesoid X Receptor and Metabolizes Bile Acids*

    PubMed Central

    Schmidt, Daniel R.; Schmidt, Samuel; Holmstrom, Sam R.; Makishima, Makoto; Yu, Ruth T.; Cummins, Carolyn L.; Mangelsdorf, David J.; Kliewer, Steven A.

    2011-01-01

    Although bile acids are crucial for the absorption of lipophilic nutrients in the intestine, they are cytotoxic at high concentrations and can cause liver damage and promote colorectal carcinogenesis. The farnesoid X receptor (FXR), which is activated by bile acids and abundantly expressed in enterohepatic tissues, plays a crucial role in maintaining bile acids at safe concentrations. Here, we show that FXR induces expression of Akr1b7 (aldo-keto reductase 1b7) in murine small intestine, colon, and liver by binding directly to a response element in the Akr1b7 promoter. We further show that AKR1B7 metabolizes 3-keto bile acids to 3β-hydroxy bile acids that are less toxic to cultured cells than their 3α-hydroxy precursors. These findings reveal a feed-forward, protective pathway operative in murine enterohepatic tissues wherein FXR induces AKR1B7 to detoxify bile acids. PMID:21081494

  9. 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

  10. Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism.

    PubMed

    Huang, Yung-yu; Oquendo, Maria A; Friedman, Jill M Harkavy; Greenhill, Lawrence L; Brodsky, Beth; Malone, Kevin M; Khait, Vadim; Mann, J John

    2003-01-01

    The 5-HT(1B) receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT(1B) receptor (h5-HTR(1B)) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR(1B) G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR(1B) G861C locus with a history of substance abuse disorder (chi(2) = 9.51, df = 2, p = 0.009; chi(2) = 7.31, df = 1, p = 0.007, respectively) and with a diagnosis of a major depressive episode (chi(2) = 6.83, df = 2, p = 0.033; chi(2) = 5.81, df = 1, p = 0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test: chi(2) = 7.20, df = 1, p = 0.008; chi(2) = 6.80, df = 1, p = 0.009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR(1B) G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies. PMID:12496953

  11. Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine palmitoyltransferase 1B (CPT1B).

    PubMed

    Boukouvala, Evridiki; Leaver, Michael J; Favre-Krey, Laurence; Theodoridou, Maria; Krey, Grigorios

    2010-10-01

    Understanding the control of piscine fatty acid metabolism is important for determining the nutritional requirements of fish, and hence for the production of optimal aquaculture diets. The regulation and expression of carnitine palmitoyltransferase 1 (CPT1; EC No 2.3.1.21) are critical processes in the control of fatty acid metabolism, and here we report a cDNA from gilthead sea bream (Sparus aurata) which encodes a protein with high identity to vertebrate CPT1. This sea bream CPT1 mRNA is predominantly expressed in skeletal and cardiac muscle, with little expression in other tissues. Phylogenetic analysis of other vertebrate CPT1 sequences show that fish genomes contain a single gene related to mammalian CPT1B, and a further two multi-gene families related to mammalian CPT1A. Genes related to mammalian CPT1C are absent in fish. Therefore, based on both functional and evolutionary orthology to mammalian CPT1B, the sea bream CPT1 reported here is a CPT1B isoform. Sea bream CPT1B mRNA expression progressively decreases in heart and muscle up to 12h after last feeding, but returns to initial, non-fasted levels after 72h. In contrast, in liver non-fasted expression is low, but strongly increases at 24 and 72h after last feeding. In white muscle and liver, CPT1B mRNA expression is highly correlated with the expression of peroxisomal proliferator-activated receptor beta (PPARbeta). Thus fatty acid metabolism by CPT1B and its control by PPARs are similar in fish and mammals, but multiple genes for CPT1A-like proteins in fish also suggest different and more complex pathways of lipid utilisation than in mammals. PMID:20601065

  12. A functional null mutation of SCN1B in a patient with Dravet syndrome.

    PubMed

    Patino, Gustavo A; Claes, Lieve R F; Lopez-Santiago, Luis F; Slat, Emily A; Dondeti, Raja S R; Chen, Chunling; O'Malley, Heather A; Gray, Charles B B; Miyazaki, Haruko; Nukina, Nobuyuki; Oyama, Fumitaka; De Jonghe, Peter; Isom, Lori L

    2009-08-26

    Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na(v)1.1 alpha subunits. Sodium channels are modulated by beta1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b(-/-) versus Scn1b(+/+) mice. Scn1b(-/-) CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b(-/-) mice seize spontaneously, the seizure susceptibility of Scn1b(+/-) mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation. PMID:19710327

  13. Chromatin-Remodeling-Factor ARID1B Represses Wnt/β-Catenin Signaling.

    PubMed

    Vasileiou, Georgia; Ekici, Arif B; Uebe, Steffen; Zweier, Christiane; Hoyer, Juliane; Engels, Hartmut; Behrens, Jürgen; Reis, André; Hadjihannas, Michel V

    2015-09-01

    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

  14. 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

  15. Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation

    PubMed Central

    Xu, Yiliang; Sun, Yuhui; Ye, Haihong; Zhu, Li; Liu, Jianghong; Wu, Xiaofeng; Wang, Le; He, Tingting; Shen, Yan; Wu, Jane Y; Xu, Qi

    2015-01-01

    Genetic variations in the human dysbindin-1 gene (DTNBP1) have been associated with schizophrenia. As a result of alternative splicing, the human DTNBP1 gene generates at least three distinct protein isoforms, dysbindin-1A, -1B and -1C. Significant effort has focused on dysbindin-1A, an important player in multiple steps of neurodevelopment. However, the other isoforms, dysbindin-1B and dysbindin-1C have not been well characterized. Nor have been associated with human diseases. Here we report an increase in expression of DTNBP1b mRNA in patients with paranoid schizophrenia as compared with healthy controls. A single-nucleotide polymorphism located in intron 9, rs117610176, has been identified and associated with paranoid schizophrenia, and its C allele leads to an increase of DTNBP1b mRNA splicing. Our data show that different dysbindin splicing isoforms exhibit distinct subcellular distribution, suggesting their distinct functional activities. Dysbindin-1B forms aggresomes at the perinuclear region, whereas dysbindin-1A and -1C proteins exhibit diffused patterns in the cytoplasm. Dysbindin-1A interacts with dysbindin-1B, getting recruited to the aggresome structure when co-expressed with dysbindin-1B. Moreover, cortical neurons over-expressing dysbindin-1B show reduction in neurite outgrowth, suggesting that dysbindin-1B may interfere with dysbindin-1A function in a dominant-negative manner. Taken together, our study uncovers a previously unknown association of DTNBP1b expression with schizophrenia in addition to its distinct biochemical and functional properties.

  16. Functional characterization of polypeptide release factor 1b in the ciliate Euplotes.

    PubMed

    Wang, Yan; Chai, Baofeng; Wang, Wei; Liang, Aihua

    2010-12-01

    In higher eukaryotes, RF-I (class I release factor) [eRF1 (eukaryotic release factor 1)] is responsible for stop codon recognition and promotes nascent polypeptide release from the ribosome. Interestingly, two class I RFs, eRF1a and eRF1b, have been identified among the ciliates Euplotes, which are variant code organisms. In the present study, we analysed the comparative expression of eRF1a and eRF1b in Euplotes cells, demonstrating that the expression of eRF1b was higher than that of eRF1a. An interaction between eRF1b and eRF3 was confirmed, suggesting that an eRF1b function is facilitated by eRF3. Co-localization of both eRF1s indicated that they function in the same subcellular location in Euplotes cells. We also analysed the characteristics of stop codon discrimination by eRF1b. Like eRF1a, eRF1b recognized UAA and UAG as stop codons, but not UGA. This finding disagreed with the deduced characteristics of eRF1a/eRF1b from the classic hypothesis of 'anticodon-mimicry' proposed by Muramatsu et al. [Muramatsu, Heckmann, Kitanaka and Kuchino (2001) FEBS Lett. 488, 105-109]. Mutagenesis experiments indicated that the absolutely conserved amino acid motif 'G31T32' (numbered as for human eRF1) in eRF1b was the key to efficient stop codon recognition by eRF1b. In conclusion, these findings support and improve the 'cavity model' of stop codon discrimination by eRF1 proposed by Bertram et al. [Bertram, Bell, Ritchie, Fullerton and Stansfield (2000) RNA 6, 1236-1247] and Inagaki et al. [Inagaki, Blouin, Doolittle and Roger (2002) Nucleic Acids Res. 30, 532-544]. PMID:20136636

  17. PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms.

    PubMed

    Wu, Bo; Guo, Bo-Min; Kang, Jie; Deng, Xian-Zhao; Fan, You-Ben; Zhang, Xiao-Ping; Ai, Kai-Xing

    2016-03-01

    Protein phosphatase, Mg(2+)/Mn(2+) dependent, 1D (PPM1D) is emerging as an oncogene by virtue of its negative control on several tumor suppressor pathways. However, the clinical significance of PPM1D in pancreatic cancer (PC) has not been defined. In this study, we determined PPM1D expression in human PC tissues and cell lines and their irrespective noncancerous controls. We subsequently investigated the functional role of PPM1D in the migration, invasion, and apoptosis of MIA PaCa-2 and PANC-1 PC cells in vitro and explored the signaling pathways involved. Furthermore, we examined the role of PPM1D in PC tumorigenesis in vivo. Our results showed that PPM1D is overexpressed in human PC tissues and cell lines and significantly correlated with tumor growth and metastasis. PPM1D promotes PC cell migration and invasion via potentiation of the Wnt/β-catenin pathway through downregulation of apoptosis-stimulating of p53 protein 2 (ASPP2). In contrast to PPM1D, our results showed that ASPP2 is downregulated in PC tissues. Additionally, PPM1D suppresses PC cell apoptosis via inhibition of the p38 MAPK/p53 pathway through both dephosphorylation of p38 MAPK and downregulation of ASPP2. Furthermore, PPM1D promotes PC tumor growth in vivo. Our results demonstrated that PPM1D is an oncogene in PC. PMID:26714478

  18. Preliminary abatement device evaluation: 1D-2D KGM cyclone design

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cyclones are predominately used in controlling cotton gin particulate matter (PM) emissions. The most commonly used cyclone designs are the 2D-2D and 1D-3D; however other designs such as the 1D-2D KGM have or are currently being used. A 1D-2D cyclone has a barrel length equal to the barrel diamete...

  19. α1D-Adrenoceptors are responsible for the high sensitivity and the slow time-course of noradrenaline-mediated contraction in conductance arteries

    PubMed Central

    Flacco, Nicla; Parés, Jaime; Serna, Eva; Segura, Vanessa; Vicente, Diana; Pérez-Aso, Miguel; Noguera, María Antonia; Ivorra, María Dolores; McGrath, John C; D'Ocon, Pilar

    2013-01-01

    The objective of this study was to determine whether the different time-course characteristics of α1-adrenoceptor-mediated contraction in arteries can be related to the subtypes involved. Contractile responses to noradrenaline (NA) were compared with inositol phosphate accumulation and extracellular signal-regulated kinase (ERK)1/2 phosphorylation after α1-agonist stimuli in the same vessels in the presence or absence of α1-antagonists in rat or in α1-subtype knockout (KO) mice. Aorta, where α1D-AR is the main functional subtype, had higher sensitivity to NA (in respect of inositol phosphate [IP], pERK1/2, and contractile response) than tail artery, where the α1A-adrenoceptor subtype is predominant. Furthermore, the contraction in aorta exhibited a slower decay after agonist removal and this was consistent in all strains harboring α1D-adrenoceptors (from rat, α1B-KO, and wild-type [WT] mice) but was not observed in the absence of the α1D-adrenoceptor signal (α1D-adrenoceptor blocked rat aorta or aorta from α1D-KO). IP formation paralleled α1-adrenoceptor-mediated contraction (agonist present or postagonist) in aorta and tail artery. High sensitivity to agonist and persistence of response after agonist removal is a property of α1D-adrenoceptors. Therefore, the preponderance of this subtype in noninnervated conductance arteries such as aorta allows responsiveness to circulating catecholamines and prevents abrupt changes in vessel caliber when the stimulus fluctuates. Conversely, in innervated distributing arteries, high local concentrations of NA are required to activate α1A-adrenoceptors for a response that is rapid but short lived allowing fine adjustment of the contractile tone by perivascular sympathetic nerves. PMID:25505555

  20. 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. PMID:25908624

  1. From nonfinite to finite 1D arrays of origami tiles.

    PubMed

    Wu, Tsai Chin; Rahman, Masudur; Norton, Michael L

    2014-06-17

    average solution structures for blocks is more readily achieved using computer models than using direct imaging methods. The development of scalable 1D-origami arrays composed of uniquely addressable components is a logical, if not necessary, step in the evolution of higher order fully addressable structures. Our research into the fabrication of arrays has led us to generate a listing of several important areas of future endeavor. Of high importance is the re-enforcement of the mechanical properties of the building blocks and the organization of multiple arrays on a surface of technological importance. While addressing this short list of barriers to progress will prove challenging, coherent development along each of these lines of inquiry will accelerate the appearance of commercial scale molecular manufacturing. PMID:24803094

  2. 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

  3. Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B).

    PubMed

    Parsons, Zachary D; Ruddraraju, Kasi Viswanatharaju; Santo, Nicholas; Gates, Kent S

    2016-06-15

    Redox regulation of protein tyrosine phosphatase 1B (PTP1B) involves oxidative conversion of the active site cysteine thiolate into an electrophilic sulfenyl amide residue. Reduction of the sulfenyl amide by biological thiols regenerates the native cysteine residue. Here we explored fundamental chemical reactions that may enable covalent capture of the sulfenyl amide residue in oxidized PTP1B. Various sulfone-containing carbon acids were found to react readily with a model peptide sulfenyl amide via attack of the sulfonyl carbanion on the electrophilic sulfur center in the sulfenyl amide. Both the products and the rates of these reactions were characterized. The results suggest that capture of a peptide sulfenyl amide residue by sulfone-stabilized carbanions can slow, but not completely prevent, thiol-mediated generation of the corresponding cysteine-containing peptide. Sulfone-containing carbon acids may be useful components in the construction of agents that knock down PTP1B activity in cells via transient covalent capture of the sulfenyl amide oxoform generated during insulin signaling processes. PMID:27132865

  4. Wave-of-Advance Models of the Diffusion of the Y Chromosome Haplogroup R1b1b2 in Europe

    PubMed Central

    Sjödin, Per; François, Olivier

    2011-01-01

    Whether or not the spread of agriculture in Europe was accompanied by movements of people is a long-standing question in archeology and anthropology, which has been frequently addressed with the help of population genetic data. Estimates on dates of expansion and geographic origins obtained from genetic data are however sensitive to the calibration of mutation rates and to the mathematical models used to perform inference. For instance, recent data on the Y chromosome haplogroup R1b1b2 (M269) have either suggested a Neolithic origin for European paternal lineages or a more ancient Paleolithic origin depending on the calibration of Y-STR mutation rates. Here we examine the date of expansion and the geographic origin of hgR1b1b2 considering two current estimates of mutation rates in a total of fourteen realistic wave-of-advance models. We report that a range expansion dating to the Paleolithic is unlikely to explain the observed geographical distribution of microsatellite diversity, and that whether the data is informative with respect to the spread of agriculture in Europe depends on the mutation rate assumption in a critical way. PMID:21720564

  5. 20 CFR 655.705 - What Federal agencies are involved in the H-1B and H-1B1 programs, and what are the...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... CFR 214.2(h)(4)(iii)(B)(2), which specifies the employer will comply with the terms of the LCA for the... petition, whether the occupation named in the labor condition application is a specialty occupation or... § 655.700(d)(4). Each employer seeking an H-1B nonimmigrant in a specialty occupation or as a...

  6. Protein Tyrosine Phosphatase-1B Negatively Impacts Host Defense against Pseudomonas aeruginosa Infection.

    PubMed

    Yue, Lei; Xie, Zhongping; Li, Hua; Pang, Zheng; Junkins, Robert D; Tremblay, Michel L; Chen, Xiaochun; Lin, Tong-Jun

    2016-05-01

    Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals. Mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa infection. PTP1B-deficient mice display greatly enhanced bacterial clearance and reduced disease scores, which are accompanied by increased neutrophil infiltration and cytokine production. Interestingly, PTP1B deficiency mainly up-regulates the production of interferon-stimulated response elements-regulated cytokines and chemokines, including chemokine ligand 5 (regulated on activation normal T cell expressed and secreted), CXCL10 (interferon γ-inducible protein 10), and interferon-β production. Further studies reveal that PTP1B deficiency leads to increased interferon regulatory factor 7 (IRF7) expression and activation. These findings demonstrate a novel regulatory mechanism of the immune response to P. aeruginosa infection through PTP1B-IRF7 interaction. This novel PTP1B-IRF7-interferon-stimulated response elements pathway may have broader implications in Toll-like receptor-mediated innate immunity. PMID:27105736

  7. Ultrastructural abnormalities of the trabecular meshwork extracellular matrix in Cyp1b1-deficient mice.

    PubMed

    Teixeira, L B C; Zhao, Y; Dubielzig, R R; Sorenson, C M; Sheibani, N

    2015-03-01

    Cytochrome P450 1B1 (CYP1B1) is highly expressed in human and murine ocular tissues during development. Mutations in this gene are implicated in the development of primary congenital glaucoma (PCG) in humans. Mice deficient in Cyp1b1 (Cyp1b1(-/-) ) present developmental abnormalities similar to human primary congenital glaucoma. The present work describes the ultrastructural morphology of the iridocorneal angle of 21 eyes from 1-week-old to 8-month-old Cyp1b1(-/-) mice. Morphometric and semiquantitative analysis of the data revealed that 3-week-old Cyp1b1(-/-) mice present a significantly (P < .005) decreased amount of trabecular meshwork (TM) collagen and higher TM endothelial cell and collagen lesion scores (P < .005) than age-matched controls. Collagen loss and lesion scores were progressively increased in older animals, with 8-month-old animals presenting severe atrophy of the TM. Our findings advance the understanding of the effects of CYP1B1 mutations in TM development and primary congenital glaucoma, as well as suggest a link between TM morphologic alterations and increased intraocular pressure. PMID:24879660

  8. 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

  9. 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

  10. Targeting the disordered C-terminus of PTP1B with an allosteric inhibitor

    PubMed Central

    Krishnan, Navasona; Koveal, Dorothy; Miller, Daniel H.; Xue, Bin; Akshinthala, Sai Dipikaa; Kragelj, Jaka; Jensen, Malene Ringkjøbing; Gauss, Carla-Maria; Page, Rebecca; Blackledge, Martin; Muthuswamy, Senthil K.; Peti, Wolfgang; Tonks, Nicholas K.

    2014-01-01

    PTP1B, a validated therapeutic target for diabetes and obesity, plays a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We defined a novel mechanism of allosteric inhibition that targets the C-terminal, non-catalytic segment of PTP1B. We present the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small molecule inhibitor, MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules. PMID:24845231

  11. 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

  12. The Role of PTP1B O-GlcNAcylation in Hepatic Insulin Resistance

    PubMed Central

    Zhao, Yun; Tang, Zhuqi; Shen, Aiguo; Tao, Tao; Wan, Chunhua; Zhu, Xiaohui; Huang, Jieru; Zhang, Wanlu; Xia, Nana; Wang, Suxin; Cui, Shiwei; Zhang, Dongmei

    2015-01-01

    Protein tyrosine phosphatase 1B (PTP1B), which can directly dephosphorylate both the insulin receptor and insulin receptor substrate 1 (IRS-1), thereby terminating insulin signaling, reportedly plays an important role in insulin resistance. Accumulating evidence has demonstrated that O-GlcNAc modification regulates functions of several important components of insulin signal pathway. In this study, we identified that PTP1B is modified by O-GlcNAcylation at three O-GlcNAc sites (Ser104, Ser201, and Ser386). Palmitate acid (PA) impaired the insulin signaling, indicated by decreased phosphorylation of both serine/threonine-protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) following insulin administration, and upregulated PTP1B O-GlcNAcylation in HepG2 cells. Compared with the wild-type, intervention PTP1B O-GlcNAcylation by site-directed gene mutation inhibited PTP1B phosphatase activity, resulted in a higher level of phosphorylated Akt and GSK3β, recovered insulin sensitivity, and improved lipid deposition in HepG2 cells. Taken together, our research showed that O-GlcNAcylation of PTP1B can influence insulin signal transduction by modulating its own phosphatase activity, which participates in the process of hepatic insulin resistance. PMID:26402673

  13. 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

  14. 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.

  15. KIF1B promotes glioma migration and invasion via cell surface localization of MT1-MMP.

    PubMed

    Chen, Songyu; Han, Mingzhi; Chen, Weiliang; He, Ying; Huang, Bin; Zhao, Peng; Huang, Qibing; Gao, Liang; Qu, Xun; Li, Xingang

    2016-02-01

    Malignant glioma is notorious for its aggressiveness and poor prognosis, and the invasiveness of glioma cells is the major obstacle. Accumulating evidence indicates that kinesin superfamily proteins (KIFs) may play key roles in tumor invasiveness, but the mechanisms remained unresolved. Our previous study demonstrated that membrane type 1-matrix metalloproteinase (MT1-MMP) was involved in Kinesin family member 1B (KIF1B)-modulated invasion of gastric cancer cells. Therefore, the role of KIF1B in glioma cell invasion and its relationship with MT1-MMP were explored in the present study. We found that aberrantly increased expression of KIF1B was associated with worse WHO pathological classification and Karnofsky performance status (KPS), which also showed a trend towards worse prognosis. In the transwell assay, knockdown of KIF1B using siRNA repressed U87MG and A172 glioma cell migration and invasion. Silencing KIF1B inhibited expression of membranal MT1-MMP; however, the amount of MT1-MMP in the whole cell lysate was not affected. In conclusion, targeting KIF1B may be an option for anti-invasive therapies targeting glioma. PMID:26576027

  16. Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia.

    PubMed

    Drenberg, C D; Paugh, S W; Pounds, S B; Shi, L; Orwick, S J; Li, L; Hu, S; Gibson, A A; Ribeiro, R C; Rubnitz, J E; Evans, W E; Sparreboom, A; Baker, S D

    2016-06-01

    Using broad interrogation of clinically relevant drug absorption, distribution, metabolism, and excretion (ADME) genes on the DMET platform, we identified a genetic variant in SLCO1B1 (rs2291075; c.597C>T), encoding the transporter OATP1B1, associated with event-free (P = 0.006, hazard ratio = 1.74) and overall survival (P = 0.012, hazard ratio = 1.85) in children with de novo acute myeloid leukemia (AML). Lack of SLCO1B1 expression in leukemic blasts suggested the association might be due to an inherited rather than a somatic effect. rs2291075 was in strong linkage with known functional variants rs2306283 (c.388A>G) and rs4149056 (c.521T>C). Functional studies in vitro determined that four AML-directed chemotherapeutics (cytarabine, daunorubicin, etoposide, and mitoxantrone) are substrates for OATP1B1 and the mouse ortholog Oatp1b2. In vivo pharmacokinetic studies using Oatp1b2-deficient mice further confirmed our results. Collectively, these findings demonstrate an important role for OATP1B1 in the systemic pharmacokinetics of multiple drugs used in the treatment of AML and suggest that inherited variability in host transporter function influences the effectiveness of therapy. PMID:26663398

  17. 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

  18. 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

  19. 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

  20. New Insights In Intestinal Sar1B GTPase Regulation and Role in Cholesterol Homeostasis.

    PubMed

    Sané, Alain; Seidman, Ernest; Spahis, Schohraya; Lamantia, Valérie; Garofalo, Carole; Montoudis, Alain; Marcil, Valérie; Levy, Emile

    2015-10-01

    Sar1B GTPase is a key component of Coat protein complex II (COPII)-coated vesicles that bud from the endoplasmic reticulum to export newly synthesized proteins. The aims of this study were to determine whether Sar1B responds to lipid regulation and to evaluate its role in cholesterol (CHOL) homeostasis. The influence of lipids on Sar1B protein expression was analyzed in Caco-2/15 cells by Western blot. Our results showed that the presence of CHOL (200 μM) and oleic acid (0.5 mM), bound to albumin, increases Sar1B protein expression. Similarly, supplementation of the medium with micelles composed of taurocholate with monooleylglycerol or oleic acid also stimulated Sar1B expression, but the addition of CHOL (200 μM) to micelle content did not modify its regulation. On the other hand, overexpression of Sar1B impacted on CHOL transport and metabolism in view of the reduced cellular CHOL content along with elevated secretion when incubated with oleic acid-containing micelles for 24 h, thereby disclosing induced CHOL transport. This was accompanied with higher secretion of free- and esterified-CHOL within chylomicrons, which was not the case when oleic acid was replaced with monooleylglycerol or when albumin-bound CHOL was given alone. The aforementioned cellular CHOL depletion was accompanied with a low phosphorylated/non phosphorylated HMG-CoA reductase ratio, indicating elevated enzymatic activity. Combination of Sar1B overexpression with micelle incubation led to reduction in intestinal CHOL transporters (NPC1L1, SR-BI) and metabolic regulators (PCSK9 and LDLR). The present work showed that Sar1B is regulated in a time- and concentration-dependent manner by dietary lipids, suggesting an adaptation to alimentary lipid flux. Our data also suggest that Sar1B overexpression contributes to regulation of CHOL transport and metabolism by facilitating rapid uptake and transport of CHOL. PMID:25826777

  1. Coumarins from Angelica decursiva inhibit α-glucosidase activity and protein tyrosine phosphatase 1B.

    PubMed

    Ali, Md Yousof; Jannat, Susoma; Jung, Hyun Ah; Jeong, Hyong Oh; Chung, Hae Young; Choi, Jae Sue

    2016-05-25

    In the present study, we investigated the anti-diabetic potential of six natural coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), decursinol (3), decursidin (4), umbelliferone 6-carboxylic acid (5), and 2'-isopropyl psoralene (6) isolated from Angelica decursiva and evaluated their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO(-)-mediated protein tyrosine nitration. Coumarins 1-6 showed potent PTP1B and α-glucosidase inhibitory activities with ranges of IC50 values of 5.39-58.90 μM and 65.29-172.10 μM, respectively. In the kinetic study for PTP1B enzyme inhibition, compounds 1, 5, and 6 were competitive, whereas 2 and 4 showed mixed type, and 3 displayed noncompetitive type inhibition. For α-glucosidase enzyme inhibition, compounds 1 and 3 exhibited good mixed-type, while 2, 5, and 6 showed noncompetitive and 4 displayed competitive type inhibition. Furthermore, these coumarins also effectively suppressed ONOO(-)-mediated tyrosine nitration in a dose-dependent manner. To further investigate PTP1B inhibition, we generated a 3D structure of PTP1B using Autodock 4.2 and simulated the binding of compounds 1-6. Docking simulations showed that different residues of PTP1B interacted with different functional groups of compounds 1-6 through hydrogen and hydrophobic interactions. In addition, the binding energies of compounds 1-6 were negative, suggesting that hydrogen bonding may stabilize the open form of the enzyme and potentiate tight binding of the active site of PTP1B, thereby resulting in more effective PTP1B inhibition. These results demonstrate that the whole plant of A. decursiva and its coumarins are useful as potential functional food ingredients for the prevention and treatment of type 2 diabetes. PMID:27085377

  2. Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance

    PubMed Central

    Kim, Teayoun; He, Lan; Johnson, Maria S.; Li, Yan; Zeng, Ling; Ding, Yishu; Long, Qinqiang; Moore, John F.; Sharer, Jon D.; Nagy, Tim R.; Young, Martin E.; Wood, Philip A.; Yang, Qinglin

    2014-01-01

    Background Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved. Methods We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b+/−) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways. Results We found that Cpt1b+/− mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b+/− mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b+/− skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b+/− but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver. Conclusion The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy. PMID:25309812

  3. Caspase-1 autoproteolysis is differentially required for NLRP1b and NLRP3 inflammasome function.

    PubMed

    Guey, Baptiste; Bodnar, Mélanie; Manié, Serge N; Tardivel, Aubry; Petrilli, Virginie

    2014-12-01

    Inflammasomes are caspase-1-activating multiprotein complexes. The mouse nucleotide-binding domain and leucine rich repeat pyrin containing 1b (NLRP1b) inflammasome was identified as the sensor of Bacillus anthracis lethal toxin (LT) in mouse macrophages from sensitive strains such as BALB/c. Upon exposure to LT, the NLRP1b inflammasome activates caspase-1 to produce mature IL-1β and induce pyroptosis. Both processes are believed to depend on autoproteolysed caspase-1. In contrast to human NLRP1, mouse NLRP1b lacks an N-terminal pyrin domain (PYD), indicating that the assembly of the NLRP1b inflammasome does not require the adaptor apoptosis-associated speck-like protein containing a CARD (ASC). LT-induced NLRP1b inflammasome activation was shown to be impaired upon inhibition of potassium efflux, which is known to play a major role in NLRP3 inflammasome formation and ASC dimerization. We investigated whether NLRP3 and/or ASC were required for caspase-1 activation upon LT stimulation in the BALB/c background. The NLRP1b inflammasome activation was assessed in both macrophages and dendritic cells lacking either ASC or NLRP3. Upon LT treatment, the absence of NLRP3 did not alter the NLRP1b inflammasome activity. Surprisingly, the absence of ASC resulted in IL-1β cleavage and pyroptosis, despite the absence of caspase-1 autoprocessing activity. By reconstituting caspase-1/caspase-11(-/-) cells with a noncleavable or catalytically inactive mutant version of caspase-1, we directly demonstrated that noncleavable caspase-1 is fully active in response to the NLRP1b activator LT, whereas it is nonfunctional in response to the NLRP3 activator nigericin. Taken together, these results establish variable requirements for caspase-1 cleavage depending on the pathogen and the responding NLR. PMID:25404286

  4. 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

  5. Etv2 and Fli1b Function Together as Key Regulators of Vasculogenesis and Angiogenesis

    PubMed Central

    Craig, Michael P.; Grajevskaja, Viktorija; Liao, Hsin-Kai; Balciuniene, Jorune; Ekker, Stephen C.; Park, Joo-Seop; Essner, Jeffrey J.; Balciunas, Darius; Sumanas, Saulius

    2015-01-01

    Objective The E26 transformation-specific domain transcription factor Etv2/Etsrp/ER71 is a master regulator of vascular endothelial differentiation during vasculogenesis, although its later role in sprouting angiogenesis remains unknown. Here, we investigated in the zebrafish model a role for Etv2 and related E26 transformation-specific factors, Fli1a and Fli1b in developmental angiogenesis. Approach and Results Zebrafish fli1a and fli1b mutants were obtained using transposon-mediated gene trap approach. Individual fli1a and fli1b homozygous mutant embryos display normal vascular patterning, yet the angiogenic recovery observed in older etv2 mutant embryos does not occur in embryos lacking both etv2 and fli1b. Etv2 and fli1b double-deficient embryos fail to form any angiogenic sprouts and show greatly increased apoptosis throughout the axial vasculature. In contrast, fli1a mutation did not affect the recovery of etv2 mutant phenotype. Overexpression analyses indicate that both etv2 and fli1b, but not fli1a, induce the expression of multiple vascular markers and of each other. Temporal inhibition of Etv2 function using photoactivatable morpholinos indicates that the function of Etv2 and Fli1b during angiogenesis is independent from the early requirement of Etv2 during vasculogenesis. RNA-Seq analysis and chromatin immunoprecipitation suggest that Etv2 and Fli1b share the same transcriptional targets and bind to the same E26 transformation-specific sites. Conclusions Our data argue that there are 2 phases of early vascular development with distinct requirements of E26 transformation-specific transcription factors. Etv2 alone is required for early vasculogenesis, whereas Etv2 and Fli1b function redundantly during late vasculogenesis and early embryonic angiogenesis. PMID:25722433

  6. Caspase-1 autoproteolysis is differentially required for NLRP1b and NLRP3 inflammasome function

    PubMed Central

    Guey, Baptiste; Bodnar, Mélanie; Manié, Serge N.; Tardivel, Aubry; Petrilli, Virginie

    2014-01-01

    Inflammasomes are caspase-1–activating multiprotein complexes. The mouse nucleotide-binding domain and leucine rich repeat pyrin containing 1b (NLRP1b) inflammasome was identified as the sensor of Bacillus anthracis lethal toxin (LT) in mouse macrophages from sensitive strains such as BALB/c. Upon exposure to LT, the NLRP1b inflammasome activates caspase-1 to produce mature IL-1β and induce pyroptosis. Both processes are believed to depend on autoproteolysed caspase-1. In contrast to human NLRP1, mouse NLRP1b lacks an N-terminal pyrin domain (PYD), indicating that the assembly of the NLRP1b inflammasome does not require the adaptor apoptosis-associated speck-like protein containing a CARD (ASC). LT-induced NLRP1b inflammasome activation was shown to be impaired upon inhibition of potassium efflux, which is known to play a major role in NLRP3 inflammasome formation and ASC dimerization. We investigated whether NLRP3 and/or ASC were required for caspase-1 activation upon LT stimulation in the BALB/c background. The NLRP1b inflammasome activation was assessed in both macrophages and dendritic cells lacking either ASC or NLRP3. Upon LT treatment, the absence of NLRP3 did not alter the NLRP1b inflammasome activity. Surprisingly, the absence of ASC resulted in IL-1β cleavage and pyroptosis, despite the absence of caspase-1 autoprocessing activity. By reconstituting caspase-1/caspase-11−/− cells with a noncleavable or catalytically inactive mutant version of caspase-1, we directly demonstrated that noncleavable caspase-1 is fully active in response to the NLRP1b activator LT, whereas it is nonfunctional in response to the NLRP3 activator nigericin. Taken together, these results establish variable requirements for caspase-1 cleavage depending on the pathogen and the responding NLR. PMID:25404286

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

    PubMed

    Moul, Caroline; Dobson-Stone, Carol; Brennan, John; Hawes, David J; Dadds, Mark R

    2015-01-01

    The serotonin system is thought to play a role in the aetiology of callous-unemotional (CU) traits in children. Previous research identified a functional single nucleotide polymorphism (SNP) from the promoter region of the serotonin 1B receptor gene as being associated with CU traits in boys with antisocial behaviour problems. This research tested the hypothesis that CU traits are associated with reduced methylation of the promoter region of the serotonin 1B receptor gene due to the influence of methylation on gene expression. Participants (N = 117) were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered a saliva sample from which the genotype of a SNP from the promoter region of the serotonin 1B receptor gene and the methylation levels of 30 CpG sites from 3 CpG regions surrounding the location of this polymorphism were assayed. Lower levels of serotonin 1B receptor gene methylation were associated with higher levels of CU traits. This relationship, however, was found to be moderated by genotype and carried exclusively by two CpG sites for which levels of methylation were negatively associated with overall methylation levels in this region of the gene. Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of CU traits. Furthermore, the results suggest that there may be two pathways to CU traits that involve methylation of the serotonin 1B receptor gene; one that is driven by a genotypic risk and another that is associated with risk for generally increased levels of methylation. Future research that aims to replicate and further investigate these results is required. PMID:25993020

  8. 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

  9. Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B.

    PubMed

    Wallace, R H; Scheffer, I E; Parasivam, G; Barnett, S; Wallace, G B; Sutherland, G R; Berkovic, S F; Mulley, J C

    2002-05-14

    Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome. PMID:12011299

  10. EEF1D modulates proliferation and epithelial-mesenchymal transition in oral squamous cell carcinoma.

    PubMed

    Flores, Isadora L; Kawahara, Rebeca; Miguel, Márcia C C; Granato, Daniela C; Domingues, Romênia R; Macedo, Carolina C S; Carnielli, Carolina M; Yokoo, Sami; Rodrigues, Priscila C; Monteiro, Bárbara V B; Oliveira, Carine E; Salmon, Cristiane R; Nociti, Francisco H; Lopes, Márcio A; Santos-Silva, Alan; Winck, Flavia V; Coletta, Ricardo D; Paes Leme, Adriana F

    2016-05-01

    EEF1D (eukaryotic translation elongation factor 1δ) is a subunit of the elongation factor 1 complex of proteins that mediates the elongation process during protein synthesis via enzymatic delivery of aminoacyl-tRNAs to the ribosome. Although the functions of EEF1D in the translation process are recognized, EEF1D expression was found to be unbalanced in tumours. In the present study, we demonstrate the overexpression of EEF1D in OSCC (oral squamous cell carcinoma), and revealed that EEF1D and protein interaction partners promote the activation of cyclin D1 and vimentin proteins. EEF1D knockdown in OSCC reduced cell proliferation and induced EMT (epithelial-mesenchymal transition) phenotypes, including cell invasion. Taken together, these results define EEF1D as a critical inducer of OSCC proliferation and EMT. PMID:26823560

  11. 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

  12. 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.

  13. 52. G.E.H. photographer August 1930 1HUM1B #59, OILING OPERATIONS, GEH ...

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

    52. G.E.H. photographer August 1930 1-HUM-1-B #59, OILING OPERATIONS, GEH 8-30. Stamped office copy. - Redwood National & State Parks Roads, California coast from Crescent City to Trinidad, Crescent City, Del Norte County, CA

  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. Nature of Pi1B pulsations as inferred from ground and satellite observations

    NASA Astrophysics Data System (ADS)

    Lessard, M. R.; Lund, E. J.; Jones, S. L.; Arnoldy, R. L.; Posch, J. L.; Engebretson, M. J.; Hayashi, K.

    2006-07-01

    The occurrence of Pi1B pulsations is well-documented, including the fact that these pulsations can be observed both on the ground and at geosynchronous orbit at substorm onset, although information about their propagation characteristics has been lacking. In this paper, data are presented from FAST, GOES 9 and various ground stations that show the simultaneous observations of Pi1B pulsations in association with an onset. While the data at GOES 9 show that the pulsations are compressional in nature, data from FAST show the presence of shear mode waves, implying that Pi1B mode conversion of some type must take place in the region between geosynchronous orbit and FAST altitudes. An additional point is that Pi1B pulsations apparently propagate through auroral phenomena routinely, begging the question of what role they may play.

  16. Prediction and verification of novel peptide targets of protein tyrosine phosphatase 1B.

    PubMed

    Li, Xun; Köhn, Maja

    2016-08-01

    Phosphotyrosine peptides are useful starting points for inhibitor design and for the search for protein tyrosine phosphatase (PTP) phosphoprotein substrates. To identify novel phosphopeptide substrates of PTP1B, we developed a computational prediction protocol based on a virtual library of protein sequences with known phosphotyrosine sites. To these we applied sequence-based methods, biologically meaningful filters and molecular docking. Five peptides were selected for biochemical testing of their potential as PTP1B substrates. All five peptides were equally good substrates for PTP1B compared to a known peptide substrate whereas appropriate control peptides were not recognized, showing that our protocol can be used to identify novel peptide substrates of PTP1B. PMID:27025565

  17. Gfi1 and Gfi1b Repress Rag Transcription in Plasmacytoid Dendritic Cells In Vitro

    PubMed Central

    Chow, Kwan T.; Schulz, Danae; McWhirter, Sarah M.; Schlissel, Mark S.

    2013-01-01

    Growth factor independence genes (Gfi1 and Gfi1b) repress recombination activating genes (Rag) transcription in developing B lymphocytes. Because all blood lineages originate from hematopoietic stem cells (HSCs) and different lineage progenitors have been shown to share transcription factor networks prior to cell fate commitment, we hypothesized that GFI family proteins may also play a role in repressing Rag transcription or a global lymphoid transcriptional program in other blood lineages. We tested the level of Rag transcription in various blood cells when Gfi1 and Gfi1b were deleted, and observed an upregulation of Rag expression in plasmacytoid dendritic cells (pDCs). Using microarray analysis, we observed that Gfi1 and Gfi1b do not regulate a lymphoid or pDC-specific transcriptional program. This study establishes a role for Gfi1 and Gfi1b in Rag regulation in a non-B lineage cell type. PMID:24086657

  18. Metabolic Profiling Reveals PAFAH1B3 as a Critical Driver of Breast Cancer Pathogenicity

    PubMed Central

    Mulvihill, Melinda M.; Benjamin, Daniel I.; Ji, Xiaodan; Le Scolan, Erwan; Louie, Sharon M.; Shieh, Alice; Green, McKenna; Narasimhalu, Tara; Morris, Patrick J.; Luo, Kunxin; Nomura, Daniel K.

    2014-01-01

    Many studies have identified metabolic pathways that underlie cellular transformation, but the metabolic drivers of cancer progression remain less well understood. The Hippo transducer pathway has been shown to confer malignant traits on breast cancer cells. In this study, we used metabolic mapping platforms to identify biochemical drivers of cellular transformation and malignant progression driven through RAS and the Hippo pathway in breast cancer, and identified platelet activating factor acetylhydrolase 1B3 (PAFAH1B3) as a key metabolic driver of breast cancer pathogenicity that is upregulated in primary human breast tumors and correlated with poor prognosis. Metabolomic profiling suggests that PAFAH1B3 inactivation attenuates cancer pathogenicity through enhancing tumor-suppressing signaling lipids. Our studies provide a map of altered metabolism that underlies breast cancer progression and put forth PAFAH1B3 as a critical metabolic node in breast cancer. PMID:24954006

  19. 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.

  20. BAZ1B is dispensable for H2AX phosphorylation on Tyrosine 142 during spermatogenesis

    PubMed Central

    Broering, Tyler J.; Wang, Yuan-Liang; Pandey, Ram Naresh; Hegde, Rashmi S.; Wang, Shao-Chun; Namekawa, Satoshi H.

    2015-01-01

    ABSTRACT Meiosis is precisely regulated by the factors involved in DNA damage response in somatic cells. Among them, phosphorylation of H2AX on Serine 139 (γH2AX) is an essential signal for the silencing of unsynapsed sex chromosomes during male meiosis. However, it remains unknown how adjacent H2AX phosphorylation on Tyrosine 142 (pTyr142) is regulated in meiosis. Here we investigate the meiotic functions of BAZ1B (WSTF), the only known Tyr142 kinase in somatic cells, using mice possessing a conditional deletion of BAZ1B. Although BAZ1B deletion causes ectopic γH2AX signals on synapsed autosomes during the early pachytene stage, BAZ1B is dispensable for fertility and critical events during spermatogenesis. BAZ1B deletion does not alter events on unsynapsed axes and pericentric heterochromatin formation. Furthermore, BAZ1B is dispensable for localization of the ATP-dependent chromatin remodeling protein SMARCA5 (SNF2h) during spermatogenesis despite the complex formation between BAZ1B and SMARCA5, known as the WICH complex, in somatic cells. Notably, pTyr142 is regulated independently of BAZ1B and is dephosphorylated on the sex chromosomes during meiosis in contrast with the presence of adjacent γH2AX. Dephosphorylation of pTyr142 is regulated by MDC1, a binding partner of γH2AX. These results reveal the distinct regulation of two adjacent phosphorylation sites of H2AX during meiosis, and suggest that another kinase mediates Tyr142 phosphorylation. PMID:25979708

  1. Structure and Promoter Characterization of Aldo-Keto Reductase Family 1 B10 Gene

    PubMed Central

    Liu, Ziwen; Zhong, Linlin; Krishack, Paulette A; Robbins, Sarah; Cao, Julia X; Zhao, Yupei; Chung, Stephen; Cao, Deliang

    2009-01-01

    Aldo-keto reductase family 1 member B10 (AKR1B10) is overexpressed in human hepatocellular carcinoma, lung squamous carcinoma, and lung adenocarcinoma in smokers. Our recent studies have showed that AKR1B10 plays a critical role in the growth and proliferation of cancer cells by detoxifying reactive carbonyls and regulating fatty acid biosynthesis. However, little is known about the regulatory mechanisms of AKR1B10 expression. In this study, we determined the structure of AKR1B10 gene and characterized its promoter. The results demonstrated that AKR1B10 consists of 10 exons and 9 introns, stretching approximately 13.8 kb. A 5′-RACE study determined the transcriptional start site of AKR1B10 at 320 bp upstream of the ATG translational start codon. A TATA-like (TAATAA) and a CAAT box are present from −145 to −140 bp and −193 to −190 bp upstream of the transcriptional start site, respectively. Motif analysis recognized multiple putative oncogenic and tumor suppressor protein binding sites in the AKR1B10 promoter, including c-Ets-1, C/EBP, AP-1, and p53, but osmolytic response elements were not found. A -4,091 bp of the 5′-flanking fragment of the AKR1B10 gene was capable of driving GFP and luciferase reporter gene expression in HepG2 cells derived from human hepatocellular carcinoma; progressive 5′-deletions revealed that a −255 bp fragment possesses full promoter activity. PMID:19236911

  2. B1b cells recognize protective antigens after natural infection and vaccination.

    PubMed

    Cunningham, Adam F; Flores-Langarica, Adriana; Bobat, Saeeda; Dominguez Medina, Carmen C; Cook, Charlotte N L; Ross, Ewan A; Lopez-Macias, Constantino; Henderson, Ian R

    2014-01-01

    There are multiple, distinct B-cell populations in human beings and other animals such as mice. In the latter species, there is a well-characterized subset of B-cells known as B1 cells, which are enriched in peripheral sites such as the peritoneal cavity but are rare in the blood. B1 cells can be further subdivided into B1a and B1b subsets. There may be additional B1 subsets, though it is unclear if these are distinct populations or stages in the developmental process to become mature B1a and B1b cells. A limitation in understanding B1 subsets is the relative paucity of specific surface markers. In contrast to mice, the existence of B1 cells in human beings is controversial and more studies are needed to investigate the nature of these enigmatic cells. Examples of B1b antigens include pneumococcal polysaccharide and the Vi antigen from Salmonella Typhi, both used routinely as vaccines in human beings and experimental antigens such as haptenated-Ficoll. In addition to inducing classical T-dependent responses some proteins are B1b antigens and can induce T-independent (TI) immunity, examples include factor H binding protein from Borrelia hermsii and porins from Salmonella. Therefore, B1b antigens can be proteinaceous or non-proteinaceous, induce TI responses, memory, and immunity, they exist in a diverse range of pathogenic bacteria, and a single species can contain multiple B1b antigens. An unexpected benefit to studying B1b cells is that they appear to have a propensity to recognize protective antigens in bacteria. This suggests that studying B1b cells may be rewarding for vaccine design as immunoprophylactic and immunotherapeutic interventions become more important due to the decreasing efficacy of small molecule antimicrobials. PMID:25400633

  3. 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

  4. 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

  5. B1b Cells Recognize Protective Antigens after Natural Infection and Vaccination

    PubMed Central

    Cunningham, Adam F.; Flores-Langarica, Adriana; Bobat, Saeeda; Dominguez Medina, Carmen C.; Cook, Charlotte N. L.; Ross, Ewan A.; Lopez-Macias, Constantino; Henderson, Ian R.

    2014-01-01

    There are multiple, distinct B-cell populations in human beings and other animals such as mice. In the latter species, there is a well-characterized subset of B-cells known as B1 cells, which are enriched in peripheral sites such as the peritoneal cavity but are rare in the blood. B1 cells can be further subdivided into B1a and B1b subsets. There may be additional B1 subsets, though it is unclear if these are distinct populations or stages in the developmental process to become mature B1a and B1b cells. A limitation in understanding B1 subsets is the relative paucity of specific surface markers. In contrast to mice, the existence of B1 cells in human beings is controversial and more studies are needed to investigate the nature of these enigmatic cells. Examples of B1b antigens include pneumococcal polysaccharide and the Vi antigen from Salmonella Typhi, both used routinely as vaccines in human beings and experimental antigens such as haptenated-Ficoll. In addition to inducing classical T-dependent responses some proteins are B1b antigens and can induce T-independent (TI) immunity, examples include factor H binding protein from Borrelia hermsii and porins from Salmonella. Therefore, B1b antigens can be proteinaceous or non-proteinaceous, induce TI responses, memory, and immunity, they exist in a diverse range of pathogenic bacteria, and a single species can contain multiple B1b antigens. An unexpected benefit to studying B1b cells is that they appear to have a propensity to recognize protective antigens in bacteria. This suggests that studying B1b cells may be rewarding for vaccine design as immunoprophylactic and immunotherapeutic interventions become more important due to the decreasing efficacy of small molecule antimicrobials. PMID:25400633

  6. Association Between 5HT1b Receptor Gene and Methamphetamine Dependence

    PubMed Central

    Ujike, H; Kishimoto, M; Okahisa, Y; Kodama, M; Takaki, M; Inada, T; Uchimura, N; Yamada, M; Iwata, N; Iyo, M; Sora, I; Ozaki, N

    2011-01-01

    Several lines of evidence implicate serotonergic dysfunction in diverse psychiatric disorders including anxiety, depression, and drug abuse. Mice with a knock-out of the 5HT1b receptor gene (HTR1B) displayed increased locomotor response to cocaine and elevated motivation to self-administer cocaine and alcohol. Previous genetic studies showed significant associations of HTR1B with alcohol dependence and substance abuse, but were followed by inconsistent results. We examined a case-control genetic association study of HTR1B with methamphetamine-dependence patients in a Japanese population. The subjects were 231 patients with methamphetamine dependence, 214 of whom had a co-morbidity of methamphetamine psychosis, and 248 age- and sex-matched healthy controls. The three single nucleotide polymorphisms (SNPs), rs130058 (A-165T), rs1228814 (A-700C) and rs1228814 (A+1180G) of HTR1B were genotyped. There was no significant difference in allelic and genotypic distributions of the SNPs between methamphetamine dependence and the control. Genetic associations of HTR1B were tested with several clinical phenotypes of methamphetamine dependence and/or psychosis, such as age at first abuse, duration of latency from the first abuse to onset of psychosis, prognosis of psychosis after therapy, and complication of spontaneous relapse of psychotic state. There was, however, no asscocation between any SNP and the clinical phenotypes. Haplotype analyses showed the three SNPs examined were within linkage disequilibrium, which implied that the three SNPs covered the whole HTR1B, and distribution of estimated haplotype frequency was not different between the groups. The present findings may indicate that HTR1B does not play a major role in individual susceptibility to methamphetamine dependence or development of methamphetamine-induced psychosis. PMID:21886584

  7. MODIS technical report series. Volume 3: MODIS airborne simulator level 1B data user's guide

    NASA Technical Reports Server (NTRS)

    Gumley, Liam E.; Hubanks, Paul A.; Masuoka, Edward J.

    1994-01-01

    The purpose of this document is to describe the characteristics of moderate resolution imaging spectroradiometer (MODIS) airborne simulator level 1B data, the calibration and geolocation methods used in processing, the structure and format of the level 1B data files, and methods for accessing the data. The MODIS airborne simulator is a scanning spectrometer which flies on a NASA ER-2 and provides spectral information similar to that which will be provided by the MODIS.

  8. 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

  9. 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.

  10. 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

  11. Impairment of calcium mobilization in phagocytic cells in glycogen storage disease type 1b.

    PubMed

    Korchak, H M; Garty, B Z; Stanley, C A; Baker, L; Douglas, S D; Kilpatrick, L

    1993-01-01

    Patients with glycogen storage disease (GSD) type 1b, in contrast to patients with GSD 1a, are susceptible to recurrent bacterial infections suggesting defective phagocytic function. We have demonstrated a selective defect in respiratory burst activity but not in degranulation by phagocytic cells in GSD 1b but not in GSD 1a. The respiratory burst abnormality in phagocytic cells from GSD 1b patients was associated with impaired calcium mobilization, whereas these processes were normal in GSD 1a patients. Therefore, the alteration in calcium mobilization was an indication of a signalling defect in phagocytic cells from GSD 1b. However, calcium mobilization was normal in lymphocytes, indicating that defective calcium mobilization was not a global finding in circulating leukocytes, but was specific to phagocytic cells. Calcium mobilization in response to ionomycin was reduced suggesting decreased calcium stores in GSD 1b neutrophils. Therefore, altered phagocytic cell function in GSD 1b patients appears to be associated with diminished calcium mobilization and defective calcium stores. This defective calcium signalling was associated with a selective defect in respiratory burst activity but not degranulation. PMID:8319725

  12. 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

  13. 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.

  14. Structural and functional analysis of the mouse mdr1b gene promoter.

    PubMed

    Cohen, D; Piekarz, R L; Hsu, S I; DePinho, R A; Carrasco, N; Horwitz, S B

    1991-02-01

    The overproduction of P-glycoprotein, an integral membrane protein thought to function as a drug efflux pump, is the hallmark of the multidrug resistance phenotype. In murine multidrug resistant J774.2 cell lines, distinct mdr genes, mdr1a and mdr1b, encode unique P-glycoprotein isoforms. To examine the transcriptional regulation of the mdr1b gene, its promoter was isolated and characterized. The transcription initiation site was mapped by primer extension, and the 5'-flanking region was sequenced. Several potential regulatory elements were identified in this region. A transient expression vector was constructed by fusion of 540 base pairs of 5'-flanking sequence and part of the first untranslated exon to the chloramphenicol acetyltransferase (CAT) gene. When transfected into monkey kidney COS-1, rat pituitary GH3 or T47D human breast cells, the mdr1b 5'-flanking sequences were capable of driving CAT expression. Transient transfection studies using deletion subclones of the mdr1b-CAT construct were done to locate potential cis-acting sequences. The studies indicate the presence of cis-acting elements in the 5'-flanking region of the mdr1b gene. The implications of these findings for expression and regulation of the mdr1b gene are discussed. PMID:1671222

  15. An evolutionarily-conserved role for murine Ly-1 B cells in protection against bacterial infections.

    PubMed

    Lalor, P A

    1991-01-01

    The murine Ly-1 B cell lineage, although comprising only a minority of peripheral IgM+ B cells, secretes a major proportion of the IgM antibodies occurring naturally in serum. Ly-1 B cells also seed a large number of IgA+ plasma cells to the gut walls, thereby contributing significantly to production of natural IgA antibodies in response to chronic stimulation by the normal gut flora. Apart from these naturally-produced antibodies, Ly-1 B cells also produce specific antibodies following deliberate immunisation with the bacterial cell wall antigens, phosphorylcholine and dextran. The inability of the X-linked immunodeficient CBA/N mice to produce antibody responses to these two antigens is overcome by reconstitution with normal Ly-1 B cells from the parental CBA strain. Ly-1 B cells therefore appear to play a dominant role in natural immunity and protection against bacterial infections. The compartmentalisation of development and function within murine B cells is suggestive of an evolutionary structuring of the murine immune system, with Ly-1 B cells representing a conserved, primitive B cell lineage and retaining key, associated functions. PMID:1742426

  16. Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound.

    PubMed

    Qin, Zhaohong; Pandey, Nihar R; Zhou, Xun; Stewart, Chloe A; Hari, Aswin; Huang, Hua; Stewart, Alexandre F R; Brunel, Jean Michel; Chen, Hsiao-Huei

    2015-02-27

    Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a "first-in-class" highly selective inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-β (IRβ), Akt and GSK3β. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes. PMID:25623533

  17. The Nuclear Envelope Protein, LAP1B, Is a Novel Protein Phosphatase 1 Substrate

    PubMed Central

    Santos, Mariana; Rebelo, Sandra; Van Kleeff, Paula J. M.; Kim, Connie E.; Dauer, William T.; Fardilha, Margarida; da Cruz e Silva, Odete A.; da Cruz e Silva, Edgar F.

    2013-01-01

    Protein phosphatase 1 (PP1) binding proteins are quintessential regulators, determining substrate specificity and defining subcellular localization and activity of the latter. Here, we describe a novel PP1 binding protein, the nuclear membrane protein lamina associated polypeptide 1B (LAP1B), which interacts with the DYT1 dystonia protein torsinA. The PP1 binding domain in LAP1B was here identified as the REVRF motif at amino acids 55-59. The LAP1B:PP1 complex can be immunoprecipitated from cells in culture and rat cortex and the complex was further validated by yeast co-transformations and blot overlay assays. PP1, which is enriched in the nucleus, binds to the N-terminal nuclear domain of LAP1B, as shown by immunocolocalization and domain specific binding studies. PP1 dephosphorylates LAP1B, confirming the physiological relevance of this interaction. These findings place PP1 at a key position to participate in the pathogenesis of DYT1 dystonia and related nuclear envelope-based diseases. PMID:24116158

  18. 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

  19. A Contextual Fire Detection Algorithm for Simulated HJ-1B Imagery

    PubMed Central

    Qian, Yonggang; Yan, Guangjian; Duan, Sibo; Kong, Xiangsheng

    2009-01-01

    The HJ-1B satellite, which was launched on September 6, 2008, is one of the small ones placed in the constellation for disaster prediction and monitoring. HJ-1B imagery was simulated in this paper, which contains fires of various sizes and temperatures in a wide range of terrestrial biomes and climates, including RED, NIR, MIR and TIR channels. Based on the MODIS version 4 contextual algorithm and the characteristics of HJ-1B sensor, a contextual fire detection algorithm was proposed and tested using simulated HJ-1B data. It was evaluated by the probability of fire detection and false alarm as functions of fire temperature and fire area. Results indicate that when the simulated fire area is larger than 45 m2 and the simulated fire temperature is larger than 800 K, the algorithm has a higher probability of detection. But if the simulated fire area is smaller than 10 m2, only when the simulated fire temperature is larger than 900 K, may the fire be detected. For fire areas about 100 m2, the proposed algorithm has a higher detection probability than that of the MODIS product. Finally, the omission and commission error were evaluated which are important factors to affect the performance of this algorithm. It has been demonstrated that HJ-1B satellite data are much sensitive to smaller and cooler fires than MODIS or AVHRR data and the improved capabilities of HJ-1B data will offer a fine opportunity for the fire detection. PMID:22399950

  20. 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

  1. Endogenous N-terminal Domain Cleavage Modulates α1D-Adrenergic Receptor Pharmacodynamics.

    PubMed

    Kountz, Timothy S; Lee, Kyung-Soon; Aggarwal-Howarth, Stacey; Curran, Elizabeth; Park, Ji-Min; Harris, Dorathy-Ann; Stewart, Aaron; Hendrickson, Joseph; Camp, Nathan D; Wolf-Yadlin, Alejandro; Wang, Edith H; Scott, John D; Hague, Chris

    2016-08-26

    The α1D-adrenergic receptor (ADRA1D) is a key regulator of cardiovascular, prostate, and central nervous system functions. This clinically relevant G protein-coupled receptor has proven difficult to study, as it must form an obligate modular homodimer containing the PDZ proteins scribble and syntrophin or become retained in the endoplasmic reticulum as non-functional protein. We previously determined that targeted removal of the N-terminal (NT) 79 amino acids facilitates ADRA1D plasma membrane expression and agonist-stimulated functional responses. However, whether such an event occurs in physiological contexts was unknown. Herein, we report the ADRA1D is subjected to innate NT processing in cultured human cells. SNAP near-infrared imaging and tandem-affinity purification revealed the ADRA1D is expressed as both full-length and NT truncated forms in multiple human cell lines. Serial truncation mapping identified the cleavage site as Leu(90)/Val(91) in the 95-amino acid ADRA1D NT domain, suggesting human cells express a Δ1-91 ADRA1D species. Tandem-affinity purification MS/MS and co-immunoprecipitation analysis indicate NT processing of ADRA1D is not required to form scribble-syntrophin macromolecular complexes. Yet, label-free dynamic mass redistribution signaling assays demonstrate that Δ1-91 ADRA1D agonist responses were greater than WT ADRA1D. Mutagenesis of the cleavage site nullified the processing event, resulting in ADRA1D agonist responses less than the WT receptor. Thus, we propose that processing of the ADRA1D NT domain is a physiological mechanism employed by cells to generate a functional ADRA1D isoform with optimal pharmacodynamic properties. PMID:27382054

  2. Phosphoinositide-specific Phospholipase C β 1b (PI-PLCβ1b) Interactome: Affinity Purification-Mass Spectrometry Analysis of PI-PLCβ1b with Nuclear Protein*

    PubMed Central

    Piazzi, Manuela; Blalock, William L.; Bavelloni, Alberto; Faenza, Irene; D'Angelo, Antonietta; Maraldi, Nadir M.; Cocco, Lucio

    2013-01-01

    Two isoforms of inositide-dependent phospholipase C β1 (PI-PLCβ1) are generated by alternative splicing (PLCβ1a and PLCβ1b). Both isoforms are present within the nucleus, but in contrast to PLCβ1a, the vast majority of PLCβ1b is nuclear. In mouse erythroid leukemia cells, PI-PLCβ1 is involved in the regulation of cell division and the balance between cell proliferation and differentiation. It has been demonstrated that nuclear localization is crucial for the enzymatic function of PI-PLCβ1, although the mechanism by which this nuclear import occurs has never been fully characterized. The aim of this study was to characterize both the mechanism of nuclear localization and the molecular function of nuclear PI-PLCβ1 by identifying its interactome in Friend's erythroleukemia isolated nuclei, utilizing a procedure that coupled immuno-affinity purification with tandem mass spectrometry analysis. Using this procedure, 160 proteins were demonstrated to be in association with PI-PLCβ1b, some of which have been previously characterized, such as the splicing factor SRp20 (Srsf3) and Lamin B (Lmnb1). Co-immunoprecipitation analysis of selected proteins confirmed the data obtained via mass spectrometry. Of particular interest was the identification of the nuclear import proteins Kpna2, Kpna4, Kpnb1, Ran, and Rangap1, as well as factors involved in hematological malignancies and several anti-apoptotic proteins. These data give new insight into possible mechanisms of nuclear trafficking and functioning of this critical signaling molecule. PMID:23665500

  3. [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

  4. Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis

    PubMed Central

    Jankovic, Slobodan M

    2010-01-01

    Multiple sclerosis (MS) is chronic inflammatory and demyelinating disease with either a progressive (10%–15%) or relapsing-remitting (85%–90%) course. The pathological hallmarks of MS are lesions of both white and grey matter in the central nervous system. The onset of the disease is usually around 30 years of age. The patients experience an acute focal neurologic dysfunction which is not characteristic, followed by partial or complete recovery. Acute episodes of neurologic dysfunction with diverse signs and symptoms will then recur throughout the life of a patient, with periods of partial or complete remission and clinical stability in between. Currently, there are several therapeutic options for MS with disease-modifying properties. Immunomodulatory therapy with interferon beta-1b (IFN-β1b) or -1a, glatiramer and natalizumab shows similar efficacy; in a resistant or intolerant patient, the most recently approved therapeutic option is mitoxantrone. IFN-β1b in patients with MS binds to specific receptors on surface of immune cells, changing the expression of several genes and leading to a decrease in quantity of cell-associated adhesion molecules, inhibition of major histocompatibility complex class II expression and reduction in inflammatory cells migration into the central nervous system. After 2 years of treatment, IFN-β1b reduces the risk of development of clinically defined MS from 45% (with placebo) to 28% (with IFN-β1b). It also reduces relapses for 34% (1.31 exacerbations annually with placebo and 0.9 with higher dose of IFN-β1b) and makes 31% more patients relapse-free. In secondary-progressive disease annual rate of progression is 3% lower with IFN-β1b. In recommended doses IFN-β1b causes the following frequent adverse effects: injection site reactions (redness, discoloration, inflammation, pain, necrosis and non-specific reactions), insomnia, influenza-like syndrome, asthenia, headache, myalgia, hypoesthesia, nausea, paresthesia, myasthenia

  5. Myelin protein zero gene sequencing diagnoses Charcot-Marie-Tooth Type 1B disease

    SciTech Connect

    Su, Y.; Zhang, H.; Madrid, R.

    1994-09-01

    Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, affects about 1 in 2600 people in Norway and is found worldwide. CMT Type 1 (CMT1) has slow nerve conduction with demyelinated Schwann cells. Autosomal dominant CMT Type 1B (CMT1B) results from mutations in the myelin protein zero gene which directs the synthesis of more than half of all Schwann cell protein. This gene was mapped to the chromosome 1q22-1q23.1 borderline by fluorescence in situ hybridization. The first 7 of 7 reported CMT1B mutations are unique. Thus the most effective means to identify CMT1B mutations in at-risk family members and fetuses is to sequence the entire coding sequence in dominant or sporadic CMT patients without the CMT1A duplication. Of the 19 primers used in 16 pars to uniquely amplify the entire MPZ coding sequence, 6 primer pairs were used to amplify and sequence the 6 exons. The DyeDeoxy Terminator cycle sequencing method used with four different color fluorescent lables was superior to manual sequencing because it sequences more bases unambiguously from extracted genomic DNA samples within 24 hours. This protocol was used to test 28 CMT and Dejerine-Sottas patients without CMT1A gene duplication. Sequencing MPZ gene-specific amplified fragments identified 9 polymorphic sites within the 6 exons that encode the 248 amino acid MPZ protein. The large number of major CMT1B mutations identified by single strand sequencing are being verified by reverse strand sequencing and when possible, by restriction enzyme analysis. This protocol can be used to distringuish CMT1B patients from othre CMT phenotypes and to determine the CMT1B status of relatives both presymptomatically and prenatally.

  6. Evaluation of Interferon Resistance in Newly Established Genotype 1b Hepatitis C Virus Cell Culture System

    PubMed Central

    Taniguchi, Miki; Tasaka-Fujita, Megumi; Nakagawa, Mina; Watanabe, Takako; Kawai-Kitahata, Fukiko; Otani, Satoshi; Goto, Fumio; Nagata, Hiroko; Kaneko, Shun; Nitta, Sayuri; Murakawa, Miyako; Nishimura-Sakurai, Yuki; Azuma, Seishin; Itsui, Yasuhiro; Mori, Kenichi; Yagi, Shintaro; Kakinuma, Sei; Asahina, Yasuhiro; Watanabe, Mamoru

    2016-01-01

    Background and Aims: The hepatitis C virus (HCV) genotype 1b is known to exhibit treatment resistance with respect to interferon (IFN) therapy. Substitution of amino acids 70 and 91 in the core region of the 1b genotype is a significant predictor of liver carcinogenesis and poor response to pegylated-IFN-α and ribavirin therapy. However, the molecular mechanism has not yet been clearly elucidated because of limitations of the HCV genotype 1b infectious model. Recently, the TPF1-M170T HCV genotype 1b cell culture system was established, in which the clone successfully replicates and infects Huh-7-derived Huh7-ALS32.50 cells. Therefore, the purpose of this study was to compare IFN resistance in various HCV clones using this system. Methods: HCV core amino acid substitutions R70Q and L91M were introduced to the TPF1-M170T clone and then transfected into Huh7-ALS32.50 cells. To evaluate the production of each virus, intracellular HCV core antigens were measured. Results were confirmed with Western blot analysis using anti-NS5A antibodies, and IFN sensitivity was subsequently measured. Results: Each clone was transfected successfully compared with JFH-1, with a significant difference in intracellular HCV core antigen (p < 0.05), an indicator of continuous HCV replication. Among all clones, L91M showed the highest increase in the HCV core antigen and HCV protein. There was no significant resistance against IFN treatment in core substitutions; however, IFN sensitivity was significantly different between the wildtype core and JFH-1 (p < 0.05). Conclusions: A novel genotype 1b HCV cell culture was constructed with core amino acid substitutions, which demonstrated IFN resistance of genotype 1b. This system will be useful for future analyses into the mechanisms of HCV genotype 1b treatment. PMID:27047766

  7. Seasonally Changing Cryptochrome 1b Expression in the Retinal Ganglion Cells of a Migrating Passerine Bird.

    PubMed

    Nießner, Christine; Gross, Julia Christina; Denzau, Susanne; Peichl, Leo; Fleissner, Gerta; Wiltschko, Wolfgang; Wiltschko, Roswitha

    2016-01-01

    Cryptochromes, blue-light absorbing proteins involved in the circadian clock, have been proposed to be the receptor molecules of the avian magnetic compass. In birds, several cryptochromes occur: Cryptochrome 2, Cryptochrome 4 and two splice products of Cryptochrome 1, Cry1a and Cry1b. With an antibody not distinguishing between the two splice products, Cryptochrome 1 had been detected in the retinal ganglion cells of garden warblers during migration. A recent study located Cry1a in the outer segments of UV/V-cones in the retina of domestic chickens and European robins, another migratory species. Here we report the presence of cryptochrome 1b (eCry1b) in retinal ganglion cells and displaced ganglion cells of European Robins, Erithacus rubecula. Immuno-histochemistry at the light microscopic and electron microscopic level showed eCry1b in the cell plasma, free in the cytosol as well as bound to membranes. This is supported by immuno-blotting. However, this applies only to robins in the migratory state. After the end of the migratory phase, the amount of eCry1b was markedly reduced and hardly detectable. In robins, the amount of eCry1b in the retinal ganglion cells varies with season: it appears to be strongly expressed only during the migratory period when the birds show nocturnal migratory restlessness. Since the avian magnetic compass does not seem to be restricted to the migratory phase, this seasonal variation makes a role of eCry1b in magnetoreception rather unlikely. Rather, it could be involved in physiological processes controlling migratory restlessness and thus enabling birds to perform their nocturnal flights. PMID:26953690

  8. Seasonally Changing Cryptochrome 1b Expression in the Retinal Ganglion Cells of a Migrating Passerine Bird

    PubMed Central

    Nießner, Christine; Gross, Julia Christina; Denzau, Susanne; Peichl, Leo; Fleissner, Gerta; Wiltschko, Wolfgang; Wiltschko, Roswitha

    2016-01-01

    Cryptochromes, blue-light absorbing proteins involved in the circadian clock, have been proposed to be the receptor molecules of the avian magnetic compass. In birds, several cryptochromes occur: Cryptochrome 2, Cryptochrome 4 and two splice products of Cryptochrome 1, Cry1a and Cry1b. With an antibody not distinguishing between the two splice products, Cryptochrome 1 had been detected in the retinal ganglion cells of garden warblers during migration. A recent study located Cry1a in the outer segments of UV/V-cones in the retina of domestic chickens and European robins, another migratory species. Here we report the presence of cryptochrome 1b (eCry1b) in retinal ganglion cells and displaced ganglion cells of European Robins, Erithacus rubecula. Immuno-histochemistry at the light microscopic and electron microscopic level showed eCry1b in the cell plasma, free in the cytosol as well as bound to membranes. This is supported by immuno-blotting. However, this applies only to robins in the migratory state. After the end of the migratory phase, the amount of eCry1b was markedly reduced and hardly detectable. In robins, the amount of eCry1b in the retinal ganglion cells varies with season: it appears to be strongly expressed only during the migratory period when the birds show nocturnal migratory restlessness. Since the avian magnetic compass does not seem to be restricted to the migratory phase, this seasonal variation makes a role of eCry1b in magnetoreception rather unlikely. Rather, it could be involved in physiological processes controlling migratory restlessness and thus enabling birds to perform their nocturnal flights. PMID:26953690

  9. Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence?

    PubMed

    Hart, Amy B; Lynch, Kevin G; Farrer, Lindsay; Gelernter, Joel; Kranzler, Henry R

    2016-07-01

    Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding. PMID:25828809

  10. Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A

    PubMed Central

    Gupta, Swati; Fahiminiya, Somayyeh; Wang, Tracy; Dempsey Nunez, Laura; Rosenblatt, David S.; Gibson, William T.; Gilfix, Brian; Bergeron, John J. M.; Jerome-Majewska, Loydie A.

    2016-01-01

    Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (p.M400I) and MAN1B1 c.1000C>T (p.R334C), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in SEC23A only. Mutations in SEC23A are responsible for craniolenticosultura dysplasia (CLSD). CLSD patients are short, have late-closing fontanels, and have reduced procollagen (pro-COL1A1) secretion because of abnormal pro-COL1A1 retention in the endoplasmic reticulum (ER). The mutation we identified in MAN1B1 was previously associated with reduced MAN1B1 protein and congenital disorders of glycosylation (CDG). CDG patients are also short, are obese, and have abnormal glycan remodeling. Molecular analysis of fibroblasts from the family revealed normal levels of SEC23A in all cells and reduced levels of MAN1B1 in cells with heterozygous or homozygous mutations in SEC23A and MAN1B1. Secretion of pro-COL1A1 was increased in fibroblasts from the siblings and patients, and pro-COL1A1 was retained in Golgi of heterozygous and homozygous mutant cells, although intracellular pro-COL1A1 was increased in patient fibroblasts only. We postulate that increased pro-COL1A1 secretion is responsible for tall stature in these patients and an unaffected sibling, and not previously discovered in patients with mutations in either SEC23A or MAN1B1. The patients in this study share biochemical and cellular characteristics consistent with mutations in MAN1B1 and SEC23A, indicating a digenic disease. PMID:27148587

  11. Somatic overgrowth