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Sample records for abs 1b bis

  1. Antidiabetic Bis-Maltolato-OxoVanadium(IV): conversion of inactive trans- to bioactive cis-BMOV for possible binding to target PTP-1B.

    Science.gov (United States)

    Scior, Thomas; Mack, Hans-Georg; García, José Antonio Guevara; Koch, Wolfhard

    2009-02-06

    The postulated transition of Bis-Maltolato-OxoVanadium(IV) (BMOV) from its inactive trans- into its cis-aquo-BMOV isomeric form in solution was simulated by means of computational molecular modeling. The rotational barrier was calculated with DFT - B3LYP under a stepwise optimization protocol with STO-3G, 3-21G, 3-21G*, and 6-31G ab initio basis sets. Our computed results are consistent with reports on the putative molecular mechanism of BMOV triggering the insulin-like cellular response (insulin mimetic) as a potent inhibitor of the protein tyrosine phosphatase-1B (PTP-1B). Initially, trans-BMOV is present in its solid dosage form but in aqueous solution, and during oral administration, it is readily converted into a mixture of "open-type" and "closed-type" complexes of cis-aquo-BMOV under equilibrium conditions. However, in the same measure as the "closed-type" complex binds to the cytosolic PTP-1B, it disappears from solution, and the equilibrium shifts towards the "closed-type" species. In full accordance, the computed binding mode of cis-BMOV is energetically favored over sterically hindered trans-BMOV. In view of our earlier report on prodrug hypothesis of vanadium organic compounds the present results suggest that cis-BMOV is the bioactive species.

  2. Antidiabetic Bis-Maltolato-OxoVanadium(IV: Conversion of inactive trans- to bioactive cis-BMOV for possible binding to target PTP-1B

    Directory of Open Access Journals (Sweden)

    Thomas Scior

    2008-11-01

    Full Text Available Thomas Scior1, Hans-Georg Mack2, José Antonio Guevara García3, Wolfhard Koch41Departamento de Farmacia. Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Colonia San Manuel, Puebla, Mexico; 2Institut für Physikalische Chemie, Universität Tübingen, Tübingen, Germany; 3Laboratorio de Investigación en Bioinorgánica y Biorremediación (LIByB. Departamento de Ciencias Básicas, Ingeniería y Tecnología, Universidad Autónoma de Tlaxcala, Apizaco, Tlaxcala, Mexico; 4Facultad de Estudios Superiores Zaragoza (FESZ, Universidad Nacional Autónoma de México (UNAM, Colonia Ejército de Oriente, Delegación Iztapalapa, Mexico City, MexicoAbstract: The postulated transition of Bis-Maltolato-OxoVanadium(IV (BMOV from its inactive trans- into its cis-aquo-BMOV isomeric form in solution was simulated by means of computational molecular modeling. The rotational barrier was calculated with DFT – B3LYP under a stepwise optimization protocol with STO-3G, 3-21G, 3-21G*, and 6-31G ab initio basis sets. Our computed results are consistent with reports on the putative molecular mechanism of BMOV triggering the insulin-like cellular response (insulin mimetic as a potent inhibitor of the protein tyrosine phosphatase-1B (PTP-1B. Initially, trans-BMOV is present in its solid dosage form but in aqueous solution, and during oral administration, it is readily converted into a mixture of “open-type” and “closed-type” complexes of cis-aquo-BMOV under equilibrium conditions. However, in the same measure as the “closed-type” complex binds to the cytosolic PTP-1B, it disappears from solution, and the equilibrium shifts towards the “closed-type” species. In full accordance, the computed binding mode of cis-BMOV is energetically favored over sterically hindered trans-BMOV. In view of our earlier report on prodrug hypothesis of vanadium organic compounds the present results suggest that cis-BMOV is the bioactive species

  3. A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B).

    Science.gov (United States)

    Grigelioniene, Giedre; Nevalainen, Pasi I; Reyes, Monica; Thiele, Susanne; Tafaj, Olta; Molinaro, Angelo; Takatani, Rieko; Ala-Houhala, Marja; Nilsson, Daniel; Eisfeldt, Jesper; Lindstrand, Anna; Kottler, Marie-Laure; Mäkitie, Outi; Jüppner, Harald

    2017-04-01

    Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most cases without evidence for Albright hereditary osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially-methylated regions (DMRs) within GNAS, which encodes the α-subunit of the stimulatory G protein (Gsα) and splice variants thereof. Heterozygous, maternally inherited STX16 or GNAS deletions leading to isolated loss-of-methylation (LOM) at exon A/B alone or at all maternal DMRs are the cause of autosomal dominant PHP1B (AD-PHP1B). In this study, we analyzed three affected individuals, the female proband and her two sons. All three revealed isolated LOM at GNAS exon A/B, whereas the proband's healthy maternal grandmother and uncle showed normal methylation at this locus. Haplotype analysis was consistent with linkage to the STX16/GNAS region, yet no deletion could be identified. Whole-genome sequencing of one of the patients revealed a large heterozygous inversion (1,882,433 bp). The centromeric breakpoint of the inversion is located 7,225 bp downstream of GNAS exon XL, but its DMR showed no methylation abnormality, raising the possibility that the inversion disrupts a regulatory element required only for establishing or maintaining exon A/B methylation. Because our three patients presented phenotypes consistent with PHP1B, and not with PHP1A, the Gsα promoter is probably unaffected by the inversion. Our findings expand the spectrum of genetic mutations that lead to LOM at exon A/B alone and thus biallelic expression of the transcript derived from this alternative first GNAS exon. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

  4. Ab-initio simulations of chemical stability indicators of the bis-DGA-type molecule and its radiation degradation products

    Energy Technology Data Exchange (ETDEWEB)

    Koubsky, T.; Kalvoda, L.; Drab, M. [Czech Technical University in Prague, Faculty of Nuclear Sciences and Physical Engineering, Dept. of Solid State Engineering, Trojanova 13, 120 00 Prague 2 (Czech Republic)

    2013-07-01

    For hydrometallurgical treatment of the high level liquid waste (HLLW) in the DIAMEX and SANEX processes, organic compounds of the bis-DGA family are used as cation extractants in apolar solvents. For the compound of m-xylylene-bis-diglycolamide high distribution coefficients for Eu and Am were found. Since the environment of the process is highly radioactive and acidic (nitric acid), it is necessary to ensure the stability of the extractants. In order to analyse the process theoretically, the molecule of m-xylylene-bis- diglycolamide and two of its degradation products were simulated by the DFT computational methods (PBE, RPBE, BLYP, B3LYP) available within the simulation environment DMol{sup 3} 6.1 and Gaussian 09 software. The local chemical stability of some locations of the molecule was assessed from the calculated stability indicators (electrostatic potential, Fukui function, HOMO localization). In connection with the chemical treatment, especially the stability against an electrophilic attack was tested. The results of calculated bond orders and spatial distribution of electrostatic potential and HOMO were are successfully correlated with the local and general stability determined by the experiment. These results should be helpful for the further development of the separation process. (authors)

  5. Crystal Structure, Vibrational Spectroscopy and ab Initio Density Functional Theory Calculations on the Ionic Liquid forming 1,1,3,3-Tetramethylguanidinium bis{(trifluoromethyl)sulfonyl}amide

    DEFF Research Database (Denmark)

    Berg, Rolf W.; Riisager, Anders; Nguyen van Buu, Olivier

    2009-01-01

    The salt 1,1,3,3-tetramethylguanidinium bis{(trifluoromethyl)sulfonyl}amide, [((CH3)(2)N)(2)C=NH2](+)[N(SO2-CF3)(2)](-) or [tmgH][NTf2], easily forms an ionic liquid with high SO2 absorbing capacity. The crystal structure of the salt was determined at 120(2) K by X-ray diffraction. The structure...

  6. AB(2) functional polyesters via ring opening polymerization: synthesis and characterization

    NARCIS (Netherlands)

    Velthoen, I.W.; Dijkstra, Pieter J.; Feijen, Jan

    2009-01-01

    Aliphatic AB2 functional polyesters were conveniently prepared by the ring opening polymerization of ε-caprolactone and L-lactide in the presence of the AB2 functional initiator 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and Sn(Oct)2 as the catalyst. In L-lactide polymerization, both bis-MPA

  7. Interferon Gamma-1b Injection

    Science.gov (United States)

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

  8. In silico interaction analysis of cannabinoid receptor interacting protein 1b (CRIP1b) - CB1 cannabinoid receptor.

    Science.gov (United States)

    Singh, Pratishtha; Ganjiwale, Anjali; Howlett, Allyn C; Cowsik, Sudha M

    2017-10-01

    Cannabinoid Receptor Interacting Protein isoform 1b (CRIP1b) is known to interact with the CB1 receptor. Alternative splicing of the CNRIP1 gene produces CRIP1a and CRIP1b with a difference in the third exon only. Exons 1 and 2 encode for a functional domain in both proteins. CRIP1a is involved in regulating CB1 receptor internalization, but the function of CRIP1b is not very well characterized. Since there are significant identities in functional domains of these proteins, CRIP1b is a potential target for drug discovery. We report here predicted structure of CRIP1b followed by its interaction analysis with CB1 receptor by in-silico methods A number of complementary computational techniques, including, homology modeling, ab-initio and protein threading, were applied to generate three-dimensional molecular models for CRIP1b. The computed model of CRIP1b was refined, followed by docking with C terminus of CB1 receptor to generate a model for the CRIP1b- CB1 receptor interaction. The structure of CRIP1b obtained by homology modelling using RHO_GDI-2 as template is a sandwich fold structure having beta sheets connected by loops, similar to predicted CRIP1a structure. The best scoring refined model of CRIP1b in complex with the CB1 receptor C terminus peptide showed favourable polar interactions. The overall binding pocket of CRIP1b was found to be overlapping to that of CRIP1a. The Arg82 and Cys126 of CRIP1b are involved in the majority of hydrogen bond interactions with the CB1 receptor and are possible key residues required for interactions between the CB1 receptor and CRIP1b. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Electronic structure of square planar bis(benzene-1,2-dithiolato)metal complexes [M(L)(2)](z) (z = 2-, 1-, 0; M = Ni, Pd, Pt, Cu, Au): an experimental, density functional, and correlated ab initio study.

    Science.gov (United States)

    Ray, Kallol; Weyhermüller, Thomas; Neese, Frank; Wieghardt, Karl

    2005-07-25

    The three diamagnetic square planar complexes of nickel(II), palladium(II), and platinum(II) containing two S,S-coordinated 3,5-di-tert-butylbenzene-1,2-dithiolate ligands, (L(Bu))(2-), namely [M(II)(L(Bu))(2)](2-), have been synthesized. The corresponding paramagnetic monoanions [M(II)(L(Bu))(L(Bu)(*))](-) (S = (1)/(2)) and the neutral diamagnetic species [M(II)(L(Bu)(*))(2)] (M = Ni, Pd, Pt) have also been generated in solution or in the solid state as [N(n-Bu)(4)][M(II)(L(Bu))(L(Bu)(*))] salts. The corresponding complex [Cu(III)(L(Bu))(2)](-) has also been investigated. The complexes have been studied by UV-vis, IR, and EPR spectroscopy and by X-ray crystallography; their electro- and magnetochemistry is reported. The electron-transfer series [M(L(Bu))(2)](2-,-,0) is shown to be ligand based involving formally one (L(Bu)(*))(-) pi radical in the monoanion or two in the neutral species [M(II)(L(Bu)(*))(2)] (M = Ni, Pd, Pt). Geometry optimizations using all-electron density functional theory with scalar relativistic corrections at the second-order Douglas-Kroll-Hess (DKH2) and zeroth-order regular approximation (ZORA) levels result in excellent agreement with the experimentally determined structures and electronic spectra. For the three neutral species a detailed analysis of the orbital structures reveals that the species may best be described as containing two strongly antiferromagnetically interacting ligand radicals. Furthermore, multiconfigurational ab initio calculations using the spectroscopy oriented configuration interaction (SORCI) approach including the ZORA correction were carried out. The calculations predict the position of the intervalence charge-transfer band well. Chemical trends in the diradical characters deduced from the multiconfigurational singlet ground-state wave function along a series of metals and ligands were discussed.

  10. Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis.

    Science.gov (United States)

    Sticova, Eva; Lodererova, Alena; van de Steeg, Evita; Frankova, Sona; Kollar, Marek; Lanska, Vera; Kotalova, Radana; Dedic, Tomas; Schinkel, Alfred H; Jirsa, Milan

    2015-01-01

    Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane transporters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xenobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases. Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains transgenic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyping was performed to rule out individuals predisposed to hyperbilirubinemia. The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross-reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B proteins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009). Down-regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.

  11. Data of evolutionary structure change: 1B98M-1B8MB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available RGELAVCDAVSGWVTDRRTAVDLRGREVEVLGEVPAAGGSPLRQYFFETRCKADEGGPGAGGGGCRGVDRRHWVSECKAKQSYVRALTADAQGRVGWRWI...-GELAVCDAVSGWVTDRRTAVDLRGREVEVLGEVPAAGGSPLRQYFFETRCK-AAGGPGAGGGGCRGVDRRHWVSECKAKQSYVRALTADAQGRVGWRWI...> 1B8MB ETRCK-AAGGP EEE - ...> 1B98M ETRCKADEGGP EEEEE

  12. Antiblockiersystem ABS

    Science.gov (United States)

    Koch-Dücker, Heinz-Jürgen

    Bei kritischen Fahrverhältnissen kann es während des Bremsvorgangs zum Blockieren der Räder kommen. Ursachen dafür können z.B. nasse oder glatte Fahrbahnen sowie eine schreckhafte Reaktion des Fahrers (unvorhergesehenes Hindernis) sein. Das Fahrzeug kann dadurch lenkunfähig werden, es kann ins Schleudern geraten und/oder von der Fahrbahn abkommen. Das Antiblockiersystem (ABS) erkennt beim Bremsen frühzeitig die Blockierneigung eines oder mehrerer Räder und sorgt dann sofort dafür, dass der Bremsdruck konstant gehalten oder verringert wird. So blockieren die Räder nicht und das Fahrzeug folgt der Lenkung. Damit lässt sich ein Auto sicher und schnell abbremsen bzw. zum Stillstand bringen.

  13. Snm1B interacts with PSF2.

    Directory of Open Access Journals (Sweden)

    Jay R Stringer

    Full Text Available The protein Snm1B plays a key role in interstrand crosslink (ICL repair. In a yeast two-hybrid screen we identified the protein PSF2 to bind Snm1B. PSF2 is a member of the GINS complex involved in replication initiation and elongation, and is known to play a role in ICL repair. Snm1B was shown to bind PSF2 in human cells through two regions, strongly to a 144 amino acid N-terminal region and weakly to a second smaller 37 amino acid C-terminal region. Ectopic expression of PSF2 increased the amount of Mus81, a protein component of the endonucleolytic complex involved in ICL repair, co-immunoprecipitating with Snm1B. Moreover, deleting the N-terminal, but not C-terminal region of Snm1B reduced the amount of co-immunoprecipitated Mus81. Conversely, the telomere-binding protein TRF2 competed with PSF2 for binding to the C-terminus of Snm1B, and deletion of this region, but not the N-terminal region, reduced Snm1B chromatin association. We speculate that the N-terminal region of Snm1B forms a complex containing PSF2 and Mus81, while the C-terminal region is important for PSF2-mediated chromatin association.

  14. PODAAC-RSCAT-L1B12

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the ISS-RapidScat Version 1.2 Level 1B geo-located Sigma-0 measurements and antenna pulse "egg" and "slice" geometries as derived from...

  15. PODAAC-RSCAT-L1B13

    Data.gov (United States)

    National Aeronautics and Space Administration — This dataset contains the ISS-RapidScat Version 1.3 Level 1B geo-located Sigma-0 measurements and antenna pulse "egg" and "slice" geometries as derived from...

  16. Independent System Calibration of Sentinel-1B

    OpenAIRE

    Marco Schwerdt; Kersten Schmidt; Núria Tous Ramon; Patrick Klenk; Nestor Yague-Martinez; Pau Prats-Iraola; Manfred Zink; Dirk Geudtner

    2017-01-01

    Sentinel-1B is the second of two C-Band Synthetic Aperture Radar (SAR) satellites of the Sentinel-1 mission, launched in April 2016—two years after the launch of the first satellite, Sentinel-1A. In addition to the commissioning of Sentinel-1B executed by the European Space Agency (ESA), an independent system calibration was performed by the German Aerospace Center (DLR) on behalf of ESA. Based on an efficient calibration strategy and the different calibration procedures already developed and...

  17. 2000 Johnston Site 1B-P

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Underwater Site 1B-P was established at Johnston Atoll by Dr. James Maragos, U.S. Fish & Wildlife Service, on June 29, 2000. With a start point (meter 0) at...

  18. 18 CFR 1b.1 - Definitions.

    Science.gov (United States)

    2010-04-01

    ... ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part— (a) Formal investigation means an investigation instituted by a Commission Order of Investigation. (b) Preliminary Investigation means an inquiry conducted by the Commission or its staff, other than a formal...

  19. Suomi NPP ATMS Level 1B Brightness Temperature V1 (SNPPATMSL1B) at GES DISC

    Data.gov (United States)

    National Aeronautics and Space Administration — The Advanced Technology Microwave Sounder (ATMS) Level 1B data files contain brightness temperature measurements along with ancillary spacecraft, instrument, and...

  20. Deletion of SNURF/SNRPN U1B and U1B* upstream exons in a ...

    Indian Academy of Sciences (India)

    we report the case of a patient who was referred to us with Prader–Willi syndrome-like symptoms including obesity and developmental delay. Examination of this patient revealed that he was a carrier of a paternally inherited deletion that affected the U1B and U1B* upstream exons of the SNURF–SNRNP gene within the ...

  1. Deletion of SNURF/SNRPN U1B and U1B* upstream exons in a ...

    Indian Academy of Sciences (India)

    Here, we report the case of a patient who was referred to us with Prader–Willi syndrome-like symptoms including obesity and developmental delay. Examination of this patient revealed that he was a carrier of a paternally inherited deletion that affected the U1B and U1B* upstream exons of the SNURF–SNRNP gene within ...

  2. Fluorescence dye-based detection of mAb aggregates in CHO culture supernatants.

    Science.gov (United States)

    Paul, Albert Jesuran; Schwab, Karen; Prokoph, Nina; Haas, Elena; Handrick, René; Hesse, Friedemann

    2015-06-01

    Product yields, efficacy, and safety of monoclonal antibodies (mAbs) are reduced by the formation of higher molecular weight aggregates during upstream processing. In-process characterization of mAb aggregate formation is a challenge since there is a lack of a fast detection method to identify mAb aggregates in cell culture. In this work, we present a rapid method to characterize mAb aggregate-containing Chinese hamster ovary (CHO) cell culture supernatants. The fluorescence dyes thioflavin T (ThT) and 4-4-bis-1-phenylamino-8-naphthalene sulfonate (Bis-ANS) enabled the detection of soluble as well as large mAb aggregates. Partial least square (PLS) regression models were used to evaluate the linearity of the dye-based mAb aggregate detection in buffer down to a mAb aggregate concentration of 2.4 μg mL(-1). Furthermore, mAb aggregates were detected in bioprocess medium using Bis-ANS and ThT. Dye binding to aggregates was stable for 60 min, making the method robust and reliable. Finally, the developed method using 10 μmol L(-1) Bis-ANS enabled discrimination between CHO cell culture supernatants containing different levels of mAb aggregates. The method can be adapted for high-throughput screening, e.g., to screen for cell culture conditions influencing mAb product quality, and hence can contribute to the improvement of production processes of biopharmaceuticals in mammalian cell culture.

  3. mAbs: a business perspective.

    Science.gov (United States)

    Scolnik, Pablo A

    2009-01-01

    The twenty two monoclonal antibodies (mAbs) currently marketed in the U.S. have captured almost half of the top-20 U.S. therapeutic biotechnology sales for 2007. Eight of these products have annual sales each of more than $1 B, were developed in the relatively short average period of six years, qualified for FDA programs designed to accelerate drug approval, and their cost has been reimbursed liberally by payers. With growth of the product class driven primarily by advancements in protein engineering and the low probability of generic threats, mAbs are now the largest class of biological therapies under development. The high cost of these drugs and the lack of generic competition conflict with a financially stressed health system, setting reimbursement by payers as the major limiting factor to growth. Advances in mAb engineering are likely to result in more effective mAb drugs and an expansion of the therapeutic indications covered by the class. The parallel development of biomarkers for identifying the patient subpopulations most likely to respond to treatment may lead to a more cost-effective use of these drugs. To achieve the success of the current top-tier mAbs, companies developing new mAb products must adapt to a significantly more challenging commercial environment.

  4. The role of B cell-mediated T cell costimulation in the efficacy of the T cell retargeting bispecific antibody BIS20x3

    NARCIS (Netherlands)

    Stel, AJ; Kroesen, BJ; Jacobs, Susan; Groen, H; de Leij, LFMH; Kluin-Nelemans, HC; Withoff, S

    2004-01-01

    In this study, we investigated the role of the naturally occurring B cell-mediated T cell costimulation in the antitumor efficacy of the bispecific Ab BIS20x3. BIS20x3 has a dual specificity for both CD20 and CD3 and has previously been shown to effectively direct the lytic potential of cytolytic T

  5. Comprehensive and Facile Synthesis of Some Functionalized Bis-Heterocyclic Compounds Containing a Thieno[2,3-b]thiophene Motif

    Science.gov (United States)

    Mabkhot, Yahia N.; Barakat, Assem; Al-Majid, Abdullah M.; Alshahrani, Saeed A.

    2012-01-01

    A comprehensive and facile method for the synthesis of new functionalized bis-heterocyclic compounds containing a thieno[2,3-b]thiophene motif is described. The hitherto unknown bis-pyrazolothieno[2,3-b]thiophene derivatives 2a–c, bis-pyridazin othieno[2,3-b]thiophene derivatives 4, bis-pyridinothieno[2,3-b]thiophene derivatives 6a,b, and to an analogous bis-pyridinothieno[2,3-b]thiophene nitrile derivatives 7 are obtained. Additionally, the novel bis-pyradazinonothieno[2,3-b]thiophene derivatives 9, and nicotinic acid derivatives 10, 11 are obtained via bis-dienamide 8. The structures of all newly synthesized compounds have been elucidated by 1H, 13C NMR, GCMS, and IR spectrometry. These compounds represent a new class of sulfur and Nitrogen containing heterocycles that should also be of interest as new materials. PMID:22408452

  6. Study of external dynamic flap loads on a 6 percent B-1B model

    Science.gov (United States)

    Seiner, John M.; Manning, James C.; Capone, Francis J.; Pendergraft, Odis C., Jr.

    1991-01-01

    The origin of dynamic pressure loads on external divergent engine nozzle flaps of the B-1B aircraft was investigated in the NASA/LaRC 16 foot transonic tunnel using a 6 percent full span model with powered engine nacelles. External flap dynamic loads and afterbody drag associated with flap removal were measured using this model. Both dry and max. A/B power nozzles were evaluated in this study. As a result of this study, the principal mechanisms responsible for high dynamic external flap loads were determined along with performance penalty associated with flap removal.

  7. IceBridge Atmospheric Chemistry L1B Data

    Data.gov (United States)

    National Aeronautics and Space Administration — The IceBridge Atmospheric Chemistry L1B Data set (ICHEM1B) contains measurements acquired over Antarctica using the AVOCET differential Non-Dispersive Infrared...

  8. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes

    Science.gov (United States)

    Bonnefond, Amélie; Clément, Nathalie; Fawcett, Katherine; Yengo, Loïc; Vaillant, Emmanuel; Guillaume, Jean-Luc; Dechaume, Aurélie; Payne, Felicity; Roussel, Ronan; Czernichow, Sébastien; Hercberg, Serge; Hadjadj, Samy; Balkau, Beverley; Marre, Michel; Lantieri, Olivier; Langenberg, Claudia; Bouatia-Naji, Nabila; Charpentier, Guillaume; Vaxillaire, Martine; Rocheleau, Ghislain; Wareham, Nicholas J.; Sladek, Robert; McCarthy, Mark I.; Dina, Christian; Barroso, Inês; Jockers, Ralf; Froguel, Philippe

    2013-01-01

    Genome-wide association studies revealed that common non-coding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT2) increase type 2 diabetes (T2D) risk1,2. Although the strongest association signal was highly significant (P<10−20), its contribution to T2D risk was modest (odds ratio, OR~1.10-1.15)1-3. We performed large-scale exon resequencing in 7,632 Europeans including 2,186 T2D patients and identified 40 non-synonymous variants, including 36 very rare variants (minor allele frequency, MAF<0.1%) associated with T2D (OR=3.31[1.78;6.18]95%); P=1.64×10−4. A four-tier functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF<1%); four were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial or total loss-of-function variants, but not the neutral ones, contributed to T2D (OR=5.67[2.17;14.82]95%; P=4.09×10−4). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (Ncases=8,153/Ncontrols=10,100; OR=3.88[1.49;10.07]95%; P=5.37×10−3). This study establishes a firm functional link between MTNR1B and T2D risk. PMID:22286214

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

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.9 Confidentiality of investigations...

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

    Science.gov (United States)

    2010-04-01

    ... 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 investigation... administered by the Commission or the rules, opinions or orders thereunder, the Commission may institute...

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

    Science.gov (United States)

    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 (pvitiligo by 2.3 fold (pvitiligo (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 Gujarat population. Up-regulation of IL1B transcript in patients advocates its possible role in autoimmune pathogenesis of vitiligo. PMID:25221996

  12. The Formal Semantics of Core ABS and ABS-NET

    OpenAIRE

    Palmskog, Karl

    2013-01-01

    ABS is a language and framework for modelling distributed object-oriented systems, developed in the EU FP7 HATS project. Core ABS formalizes the key parts of ABS, including the syntax, type system, and an operational semantics in the style of rewriting logic. ABS-NET is a novel operational semantics for Core ABS programs, developed as a part of work on decentralized runtime adaptation of distributed objects. ABS-NET describes program execution on top of a network of nodes connected point-to-p...

  13. ABS dopado con grafeno

    OpenAIRE

    Gago Velasco, Israel; Ibarra Berrocal, Isidro Jesús; León Albert, Gerardo; Miguel Hernández, Beatriz

    2016-01-01

    Número de publicación: 2570391 Número de solicitud: 201630046 La presente invención se refiere a un procedimiento para la preparación de un polímero de ABS (acrilonitrilo-butadieno-estireno) dopado con grafeno que comprende dispersar el grafeno en un disolvente, adicionar a la dispersión anterior el ABS, reflujo de la dispersión la etapa anterior y evaporación del disolvente para obtener un gel. La presente invención se refiere también al polímero obtenido por dicho procedimiento. U...

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

    Science.gov (United States)

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

    2008-01-01

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

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

    Science.gov (United States)

    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.

  16. Role of protein tyrosine phosphatase 1B in cardiovascular diseases.

    Science.gov (United States)

    Thiebaut, Pierre-Alain; Besnier, Marie; Gomez, Elodie; Richard, Vincent

    2016-12-01

    Protein Tyrosine Phosphatase 1B (PTP1B) is mostly involved in negative regulation of signaling mediated by Tyrosine Kinase Receptors, especially the insulin and leptin receptors. This enzyme thus plays a major role in the development of diseases associated with insulin resistance, such as obesity and diabetes. PTP1B inhibition is currently considered as an attractive treatment of insulin resistance and associated metabolic disorders. In parallel, emerging evidence also suggests that PTP1B is widely expressed in cardiovascular tissues, notably in the heart and the endothelium, and that it could also be a potential treatment of several cardiovascular diseases. PTP1B is especially present in endothelial cells, and appears to contribute to endothelial dysfunction. Indeed, preclinical evidence shows that pharmacological inhibition of gene deletion of PTP1B reduces endothelial dysfunction in various cardiovascular diseases associated or not with insulin resistance. In parallel, because PTP1B also negatively modulates VEGF signaling, inhibition of this enzyme also tends to favor cardiac angiogenesis. Importantly, blocking PTP1B also results in beneficial effects on cardiac dysfunction and remodeling not only in metabolic diseases but also in the context of heart failure, thus this enzyme represents an attractive new target for the treatment of this disease. This beneficial effect in heart failure may to a large extent result from the endothelial protective and/or proangiogenic effects of PTP1B blockade. Finally, PTP1B inhibition also reduces cardiac dysfunction, but also systemic inflammation and mortality in experimental models of septic shock, and thus may also constitute a new treatment of this disease. Altogether, accumulating preclinical evidence suggests that PTP1B represents an interesting molecular target to treat both cardiovascular and metabolic diseases, which often share the same risk factors. This concept now deserves to be tested in clinical studies that

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

    Science.gov (United States)

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

    2017-02-01

    The incidence of breast cancer in India is on the rise and is rapidly becoming the primary cancer in Indian women. The aldoketo reductase (AKR) family has more than 190 proteins including aldose reductase (AKR1B1) and aldose reductase like protein (AKR1B10). Apart from liver cancer, the status of AKR1B1 and AKR1B10 with respect to their expression and activity has not been reported in other human cancers. We studied the specific activity and expression of AKR1B1 and AKR1B10 in breast non tumor and tumor tissues and in the blood. Fresh post-surgical breast cancer and non-cancer tissues and blood were collected from the subjects who were admitted for surgical therapy. Malignant, benign and pre-surgical chemotherapy samples were evaluated by histopathology scoring. Expression of AKR1B1 and AKR1B10 was carried out by immunoblotting and immunohistochemistry (IHC) while specific activity was determined spectrophotometrically. The specific activity of AKR1B1 was significantly higher in red blood cells (RBC) in all three grades of primary surgical and post-chemotherapy samples. Specific activity of both AKR1B1 and AKR1B10 increased in tumor samples compared to their corresponding non tumor samples (primary surgical and post-chemotherapy). Immunoblotting and IHC data also indicated overexpression of AKR1B1 in all grades of tumors compared to their corresponding non tumor samples. There was no change in the specific activity of AKR1B1 in benign samples compared to all grades of tumor and non-tumors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. TES/Aura L1B Spectra Limb V004

    Data.gov (United States)

    National Aeronautics and Space Administration — TES Level 1B Spectra data contain radiometric calibrated spectral radiances and their corresponding noise equivalent spectral radiances (NESR). The geolocation,...

  19. MAN1B1 deficiency: an unexpected CDG-II.

    Directory of Open Access Journals (Sweden)

    Daisy Rymen

    Full Text Available 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.

  20. A cytotoxic study of eugenol and its ortho dimer (bis-eugenol)

    Energy Technology Data Exchange (ETDEWEB)

    Kashiwagi, Yasushi [Meikai Univ., Sakado, Saitama (Japan). School of Dentistry

    2000-07-01

    Eugenol is widely used not only as a dental material such as pulp capping material, provisional cement, root canal sealer, and impression paste, but also as a perfume ingredients. Eugenol has antioxidant, bactericidal, and sedative activities, inhibits and non-enzymatic peroxidation. It was previously reported that eugenol exhibited the cytotoxic activity toward pulp cells and gingial fibroblasts and also that the cytotoxic activity was predominantly performed by radicals derived from the oxidation of eugenol. This study was based on the hypothesis that the toxicity of eugenol may be greately reduced if the radicalization of eugenol was diminished by the dimerization of eugenol. Thus, bis-eugenol, the dimer of eugenol, was synthesized to characterize the effect of this eugenol-related compound. The cytotoxic activity of bis-eugenol against human gingival fibroblasts (HGF cell) or human submandibular gland cancer cells (HSG cell) was studied in the presence or absence of light irradiation (visible or ultraviolet light), and compared with that of eugenol. The cytotoxic activity of eugenol was significantly greater than that of bis-eugenol. The cytotoxic activity of irradiated eugenol, but not that of irradiated bis-eugenol, was significantly higher than that of the non-irradiated counterpart. Bis-eugenol at a relatively low concentration declined the phototoxic activity of irradiation on living cells. Also, the generation of reactive oxygen in HSG cells in the ab-sence or the presence of irradiated bis-eugenol or eugenol was evaluated by an ACAS laser cytometry, and the results indicated that eugenol, but not bis-eugenol, generated reactive oxygen in the cells. The DPPH-radical scavenging activity of bis-eugenol was larger than that of eugenol. Furthermore, eugenol had a positive apoptosis-inducing effect on HSG cells. The structure-activity relationships of eugenol-related compounds showed that the nature of the substituent at the ortho or para-position of eugenol

  1. Kurz- bis mittelfristige Ergebnisse der Druckscheibenendoprothese in der Behandlung der Femurkopfnekrose

    OpenAIRE

    Käsemann, Bertram

    2007-01-01

    In der vorliegenden klinischen Studie wurden 45 implantierte Druckscheibenendoprothesen von 39 Patienten, die ab dem Stadium ARCO II an einer Femurkopfnekrose erkrankt waren, zwischen Mai 1994 bis April 1999 beobachtet. Die mittlere Nachuntersuchungszeit belief sich, bei einer Spanne von 2-57 Monaten, auf 21,2 Monaten. Das durchschnittliche Follow-up betrug 3,1 Jahre. Im Vorfeld der Untersuchung erfolgte eine eigene Einteilung der Osteonekroseausbreitung im Stadium I-IV der röntgologischen- u...

  2. Modeling the vibrational spectrum of 4,4'-diphenylmethane- bis(methyl)carbamate

    Science.gov (United States)

    Shundalau, M. B.; Pitsevich, G. A.; Ksenofontov, M. A.; Umreiko, D. S.

    2010-07-01

    We present results of ab initio calculations of the structure and vibrational IR spectrum for 4,4'-diphenylmethane-bis(methyl)carbamate (DPMC). Calculations were carried out in the HF/6-311G approximation with subsequent force-field scaling. The calculated characteristics of the vibrational spectrum of DPMC show satisfactory agreement with experimental values, which permits them to be used in spectral and structural analysis

  3. OMI/Aura Level 1B Solar Irradiances V003

    Data.gov (United States)

    National Aeronautics and Space Administration — The Level-1B (L1B) Radiance Product OML1BIRR (Version-3) from the Aura-OMI is now available (http://disc.gsfc.nasa.gov/Aura/OMI/oml1birr_v003.shtml) to public from...

  4. Genetic polymorphism of bone morphogenetic protein receptor 1B ...

    African Journals Online (AJOL)

    The Indonesian fat-tailed sheep (IFTS) is a local sheep that has been long time raised and well adapted to the extreme environments of Lombok Island. The present study was conducted to determine the polymorphism of bone morphogenetic protein receptor 1B (BMPR-1B) gene and its association with litter size in the IFTS ...

  5. Selection of phage-displayed human antibody fragments specific for CD1b presenting the Mycobacterium tuberculosis glycolipid Ac2SGL.

    Science.gov (United States)

    Camacho, Frank; Sarmiento, María E; Reyes, Fatima; Kim, Louise; Huggett, Jim; Lepore, Marco; Otero, Oscar; Gilleron, Martine; Puzo, Germain; Norazmi, Mohd Nor; Rook, Graham; Mori, Lucia; De Libero, Gennaro; Acosta, Armando

    2016-06-01

    The development of new tools capable of targeting Mycobacterium tuberculosis (Mtb)-infected cells have potential applications in diagnosis, treatment, and prevention of tuberculosis. In Mtb-infected cells, CD1b molecules present Mtb lipids to the immune system (Mtb lipid-CD1b complexes). Because of the lack of CD1b polymorphism, specific Mtb lipid-CD1b complexes could be considered as universal Mtb infection markers. 2-Stearoyl-3-hydroxyphthioceranoyl-2'-sulfate-α-α'-d-trehalose (Ac2SGL) is specific for Mtb, and is not present in other mycobacterial species. The CD1b-Ac2SGL complexes are expressed on the surface of human cells infected with Mtb. The aim of this study was to generate ligands capable of binding these CD1b-Ac2SGL complexes. A synthetic human scFv phage antibody library was used to select phage-displayed antibody fragments that recognized CD1b-Ac2SGL using CD1b-transfected THP-1 cells loaded with Ac2SGL. One clone, D11-a single, light-variable domain (kappa) antibody (dAbκ11)-showed high relative binding to the Ac2SGL-CD1b complex. A ligand recognizing the Ac2SGL-CD1b complex was obtained, which is a potential candidate to be further tested for diagnostic and therapeutic applications. Copyright © 2016. Published by Elsevier Ltd.

  6. Blessures Skaten (BIS): Blessurevrij skaten?

    NARCIS (Netherlands)

    Hespen, A. van; Stubbe, J.; Stege, J.

    2009-01-01

    Sportblessures: niemand zit erop te wachten, maar jaarlijks krijgen ongeveer 1,5 miljoen mensen in Nederland ermee te maken. Om effectief aan preventie te doen, is inzicht in het aantal en soort sportblessures onmisbaar. Dit kan met het web-based Blessure Informatie Systeem (BIS) van TNO Kwaliteit

  7. Blessures badmington (BIS): blessurevrij badmintonnen?

    NARCIS (Netherlands)

    Hespen, A. van; Stubbe, J.; Stege, J.; Ooijendijk, W.

    2008-01-01

    Sportblessures: niemand zit erop te wachten, maar jaarlijks krijgen ongeveer 1,5 miljoen mensen in Nederland ermee te maken. Om effectief aan preventie te doen, is inzicht in het aantal en soort sportblessures onmisbaar. Dit kan met het web-based Blessure Informatie Systeem (BIS) van TNO Kwaliteit

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2015-01-01

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

  10. Evaluating autoimmunity markers (TPO Ab, Tg Ab and TM Ab in hypothyroid patients of Bushehr province

    Directory of Open Access Journals (Sweden)

    Iraj Nabipour

    2005-09-01

    Full Text Available Background: Chronic autoimmune thyroiditis (Hashimoto's Thyroiditis is the common cause of primary hypothyroidism in iodine sufficient countries. Iran is named an iodine sufficient country, in this century. Methods: A total of 88 hypothyroid patients, on suppressing dose of levothyroxine who were followed in a university endocrine disorder clinic were evaluated for serum thyroid autoimmunity markers: thyroid peroxidase antibody (TPO Ab, thyroglobulin antibody (Tg Ab and thyroid microsomal antibody (TM Ab using ELISA method. Results: The prevalence of TPO Ab, Tg Ab and TM Ab were 73.9%, 45.5% and 71.6%, respectively. Among the patients with high level of TPO Ab (> 75 u/ml, 45.3% had grade 1 or 2 of goiter (P< 0.05. Conclusion: Autoimmune thyroid disease (Hashimoto's thyroiditis is the most common cause of hypothyroidism in Bushehr province.

  11. ABS plastic RPCs

    Energy Technology Data Exchange (ETDEWEB)

    Ables, E.; Bionta, R.; Olson, H.; Ott, L.; Parker, E.; Wright, D.; Wuest, C

    1996-02-01

    After investigating a number of materials, we discovered that an ABS plastic doped with a conducting polymer performs well as the resistive electrode in a narrow gap RPC (resistive plate chamber). Operating in the streamer mode, we find efficiencies of 90-96% with low noise and low strip multiplicities. We have also studied a variety of operating gases and found that a mixture containing SF{sub 6}, a non-ozone depleting gas, argon and isobutane gives good streamer mode performance, even with isobutane concentrations of 20% or less.

  12. MISR Level 1B1 Radiance Data V002

    Data.gov (United States)

    National Aeronautics and Space Administration — The MISR Level 1B1 Radiance data product contains spectral radiances for all MISR channels. Each radiance value represents the incident radiance averaged over the...

  13. AIRS/Aqua Level 1B Calibration subset V005

    Data.gov (United States)

    National Aeronautics and Space Administration — AIRS/Aqua Level-1B calibration subset including clear cases, special calibration sites, random nadir spots, and high clouds. The Atmospheric Infrared Sounder (AIRS)...

  14. TES/Aura L1B Spectra Nadir V003

    Data.gov (United States)

    National Aeronautics and Space Administration — The L1B Nadir granule consists of radiometrically calibrated spectra & associated NESR, observed at 0.1 cm-1 resolution for an entire Global Survey &...

  15. MODIS/Terra Granule Level 1B RGB Jpeg image

    Data.gov (United States)

    National Aeronautics and Space Administration — The MOBRGB is a thermal composit Jpeg image product generated using parameters from Terra Level 1B Subsampled Calibrated Radiances product (MOD02SSH). For more...

  16. MODIS/Aqua Granule Level 1B RGB Jpeg image

    Data.gov (United States)

    National Aeronautics and Space Administration — The MYBRGB is a thermal composit Jpeg image product generated using parameters from Aqua Level 1B Subsampled Calibrated Radiances product (MYD02SSH). For more...

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

    Science.gov (United States)

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

    2017-03-30

    Hyperbilirubinemia is a pathological condition of excessive accumulation of conjugated or unconjugated bilirubin in blood. It has been associated with neurotoxicity and non-neural organ dysfunctions, while it can also be a warning of liver side effects. Hyperbilirubinemia can either be a result of overproduction of bilirubin due to hemolysis or dyserythropoiesis, or the outcome of impaired bilirubin elimination due to liver transporter malfunction or inhibition. There are several reports in literature that inhibition of organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) might lead to hyperbilirubinemia. In this study we created a set of classification models for hyperbilirubinemia, which, besides physicochemical descriptors, also include the output of classification models of human OATP1B1 and 1B3 inhibition. Models were based on either human data derived from public toxicity reports or animal data extracted from the eTOX database VITIC. The generated models showed satisfactory accuracy (68%) and area under the curve (AUC) for human data and 71% accuracy and 70% AUC for animal data. However, our results did not indicate strong association between OATP inhibition and hyperbilirubinemia, neither for humans nor for animals. Copyright © 2017. Published by Elsevier B.V.

  18. Association of transcription factor gene LMX1B with autism.

    Directory of Open Access Journals (Sweden)

    Ismail Thanseem

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

  19. Association of transcription factor gene LMX1B with autism.

    Science.gov (United States)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jeong HU

    2015-01-01

    Full Text Available Hyeon-Uk Jeong,1 Mihwa Kwon,2 Yongnam Lee,3 Ji Seok Yoo,3 Dae Hee Shin,3 Im-Sook Song,2 Hye Suk Lee1 1College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea; 2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Korea; 3Central R&D Institute, Yungjin Pharm Co., Ltd., Suwon 443-270, Korea Abstract: 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 µ

  1. Laptop induced erythema ab igne.

    Science.gov (United States)

    Nayak, Sudhir U K; Shenoi, Shrutakirthi D; Prabhu, Smitha

    2012-03-01

    Erythema ab igne is a reticular, pigmented dermatosis caused by prolonged and repeated exposure to infrared radiation that is insufficient to produce a burn. The use of laptop computers has increased manifold in the recent past. Prolonged contact of the laptop with the skin can lead to the development of erythema ab igne. We present a case of erythema ab igne secondary to laptop use in an Indian student.

  2. Synthesis, characterization, and reactivity of furan- and thiophene-functionalized bis(n-heterocyclic carbene) complexes of iron(II)

    KAUST Repository

    Rieb, Julia

    2014-09-15

    The synthesis of iron(II) complexes bearing new heteroatom-functionalized methylene-bridged bis(N-heterocyclic carbene) ligands is reported. All complexes are characterized by single-crystal X-ray diffraction (SC-XRD), nuclear magnetic resonance (NMR) spectroscopy, and elemental analysis. Tetrakis(acetonitrile)-cis-[bis(o-imidazol-2-ylidenefuran)methane]iron(II) hexafluorophosphate (2a) and tetrakis(acetonitrile)-cis-[bis(o-imidazol-2-ylidenethiophene)methane]iron(II) hexafluorophosphate (2b) were obtained by aminolysis of [Fe{N(SiMe3)2}2(THF)] with furan- and thiophene-functionalized bis(imidazolium) salts 1a and 1b in acetonitrile. The SC-XRD structures of 2a and 2b show coordination of the bis(carbene) ligand in a bidentate fashion instead of a possible tetradentate coordination. The four other coordination sites of these distorted octahedral complexes are occupied by acetonitrile ligands. Crystallization of 2a in an acetone solution by the slow diffusion of Et2O led to the formation of cisdiacetonitriledi[ bis(o-imidazol-2-ylidenefuran)methane]iron(II) hexafluorophosphate (3a) with two bis(carbene) ligands coordinated in a bidentate manner and two cis-positioned acetonitrile molecules. Compounds 2a and 2b are the first reported iron(II) carbene complexes with four coordination sites occupied by solvent molecules, and it was demonstrated that those solvent ligands can undergo ligand-exchange reactions.

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

    Science.gov (United States)

    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

  4. UBC9-dependent association between calnexin and protein tyrosine phosphatase 1B (PTP1B) at the endoplasmic reticulum.

    Science.gov (United States)

    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

    2015-02-27

    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. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. TRMM Ground Validation Radar Reflectivity L1B 1 hour V7 (TRMM_1B51) at GES DISC

    Data.gov (United States)

    National Aeronautics and Space Administration — The TRMM_1B51 product displays the existence of rain in the radar volume scan. 'Existence' is the fraction of the radar FOV which has measurable precipitation. The...

  6. Ab initio study of the electronic spectrum of BeO

    Directory of Open Access Journals (Sweden)

    MILJENKO PERIC

    1999-12-01

    Full Text Available Low-lying singlet and triplet electronic states of the BeO molecule are calculated by means of the quantum chemical ab initio method. It was found that all states in the energy range from 0 to 50000 cm-1 are of valence character. Particular attention was paid to the investigation of the dissociative behavior of the states considered. The vibrational structure of the AIP<-XIS and BIS+<-XIS+ spectral systems was calculated.

  7. Ab interno stenting procedures.

    Science.gov (United States)

    Radcliffe, Nathan M; Lynch, Mary G; Brown, Reay H

    2014-08-01

    Trabecular bypass was first used as a surgical treatment for glaucoma more than 100 years ago and aims to circumvent the trabecular meshwork, thought to be the main site of aqueous humor outflow resistance. The emerging field of microinvasive glaucoma surgery has brought a new ab interno trabecular microbypass stent through the U.S. Food and Drug Administration-approval process, and data from long-term randomized prospective trials have shown the safety and intraocular pressure-lowering value of trabecular microbypass. This review discusses the historical evolution of trabecular microbypass and describes new and forthcoming surgical options along with available clinical safety and efficacy data. Proprietary or commercial disclosures are listed after the references. Copyright © 2014 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  8. The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation.

    Science.gov (United States)

    Chiabrando, Deborah; Marro, Samuele; Mercurio, Sonia; Giorgi, Carlotta; Petrillo, Sara; Vinchi, Francesca; Fiorito, Veronica; Fagoonee, Sharmila; Camporeale, Annalisa; Turco, Emilia; Merlo, Giorgio R; Silengo, Lorenzo; Altruda, Fiorella; Pinton, Paolo; Tolosano, Emanuela

    2012-12-01

    Feline leukemia virus subgroup C receptor 1 (FLVCR1) is a cell membrane heme exporter that maintains the balance between heme levels and globin synthesis in erythroid precursors. It was previously shown that Flvcr1-null mice died in utero due to a failure of erythropoiesis. Here, we identify Flvcr1b, a mitochondrial Flvcr1 isoform that promotes heme efflux into the cytoplasm. Flvcr1b overexpression promoted heme synthesis and in vitro erythroid differentiation, whereas silencing of Flvcr1b caused mitochondrial heme accumulation and termination of erythroid differentiation. Furthermore, mice lacking the plasma membrane isoform (Flvcr1a) but expressing Flvcr1b had normal erythropoiesis, but exhibited hemorrhages, edema, and skeletal abnormalities. Thus, FLVCR1b regulates erythropoiesis by controlling mitochondrial heme efflux, whereas FLVCR1a expression is required to prevent hemorrhages and edema. The aberrant expression of Flvcr1 isoforms may play a role in the pathogenesis of disorders characterized by an imbalance between heme and globin synthesis.

  9. Oncolytic Replication of E1b-Deleted Adenoviruses

    Directory of Open Access Journals (Sweden)

    Pei-Hsin Cheng

    2015-11-01

    Full Text Available 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.

  10. Synthesis and Theoretical Study of a New Type of Pentacyclic bis-Benzothiazolium Compound

    Directory of Open Access Journals (Sweden)

    Radovan Buffa

    2002-07-01

    Full Text Available The synthesis of a new type of pentacyclic benzothiazolium compound -6,13-dihydropyrazino[2,1-b:5,4-b´]bis(1,3-benzothiazole-7,14-diiumdibromide (2, is reported. Compound 2 was prepared by dimerization of 2-(bromomethylbenzothiazole. Quantum chemical calculation studies have been carried out on the structures of possible isomers of 2, as well as the products of its deprotonation reactions.

  11. 20 CFR 655.700 - What statutory provisions govern the employment of H-1B, H-1B1, and E-3 nonimmigrants and how do...

    Science.gov (United States)

    2010-04-01

    ... issued H-1B visas— (i) 195,000 in fiscal year 2001; (ii) 195,000 in fiscal year 2002; (iii) 195,000 in... 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 as...

  12. PTP1B targets the endosomal sorting machinery

    DEFF Research Database (Denmark)

    Stuible, Matthew; Abella, Jasmine V; Feldhammer, Matthew

    2010-01-01

    Dephosphorylation and endocytic down-regulation are distinct processes that together control the signaling output of a variety of receptor tyrosine kinases (RTKs). PTP1B can directly dephosphorylate several RTKs, but it can also promote activation of downstream pathways through largely unknown me...

  13. Origin of vestibular dysfunction in Usher syndrome type 1B.

    NARCIS (Netherlands)

    Sun, J.; Alphen, A.M. van; Wagenaar, M.; Huygen, P.L.M.; Hoogenraad, C.C.; Hasson, T.; Koekkoek, S.K.; Bohne, B.A.; Zeeuw, C.I. de

    2001-01-01

    It is still debated to what extent the vestibular deficits in Usher patients are due to either central vestibulocerebellar or peripheral vestibular problems. Here, we determined the origin of the vestibular symptoms in Usher 1B patients by subjecting them to compensatory eye movement tests and by

  14. Bis(1,3-dithiole) Compounds

    DEFF Research Database (Denmark)

    Andersen, Jan Rud; Engler, E. M.; Green, D. C.

    1977-01-01

    There is described the preparation of bis-1,3-dithiole compounds (I) which are key synthetic precursors for the preparation of new polymeric metal bis(dithiolene) (i.e., II) and tetrathiafulvalene compounds (i.e., III): (Image Omitted)...

  15. Porphyrin amino acids-amide coupling, redox and photophysical properties of bis(porphyrin) amides.

    Science.gov (United States)

    Melomedov, Jascha; Wünsche von Leupoldt, Anica; Meister, Michael; Laquai, Frédéric; Heinze, Katja

    2013-07-14

    New trans-AB2C meso-substituted porphyrin amino acid esters with meso-substituents of tunable electron withdrawing power (B = mesityl, 4-C6H4F, 4-C6H4CF3, C6F5) were prepared as free amines 3a-3d, as N-acetylated derivatives Ac-3a-Ac-3d and corresponding zinc(II) complexes Zn-Ac-3a-Zn-Ac-3d. Several amide-linked bis(porphyrins) with a tunable electron density at each porphyrin site were obtained from the amino porphyrin precursors by condensation reactions (4a-4d) and mono- and bis(zinc(II)) complexes Zn(2)-4d and Zn(1)Zn(2)-4d were prepared. The electronic interaction between individual porphyrin units in bis(porphyrins) 4 is probed by electrochemical experiments (CV, EPR), electronic absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy in combination with DFT/PCM calculations on diamagnetic neutral bis(porphyrins) 4 and on respective charged mixed-valent radicals 4(+/-). The interaction via the -C6H4-NHCO-C6H4- bridge, the site of oxidation and reduction and the lowest excited singlet state S1, is tuned by the substituents on the individual porphyrins and the metalation state.

  16. Ab interno trabeculectomy.

    Science.gov (United States)

    Pantcheva, Mina B; Kahook, Malik Y

    2010-10-01

    Anterior chamber drainage angle surgery, namely trabeculotomy and goniotomy, has been commonly utilized in children for many years. Its' reported success has ranged between 68% and 100% in infants and young children with congenital glaucoma. However, the long-term success of these procedures has been limited in adults presumably due to the formation of anterior synechiae (AS) in the postoperative phase. Recently, ab interno trabeculectomy with the Trabectome™ has emerged as a novel surgical approach to effectively and selectively remove and ablate the trabecular meshwork and the inner wall of the Schlemm's canal in an attempt to avoid AS formation or other forms of wound healing with resultant closure of the cleft. This procedure seems to have an appealing safety profile with respect to early hypotony or infection if compared to trabeculectomy or glaucoma drainage device implantation. This might be advantageous in some of the impoverish regions of the Middle East and Africa where patients experience difficulties keeping up with their postoperative visits. It is important to note that no randomized trial comparing the Trabectome to other glaucoma procedures appears to have been published to date. Trabectome surgery is not a panacea, however, and it is associated with early postoperative intraocular pressure spikes that may require additional glaucoma surgery as well as a high incidence of hyphema. Reported results show that postoperative intraocular pressure (IOP) remains, at best, in the mid-teen range making it undesirable in patients with low-target IOP goals. A major advantage of Trabectome surgery is that it does not preclude further glaucoma surgery involving the conjunctiva, such as a trabeculectomy or drainage device implantation. As prospective randomized long-term clinical data become available, we will be better positioned to elucidate the exact role of this technique in the glaucoma surgical armamentarium.

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

    Science.gov (United States)

    Tautz, Lutz

    2015-08-03

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

  18. (Acetonitrile[bis(2-pyridylmethylamine]bis(perchloratocopper(II

    Directory of Open Access Journals (Sweden)

    Ray J. Butcher

    2008-01-01

    Full Text Available In the title compound, [Cu(ClO42(C12H13N3(C2H3N], the CuII atom is six-coordinate in a Jahn–Teller distorted octahedral geometry, with coordination by the tridentate chelating ligand, an acetonitrile molecule, and two axial perchlorate anions. The tridentate ligand bis(2-pyridylmethylamine chelates meridionally and equatorially while an acetonitrile molecule is coordinated at the fourth equatorial site. The two perchlorate anions are disordered with site occupancy factors of 0.72/0.28. The amine H is involved in intramolecular hydrogen bonding to the perchlorate O atoms and there are extensive but weak intermolecular C—H...O interactions.

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

    Science.gov (United States)

    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.

  20. SLCO1B1 Polymorphisms and Statin-Induced Myopathy.

    Science.gov (United States)

    Stewart, Alison

    2013-12-04

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

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

    Science.gov (United States)

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

    2017-01-01

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

  2. Molecular characterization of cytochrome P450 1B1 and effect of ...

    African Journals Online (AJOL)

    The deduced amino acid sequence of Nile tilapia CYP1B1 shows similarities of 79.7, 70.3, 65.7, 65.4, 65.0, and 63.7% with Plaice CYP1B1, Japanese eel CYP1B1, zebra fish CYP1B1, common carp CYP1B1, common carp CYP1B2 and Channel catfish CYP1B1, respectively. The phylogenetic tree based on the amino acid ...

  3. A dimeric urea of the bisabolene sesquiterpene from the Okinawan marine sponge Axinyssa sp. inhibits protein tyrosine phosphatase 1B activity in Huh-7 human hepatoma cells.

    Science.gov (United States)

    Abdjul, Delfly B; Kanno, Syu-Ichi; Yamazaki, Hiroyuki; Ukai, Kazuyo; Namikoshi, Michio

    2016-01-15

    Protein tyrosine phosphatase 1B (PTP1B) plays an important role as a negative regulator of the insulin and leptin signaling pathways. Therefore, this enzyme is regarded as an attractive therapeutic target for the treatment of type 2 diabetes and obesity. Our screening program for PTP1B inhibitors led to the isolation of four sesquiterpenes and sterol: N,N'-bis[(6R,7S)-7-amino-7,8-dihydro-α-bisabolen-7-yl]urea (1), (6R,7S)-7-amino-7,8-dihydro-α-bisabolene (2), (1R,6S,7S,10S)-10-isothiocyanato-4-amorphene (3), axinisothiocyanate J (4), and axinysterol (5) from the marine sponge Axinyssa sp. collected at Iriomote Island. Of these, compound 1 was the most potent inhibitor of PTP1B activity (IC50=1.9μM) without cytotoxicity at 50μM in two human cancer cell lines, hepatoma Huh-7 and bladder carcinoma EJ-1 cells. Compound 1 also moderately enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells. Therefore, compound 1 has potential as a new type of anti-diabetic drug candidate possessing PTP1B inhibitory activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    Beky, Bence; Holman, Matthew J.; Noyes, Robert W.; Sasselov, Dimitar D. [Harvard-Smithsonian Center for Astrophysics, 60 Garden St, Cambridge, MA 02138 (United States); Gilliland, Ronald L. [Center for Exoplanets and Habitable Worlds, Pennsylvania State University, 525 Davey Laboratory, University Park, PA 16802 (United States); Bakos, Gaspar A. [Department of Astrophysical Sciences, Princeton University, 4 Ivy Lane, Princeton, NJ 08544 (United States); Winn, Joshua N., E-mail: bbeky@cfa.harvard.edu [Department of Physics, and Kavli Institute for Astrophysics and Space Research, Massachusetts Institute of Technology, 70 Vassar Street, Cambridge, MA 02139 (United States)

    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. methanes and di-bis(indolyl)methanes

    African Journals Online (AJOL)

    a

    INDOLYL)METHANES AND DI-BIS(INDOLYL)METHANES. Alireza Hasaninejad1*, Abdolkarim Zare2*, Hashem Sharghi3, Reza Khalifeh3 and Ahmad Reza. Moosavi Zare3. 1Department of Chemistry, Faculty of Sciences, Persian Gulf University ...

  6. Data of evolutionary structure change: 1B3JA-1TVBD [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B3JA-1TVBD 1B3J 1TVB A D EPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQ----KCRAKPQ---GQW...LAMNVR------NFLKEDAMADCLQELRRYLKSGVVL-RRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGT...WIEQEGPEYW------DGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTA-ADMAAQTT... 1TVB D 1TVBD 1B3JA SGVVL-RRTVP -

  7. Data of evolutionary structure change: 1B3JA-1TVHA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B3JA-1TVHA 1B3J 1TVH A A EPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQ----KCRAKPQ---GQW...LAMNVR------NFLKEDAMADCLQELRRYLKSGVVL-RRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGT...WIEQEGPEYW------DGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAAD-MAAQTT... 1TVH A 1TVHA 1B3JA SGVVL-RRTVP -

  8. TRMM Visible and Infrared Scanner Calibrated Radiances L1B 1.5 hours V7 (TRMM_1B01) at GES DISC

    Data.gov (United States)

    National Aeronautics and Space Administration — This TRMM Visible and Infrared Scanner (VIRS) Level 1B Calibrated Radiance Product (1B01) contains calibrated radiances and auxiliary geolocation information from...

  9. Daclatasvir Plus Asunaprevir for Chronic HCV Genotype 1b Infection

    Science.gov (United States)

    Kumada, Hiromitsu; Suzuki, Yoshiyuki; Ikeda, Kenji; Toyota, Joji; Karino, Yoshiyasu; Chayama, Kazuaki; Kawakami, Yoshiiku; Ido, Akio; Yamamoto, Kazuhide; Takaguchi, Koichi; Izumi, Namiki; Koike, Kazuhiko; Takehara, Tetsuo; Kawada, Norifumi; Sata, Michio; Miyagoshi, Hidetaka; Eley, Timothy; McPhee, Fiona; Damokosh, Andrew; Ishikawa, Hiroki; Hughes, Eric

    2014-01-01

    All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24). This study is registered with http://ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia. Conclusion: Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;59:2083–2091) PMID:24604476

  10. Ab initio calculations of biomolecules

    Science.gov (United States)

    Leś, Andrzej; Adamowicz, Ludwik

    1995-08-01

    Ab initio quantum mechanical calculations are valuable tools for interpretation and elucidation of elemental processes in biochemical systems. With the ab initio approach one can calculate data that sometimes are difficult to obtain by experimental techniques. The most popular computational theoretical methods include the Hartree-Fock method as well as some lower-level variational and perturbational post-Hartree Fock approaches which allow to predict molecular structures and to calculate spectral properties. We have been involved in a number of joined theoretical and experimental studies in the past and some examples of these studies are given in this presentation. The systems chosen cover a wide variety of simple biomolecules, such as precursors of nucleic acids, double-proton transferring molecules, and simple systems involved in processes related to first stages of substrate-enzyme interactions. In particular, examples of some ab initio calculations used in the assignment of IR spectra of matrix isolated pyrimidine nucleic bases are shown. Some radiation-induced transformations in model chromophores are also presented. Lastly, we demonstrate how the ab-initio approach can be used to determine the initial several steps of the molecular mechanism of thymidylate synthase inhibition by dUMP analogues.

  11. Extraction of Proteins with ABS

    NARCIS (Netherlands)

    Desai, R.K.; Streefland, M.; Wijffels, R.H.; Eppink, M.H.M.

    2016-01-01

    Over the past years, there has been an increasing trend in research on the extraction and purification of proteins using aqueous biphasic systems (ABS) formed by polymers, e.g., polyethylene glycol (PEG). In general, when dealing with protein purification processes, it is essential to maintain their

  12. Ab initio potential for solids

    DEFF Research Database (Denmark)

    Chetty, N.; Stokbro, Kurt; Jacobsen, Karsten Wedel

    1992-01-01

    . At the most approximate level, the theory is equivalent to the usual effective-medium theory. At all levels of approximation, every term in the total-energy expression is calculated ab initio, that is, without any fitting to experiment or to other calculations. Every step in the approximation procedure can...

  13. Briefwechsel uber die Partikel "bis" (An Exchange of Letters about the Particle "bis").

    Science.gov (United States)

    Ludwig, Horst; Holschuh, Albrecht

    1990-01-01

    A discussion, in the form of an animated letter exchange, argues that, contrary to most current grammatical descriptions, the German particle "bis" should not be viewed as a preposition governing the accusative case. Rather, it is demonstrated that "bis" most often occurs as a proclitic adverb. (16 references) (JTC)

  14. coordination polymers derived from two different bis-pyridyl-bis-am

    Indian Academy of Sciences (India)

    Three new Ni(II) coordination polymers exhibiting different 1D and 2D framework structures have been hydrothermally ... Keywords. Metal-organic coordination polymer; crystal structure; bis-pyridyl-bis-amide ligand; fluorescence; photocatalysis ... materials for luminescence, catalysis, gas storage and separation, magnetism ...

  15. Ab interno Schlemm's Canal Surgery.

    Science.gov (United States)

    Francis, Brian A; Akil, Handan; Bert, Benjamin B

    2017-01-01

    In primary open-angle glaucoma, the site of greatest resistance to aqueous outflow is thought to be the trabecular meshwork (TM) and inner wall of Schlemm's canal. Augmentation of the conventional (trabecular) outflow pathway can facilitate physiologic outflow and subsequently lower intraocular pressure. The most recent approach to enhancing the conventional outflow pathway is via an internal approach to the TM and Schlemm's canal. Ab interno Schlemm's canal surgery includes 4 novel surgical approaches: (1) removal of the TM and inner wall of Schlemm's canal by an internal approach (ab interno trabeculectomy), (2) implantation of a microstent to bypass the TM, (3) disruption of the TM and inner wall of Schlemm's canal via an internal approach (ab interno trabeculotomy), and (4) dilation of Schlemm's canal via an internal approach (ab interno canaloplasty). The first category includes the Trabectome (Neomedix, Tustin, CA, USA), and Kahook Dual Blade (New World Medical, Rancho Cucamonga, CA, USA). The second category includes the iStent (Glaukos, Laguna Hills, CA, USA), as well as the investigational Hydrus Microstent implant (Ivantis, Irvine, CA, USA). The third category includes gonioscopic-assisted transluminal trabeculotomy (iSciences catheter; Ellex, Adelaide, Australia), and 360° suture trabeculotomy (TRAB360, Sight Sciences, Menlo Park, CA, USA). The fourth category includes ab interno canaloplasty or AbiC (Ellex), and Visco360 (Sight Sciences). In contrast to external filtration surgeries, such as trabeculectomy and aqueous tube shunt, these procedures are categorized as internal filtration surgeries and are performed from an internal approach via gonioscopic guidance. Published results suggest that these surgical procedures are both safe and efficacious for the treatment of open-angle glaucoma. © 2017 S. Karger AG, Basel.

  16. N-type calcium channel/syntaxin/SNAP-25 complex probed by antibodies to II-III intracellular loop of the {alpha}{sub 1B} subunit

    Energy Technology Data Exchange (ETDEWEB)

    Vance, C.L.; Begg, C.M.; Lee, W.-L.; Dubel, S.J. [Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue Cleveland, OH (United States); Copeland, T.D. [ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD (United States); Soennichsen, F.D.; McEnery, M.W. [Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH (United States)

    1999-02-22

    Neuronal voltage-dependent calcium channels are integral components of cellular excitation and neurosecretion. In addition to mediating the entry of calcium across the plasma membrane, both N-type and P/Q-type voltage-dependent calcium channels have been shown to form stable complexes with synaptic vesicle and presynaptic membrane proteins, indicating a structural role for the voltage-dependent calcium channels in secretion. Recently, detailed structural analyses of N-type calcium channels have identified residues amino acids 718-963 as the site in the rat {alpha}{sub 1B} subunit that mediates binding to syntaxin, synaptosome-associated protein of 25andpuncsp; omitted000 mol. wt and synaptotagmin [Sheng et al. (1996) Nature 379, 451-454]. The purpose of this study was to employ site-directed antibodies to target domains within and outside of the interaction site on the rat {alpha}{sub 1B} to probe potential binding sites for syntaxin/SNAP-25/synaptotagmin.Our results demonstrate that both antibodies employed in this study have access to their epitopes on the {alpha}{sub 1B} as evidenced by equivalent immunoprecipitation of native [{sup 125}I]omega-conotoxin GVIA-labeled {alpha}{sub 1B} protein from CHAPS-solubilized preparations. The N-type voltage-dependent calcium channel immunoprecipitated by Ab CW14, the antibody directed to a domain outside of the synprint site, is associated with syntaxin and SNAP-25 with the recovery of these proteins, increasing in parallel to the recovery of {alpha}{sub 1B}. However, when we used the antibody raised to an epitope within the synprint site (Ab CW8) to immunoprecipitate N-type calcium channels, the {alpha}{sub 1B} was depleted of more than 65% of syntaxin and 80% of SNAP-25 when compared to the recovery of these proteins using Ab CW14. This is the first report of a defined epitope on the {alpha}{sub 1B} subunit II-III loop (amino acids 863-875) whose perturbation by a site-directed antibody influences the dissociation of SNAP

  17. Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2.

    Science.gov (United States)

    Wu, Di; Zhu, Xiaoxi; Jimenez-Cowell, Kevin; Mold, Alexander J; Sollecito, Christopher C; Lombana, Nicholas; Jiao, Meng; Wei, Qize

    2015-04-10

    Pitx2 is a bicoid-related homeobox transcription factor implicated in regulating left-right patterning and organogenesis. However, only a limited number of Pitx2 downstream target genes have been identified and characterized. Here we demonstrate that Pitx2 is a transcriptional repressor of DEP domain containing 1B (DEPDC1B). The first intron of the human and mouse DEP domain containing 1B genes contains multiple consensus DNA-binding sites for Pitx2. Chromatin immunoprecipitation assays revealed that Pitx2, along with histone deacetylase 1, was recruited to the first intron of Depdc1b. In contrast, RNAi-mediated depletion of Pitx2 not only enhanced the acetylation of histone H4 in the first intron of Depdc1b, but also increased the protein level of Depdc1b. Luciferase reporter assays also showed that Pitx2 could repress the transcriptional activity mediated by the first intron of human DEPDC1B. The GAP domain of DEPDC1B interacted with nucleotide-bound forms of RAC1 in vitro. In addition, exogenous expression of DEPDC1B suppressed RAC1 activation and interfered with actin polymerization induced by the guanine nucleotide exchange factor TRIO. Moreover, DEPDC1B interacted with various signaling molecules such as U2af2, Erh, and Salm. We propose that Pitx2-mediated repression of Depdc1b expression contributes to the regulation of multiple molecular pathways, such as Rho GTPase signaling. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Anomalous Higgs Couplings in the SO(5) × U(1)B-L Gauge-Higgs Unification in Warped Spacetime

    Science.gov (United States)

    Hosotani, Y.; Sakamura, Y.

    2007-11-01

    The gauge couplings WWZ, WWWW, and WWZZ in the gauge-Higgs unification scenario in the Randall-Sundrum warped spacetime remain almost universal as in the standard model, but substantial deviation results for the Higgs couplings. In the SO(5) × U(1)_{B-L} model, the couplings WWH and ZZH are suppressed by a factor cos θ_{H} from the values in the standard model, while the bare couplings WWHH and ZZHH are suppressed by a factor 1 - (2/3) sin^2 θ_{H}. Here θ_{H} is the Yang-Mills AB phase (Wilson line phase) along the fifth dimension, which characterizes the electroweak symmetry breaking. The suppression can be used to test the gauge-Higgs unification scenario at LHC and ILC. It is also shown that the WWZ coupling in flat spacetime deviates from the standard model value at moderate values of θ_{H}, contradicting with the LEP2 data.

  19. Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene

    Science.gov (United States)

    2012-01-01

    Background Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene. Methods To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene. Results Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-β-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3), interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene. Conclusions These findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene. PMID:22533838

  20. Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene

    Directory of Open Access Journals (Sweden)

    Trdan Lušin Tina

    2012-04-01

    Full Text Available Abstract Background Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene. Methods To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene. Results Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-β-glucuronide (M2 and raloxifene-6,4'-diglucuronide (M3, interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene. Conclusions These findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene.

  1. XENON ANESTHESIA IN CHILDREN: BIS-MONITORING

    Directory of Open Access Journals (Sweden)

    V. G. Bagaev

    2013-01-01

    Full Text Available We conducted 60 low-flow xenon anesthesias in children of 1-18 years of age. We measured the sedation level using bispectral (BIS index and clinically on the stage of induction, xenon anesthesia maintenance and during recovery. The trial showed that, according to the clinical and BIS-monitoring data, sevoflurane inhalational induction in children of 1-5 years of age and propofol intravenous induction in children of 6-18 years of age provides children with the required sedation level. BIS index objectively reflects intensity of the sedative component of an anesthesia both in the junior and the senior age groups on the stages of xenon anesthesia maintenance and during recovery.

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

    LENUS (Irish Health Repository)

    Jabeen, T

    2012-02-03

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

  3. A facile microwave assisted one-pot synthesis of novel 1-methylhexahydroquinazolin-5(6H-ones and bis-1-methylhexahydroquinazolin-5(6H-ones

    Directory of Open Access Journals (Sweden)

    Madhusudhan Saha

    2011-03-01

    Full Text Available Novel hexahydroquinazolin-5(6H-ones 3a-j have been synthesized in good yields by the reaction of enaminones 2a-b with primary amines and formaldehyde under the influence microwaves. Enaminones 2a-b have also been reacted with diamines and formaldehyde under similar conditions resulting in hitherto unreported bis- hexahydroquinazolin-5(6H-ones 4a-d and 5a-d. The structures of the molecules have been established with the help of spectral and analytical data.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Lothar Vassen

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

  6. 40 CFR 721.1187 - Bis(imidoethylene) benzene.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Bis(imidoethylene) benzene. 721.1187... Substances § 721.1187 Bis(imidoethylene) benzene. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance bis(imidoethylene)benzene (PMN P-93-1447) is subject to reporting...

  7. 40 CFR 721.5925 - Bis heterocyclic phenylene derivative (generic).

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Bis heterocyclic phenylene derivative... Specific Chemical Substances § 721.5925 Bis heterocyclic phenylene derivative (generic). (a) Chemical... as bis heterocyclic phenylene derivative (PMN P-01-0432) is subject to reporting under this section...

  8. Analys av Husqvarna AB:s lastbilstransporter till Italien

    OpenAIRE

    Edh, Nina; Jönegård, Mattias

    2008-01-01

    The thesis has been written as a part of the Bachelor degree in Industrial engineering and management at the School of Engineering in Jönköping. The work is focused on the part of Husqvarna AB’s supply chain that is associated with the lorry transports to Italy. Husqvarna AB has approximately ten Italian customers, whose delivery patterns have been studied from January 2007 to July 2008. Some of the customers have a low delivery frequency and small amounts of goods that they therefore have no...

  9. Molecular characterisation and ovine live vaccine 1B evaluation toward a Chlamydophila abortus strain isolated from springbok antelope abortion.

    Science.gov (United States)

    Berri, M; Bernard, F; Lecu, A; Ollivet-Courtois, F; Rodolakis, A

    2004-11-15

    Chlamydiosis is a zoonosis with a worldwide distribution. The reservoir of susceptible hosts is large and includes birds and both domestic and wild mammals. Chlamydial infection, determined serologically, seems to be widespread among wild ruminants in the Paris zoo (France). In February 2003, an abortion case was reported within the springbok (Antidorcas marsupialis) herd of the zoo. PCR assay using primers targeting the polymorph membrane protein gene (pmp) family was performed on both vaginal swab and placenta samples revealing the presence of Chlamydophila. The inoculation into chicken embryos of an infected placenta extract led to the successful isolation of a C. abortus strain referred to as ASb1. The omp1 gene coding the major outer membrane protein (momp) and the 16S-23S rRNA spacer region of ASb1 were compared to those of various strains by restriction fragment length polymorphism (RFLP). The RFLP analysis showed that this isolate belonged to Chlamydophila abortus species and is highly related to known domestic ruminant's strains causing abortion. The efficacy of a live vaccine 1B, based on a temperature-sensitive mutant of the ovine abortion reference strain AB7, was tested. Protection-challenge experiments in a mouse model show that the ASb1 strain led to mice abortions and that vaccination with 1B vaccine provided them with effective protection.

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

    Science.gov (United States)

    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. Infrared characteristics of the BIS catalog objects

    Science.gov (United States)

    Gaudenzi, S.; Nesci, R.; Rossi, C.; Sclavi, S.; Gigoyan, K. S.; Mickaelian, A. M.

    2017-10-01

    We studied several color-color infrared diagrams of the 276 late type stars of the BIS catalog. For 95 of these stars we derived spectral classification from our slit spectroscopy. From the 2MASS color diagram we concluded that none of the sample stars is a dwarf. The WISE 3.4-12 vs 12-22 plot is the best to discriminate the variability type (Mira, irregular and not-variable), as well as carbon stars. IRAS colors are less useful due to the poor quality of the data for most of the BIS stars. Mixed plots involving 2MASS, AKARI and WISE were also explored: the 2MASS-AKARI J-[S09] vs [S09]-[L18] plot is efficient to discriminate carbon and Mira stars. From the color plots and our spectroscopy we can statistically predict that in the whole BIS catalog no other dusty carbon star is present, while a few Miras and CH or R carbon stars could be discovered. Only about 15% of the BIS stars are of early M type.

  12. IL1B promoter polymorphism regulates the expression of gastric acid stimulating hormone gastrin.

    Science.gov (United States)

    Chakravorty, Meenakshi; Datta De, Dipanjana; Choudhury, Abhijit; Roychoudhury, Susanta

    2009-07-01

    It is important to dissect the effect of the alternative alleles of a functional SNP on the entire biochemical pathway for the complete understanding of the mechanism of the manifestation of complex diseases. IL1B-511C>T and -31C>T promoter polymorphisms have been suggested as potential susceptibility loci for Helicobacter pylori associated gastroduodenal diseases. We report that altered expression of IL1B due to a specific polymorphism in its promoter modulates the expression of gastrin, an acid regulating hormone. Treatment of gastric carcinoma cells, AGS, with IL1B resulted in a 20-fold reduction in gastrin expression. Gastrin promoter assay showed that IL1B inhibits gastrin expression at the transcriptional level and part of this inhibitory process is mediated via activation of NFkappaB and involvement of HDACs. An almost 3-fold increase in IL1B expression was observed when AGS cells were transfected with -31TIL1B expression plasmid in comparison to -31CIL1B. The -31TIL1B induced a 2-fold greater repression of the gastrin luciferase activity compared to -31CIL1B. This signaling of the -31TIL1B variant allele driven IL1B revealed an almost 1.5-fold greater expression of NFkappaB. Thus, this study showed that a single base substitution at the -31 position of the IL1B promoter brought about differential expression of IL1B which differentially altered both NFkappaB activation and gastrin expression.

  13. ABS: Sequence alignment by scanning

    KAUST Repository

    Bonny, Mohamed Talal

    2011-08-01

    Sequence alignment is an essential tool in almost any computational biology research. It processes large database sequences and considered to be high consumers of computation time. Heuristic algorithms are used to get approximate but fast results. We introduce fast alignment algorithm, called Alignment By Scanning (ABS), to provide an approximate alignment of two DNA sequences. We compare our algorithm with the well-known alignment algorithms, the FASTA (which is heuristic) and the \\'Needleman-Wunsch\\' (which is optimal). The proposed algorithm achieves up to 76% enhancement in alignment score when it is compared with the FASTA Algorithm. The evaluations are conducted using different lengths of DNA sequences. © 2011 IEEE.

  14. AP calculus AB/BC

    CERN Document Server

    Schwartz, Stu

    2013-01-01

    All Access for the AP® Calculus AB & BC Exams Book + Web + Mobile Everything you need to prepare for the Advanced Placement® exam, in a study system built around you! There are many different ways to prepare for an Advanced Placement® exam. What's best for you depends on how much time you have to study and how comfortable you are with the subject matter. To score your highest, you need a system that can be customized to fit you: your schedule, your learning style, and your current level of knowledge. This book, and the free online tools that come with it, will help you personalize your AP® Cal

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

    Science.gov (United States)

    2010-04-01

    ... offer a position filled by an H-1B nonimmigrant to an equally or better qualified United States worker....S. workers, to offer the job to U.S. applicants who are equally or better qualified than the H-1B... EMPLOYMENT OF FOREIGN WORKERS IN THE UNITED STATES Labor Condition Applications and Requirements for...

  16. Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies

    National Research Council Canada - National Science Library

    Marie Jazmín Sarabia-Sanchez; Pedro Josue Trejo-Soto; Jose Miguel Velazquez-López; Carlos Carvente-García; Rafael Castillo; Alicia Hernandez-Campos; Claudia Avitia-Domínguez; Daniel Enríquez-Mendiola; Erick Sierra-Campos; Mónica Valdez-Solana; Jose Manuel Salas-Pacheco; Alfredo Tellez-Valencia

    2017-01-01

    .... In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B), a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance...

  17. IceBridge NSERC L1B Geolocated Meteorologic and Surface Temperature Data, Version 1

    Data.gov (United States)

    National Aeronautics and Space Administration — The IceBridge National Suborbital Education & Research Center (NSERC) L1B Geolocated Meteorologic and Surface Temperature (IAMET1B) data set is a collection of...

  18. MISR Level 1B1 Local Mode Radiance Data V002

    Data.gov (United States)

    National Aeronautics and Space Administration — The MISR Local Mode Level 1B1 Product contains the data numbers (DNs) radiometrically scaled to radiances with no geometric resampling.The MISR Level 1B1 Radiance...

  19. Data of evolutionary structure change: 1B3IA-2AANA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B3IA-2AANA 1B3I 2AAN A A ASVQIKMGTDKYAPLYEPKALSISAGDTVE--FVMN-KVGPHNVIFDKVPAGESAP...GPVTIEIGSKGEELAFDKTELTVSAGQTVTIRFKNNSAVQQHNWILV-KGGEAEAANIANAGLSAGPAANYLPADKSNIIAESPLANGNETVEVTFTAPAAGTYLYICTV...2AAN A 2AANA VEVTFTAPAAGTYL...2AAN A 2AANA NWILV-KGGEA

  20. Data of evolutionary structure change: 1B3JA-1TVHD [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B3JA-1TVHD 1B3J 1TVH A D EPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQ----KCRAKPQ---GQW...LAMNVR------NFLKEDAMADCLQELRRYLKS-GVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGT...WIEQEGPEYW------DGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTA-ADMAAQTT... 1TVH D 1TVHD 1TVH D 1TVHD

  1. Data of evolutionary structure change: 1B3JA-1TVBA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B3JA-1TVBA 1B3J 1TVB A A EPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQ----KCRAK--------...LAMNVR------NFLKEDAMADCLQELRRYLKS-GVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGT...GPEYW-----------DGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAAD-MAAQTT... 1TVB A 1TVBA 1TVB A 1TVBA

  2. Pre-IceBridge ATM L1B Qfit Elevation and Return Strength

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA Pre-IceBridge ATM Level-1B Qfit Elevation and Return Strength (BLATM1B) data set contains spot elevation measurements of Arctic, Greenland, and Antarctic...

  3. IceBridge LVIS L1B Geolocated Return Energy Waveforms V002

    Data.gov (United States)

    National Aeronautics and Space Administration — The IceBridge LVIS L1B Geolocated Return Energy Waveforms (ILVIS1B) data set contains Greenland and Antarctica laser altimetry return energy waveform measurements...

  4. IceBridge NSERC L1B Geolocated Meteorologic and Surface Temperature Data

    Data.gov (United States)

    National Aeronautics and Space Administration — The IceBridge National Suborbital Education & Research Center (NSERC) L1B Geolocated Meteorologic and Surface Temperature (IAMET1B) data set is a collection of...

  5. IceBridge Riegl Laser Altimeter L1B Time-Tagged Laser Ranges, Version 1

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA IceBridge Riegl Laser Altimeter L1B Time-Tagged Laser Ranges (ILUTP1B) data set contains laser ranges, returned pulses, and deviation for returned pulses in...

  6. SAGE III Meteor-3M L1B Solar Event Transmission Data (Native) V004

    Data.gov (United States)

    National Aeronautics and Space Administration — SAGE III Meteor-3M L1B Solar Event Transmission Data are Level 1B pixel group transmission profiles for a single solar event. The Stratospheric Aerosol and Gas...

  7. Pre-IceBridge MCoRDS L1B Geolocated Radar Echo Strength Profiles

    Data.gov (United States)

    National Aeronautics and Space Administration — The Pre-IceBridge MCoRDS L1B Geolocated Radar Echo Strength Profiles (BRMCR1B) data set contains Arctic and Antarctic radio echo-sounding measurements taken from the...

  8. Data of evolutionary structure change: 1B8DK-2UUMK [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B8DK-2UUMK 1B8D 2UUM K K MKSVITTTISAADAAGRFPSSSDLESIQGNIQRAAARLEAAQKLSGNHEAVVKEAG...AFTFTRDRLCVPRDMSSQAGVEFTSALDYVINSLC MKTPLTEAVSVADSQGRFLSSTEIQVAFGRFRQAKAGLEAAKALTSKADSL...2UUM K 2UUMK QMQGPNYAADQR...2UUM K 2UUMK KANHG----LSGDA

  9. IceBridge GPS/IMU L1B Primary Position and Attitude Solution, Version 1

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA IceBridge GPS/IMU L1B Primary Position and Attitude Solution (IPUTG1B) data set contains elevation, roll, pitch, heading, north-south acceleration,...

  10. IceBridge ZLS Dynamic Gravity Meter Time-Registered L1B Vertical Accelerations

    Data.gov (United States)

    National Aeronautics and Space Administration — The IceBridge ZLS Dynamic Gravity Meter Time-Registered L1B Vertical Accelerations (IGZLS1B) data set contains vertical, cross body, and along body acceleration...

  11. IceBridge GPS/IMU L1B Primary Position and Attitude Solution

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA IceBridge GPS/IMU L1B Primary Position and Attitude Solution (IPUTG1B) data set contains elevation, roll, pitch, heading, north-south acceleration,...

  12. IceBridge Paroscientific S-1000 L1B Pressure Altimeter Time-Tagged Air Pressure

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA IceBridge Paroscientific S-1000 L1B Pressure Altimeter Time-Tagged Air Pressure (IAPRS1B) data set contains static pressure values for Antarctica using the...

  13. IceBridge Riegl Laser Altimeter L1B Time-Tagged Laser Ranges

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA IceBridge Riegl Laser Altimeter L1B Time-Tagged Laser Ranges (ILUTP1B) data set contains laser ranges, returned pulses, and deviation for returned pulses in...

  14. Deletion of Protein Tyrosine Phosphatase 1B (PTP1B Enhances Endothelial Cyclooxygenase 2 Expression and Protects Mice from Type 1 Diabetes-Induced Endothelial Dysfunction.

    Directory of Open Access Journals (Sweden)

    David J Herren

    Full Text Available Protein tyrosine phosphatase 1B (PTP1B dephosphorylates receptors tyrosine kinase and acts as a molecular brake on insulin signaling pathway. Conditions of metabolic dysfunction increase PTP1B, when deletion of PTP1B protects against metabolic disorders by increasing insulin signaling. Although vascular insulin signaling contributes to the control of glucose disposal, little is known regarding the direct role of PTP1B in the control of endothelial function. We hypothesized that metabolic dysfunctions increase PTP1B expression in endothelial cells and that PTP1B deletion prevents endothelial dysfunction in situation of diminished insulin secretion. Type I diabetes (T1DM was induced in wild-type (WT and PTP1B-deficient mice (KO with streptozotocin (STZ injection. After 28 days of T1DM, KO mice exhibited a similar reduction in body weight and plasma insulin levels and a comparable increase in glycemia (WT: 384 ± 20 vs. Ko: 432 ± 29 mg/dL, cholesterol and triglycerides, as WT mice. T1DM increased PTP1B expression and impaired endothelial NO-dependent relaxation, in mouse aorta. PTP1B deletion did not affect baseline endothelial function, but preserved endothelium-dependent relaxation, in T1DM mice. NO synthase inhibition with L-NAME abolished endothelial relaxation in control and T1DM WT mice, whereas L-NAME and the cyclooxygenases inhibitor indomethacin were required to abolish endothelium relaxation in T1DM KO mice. PTP1B deletion increased COX-2 expression and PGI2 levels, in mouse aorta and plasma respectively, in T1DM mice. In parallel, simulation of diabetic conditions increased PTP1B expression and knockdown of PTP1B increased COX-2 but not COX-1 expression, in primary human aortic endothelial cells. Taken together these data indicate that deletion of PTP1B protected endothelial function by compensating the reduction in NO bioavailability by increasing COX-2-mediated release of the vasodilator prostanoid PGI2, in T1DM mice.

  15. Aldo-keto Reductase Family 1 B10 as a Novel Target for Breast Cancer Treatment

    Science.gov (United States)

    2010-08-01

    aldo-keto reductase family protein AKR1B10 is highly correlated with smokers ’ non -small cell lung carcinomas. Clin Cancer Res 11: 1776-1785. Gallego...reductase family 1 B10 protein detoxifies dietary and lipid -derived alpha, beta-unsaturated carbonyls at physiological levels . Biochem Biophys Res...AKR1B10 expression in breast cancer, define the role of AKR1B10 in lipid metabolism, proliferation, and tumorigenicity of breast cancer cells using

  16. Interaction of CPCCOEt with a chimeric mGlu1b and calcium sensing receptor

    DEFF Research Database (Denmark)

    Bräuner-Osborne, H; Jensen, Anders A.; Krogsgaard-Larsen, P

    1999-01-01

    R) and a chimeric receptor consisting of the agonist binding amino-terminal domain (ATD) of CaR and the seven transmembrane (7TM) domain of mGlu1b (named Ca/1b). CPCCOEt inhibited responses of (S)-glutamic acid and Ca2+ at mGlu1b and Ca/1b, applied at EC50 values, with IC50 values of 10.2 microM and 13.4 micro...

  17. Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel.

    Science.gov (United States)

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

    2012-08-15

    Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination. Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213). Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05). The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3.

  18. Data of evolutionary structure change: 1B8MB-1HCFA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available -----------GELAVCDAVSGWVTDRRTAVDLRGREVEVLGEVPAAGGSPLRQYFFETRCKAAGGPGAGGGGCRGVDRRHWVSECKAKQSYVRALTADAQGRVGWRWIR...GVSETAPASRRGELAVCDAVSGWVTDRRTAVDLRGREVEVLGEVPAAGGSPLRQYFFETRCK--ADPGAGGGGCRGVDRRHWVSECKAKQSYVRALTADAQGRVGWRWIR...> 1HCFA ETRCK--ADPGA EEEEE-- ...> 1B8MB ETRCKAAGGPGA EEE

  19. An Lmx1b-miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool.

    Directory of Open Access Journals (Sweden)

    Angela Anderegg

    Full Text Available MicroRNAs regulate gene expression in diverse physiological scenarios. Their role in the control of morphogen related signaling pathways has been less studied, particularly in the context of embryonic Central Nervous System (CNS development. Here, we uncover a role for microRNAs in limiting the spatiotemporal range of morphogen expression and function. Wnt1 is a key morphogen in the embryonic midbrain, and directs proliferation, survival, patterning and neurogenesis. We reveal an autoregulatory negative feedback loop between the transcription factor Lmx1b and a newly characterized microRNA, miR135a2, which modulates the extent of Wnt1/Wnt signaling and the size of the dopamine progenitor domain. Conditional gain of function studies reveal that Lmx1b promotes Wnt1/Wnt signaling, and thereby increases midbrain size and dopamine progenitor allocation. Conditional removal of Lmx1b has the opposite effect, in that expansion of the dopamine progenitor domain is severely compromised. Next, we provide evidence that microRNAs are involved in restricting dopamine progenitor allocation. Conditional loss of Dicer1 in embryonic stem cells (ESCs results in expanded Lmx1a/b+ progenitors. In contrast, forced elevation of miR135a2 during an early window in vivo phenocopies the Lmx1b conditional knockout. When En1::Cre, but not Shh::Cre or Nes::Cre, is used for recombination, the expansion of Lmx1a/b+ progenitors is selectively reduced. Bioinformatics and luciferase assay data suggests that miR135a2 targets Lmx1b and many genes in the Wnt signaling pathway, including Ccnd1, Gsk3b, and Tcf7l2. Consistent with this, we demonstrate that this mutant displays reductions in the size of the Lmx1b/Wnt1 domain and range of canonical Wnt signaling. We posit that microRNA modulation of the Lmx1b/Wnt axis in the early midbrain/isthmus could determine midbrain size and allocation of dopamine progenitors. Since canonical Wnt activity has recently been recognized as a key

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

    Science.gov (United States)

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

    2015-01-01

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

  1. Interference of kallikrein 1b26 (klk1b26 translation by microRNA specifically expressed in female mouse submandibular glands: an additional mechanism for sexual dimorphism of klk1b26 protein in the glands

    Directory of Open Access Journals (Sweden)

    Kurihara Kinji

    2011-11-01

    Full Text Available Abstract Background Mouse kallikrein 1b26 (klk1b26 protein is more abundant in male submandibular glands (SMGs than in female ones. This sexual dimorphism has been thought to be due to increased mRNA synthesis stimulated by androgen. However, the klk1b26 protein level in female SMG is far less than that expected from the mRNA level, suggesting an additional mechanism for down-regulation of klk1b26 expression in female SMGs. Methods We examined the effects of small non-coding RNAs in mouse SMGs on in vitro translation of klk1b26 using a reticulocyte lysate system and reverse transcription (RT-PCR for klk1b26 mRNA. Statistical analyses were performed with a computer package (Microsoft Excel. Results The microRNA (miRNA preparation from female SMGs, but not male SMGs, interfered with the in vitro translation of the klk1b26 protein and inhibited the RT-PCR for klk1b26 mRNA with forward primers targeting its 5'-terminal region (between the 15th and 40th nucleotide from the 5'-terminal. The miRNA preparation from castrated mouse SMGs showed the inhibitory effect on the klk1b26 translation, but that from a 5α-dihydrotestosterone-treated female mouse SMGs did not. Synthetic miRNAs (miR-325 and miR-1497a, which have partial complementarity with klk1b26 mRNA at its 5'-terminal region (15th to 40th nucleotide position from the 5'-terminal, also interfered with the in vitro klk1b26 translation. When the female miRNA preparation was incubated with a 30-nucleotide-long single-strand oligoDNA (named [15th-44th]ssDNA, whose sequence corresponded to the 15th to 44th position from the 5'-terminal of klk1b26 mRNA prior to the addition into the in vitro translation system, the inhibitory effect of the miRNA preparation on klk1b26 translation disappeared, while [15th-44th]ssDNA itself had no effect on the translation. Preincubation of the miRNA preparation with another single-strand DNA ([169th-198th]ssDNA, whose sequence corresponded with 169th to 198th position

  2. 18 CFR 1b.17 - Appearance and practice before the Commission.

    Science.gov (United States)

    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 Appearance...

  3. Data of evolutionary structure change: 1CG8A-2DN1B [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available equence>FSGFE-----ACNEQ ure> ----- HH> B 2DN1B FGDLSTPDAVMGNPK re>G HHHH HH...ence>VNLQA-FTPVT >HH - HHH> 2DN1 B 2DN1B HHFGKEFTPPV ...>HHHGGG HHH> ATOM 1931 CA HIS B 116 17.758 39.

  4. HNF1B mutations associate with hypomagnesemia and renal magnesium wasting

    NARCIS (Netherlands)

    Adalat, Shazia; Woolf, Adrian S.; Johnstone, Karen A.; Wirsing, Andrea; Harries, Lorna W.; Long, David A.; Hennekam, Raoul C.; Ledermann, Sarah E.; Rees, Lesley; van't Hoff, William; Marks, Stephen D.; Trompeter, Richard S.; Tullus, Kjell; Winyard, Paul J.; Cansick, Janette; Mushtaq, Imran; Dhillon, Harjeeta K.; Bingham, Coralie; Edghill, Emma L.; Shroff, Rukshana; Stanescu, Horia; Ryffel, Gerhart U.; Ellard, Sian; Bockenhauer, Detlef

    2009-01-01

    Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and

  5. Endothelial cell PTP1B regulates leukocyte recruitment during allergic inflammation.

    Science.gov (United States)

    Berdnikovs, Sergejs; Abdala-Valencia, Hiam; Cook-Mills, Joan M

    2013-02-15

    Pulmonary eosinophilia is a consistent hallmark of allergic lung inflammation. Infiltration of eosinophils into ovalbumin (OVA)-challenged lungs is dependent on the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Ligation of VCAM-1 activates endothelial cell protein tyrosine phosphatase 1B (PTP1B), which is required for VCAM-1-dependent leukocyte migration in vitro. To examine whether nonhematopoietic PTP1B modulates eosinophil recruitment in vivo, mice deficient in PTP1B were irradiated and received wild-type hematopoietic cells to generate chimeric PTP1B-/- mice. In response to OVA challenge, the chimeric PTP1B-/- mice had reduced eosinophilia in the lung tissue and bronchoalveolar lavage, indicating a role for PTP1B in nonhematopoietic cells during leukocyte recruitment. To determine whether endothelial cell PTP1B modulates eosinophil recruitment, mice with an inducible endothelial cell-specific PTP1B deletion (iePTP1B mice) were generated and the PTP1B deletion was induced after antigen sensitization before antigen challenge. In response to OVA challenge, the iePTP1B mice with the endothelial cell PTP1B deletion had an increased accumulation of eosinophils bound to the luminal surface of the endothelium in the lung vasculature and had a decrease in leukocyte recruitment into the lung tissue. In the iePTP1B mice, expression of adhesion molecules, cytokines, or chemokines that regulate leukocyte recruitment during inflammation was not altered, consistent with other studies that deletion of endothelial adhesion molecule signals does not alter lung cytokines and chemokines. In summary, these data suggest that VCAM-1 activation of PTP1B in the endothelium is necessary for eosinophil recruitment during allergic inflammation. Moreover, these studies provide a basis for targeting VCAM-1-dependent signaling pathways in allergy therapies.

  6. Ab interno trabeculectomy: patient selection and perspectives

    National Research Council Canada - National Science Library

    Vinod, Kateki; Gedde, Steven J

    2016-01-01

    Ab interno trabeculectomy is one among several recently introduced minimally invasive glaucoma surgeries that avoid a conjunctival incision and full-thickness sclerostomy involved in traditional glaucoma surgery...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  8. Low 5-HT1B receptor binding in the migraine brain

    DEFF Research Database (Denmark)

    Deen, Marie; Hansen, Hanne D; Hougaard, Anders

    2017-01-01

    Background The pathophysiology of migraine may involve dysfunction of serotonergic signaling. In particular, the 5-HT1B receptor is considered a key player due to the efficacy of 5-HT1B receptor agonists for treatment of migraine attacks. Aim To examine the cerebral 5-HT1B receptor binding...... in interictal migraine patients without aura compared to controls. Methods Eighteen migraine patients, who had been migraine free for >48 hours, and 16 controls were scanned after injection of the 5-HT1B receptor specific radioligand [11C]AZ10419369 for quantification of cerebral 5-HT1B receptor binding....... Patients who reported migraine

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

    Science.gov (United States)

    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. Copyright © 2015 the American Physiological Society.

  10. Overexpression of oligouridylate binding protein 1b results in ABA hypersensitivity.

    Science.gov (United States)

    Nguyen, Cam Chau; Nakaminami, Kentaro; Matsui, Akihiro; Watanabe, Shunsuke; Kanno, Yuri; Seo, Mitsunori; Seki, Motoaki

    2017-02-01

    Oligouridylate binding protein 1b (UBP1b), a marker protein of plant stress granules (SGs), plays a role in heat stress tolerance in plants. A previous microarray analysis revealed that the expression of several ABA signaling-related genes is higher in UBP1b-overexpressing Arabidopsis plants (UBP1b-ox) subjected to both non-stressed and heat stress conditions. Root elongation and seed germination assays demonstrated that UBP1b-ox exhibited hypersensitivity to ABA. RT-qPCR analysis confirmed that mitogen-activated protein kinase (MAPK) cascade genes, such as MPK3, MKK4, and MKK9 were upregulated in UBP1b-ox plants. ABA receptor genes, including PYL5 and PYL6, were also upregulated in UBP1b-ox plants. mRNA of WRKY33 - a downstream gene of MPK3 and an upstream gene of ethylene biosynthesis, exhibited high levels of accumulation, although the level of endogenous ABA was not significantly different between UBP1b-ox and control plants. In addition, RNA decay analysis revealed that WRKY33 was more stable in UBP1b-ox plants, indicating that the mRNA of WRKY33 was protected within UBP1b SGs. Collectively, these data demonstrate that UBP1b plays an important role in plant response to ABA.

  11. GFI1B controls its own expression binding to multiple sites.

    Science.gov (United States)

    Anguita, Eduardo; Villegas, Ana; Iborra, Francisco; Hernández, Aurora

    2010-01-01

    Transcription factors play essential roles in both normal and malignant hematopoiesis. This is the case for the growth factor independent 1b (GFI1B) transcription factor, which is required for erythroid and megakaryocytic differentiation and over-expressed in leukemic patients and cell lines. To investigate GFI1B regulation, we searched for multispecies conserved non-coding elements between GFI1B and neighboring genes. We used a formaldehyde-assisted isolation of regulatory elements (FAIRE) assay and DNase1 hypersensitivity to assess the chromatin conformation of these sites. Next, we analyzed transcription factor binding and histone modifications at the GFI1B locus including the conserved non-coding elements by a chromatin immunoprecipitation assay. Finally, we studied the interaction of the GFI1B promoter and the conserved non-coding elements with the chromatin conformation capture technique and used immunofluorescence to evaluate GFI1B levels in individual cells. We localized several conserved non-coding elements containing multiple erythroid specific transcription factor binding sites at the GFI1B locus. In GFI1B-expressing cells a subset of these conserved non-coding elements and the promoter adopt a close spatial conformation, localize with open chromatin sites, harbor chromatin modifications associated with gene activation and bind multiple transcription factors and co-repressors. Conclusions Our findings indicate that GFI1B regulatory elements behave as activators and repressors. Different protein levels within a cell population suggest that cells must activate and repress GFI1B continuously to control its final level. These data are consistent with a model of GFI1B regulation in which GFI1B binds to its own promoter and to the conserved non-coding elements as its levels rise. This would attract repressor complexes that progressively down-regulate the gene. GFI1B expression would decrease until a stage at which the activating complexes predominate and

  12. Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning.

    Directory of Open Access Journals (Sweden)

    Federico Fuentes

    Full Text Available ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates ß-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP-PTP1B, are present in dendritic spines of hippocampal neurons in culture. GFP-PTP1B overexpression does not affect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of ß-catenin-Tyr-654 phosphorylation increased ∼5-fold in the hippocampus of adult PTP1B(-/- (KO mice compared to wild type (WT mice and this was accompanied by a reduction in the amount of ß-catenin associated with N-cadherin. To determine whether PTP1B-deficiency alters learning and memory, we generated mice lacking PTP1B in the hippocampus and cortex (PTP1B(fl/fl-Emx1-Cre. PTP1B(fl/fl-Emx1-Cre mice displayed improved performance in the Barnes maze (decreased time to find and enter target hole, utilized a more efficient strategy (cued, and had better recall compared to WT controls. Our results implicate PTP1B in structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylation of ß-catenin on Tyr-654. Disruption of hippocampal PTP1B function or expression leads to elongation of dendritic filopodia and improved learning and memory, demonstrating an exciting novel role for this phosphatase.

  13. Ultrasound Biomicroscopy Comparison of Ab Interno and Ab Externo Intraocular Lens Scleral Fixation.

    Science.gov (United States)

    Horiguchi, Lie; Garcia, Patricia Novita; Malavazzi, Gustavo Ricci; Allemann, Norma; Gomes, Rachel L R

    2016-01-01

    Purpose. To compare ab interno and ab externo scleral fixation of posterior chamber intraocular lenses (PCIOL) using ultrasound biomicroscopy (UBM). Methods. Randomized patients underwent ab externo or ab interno scleral fixation of a PCIOL. Ultrasound biomicroscopy was performed 3 to 6 months postoperatively, to determine PCIOL centration, IOL distance to the iris at 12, 3, 6, and 9 hours, and haptics placement in relation to the ciliary sulcus. Results. Fifteen patients were enrolled in the study. The ab externo technique was used in 7 eyes (46.6%) and the ab interno in 8 eyes (53.3%). In the ab externo technique, 14 haptics were located: 4 (28.57%) in the ciliary sulcus; 2 (14.28%) anterior to the sulcus; and 8 (57.14%) posterior to the sulcus, 6 in the ciliary body and 2 posterior to the ciliary body. In the ab interno group, 4 haptics (25.0%) were in the ciliary sulcus, 2 (12.50%) anterior to the sulcus, and 10 (75.0%) posterior to the sulcus, 4 in the ciliary body and 6 posterior to the ciliary body. Conclusions. Ab externo and ab interno scleral fixation techniques presented similar results in haptic placement. Ab externo technique presented higher vertical tilt when compared to the ab interno.

  14. Ultrasound Biomicroscopy Comparison of Ab Interno and Ab Externo Intraocular Lens Scleral Fixation

    Directory of Open Access Journals (Sweden)

    Lie Horiguchi

    2016-01-01

    Full Text Available Purpose. To compare ab interno and ab externo scleral fixation of posterior chamber intraocular lenses (PCIOL using ultrasound biomicroscopy (UBM. Methods. Randomized patients underwent ab externo or ab interno scleral fixation of a PCIOL. Ultrasound biomicroscopy was performed 3 to 6 months postoperatively, to determine PCIOL centration, IOL distance to the iris at 12, 3, 6, and 9 hours, and haptics placement in relation to the ciliary sulcus. Results. Fifteen patients were enrolled in the study. The ab externo technique was used in 7 eyes (46.6% and the ab interno in 8 eyes (53.3%. In the ab externo technique, 14 haptics were located: 4 (28.57% in the ciliary sulcus; 2 (14.28% anterior to the sulcus; and 8 (57.14% posterior to the sulcus, 6 in the ciliary body and 2 posterior to the ciliary body. In the ab interno group, 4 haptics (25.0% were in the ciliary sulcus, 2 (12.50% anterior to the sulcus, and 10 (75.0% posterior to the sulcus, 4 in the ciliary body and 6 posterior to the ciliary body. Conclusions. Ab externo and ab interno scleral fixation techniques presented similar results in haptic placement. Ab externo technique presented higher vertical tilt when compared to the ab interno.

  15. A P387L variant in protein tyrosine phosphatase-1B (PTP-1B) is associated with type 2 diabetes and impaired serine phosphorylation of PTP-1B in vitro

    DEFF Research Database (Denmark)

    Echwald, Søren M; Riis, Helle Bach; Vestergaard, Henrik

    2002-01-01

    as well as cDNA from 56 obese patients. Four silent variants, (NT CGA-->CGG) R199R, (NT CCC-->CCT) P303P, 3'UTR+104insG, and 3'UTR+86T-->G, and one missense variant, P387L, were found. Subsequent analysis on genomic DNA revealed two intron variants, IVS9+57C-->T and IVS9+58G-->A, and two missense variants......In the present study, we tested the hypothesis that variability in the protein tyrosine phosphatase-1B (PTP-1B) gene is associated with type 2 diabetes. Using single-strand conformational polymorphism analysis, we examined cDNA of PTP-1B from 56 insulin-resistant patients with type 2 diabetes.......0012). In summary, a rare P387L variant of the PTP-1B gene is associated with a 3.7 (CI 1.26-10.93, P = 0.02) genotype relative risk of type 2 diabetes in the examined population of Danish Caucasian subjects and results in impaired in vitro serine phosphorylation of the PTP-1B peptide....

  16. Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor

    DEFF Research Database (Denmark)

    Pedersen, U B; Norby, B; Jensen, Anders A.

    1994-01-01

    Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines...

  17. Solvent (acetone-butanol: ab) production

    Science.gov (United States)

    This article describes production of butanol [acetone-butanol-ethanol, (also called AB or ABE or solvent)] by fermentation using both traditional and current technologies. AB production from agricultural commodities, such as corn and molasses, was an important historical fermentation. Unfortunately,...

  18. Co-continuous polycarbonate/ABS blends

    NARCIS (Netherlands)

    Inberg, J.P.F.; Gaymans, R.J.

    2002-01-01

    Co-continuous PC/ABS (50/50) blends were studied with a variable polybutadiene (PB) content (0–40%) in ABS. Polycarbonate (PC), styrene-acrylonitrile (SAN) and PB were blended in two steps using a twin screw extruder. Rectangular bars were injection moulded and notched Izod impact tested at

  19. Gfi1b controls integrin signaling-dependent cytoskeleton dynamics and organization in megakaryocytes.

    Science.gov (United States)

    Beauchemin, Hugues; Shooshtarizadeh, Peiman; Vadnais, Charles; Vassen, Lothar; Pastore, Yves D; Möröy, Tarik

    2017-03-01

    Mutations in GFI1B are associated with inherited bleeding disorders called GFI1B-related thrombocytopenias. We show here that mice with a megakaryocyte-specific Gfi1b deletion exhibit a macrothrombocytopenic phenotype along a megakaryocytic dysplasia reminiscent of GFI1B-related thrombocytopenia. GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton. Gfi1b-null megakaryocytes are also unable to form proplatelets, a process independent of integrin signaling. GFI1B-deficient megakaryocytes exhibit aberrant expression of several components of both the actin and microtubule cytoskeleton, with a dramatic reduction of α-tubulin. Inhibition of FAK or ROCK, both important for actin cytoskeleton organization and integrin signaling, only partially restored their response to integrin ligands, but the inhibition of PAK, a regulator of the actin cytoskeleton, completely rescued the responsiveness of Gfi1b-null megakaryocytes to ligands, but not their ability to form proplatelets. We conclude that Gfi1b controls major functions of megakaryocytes such as integrin-dependent cytoskeleton organization, spreading and migration through the regulation of PAK activity whereas the proplatelet formation defect in GFI1B-deficient megakaryocytes is due, at least partially, to an insufficient α-tubulin content. Copyright© Ferrata Storti Foundation.

  20. Listeria monocytogenes and Shigella flexneri Activate the NLRP1B Inflammasome.

    Science.gov (United States)

    Neiman-Zenevich, Jana; Stuart, Sarah; Abdel-Nour, Mena; Girardin, Stephen E; Mogridge, Jeremy

    2017-11-01

    Activation of the innate immune receptor NLRP1B leads to the formation of an inflammasome, which induces autoproteolytic processing of pro-caspase-1, and ultimately to the release of inflammatory cytokines and to the execution of pyroptosis. One of the signals to which NLRP1B responds is metabolic stress that occurs in cells deprived of glucose or treated with metabolic inhibitors. NLRP1B might therefore sense microbial infection, as intracellular pathogens such as Listeria monocytogenes and Shigella flexneri cause metabolic stress as a result of nutrient scavenging and host cell damage. Here we addressed whether these pathogens activate the NLRP1B inflammasome. We found that Listeria infection activated the NLRP1B inflammasome in a reconstituted fibroblast model. Activation of NLRP1B by Listeria was diminished in an NLRP1B mutant shown previously to be defective at detecting energy stress and was dependent on the expression of listeriolysin O (LLO), a protein required for vacuolar escape. Infections of either Listeria or Shigella activated NLRP1B in the RAW264.7 murine macrophage line, which expresses endogenous NLRP1B. We conclude that NLRP1B senses cellular infection by distinct invasive pathogens. Copyright © 2017 American Society for Microbiology.

  1. Overexpression of SULT2B1b Promotes Angiogenesis in Human Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Wen Chen

    2016-03-01

    Full Text Available Background/Aims: Overexpression of cytosolic sulfotransferase 2B1b (SULT2B1b has been commonly found in colorectal and hepatocellular carcinoma, suggesting that SULT2B1b might act as a potential oncogenic protein. However, its clinical significance and biological role in gastric cancer progression remain largely unknown. Methods: Expressions of SULT2B1b in clinical gastric cancer (GC samples were examined using qRT-PCR and Western blot. Results: SULT2B1b was markedly overexpressed in human GC samples, and positively correlated with vessel density and associated with poor clinical features. We also demonstrated that overexpression of SULT2B1b resulted in increased tumor angiogenesis and tumor growth in mouse GC models. In addition, ablation of SULT2B1b in human GC cells lines BGC823 and MKN45 decreased the capability of the cells to recruit endothelial cells. Moreover, depletion of SULT2B1b in GC cells reduced VEGF-A expression by downregulating SP1 and AP2. Conclusion: Our results suggested that the SULT2B1b-mediated angiogenic pathway could serve as biomarkers for GC diagnosis and prognosis, and suppressing SULT2B1b-mediated angiogenic signaling might be a promising strategy for developing novel GC treatment.

  2. Synthesis of the diphenylacetylene-based, tetra-amine ligand 12,-bis(3,5-bis[(dimethylamino)metyl)acetylene by palladium-catalysed cross-coupling : Isolation and crystal structure of the catalyst trans-(3,5-bis[(dimethylamino)methyl]-phenyl)bis(triphenylphosphine palladium(II) iodide

    NARCIS (Netherlands)

    Koten, G. van; Spee, M.P.R.; Ader, B.A.; Steenwinkel, P.; Kooijman, H.; Spek, A.L.

    2000-01-01

    Reaction of 3, 5-bis[(dimethylamino)methyl]phenyl iodide with 3,5-bis[(dimethylamino)methyl]phenylacetylene in diethylamine in the presence of bis(triphenylphosphine)palladium(II) dichloride (3.6 mol%) and copper(I) iodide (3.0 mol%) gave 1,2-(bis(3,5-bis[(dimethylamino)methyl]phenyl)acetylene (1)

  3. Comparisons Between Tridentate Bis(benzazoles-pyridine and Bis(benzazolestriazine Ligands: a Theoretical Study

    Directory of Open Access Journals (Sweden)

    Mihaiela Andoni

    2015-12-01

    Full Text Available Twelve bis(benzazole structures with potential ligand character were investigated by means of computational chemistry. Global and local reactivity descriptors within DFT (Density Functional Theory theory (Fukui functions, chemical potential, hardness, electrophilicity index have been computed at B3LYP/6-31G(d,p level of theory. NICS(0 (Nucleus Independent Chemical Shift index computations were employed for the evaluation of the local aromatic character of each heterocyclic moiety. Best results have been reported for the bis(benzimidazole derivatives. Copper and zinc complexes of the investigated tridentate ligands have been proposed.

  4. Accelerated optical holographic recording using bis-DNO

    DEFF Research Database (Denmark)

    Rasmussen, Palle H.; Ramanujam, P.S.; Hvilsted, Søren

    1999-01-01

    The design, synthesis and optical holographic recording properties of bis-DNO are reported. Bis-DNO is composed of two identical azobenzene oligoornithine segments (DNO) connected via a dipeptide linker. The two segments were assembled in a parallel fashion at the two amino groups of the dipeptide...... linker by Merrifield synthesis. Surprisingly, the response time of films of bis-DNOs was found to be much faster than that of their linear counterparts. (C) 1999 Elsevier Science Ltd. All rights reserved....

  5. Aspirin Hydrolysis in Plasma Is a Variable Function of Butyrylcholinesterase and Platelet-activating Factor Acetylhydrolase 1b2 (PAFAH1b2)*

    Science.gov (United States)

    Zhou, Gang; Marathe, Gopal K.; Hartiala, Jaana; Hazen, Stanley L.; Allayee, Hooman; Tang, W. H. Wilson; McIntyre, Thomas M.

    2013-01-01

    Aspirin is rapidly hydrolyzed within erythrocytes by a heterodimer of PAFAH1b2/PAFAH1b3 but also in plasma by an unidentified activity. Hydrolysis in both compartments was variable, with a 12-fold variation in plasma among 2226 Cleveland Clinic GeneBank patients. Platelet inhibition by aspirin was suppressed in plasma that rapidly hydrolyzed aspirin. Plasma aspirin hydrolysis was significantly higher in patients with coronary artery disease compared with control subjects (16.5 ± 4.4 versus 15.1 ± 3.7 nmol/ml/min; p = 3.4 × 10−8). A genome-wide association study of 2054 GeneBank subjects identified a single locus immediately adjacent to the BCHE (butyrylcholinesterase) gene associated with plasma aspirin hydrolytic activity (lead SNP, rs6445035; p = 9.1 × 10−17). However, its penetrance was low, and plasma from an individual with an inactivating mutation in BCHE still effectively hydrolyzed aspirin. A second aspirin hydrolase was identified in plasma, the purification of which showed it to be homomeric PAFAH1b2. This is distinct from the erythrocyte PAFAH1b2/PAFAH1b3 heterodimer. Inhibitors showed that both butyrylcholinesterase (BChE) and PAFAH1b2 contribute to aspirin hydrolysis in plasma, with variation primarily reflecting non-genetic variation of BChE activity. Therefore, aspirin is hydrolyzed in plasma by two enzymes, BChE and a new extracellular form of platelet-activating factor acetylhydrolase, PAFAH1b2. Hydrolytic effectiveness varies widely primarily from non-genetic variation of BChE activity that affects aspirin bioavailability in blood and the ability of aspirin to inhibit platelet aggregation. PMID:23508960

  6. Organic anion transporting polypeptide (OATP)1B1 and OATP1B3 as important regulators of the pharmacokinetics of substrate drugs.

    Science.gov (United States)

    Maeda, Kazuya

    2015-01-01

    Nobody doubts the importance of organic anion transporting polypeptide (OATP)1B1 and 1B3 in the clinical pharmacokinetics of substrate drugs. Based on the theory of pharmacokinetics, even if a drug is eliminated from the body by extensive metabolism, the rate-determining process of the hepatic intrinsic clearance of OATP substrates is often hepatic uptake. Because of their broad substrate specificities, once the functions of OATP1B1 or OATP1B3 are altered by several kinds of special occasions such as drug-drug interactions (DDI) and genetic polymorphisms of transporter genes, the hepatic clearance of many kinds of structurally-unrelated drugs is expected to be changed. In some cases, these alterations of pharmacokinetics lead to modified pharmacological effects and adverse reactions such as statin-induced myotoxicity and the glucose-lowering effect of anti-diabetes drugs. Thus, appropriate methods with which to quantitatively predict the changes in plasma and tissue concentrations of drugs are needed in the process of drug development. As for DDI, a static model that takes into consideration of the theoretically-maximum unbound inhibitor concentration is often used for the sensitive detection of possible DDI risks and this method has been adopted in several regulatory guidance/guidelines on DDI. Regarding genetic polymorphisms, the effects of SLCO1B1 c.388A>G and c.521T>C on the pharmacokinetics of substrate drugs have been extensively investigated. Even though there are some discrepancies, c.521T>C generally decreased hepatic uptake activity, while c.388A>G tended to slightly increase it. This article briefly summarizes the current status of research on hepatic OATP1B1 and OATP1B3 and the clinical significance of their functions.

  7. The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal

    DEFF Research Database (Denmark)

    Stewart, Morag H; Albert, Mareike; Sroczynska, Patrycja

    2015-01-01

    Jarid1b/KDM5b is a histone demethylase that regulates self-renewal and differentiation in stem cells and cancer, however its function in hematopoiesis is unclear. Here, we find that Jarid1b is highly expressed in primitive hematopoietic compartments and is overexpressed in acute myeloid leukemias...... compromises hematopoietic stem cell (HSC) self-renewal capacity and suggest that Jarid1b is a positive regulator of HSC potential....

  8. Hetero-Diels-Alder approach to Bis(indolyl)methanes.

    Science.gov (United States)

    Grosso, Carla; Cardoso, Ana L; Rodrigues, Maria João; Marques, Cátia; Barreira, Luísa; Lemos, Américo; Pinho E Melo, Teresa M D V

    2017-02-01

    A novel synthetic approach to bis(indolyl)methanes has been established. Our one-pot synthetic strategy based on two consecutive hetero-Diels-Alder cycloaddition reactions of electrophilic conjugated nitrosoalkenes with indoles was extended to a range of new 1-hydroxyiminomethyl-bis(indolyl)methanes. Furthermore, a similar and broad range approach was applied to the synthesis of previously unknown 1-hydrazonomethyl-bis(indolyl)methanes. The biological evaluation of the new bis(indolyl)methanes as anti-cancer agents was investigated. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Long-term impact of interferon beta-1b in patients with CIS

    DEFF Research Database (Denmark)

    Edan, G; Kappos, L; Montalbán, X

    2014-01-01

    OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). METHODS: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 μg...... or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. RESULTS: Of the initial...

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

    Directory of Open Access Journals (Sweden)

    Michael G Connor

    2015-10-01

    Full Text Available 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.

  11. Data of evolutionary structure change: 1B98A-1HCFB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available --------ELAVCDAVSGWVTDRRTAVDLRGREVEVLGEV-----LRQYFFETRCKADNAEEGGPGAGGGGCRGVDRRHWVSECKAKQSYVRALTA-----VGW...TAPASRRGELAVCDAVSGWVTDRRTAVDLRGREVEVLGEVPAASPLRQYFFETRCKA-DAEEGGPGAGGGGCRGVDRRHWVSECKAKQSYVRALTADAQGRVGW...n> 1HCFB TRCKA-DAEEG EEEE - 1B98A TRCKADNAEEG EEEE HHH

  12. Targeting Sulfotransferase (SULT) 2B1b as a regulator of Cholesterol Metabolism in Prostate Cancer

    Science.gov (United States)

    2016-10-01

    SULT2B1b activity pro- motes hepatocellular carcinoma cell growth in vitro and in vivo, and SULT2B1b expression correlates with poor prognosis and...rescues cell growth in LNCaP with SULT2B1b KD. A) Western blot showing expression levels of indicated proteins . Cells were harvested 60 hours after...induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression hasno

  13. The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.

    Directory of Open Access Journals (Sweden)

    Shuai Li

    Full Text Available 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.

  14. Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B : A Case Series and Literature Review

    NARCIS (Netherlands)

    Van Der Made, Cas I.; Hoorn, Ewout J.; De La Faille, Renaud; Karaaslan, Huseyin; Knoers, Nine V A M; Hoenderop, Joost G J; Vargas Poussou, Rosa; De Baaij, Jeroen H F

    2015-01-01

    Background: Autosomal dominant tubulointerstitial kidney disease subtype HNF1B (ADTKD-HNF1B) is caused by a mutation in hepatocyte nuclear factor 1 homeobox beta (HNF1B). Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural

  15. Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review.

    NARCIS (Netherlands)

    Made, C.I. van der; Hoorn, E.J.; Faille, R. de la; Karaaslan, H.; Knoers, N.V.; Hoenderop, J.G.J.; Vargas Poussou, R.; Baaij, J.H.F. de

    2015-01-01

    BACKGROUND: Autosomal dominant tubulointerstitial kidney disease subtype HNF1B (ADTKD-HNF1B) is caused by a mutation in hepatocyte nuclear factor 1 homeobox beta (HNF1B). Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural

  16. Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor

    DEFF Research Database (Denmark)

    Pedersen, U B; Norby, B; Jensen, Anders A.

    1994-01-01

    Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines...... for these receptors. Besides SCH 23390, only NNC 112, fluphenazine and bulbocapnine were able to discriminate between the two states of the D1b receptor. In case of the D1a receptor, the Ki values obtained in binding experiments were very similar to Ki values obtained from inhibition of dopamine stimulated adenylyl...... cyclase. In the D1b expressing cell line, the Ki values obtained from inhibition of the dopamine stimulated adenylyl cyclase indicated a significantly better correlation with the state of the D1b receptor showing high affinity for antagonists. In agreement with observations from binding experiments...

  17. Studies of the mechanism of selectivity of protein tyrosine phosphatase 1B (PTP1B) bidentate inhibitors using molecular dynamics simulations and free energy calculations.

    Science.gov (United States)

    Fang, Lei; Zhang, Huai; Cui, Wei; Ji, Mingjun

    2008-10-01

    Bidentate inhibitors of protein tyrosine phosphatase 1B (PTP1B) are considered as a group of ideal inhibitors with high binding potential and high selectivity in treating type II diabetes. In this paper, the binding models of five bidentate inhibitors to PTP1B, TCPTP, and SHP-2 were investigated and compared by using molecular dynamics (MD) simulations and free energy calculations. The binding free energies were computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology. The calculation results show that the predicted free energies of the complexes are well consistent with the experimental data. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy decomposition analysis indicates that the residues ARG24, ARG254, and GLN262 in the second binding site of PTP1B are essential for the high selectivity of inhibitors. Furthermore, the residue PHE182 close to the active site is also important for the selectivity and the binding affinity of the inhibitors. According to our analysis, it can be concluded that in most cases the polarity of the portion of the inhibitor that binds to the second binding site of the protein is positive to the affinity of the inhibitors while negative to the selectivity of the inhibitors. We expect that the information we obtained here can help to develop potential PTP1B inhibitors with more promising specificity.

  18. Influence of drug formulation on OATP1B-mediated transport of paclitaxel.

    Science.gov (United States)

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

    2014-06-01

    Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P=0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (PPS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. ©2014 American Association for Cancer Research.

  19. Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors.

    Science.gov (United States)

    Crona, Joakim; Gustavsson, Tobias; Norlén, Olov; Edfeldt, Katarina; Åkerström, Tobias; Westin, Gunnar; Hellman, Per; Björklund, Peyman; Stålberg, Peter

    2015-12-01

    Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene. This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype-phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors. Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found. This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.

  20. LMX1B is part of a transcriptional complex with PSPC1 and PSF.

    Directory of Open Access Journals (Sweden)

    Elisa J Hoekstra

    Full Text Available The LIM homeodomain transcription factor Lmx1b is essential for the development of the isthmic organizer and mesodiencephalic dopaminergic neurons. The uncoupling of Pitx3 and Th expression, in the Lmx1b null mutant, suggests that Lmx1b may act as a positional activator of the mdDA domain, eventually leading to properly differentiating mdDA neurons. In this study, we aimed to elucidate how Lmx1b functions mechanistically in this developmental process, by searching for molecular interactors of Lmx1b at the protein level. Initially, affinity-purification of LMX1B-HIS overexpressed protein in MN9D dopaminergic cells followed by mass-spectrometry analysis, resulted in the identification of PSPC1 protein as a possible binding partner of LMX1B. Subsequent immunoprecipitation experiments revealed an interaction between LMX1B and PSPC1 in a larger protein complex also containing PSF. This complex was observed in vitro and in vivo, and we hypothesize that, via PSF and PSPC1, LMX1B may be part of the previously identified Nurr1 transcriptional complex wherein interaction with the co-repressor PSF and the transcription factor Pitx3 is needed to drive expression of Nurr1 target genes in specifying the dopaminergic phenotype. Furthermore, we identified GRLF1, DHX9, MYO1C, HSP70 and TMPO as potential LMX1B interactors. DHX9 and GRLF1 are highly expressed in the developing mdDA neuronal field, and GRLF1 and MYO1C have both been linked to neurite outgrowth. The identification of these proteins suggests that Lmx1b may act directly in the transcriptional activation of Nurr1 target genes and be involved in other processes like neurite outgrowth as well.

  1. Poly[bis[μ-1,4-bis(imidazol-1-ylmethylbenzene]dichloridocadmium(II

    Directory of Open Access Journals (Sweden)

    Xinliang Hu

    2008-07-01

    Full Text Available The title compound, [CdCl2(C14H14N42]n, has a slightly distorted octahedral coordination geometry, formed by four N atoms from 1,4-bis(imidazol-1-ylmethylbenzene ligands and two Cl atoms, giving a two-dimensional network. The Cd atom lies on a centre of inversion.

  2. AP calculus AB & BC crash course

    CERN Document Server

    Rosebush, J

    2012-01-01

    AP Calculus AB & BC Crash Course - Gets You a Higher Advanced Placement Score in Less Time Crash Course is perfect for the time-crunched student, the last-minute studier, or anyone who wants a refresher on the subject. AP Calculus AB & BC Crash Course gives you: Targeted, Focused Review - Study Only What You Need to Know Crash Course is based on an in-depth analysis of the AP Calculus AB & BC course description outline and actual AP test questions. It covers only the information tested on the exams, so you can make the most of your valuable study time. Written by experienced math teachers, our

  3. A Framework for Network AB Testing

    OpenAIRE

    Jiang, Bai; Shi, XiaoLin; Shang, Hongwei; Geng, Zhigeng; Glass, Alyssa

    2016-01-01

    A/B testing, also known as controlled experiment, bucket testing or splitting testing, has been widely used for evaluating a new feature, service or product in the data-driven decision processes of online websites. The goal of A/B testing is to estimate or test the difference between the treatment effects of the old and new variations. It is a well-studied two-sample comparison problem if each user's response is influenced by her treatment only. However, in many applications of A/B testing, e...

  4. Steered Molecular Dynamics for Investigating the Interactions Between Insulin Receptor Tyrosine Kinase (IRK) and Variants of Protein Tyrosine Phosphatase 1B (PTP1B).

    Science.gov (United States)

    Nguyen, Hung; Do, Nhat; Phan, Tuyn; Pham, Tri

    2018-02-01

    The aim of this study is to use steered molecular dynamics to investigate the dissociation process between IRK and PTP1Bs for wild type and five mutants (consisting of p.D181E, p.D181A, p.Q262A, p.D181A-Y46F, and p.D181A-Q262A). The gained results are observed not only the unbinding mechanism of IRK-PTP1B complexes came from pulling force profile, number of hydrogen bonds, and interaction energy between IRK and PTP1Bs but also described PTP1B's point mutations could variably change its binding affinity towards IRK. Additionally, the binding free energy calculated by Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) is also revealed that electrostatic energy and polar solvation energy mainly made up the binding free energy of PTP1B-IRK complexes.

  5. Ultrasound biomicroscopy comparison of ab interno and ab externo scleral fixation of posterior chamber intraocular lenses.

    Science.gov (United States)

    Kamal, Ahmed M; Hanafy, Mervat; Ehsan, Asser; Tomerak, Reham H

    2009-05-01

    To compare ab interno and ab externo scleral fixation of posterior chamber intraocular lenses (PC IOLs) using ultrasound biomicroscopy (UBM) to determine the centration of IOL optic and the position of the haptics in relation to the sulcus. Kasr Eleini Hospital, Cairo University, Cairo, Egypt. Consecutive patients with aphakia had ab externo or ab interno scleral fixation of a PC IOL. Ultrasound biomicroscopy was used preoperatively to determine whether the eyes were unsuitable for capsule fixation and 3 and 6 months postoperatively, determine the position of the haptics in relation to the ciliary sulcus, and evaluate centration of the optic. Fifteen eyes of 14 patients were studied. Eight patients had ab externo fixation, and 7 had ab interno fixation. The haptics were located in the sulcus in 31% of cases with ab externo fixation and 29% with ab interno fixation. The difference was not statistically significant. Ab interno and ab externo scleral fixation, which are both blind procedures, resulted in comparable low rates of sulcus fixation.

  6. Dimethylammonium bis(3-oxidonaphthalene-2-carboxylatoborate hemihydrate

    Directory of Open Access Journals (Sweden)

    Mustafa Tombul

    2008-01-01

    Full Text Available The title compound, C2H8N+·C22H12BO6−·0.5H2O, was synthesized under atmospheric conditions in the presence of dimethylformamide acting as a template. The structure is composed of [NH2(CH32]+ cations, bis(3-oxidonaphthalene-2-carboxylatoborate anions and water molecules. The water molecule lies on a twofold rotation axis. The stabilization of the crystal structure comes from electrostatic interactions and is assisted by intermolecular O—H...O and N—H...O hydrogen bonds between the layers.

  7. Bis(hinokitiolato)copper(II): modification (III).

    Science.gov (United States)

    Ho, Douglas M

    2010-06-01

    Bis(hinokitiolato)copper(II), Cu(hino)(2), exhibits both antibacterial and antiviral properties, and has been previously shown to exist in two modifications. A third modification has now been confirmed, namely tetrakis(mu(2)-3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)bis(3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)tricopper(II)-bis(mu(2)-3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)bis[(3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)copper(II)] (1/1), [Cu(C(10)H(11)O(2))(2)](3).[Cu(C(10)H(11)O(2))(2)](2), where 3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olate is the systematic name for the hinokitiolate anion. This new modification is composed of discrete [cis-Cu(hino)(2)](2)[trans-Cu(hino)(2)] trimers and [cis-Cu(hino)(2)](2) dimers. The Cu atoms are bridged by mu(2)-O atoms from the hinokitiolate ligands to give distorted square-pyramidal and distorted octahedral Cu(II) coordination environments. Hence, the Cu(II) environments are CuO(5)/CuO(6)/CuO(5) for the trimer and CuO(5)/CuO(5) for the dimer. Each trimer and dimer has crystallographically imposed inversion symmetry. The trimer has never been observed before, the dimer has been seen only once before, and the combination of the two together in the same lattice is unprecedented. The CuO(5) cores exhibit four strong basal Cu-O bonds [1.915 (2)-1.931 (2) A] and one weak apical Cu-O bond [2.652 (2)-2.658 (2) A]. The CuO(6) core exhibits four strong equatorial Cu-O bonds [1.922 (2)-1.929 (2) A] and two very weak axial Cu-O bonds [2.911 (3) A]. The bite angles for the chelating hinokitiolate ligands range from 83.13 (11) to 83.90 (10) degrees .

  8. Chemical segregation in the young protostars Barnard 1b-N and S. Evidence of pseudo-disk rotation in Barnard 1b-S

    Science.gov (United States)

    Fuente, A.; Gerin, M.; Pety, J.; Commerçon, B.; Agúndez, M.; Cernicharo, J.; Marcelino, N.; Roueff, E.; Lis, D. C.; Wootten, H. A.

    2017-10-01

    The extremely young Class 0 object B1b-S and the first hydrostatic core (FSHC) candidate, B1b-N, provide a unique opportunity to study the chemical changes produced in the elusive transition from the prestellar core to the protostellar phase. We present 40″ × 70″ images of Barnard 1b in the 13CO 1 → 0, C18O 1 → 0, NH2D 11,1a→ 10,1s, and SO 32→ 21 lines obtained with the NOEMA interferometer. The observed chemical segregation allows us to unveil the physical structure of this young protostellar system down to scales of 500 au. The two protostellar objects are embedded in an elongated condensation, with a velocity gradient of 0.2-0.4 m s-1 au-1 in the east-west direction, reminiscent of an axial collapse. The NH2D data reveal cold and dense pseudo-disks (R 500 - 1000 au) around each protostar. Moreover, we observe evidence of pseudo-disk rotation around B1b-S. We do not see any signature of the bipolar outflows associated with B1b-N and B1b-S, which were previously detected in H2CO and CH3OH, in any of the imaged species. The non-detection of SO constrains the SO/CH3OH abundance ratio in the high-velocity gas. Based on observations carried out with the IRAM Northern Extended Millimeter Array (NOEMA). IRAM is supported by INSU/ CNRS (France), MPG (Germany), and IGN (Spain).The reduced datacube is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/606/L3

  9. Influence of genomic ancestry on the distribution of SLCO1B1, SLCO1B3 and ABCB1 gene polymorphisms among Brazilians.

    Science.gov (United States)

    Sortica, Vinicius de A; Ojopi, Elida B; Genro, Júlia P; Callegari-Jacques, Sidia; Ribeiro-Dos-Santos, Andrea; de Moraes, Manoel Odorico; Romano-Silva, Marco A; Pena, Sérgio D J; Suarez-Kurtz, Guilherme; Hutz, Mara H

    2012-05-01

    The frequency distribution of SNPs and haplotypes in the ABCB1, SLCO1B1 and SLCO1B3 genes varies largely among continental populations. This variation can lead to biases in pharmacogenetic studies conducted in admixed populations such as those from Brazil and other Latin American countries. The aim of this study was to evaluate the influence of self-reported colour, geographical origin and genomic ancestry on distributions of the ABCB1, SLCO1B1 and SLCO1B3 polymorphisms and derived haplotypes in admixed Brazilian populations. A total of 1039 healthy adults from the north, north-east, south-east and south of Brazil were recruited for this investigation. The c.388A>G (rs2306283), c.463C>A (rs11045819) and c.521T>C (rs4149056) SNPs in the SLCO1B1 gene and c.334T>G (rs4149117) and c.699G>A (rs7311358) SNPs in the SLCO1B3 gene were determined by Taqman 5'-nuclease assays. The ABCB1 c.1236C>T (rs1128503), c.2677G>T/A (rs2032582) and c.3435C>T (rs1045642) polymorphisms were genotyped using a previously described single-base extension/termination method. The results showed that genotype and haplotype distributions are highly variable among populations of the same self-reported colour and geographical region. However, genomic ancestry showed that these associations are better explained by a continuous variable. The influence of ancestry on the distribution of alleles and haplotype frequencies was more evident in variants with large differences in allele frequencies between European and African populations. Design and interpretation of pharmacogenetic studies using these transporter genes should include genomic controls to avoid spurious conclusions based on improper matching of study cohorts from Brazilian populations and other highly admixed populations. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

  10. New phenazine-containing ladder polymer of intrinsic microporosity from a spirobisindane-based AB-type monomer

    KAUST Repository

    Ghanem, Bader

    2016-08-15

    A new solution-processable ladder polymer (PSBI-AB) of intrinsic microporosity with dibenzodioxane linkages and bis(phenazine) units was designed and synthesized by self-polymerization of an AB-type monomer containing both catechol and aromatic dichloride groups. Such polymerization is an effective way to synthesize high molecular weight polymers and has a significant advantage over AA-BB polycondensation due to the lack of the requirement for strict control over stoichiometric balance. This protocol can be used to prepare a variety of phenazine-containing ladder type PIMs from their aromatic tetramethoxy precursors. The obtained polymer had high average molecular mass, excellent thermal stability, a high BET surface area of 705 m(2) g(-1) and good solubility in some organic solvents such as chloroform, m-cresol and dichlorobenzene. Gas permeation measurements showed comparable results to the previously reported analogous PIM-7 for films made under the same formation protocol.

  11. Complex of GM1- and GD1a-like lipo-oligosaccharide mimics GM1b, inducing anti-GM1b antibodies.

    Directory of Open Access Journals (Sweden)

    Michiaki Koga

    Full Text Available Molecular mimicry between Campylobacter jejuni lipo-oligosaccharides (LOSs and human gangliosides GM1 and GD1a induces the production of anti-GM1 and anti-GD1a antibodies, and the development of Guillain-Barré syndrome. Complexes of two different gangliosides form new molecular shapes capable of enhancing recognition by anti-ganglioside antibodies. To test the hypothesis that the complex of GM1-like and GD1a-like LOSs of C. jejuni induces the development of anti-GM1b antibodies in Guillain-Barré syndrome patients.Mass spectrometry analysis determined the LOS outer core structures, with which mice were immunized. IgG antibodies to single gangliosides and complex of gangliosides were tested in sera from Guillain-Barré syndrome patients from whom C. jejuni LOS had been isolated.Two isolates from GBS patients who had anti-GM1b antibodies, but neither anti-GM1 nor -GD1a antibodies, expressed both GM1-like and GD1a-like LOSs, but not GM1b-like LOS. Anti-GM1b antibodies were induced in one of the mice immunized with the C. jejuni bearing GM1-like and GD1a-like LOS. Sera from 20 patients had antibodies to the complex of GM1 and GD1a, all of which carried anti-GM1b reactivity. Five of these sera harbored neither anti-GM1 nor anti-GD1a antibodies. IgG antibodies to the complex were absorbed by GM1b, but by neither GM1 nor GD1a.GM1-like and GD1a-like LOSs form a GM1b epitope, inducing the development of anti-GM1b antibodies in patients with Guillain-Barré syndrome subsequent to C. jejuni enteritis. Here, we present a new paradigm that the complex of two different structures forms a new molecular mimicry, inducing the production of autoantibodies.

  12. Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition.

    Directory of Open Access Journals (Sweden)

    Wenjun Ni

    2010-11-01

    Full Text Available Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings

  13. Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition.

    Science.gov (United States)

    Ni, Wenjun; Ji, Jia; Dai, Zunyan; Papp, Audrey; Johnson, Amy J; Ahn, Sunjoo; Farley, Katherine L; Lin, Thomas S; Dalton, James T; Li, Xiaobai; Jarjoura, David; Byrd, John C; Sadee, Wolfgang; Grever, Michael R; Phelps, Mitch A

    2010-11-01

    Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy. Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent. Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study

  14. Interferon beta-1b-neutralizing antibodies 5 years after clinically isolated syndrome

    NARCIS (Netherlands)

    Hartung, H.P.; Freedman, M.S.; Polman, C.H.; Edan, G.; Kappos, L.; Miller, D. H.; Montalban, X.; Barkhof, F.; Petkau, J.; White, R.; Sahajpal, V.; Knappertz, V.; Beckmann, K.; Lanius, V.; Sandbrink, R.; Pohl, C.

    2011-01-01

    Objective: To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b). Methods: In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study,

  15. Data of evolutionary structure change: 1AHPA-1B4DA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AHPA-1B4DA 1AHP 1B4D A A --SQPIFN---DKQFQEALSRQWQRYGLNSAAEMTPRQWWLAVSEALA-------E...1AHP A 1AHPA GGAVT---KDGRW...1AHP A 1AHPA KLAVV---HDKQV...1AHP A 1AHPA QPFAKPVANQRHV...1AHP A 1AHPA HLAGRELHELA

  16. OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

    Science.gov (United States)

    Lancaster, CS; Bruun, GH; Peer, CJ; Mikkelsen, TS; Corydon, TJ; Gibson, AA; Hu, S; Orwick, SJ; Mathijssen, RHJ; Figg, WD; Baker, SD; Sparreboom, A

    2012-01-01

    Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-REx 293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wildtype) with a Km of ~13 µM, and its transport was reduced by ~50% in cells expressing OATP1B1*5 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans, the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a genotype-dosage dependent decline in erythromycin metabolism (P = 0.0072). These results suggest that impaired OATP1B1 function can alter erythromycin metabolism independently of changes in CYP3A4 activity. PMID:22990751

  17. Data of evolutionary structure change: 1B9OA-1YAPA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B9OA-1YAPA 1B9O 1YAP A A KQFTKCELSQLLKDI--DGYGGIALPELICTMFHTSGYDTQAIVEND--ESTEYGL...1YAP A 1YAPA TLKRLGMDGYRG...1YAP A 1YAPA TNYNAGDRSTDY...1YAP A 1YAPA RVVRDPQGIRA ...1YAP A 1YAPA NRCQNRDVRQY

  18. Data of evolutionary structure change: 1B2KA-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B2KA-2G4NF 1B2K 2G4N A F KVFGRCELAAAMKRHGLDNYRGYSLGNWVCAAKFESNFN...G HHHH -GGGG -- EVID>EVID> 0 2G4N F 2G4NF IVQNN...>1.955286979675293 EVID>EVID> 1 2G4N F 2G4NF KKILD-KVGIN

  19. Data of evolutionary structure change: 1B7RA-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B7RA-2G4NF 1B7R 2G4N A F KVFERCELARTLKRLGMDGYRGISLANWMCLAKWESGYN...G HHHH - GGGG -- EVID>EVID> 0 2G4N... F 2G4NF IVQN...tation> 0.7171639800071716 1.2988790273666382 EVI...D> 1 2G4N F 2G4NF

  20. Data of evolutionary structure change: 1B2KB-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B2KB-2G4NF 1B2K 2G4N B F KVFGRCELAAAMKRHGLDNYRGYSLGNWVCAAKFESNFN... HHHH - GGGG -- EVID>EVID> 0 2G4N F 2G4NF IVQNN...387972831726 EVID> 1 2G4N... F 2G4NF KKILD-KVGIN

  1. Data of evolutionary structure change: 1B0DA-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available EVID>EVID> 1 2G4N F 2G4NF...1B0DA-2G4NF 1B0D 2G4N A F KVFGRCELAAAMKRHGLDNYRGYSLGNWVCAAKFESNFN...HHHH -GGGG -- EVID>EVID> 0 2G4N F 2G4NF IVQNN-D...z> 1.0584540367126465 1.9556859731674194

  2. Data of evolutionary structure change: 1B7QA-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B7QA-2G4NF 1B7Q 2G4N A F KVFERCELARTLKRLGMDGYRGISLALWMCLAKWESGYN... HHHH - GGGG -- EVID>EVID> 0 2G4N F 2G4NF VQNND...tation> 1.5742559432983398 3.2563140392303467 EVI...D> 1 2G4N F 2G4NF

  3. Data of evolutionary structure change: 1B7NA-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B7NA-2G4NF 1B7N 2G4N A F KVFERCELARTLKRLGMDGYRGISLANWMCLAKWLSGYN... HHHH - GGGG -- EVID>EVID> 0 2G4N F 2G4NF IVQNN...n> 0.6914700269699097 1.3510249853134155 EVID> 1 2G4N F 2G4NF

  4. Data of evolutionary structure change: 1B5UA-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B5UA-2G4NF 1B5U 2G4N A F KVFERCELARTLKRLGMDGYRGIALANWMCLAKWESGYN...G HHHH - GGGG -- EVID>EVID> 0 2G4N... F 2G4NF ELKD...604645 2.0628468990325928 4.0417399406433105 ...EVID> 1 2G4N F 2G4NF

  5. Data of evolutionary structure change: 1B5ZA-2G4NF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B5ZA-2G4NF 1B5Z 2G4N A F KVFERCELARTLKRLGMDGYRGISLANWMCLAKWESGYN... HHHH -GGGG -- EVID>EVID> 0 2G4N F 2G4NF IVQNN-...tion> 0.6593620181083679 1.2106510400772095 EVID>... 1 2G4N F 2G4NF

  6. Data of evolutionary structure change: 1B06E-1UNFX [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B06E-1UNFX 1B06 1UNF E X VIQLKRYEFPQLPYKVDALEPYISKDIIDVHYNGHHKGY...GGG EEEEEEE EEE EEE HHHH HHHHHHHHHH EEHHHHHHHHHHHHHH EVID> LEU CA 300 PRO CA 361 1UNF... X 1UNFX AVNPLVWGGYY....128504991531372 5.267780780792236 EVID>

  7. Data of evolutionary structure change: 1ALCA-1B7PA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1ALCA-1B7PA 1ALC 1B7P A A KQFTKCELSQNLYDI--DGYGRIALPELICTMFHTSGYDTQAIVEND--ESTEYGL...1ALC A 1ALCA NLYDI--DGYGR...1ALC A 1ALCA IVEND--ESTEY...1ALC A 1ALCA KILDI-KGIDY ...1ALC A 1ALCA ALCTE-KLEQW

  8. Data of evolutionary structure change: 1B99C-2AZ1D [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available GSDS--VESAN >E --HHHHH> ATOM 316...>D 2AZ1D HGSDHEDEGANE >E HHH...pdbID>1B99 C 1B99C EELLT-EVKPN ...> - > ATOM 3319 CA GLU C 141 17.330 5.755...DChain>2AZ1D DELVDWDRDAS re>GG EEGGHcture

  9. 76 FR 56637 - Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines

    Science.gov (United States)

    2011-09-14

    ...-21-AD; Amendment 39-16791; AD 2011-18-09] RIN 2120-AA64 Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final... model IO-720-A1B Lycoming Engines reciprocating engines. This AD requires a crankshaft inspection for...

  10. Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel

    NARCIS (Netherlands)

    A.J.M. de Graan (Anne-Joy); C.S. Lancaster (Cynthia); A. Obaidat (Amanda); B. Hagenbuch (Bruno); L. Elens (Laure); L.E. Friberg (Lena); P. de Bruijn (Peter); S. Hu (Shuiying); A.A. Gibson; G.H. Bruun (G.); T.J. Corydon (T.); T.S. Mikkelsen; A.L. Walker (Aisha); G. Du (Guoqing); W.J. Loos (Walter); R.H.N. van Schaik (Ron); S.D. Baker (Sharyn); A.H.J. Mathijssen (Ron); A. Sparreboom (Alex)

    2012-01-01

    textabstractPurpose: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii)

  11. Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis

    NARCIS (Netherlands)

    Sticova, E.; Lodererova, A.; Steeg, E. van de; Frankova, S.; Kollar, M.; Lanska, V.; Kotalova, R.; Dedic, T.; Schinkel, A.H.; Jirsa, M.

    2015-01-01

    Aim: Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane transporters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xenobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor syndrome. Our aim was to

  12. OATP1B1 polymorphism as a determinant of erythromycin disposition.

    Science.gov (United States)

    Lancaster, C S; Bruun, G H; Peer, C J; Mikkelsen, T S; Corydon, T J; Gibson, A A; Hu, S; Orwick, S J; Mathijssen, R H J; Figg, W D; Baker, S D; Sparreboom, A

    2012-11-01

    Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-Rex293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wild type) with a Michaelis-Menten constant of ~13 µmol/l, and that its transport was reduced by ~50% in cells expressing OATP1B1*5 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a decline in erythromycin metabolism (P = 0.0072). These results suggest that impairment of OATP1B1 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.

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

    DEFF Research Database (Denmark)

    Schmitz, Sandra U; Albert, Mareike; Malatesta, Martina

    2011-01-01

    -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...

  14. 29 CFR 2589.1 - Civil penalties under section 8477(e)(1)(B) of FERSA.

    Science.gov (United States)

    2010-07-01

    ... transaction penalty proceedings under FERSA section 8477(e)(1)(B). ... transaction with respect to the Thrift Savings Fund. The initial penalty under section 8477(e)(1)(B) is five percent of the “amount involved” in each such transaction for each year or part thereof during which the...

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

    DEFF Research Database (Denmark)

    Schubert, J.; Siekierska, A.; Langlois, M.

    2014-01-01

    Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encodi...

  16. Data of evolutionary structure change: 1B06F-3SDPB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B06F-3SDPB 1B06 3SDP F B VIQLKRYEFPQLPYKVDALEPYISKDIIDVHYNGHHKGYVNGANSLLDRLEKLIKG...3SDP B 3SDPB GTPEFEGKTLE ...3SDP B 3SDPB ETLEY----HHDKH...3SDP B 3SDPB NCLSP--DAGGQ...3SDP B 3SDPB LVKAD---GSLAL

  17. Origin and Evolution of the Unique Hepatitis C Virus Circulating Recombinant Form 2k/1b

    NARCIS (Netherlands)

    Raghwani, Jayna; Thomas, Xiomara V.; Koekkoek, Sylvie M.; Schinkel, Janke; Molenkamp, Richard; van de Laar, Thijs J.; Takebe, Yutaka; Tanaka, Yasuhito; Mizokami, Masashi; Rambaut, Andrew; Pybus, Oliver G.

    2012-01-01

    Since its initial identification in St. Petersburg, Russia, the recombinant hepatitis C virus (HCV) 2k/1b has been isolated from several countries throughout Eurasia. The 2k/1b strain is the only recombinant HCV to have spread widely, raising questions about the epidemiological background in which

  18. Data of evolutionary structure change: 1B5FA-3PEPA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1B5FA-3PEPA 1B5F 3PEP A A GSAVVALTNDRDTSYFGEIGIGTPPQKFTVIFDTGSSVLWVPSSKCINSKACRAHS...3PEP A 3PEPA AYPSISASGATPVF...3PEP A 3PEPA PSVYC-SSLAC ...3PEP A 3PEPA LSSND--DSGSV...3PEP A 3PEPA DGETI-ACSGG

  19. The Phosphate Exporter xpr1b Is Required for Differentiation of Tissue-Resident Macrophages

    Directory of Open Access Journals (Sweden)

    Ana M. Meireles

    2014-09-01

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

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

    Science.gov (United States)

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

    2016-02-11

    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.

  1. Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma.

    Directory of Open Access Journals (Sweden)

    María T García-Antón

    Full Text Available Mutations in the CYP1B1 gene are currently the main known genetic cause of primary congenital glaucoma (PCG, a leading cause of blindness in children. Here, we analyze for the first time the CYP1B1 genotype activity and the microscopic and clinical phenotypes in human PCG. Surgical pieces from trabeculectomy from patients with PCG (n = 5 and sclerocorneal rims (n = 3 from cadaver donors were processed for transmission electron microscopy. Patients were classified into three groups depending on goniodysgenesis severity, which was influenced by CYP1B1 enzymatic activity. The main histological changes observed in the outflow pathway of patients with PCG and mutations in CYP1B1 were: i underdeveloped collector channels and the Schlemm's canal; ii abnormal insertion of the ciliary muscle; iii death of the trabecular endothelial cells. Our findings could be useful in improving treatment strategy of PCG associated with CYP1B1 mutations.

  2. Anti-GQ1b-negative Miller Fisher syndrome after Campylobacter jejuni enteritis.

    Science.gov (United States)

    Lee, Kyung Yeon

    2012-09-01

    Miller Fisher syndrome is a clinical variant of Guillain-Barré syndrome, characterized by acute-onset ophthalmoplegia, ataxia, and areflexia. It results from an immune response to a cross-reactive antigen between GQ1b ganglioside in human neurons and lipo-oligosaccharides of certain bacteria, e.g., Campylobacter jejuni. Anti-GQ1b antibody is a powerful diagnostic marker for Miller Fisher syndrome. However, only a small number of anti-GQ1b-negative Miller Fisher syndrome cases are documented. A 13-year-old boy demonstrated typical clinical features of Miller Fisher syndrome 1 week after C. jejuni enteritis, but was anti-GQ1b and anti-GM1b antibody-negative. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. SUMOylation of the ING1b tumor suppressor regulates gene transcription

    DEFF Research Database (Denmark)

    Satpathy, Shankha; Guérillon, Claire; Kim, Tae-Sun

    2014-01-01

    and senescence, but how the proteins themselves are regulated is not yet clear. Here, we find a small ubiquitin-like modification (SUMOylation) of the ING1b protein and identify lysine 193 (K193) as the preferred ING1b SUMO acceptor site. We also show that PIAS4 is the E3 SUMO ligase responsible for ING1b...... SUMOylation on K193. Sequence alignment reveals that the SUMO consensus site on ING1b contains a phosphorylation-dependent SUMOylation motif (PDSM) and our data indicate that the SUMOylation on K193 is enhanced by the S199D phosphomimic mutant. Using an ING1b protein mutated at the major SUMOylation site (ING...

  4. Inhibition of protein tyrosine phosphatase 1B by lupeol and lupenone isolated from Sorbus commixta.

    Science.gov (United States)

    Na, Minkyun; Kim, Bo Yeon; Osada, Hiroyuki; Ahn, Jong Seog

    2009-08-01

    Protein tyrosine phosphatase 1B (PTP1B) appears to be an attractive target for the development of new drugs for type 2 diabetes and obesity. In our preliminary test, a MeOH extract of the stem barks of Sorbus commixta Hedl. (Rosaceae) showed strong PTP1B inhibitory activity. Bioassay-guided fractionation of the MeOH extract resulted in the isolation of two lupane-type triterpenes, lupenone (1) and lupeol (2). Compounds 1 and 2 inhibited PTP1B with IC(50) values of 13.7 +/- 2.1 and 5.6 +/- 0.9 microM, respectively. Kinetic studies revealed that both the compounds 1 and 2 are non-competitive inhibitors of PTP1B that decrease V(max) values with no effect on K(m) values.

  5. CYP1B1 Mutations in Individuals With Primary Congenital Glaucoma and Residing in Denmark

    DEFF Research Database (Denmark)

    Grønskov, Karen; Redó-Riveiro, Alba; Sandfeld, Lisbeth

    2016-01-01

    in Denmark. The study included 37 unrelated individuals with PCG. Individuals were investigated for CYP1B1 mutations by Sanger sequencing of polymerase chain reaction products using BigDye terminators and capillary electrophoresis. A total of 12 mutations were identified and 5 of these were novel. Six were......Primary congenital glaucoma (PCG OMIM 231300) can be caused by pathogenic sequence variations in cytochrome P450, subfamily 1, polypeptide 1 (CYP1B1). The purpose of this study was to investigate the contribution of sequence variations in CYP1B1 in a cohort of individuals with PCG residing...... was homozygous and 1 was apparently homozygous. Three individuals were heterozygous for sequence variations in CYP1B1 thought to be pathogenic-one of these was p.(Tyr81Asn). Several known sequence variations with presumably no functional effect were found in the cohort. In this study, we identified 12 CYP1B1...

  6. Modeling study of the ABS relay valve

    Science.gov (United States)

    Lei, Ming; Lin, Min; Guo, Bin; Luo, Zai; Xu, Weidong

    2011-05-01

    The ABS (anti-lock braking system) relay valve is the key component of anti-lock braking system in most commercial vehicles such as trucks, tractor-trailers, etc. In this paper, structure of ABS relay valve and its work theory were analyzed. Then a mathematical model of ABS relay valve, which was investigated by dividing into electronic part, magnetic part, pneumatic part and mechanical part, was set up. The displacement of spools and the response of pressure increasing, holding, releasing of ABS relay valve were simulated and analyzed under conditions of control pressure 500 KPa, braking pressure 600 KPa, atmospheric pressure 100 KPa and air temperature 310 K. Thisarticle provides reliable theory for improving the performance and efficiency of anti-lock braking system of vehicles.

  7. Synthesis, spectral and structural properties of bis-imidazoline selones

    Indian Academy of Sciences (India)

    New biphenyl derivatives of bis-imidazoline selones were synthesized in good yield and characterized by multinuclear (1D and 2D) NMR and UV-vis studies. The solid state structures of bis-imidazoline selones were further confirmed by single crystal X ray diffraction technique.

  8. Studies on Bis(Para Anisidine Acetylacetonato) Nickel (II) Complex ...

    African Journals Online (AJOL)

    Studies on Bis(Para Anisidine Acetylacetonato) Nickel (II) Complex. HN Aliyu, UL Bilyamin. Abstract. Schiff base was prepared from the reaction of para anisidine and acetylacetone. Bis(para anisidineacetylacetonato)nickel(II) complex was synthesized by the reaction of the prepared para anisidineacetylacetone ligand and ...

  9. Synthesis & Characterization of New bis-Symmetrical Adipoyl ...

    African Journals Online (AJOL)

    Full Title: Synthesis and Characterization of New bis-Symmetrical Adipoyl, Terepthaloyl, Chiral Diimido-di-L-alanine Diesters and Chiral Phthaloyl-L-alanine Ester of Tripropoxy p-tert-Butyl Calix[4]arene and Study of Their Hosting Ability for Alanine and Na+. Bis-symmetrical tripropoxy p-tert-butyl calix[4]arene esters were ...

  10. 29 CFR 1915.1008 - bis-Chloromethyl ether.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false bis-Chloromethyl ether. 1915.1008 Section 1915.1008 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... § 1915.1008 bis-Chloromethyl ether. Note: The requirements applicable to shipyard employment under this...

  11. 29 CFR 1910.1008 - bis-Chloromethyl ether.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 6 2010-07-01 2010-07-01 false bis-Chloromethyl ether. 1910.1008 Section 1910.1008 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... bis-Chloromethyl ether. See § 1910.1003, 13 carcinogens. ...

  12. hERG 1b is critical for human cardiac repolarization.

    Science.gov (United States)

    Jones, David K; Liu, Fang; Vaidyanathan, Ravi; Eckhardt, L Lee; Trudeau, Matthew C; Robertson, Gail A

    2014-12-16

    The human ether-à-go-go-related gene (hERG; or KCNH2) encodes the voltage-gated potassium channel underlying IKr, a repolarizing current in the heart. Mutations in KCNH2 or pharmacological agents that reduce IKr slow action potential (AP) repolarization and can trigger cardiac arrhythmias associated with long QT syndrome. Two channel-forming subunits encoded by KCNH2 (hERG 1a and 1b) are expressed in cardiac tissue. In heterologous expression systems, these subunits avidly coassemble and exhibit biophysical and pharmacological properties distinct from those of homomeric hERG 1a channels. Despite these findings, adoption of hERG 1a/1b heteromeric channels as a model for cardiac IKr has been hampered by the lack of evidence for a direct functional role for the 1b subunit in native tissue. In this study, we measured IKr and APs at physiological temperature in cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs). We found that specific knockdown of the 1b subunit using shRNA caused reductions in 1b mRNA, 1b protein levels, and IKr magnitude by roughly one-half. AP duration was increased and AP variability was enhanced relative to controls. Early afterdepolarizations, considered cellular substrates for arrhythmia, were also observed in cells with reduced 1b expression. Similar behavior was elicited when channels were effectively converted from heteromers to 1a homomers by expressing a fragment corresponding to the 1a-specific N-terminal Per-Arnt-Sim domain, which is omitted from hERG 1b by alternate transcription. These findings establish that hERG 1b is critical for normal repolarization and that loss of 1b is proarrhythmic in human cardiac cells.

  13. Par-1b is required for morphogenesis and differentiation of myoepithelial cells during salivary gland development.

    Science.gov (United States)

    Gervais, Elise M; Sequeira, Sharon J; Wang, Weihao; Abraham, Stanley; Kim, Janice H; Leonard, Daniel; DeSantis, Kara A; Larsen, Melinda

    2016-10-01

    The salivary epithelium initiates as a solid mass of epithelial cells that are organized into a primary bud that undergoes morphogenesis and differentiation to yield bilayered acini consisting of interior secretory acinar cells that are surrounded by contractile myoepithelial cells in mature salivary glands. How the primary bud transitions into acini has not been previously documented. We document here that the outer epithelial cells subsequently undergo a vertical compression as they express smooth muscle α-actin and differentiate into myoepithelial cells. The outermost layer of polarized epithelial cells assemble and organize the basal deposition of basement membrane, which requires basal positioning of the polarity protein, Par-1b. Whether Par-1b is required for the vertical compression and differentiation of the myoepithelial cells is unknown. Following manipulation of Par-1b in salivary gland organ explants, Par-1b-inhibited explants showed both a reduced vertical compression of differentiating myoepithelial cells and reduced levels of smooth muscle α-actin. Rac1 knockdown and inhibition of Rac GTPase function also inhibited branching morphogenesis. Since Rac regulates cellular morphology, we investigated a contribution for Rac in myoepithelial cell differentiation. Inhibition of Rac GTPase activity showed a similar reduction in vertical compression and smooth muscle α-actin levels while decreasing the levels of Par-1b protein and altering its basal localization in the outer cells. Inhibition of ROCK, which is required for basal positioning of Par-1b, resulted in mislocalization of Par-1b and loss of vertical cellular compression, but did not significantly alter levels of smooth muscle α-actin in these cells. Overexpression of Par-1b in the presence of Rac inhibition restored basement membrane protein levels and localization. Our results indicate that the basal localization of Par-1b in the outer epithelial cells is required for myoepithelial cell

  14. The epithelia-specific membrane trafficking factor AP-1B controls gut immune homeostasis in mice.

    Science.gov (United States)

    Takahashi, Daisuke; Hase, Koji; Kimura, Shunsuke; Nakatsu, Fubito; Ohmae, Masumi; Mandai, Yasushi; Sato, Toru; Date, Yasuhiro; Ebisawa, Masashi; Kato, Tamotsu; Obata, Yuuki; Fukuda, Shinji; Kawamura, Yuki I; Dohi, Taeko; Katsuno, Tatsuro; Yokosuka, Osamu; Waguri, Satoshi; Ohno, Hiroshi

    2011-08-01

    Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis. The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice. Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease. AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  15. A/B Testing of Auctions

    OpenAIRE

    Chawla, Shuchi; Hartline, Jason D.; Nekipelov, Denis

    2016-01-01

    For many application areas A/B testing, which partitions users of a system into an A (control) and B (treatment) group to experiment between several application designs, enables Internet companies to optimize their services to the behavioral patterns of their users. Unfortunately, the A/B testing framework cannot be applied in a straightforward manner to applications like auctions where the users (a.k.a., bidders) submit bids before the partitioning into the A and B groups is made. This paper...

  16. A bis-calixarene from olefin metathesis

    Directory of Open Access Journals (Sweden)

    Shimelis T. Hailu

    2012-06-01

    Full Text Available A ring-closing olefin metathesis reaction of tetrakis(allyloxycalix[4]arene gave the bis calixarene, (15E,40E,60E-65,74-bis(prop-2-en-1-yloxy-13,18,38,43,58,63-hexaoxadodecacyclo[28.26.8.720,36.111,45.151,55.05,57.07,12.019,24.026,64.032,37.044,49.168,72]tetraheptaconta-1,3,5(57,7,9,11,15,19(24,20,22,26,28,30(64,32,34,36,40,44(49,45,47,51,53,55(65,60,68,70,72(74-heptacosaene, C74H68O8. It is a cage formed from two calix[4]arene units joined by butenyl groups at three of the O atoms on the narrow rim. The fourth O atom on each calixarene unit is joined with an allyl group. Each of the calix[4]arene units has a flattened cone conformation in which the allyloxy-substituted aryl group and the opposite aryl group are close together and almost parallel [dihedral angle between planes = 1.09 (11°], and the other two aryl groups are splayed outward [dihedral angle between planes = 79.53 (11°]. No guest molecule (e.g. solvent was observed within the cage. The alkene C atoms of one of the links between the calixarene moieties are disordered over two orientations with occupancies of 0.533 (9 and 0.467 (9.

  17. Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.

    Science.gov (United States)

    Kang, Gaeun; Bae, Kyung-Yeol; Kim, Sung-Wan; Kim, Jin; Shin, Hee-Young; Kim, Jae-Min; Shin, Il-Seon; Yoon, Jin-Sang; Kim, Jong-Keun

    2014-06-01

    It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours (AUC0-4 ) and the peak blood concentration of EtOH (Cmax ) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results

  18. High pressure synthesis of BiS2

    DEFF Research Database (Denmark)

    Søndergaard-Pedersen, Simone; Nielsen, Morten Bormann; Bremholm, Martin

    crystal structures and electrical properties.1,2 Up until now, the most sulfur rich phase in the Bi-S phase diagram was Bi2S3.3 For BiS2 the Bi atoms have anisotropic charge distribution and more complex structures are expected when comparing the layered structures of transition metal dichalcogenides....... The possibilities of using high pressure synthesis to discover new phases in the Bi-S binary system were investigated as early as the 1960’s.4 The research led to discovery of a compound with BiS2 stoichiometry, but no structure solution of BiS2 was reported. A reason behind making this new phase is to study...

  19. Wave-of-advance models of the diffusion of the Y chromosome haplogroup R1b1b2 in Europe.

    Directory of Open Access Journals (Sweden)

    Per Sjödin

    Full Text Available 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.

  20. Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency

    DEFF Research Database (Denmark)

    Sim, J. C. H.; White, S. M.; Fitzpatrick, E.

    2014-01-01

    Background: Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predomi...

  1. CYP1B1 Cytopathy: Uncommon Phenotype of a Homozygous CYP1B1 Deletion as Internal Corneal Ulcer of Von Hippel.

    Science.gov (United States)

    Oliva-Biénzobas, Valeria; Navas, Alejandro; C Astiazarán, Mirena; Chacón-Camacho, Oscar Francisco; A Bermúdez-Magner, Jose; Takane, Mariana; Graue-Hernández, Enrique; Zenteno, Juan Carlos

    2017-10-01

    To report a mutation of CYP1B1 in a newborn with a rare phenotype without the classic features of anterior segment dysgenesis or congenital glaucoma. The newborn presented with diffuse corneal edema and bilaterally elevated intraocular pressure (IOP). Ophthalmological examination, ultrasound, and ultrasound biomicroscopy were performed; congenital infections were ruled out. Genetic analysis was performed. The patient underwent penetrating keratoplasty and goniotomy in a single surgical time. The button was subjected to histopathological examination. The patient is the first child of young, healthy, consanguineous parents. Ophthalmological examination revealed visual acuity of light perception and increased IOP in both eyes. CYP1B1 gene analysis demonstrated homozygosity for a 1-bp deletion in exon 2 (c.830delT). IOP was normalized, and the corneal button was clear after surgical treatment. Histopathological analysis revealed loss of the Bowman membrane in the central cornea, fibrosis of the stroma, absence of endothelial cells, and loss of Descemet membrane centrally. We present an uncommon mutation and clinical description of CYP1B1. This report and further studies could provide us better understanding of the mutational spectrum of CYP1B1.

  2. DJ-1 can inhibit microtubule associated protein 1 B formed aggregates

    Directory of Open Access Journals (Sweden)

    Ding Jianqing

    2011-06-01

    Full Text Available Abstract Background Abnormal accumulation and aggregation of microtubule associated proteins (MAPs plays an important role in the pathogenesis of neurodegenerative diseases. Loss-of-function mutation of DJ-1/Park7 can cause early onset of PD. DJ-1, a molecular chaperone, can inhibit α-synuclein aggregation. Currently, little is known whether or not loss of function of DJ-1 contributes to abnormal MAPs aggregation in neurodegenerative disorders such as PD. Results We presented evidence that DJ-1 could bind to microtubule associated protein1b Light Chain (MAP1b-LC. Overexpression of DJ-1 prevented MAP1b-LC aggregation in HEK293t and SH-SY5Y cells while DJ-1 knocking down (KD enhanced MAP1b-LC aggregation in SH-SY5Y cells. The increase in insoluble MAP1b-LC was also observed in the DJ-1 null mice brain. Moreover, in the DJ-1 KD SH-SY5Y cells, overexpression of MAP1B-LC led to endoplasmic reticulum (ER stress-induced apoptosis. Conclusion Our results suggest that DJ-1 acts as a molecular chaperone to inhibit MAP1B aggregation thus leading to neuronal apoptosis. Our study provides a novel insight into the mechanisms that underly the pathogenesis of Parkinson's disease (PD.

  3. Discovery and study of novel protein tyrosine phosphatase 1B inhibitors

    Science.gov (United States)

    Zhang, Qian; Chen, Xi; Feng, Changgen

    2017-10-01

    Protein tyrosine phosphatase 1B (PTP1B) is considered to be a target for therapy of type II diabetes and obesity. So it is of great significance to take advantage of a computer aided drug design protocol involving the structured-based virtual screening with docking simulations for fast searching small molecule PTP1B inhibitors. Based on optimized complex structure of PTP1B bound with specific inhibitor of IX1, structured-based virtual screening against a library of natural products containing 35308 molecules, which was constructed based on Traditional Chinese Medicine database@ Taiwan (TCM database@ Taiwan), was conducted to determine the occurrence of PTP1B inhibitors using the Lubbock module and CDOCKER module from Discovery Studio 3.1 software package. The results were further filtered by predictive ADME simulation and predictive toxic simulation. As a result, 2 good drug-like molecules, namely para-benzoquinone compound 1 and Clavepictine analogue 2 were identified ultimately with the dock score of original inhibitor (IX1) and the receptor as a threshold. Binding model analyses revealed that these two candidate compounds have good interactions with PTP1B. The PTP1B inhibitory activity of compound 2 hasn't been reported before. The optimized compound 2 has higher scores and deserves further study.

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

    Science.gov (United States)

    Wu, Nan; Shang, Siyuan; Su, Yanjie

    2015-09-01

    The vasopressin V1b receptor (AVPR1B) gene has been shown to be closely associated with bipolar disorder and depression. However, whether it relates to positive social outcomes, such as empathy and prosocial behavior, remains unknown. This study explored the possible role of the AVPR1B gene rs28373064 in empathy and prosociality. A total of 256 men, who were genetically unrelated, non-clinical ethnic Han Chinese college students, participated in the study. Prosociality was tested by measuring the prosocial tendencies of cognitive and emotional empathy using the Interpersonal Reactivity Index (IRI). The single nucleotide polymorphism (SNP), rs28373064, was genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results suggest that the AVPR1B gene rs28373064 is linked to emotional empathy and prosociality. The mediation analysis indicated that the effect of the AVPR1B gene on prosociality might be mediated by emotional empathy. This study demonstrated the link between the AVPR1B gene and prosociality and provided evidence that emotional empathy might mediate the relation between the AVPR1B gene and prosociality. © 2015 The Institute of Psychology, Chinese Academy of Sciences and Wiley Publishing Asia Pty Ltd.

  5. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

    Directory of Open Access Journals (Sweden)

    Nigel P S Crawford

    2007-11-01

    Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

  6. Social Context, Stress, Neuropsychiatric Disorders, and the Vasopressin 1b Receptor

    Directory of Open Access Journals (Sweden)

    Heather K. Caldwell

    2017-10-01

    Full Text Available The arginine vasopressin 1b receptor (Avpr1b is involved in the modulation of a variety of behaviors and is an important part of the mammalian hormonal stress axis. The Avpr1b is prominent in hippocampal CA2 pyramidal cells and in the anterior pituitary corticotrophs. Decades of research on this receptor has demonstrated its importance to the modulation of social recognition memory, social forms of aggression, and modulation of the hypothalamic-pituitary-adrenal axis, particularly under conditions of acute stress. Further, work in humans suggests that the Avpr1b may play a role in human neuropsychiatric disorders and its modulation may have therapeutic potential. This paper reviews what is known about the role of the Avpr1b in the context of social behaviors, the stress axis, and human neuropsychiatric disorders. Further, possible mechanisms for how Avpr1b activation within the hippocampus vs. Avpr1b activation within anterior pituitary may interact with one another to affect behavioral output are proposed.

  7. Review of interferon beta-1b in the treatment of early and relapsing multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Damiano Paolicelli

    2009-07-01

    Full Text Available Damiano Paolicelli, Vita Direnzo, Maria TrojanoDepartment of Neurological and Psychiatric Sciences, University of Bari, Bari, ItalyAbstract: Multiple sclerosis (MS is the most common autoimmune illness of the central nervous system. For many years the inflammatory manifestations of MS were treated using only corticosteroids. Since the 1990s the results of several clinical trials with immunomodulatory agents have changed the therapeutic approach to this disease. Interferon beta (IFNβ-1b represents the pioneer of those therapies. There is growing evidence from clinical trials on relapsing-remitting MS and clinically isolated syndromes suggestive of MS that IFNβ-1b reduces the frequency and severity of relapses and the development of new and active brain lesions as assessed by magnetic resonance imaging. Long-term data suggest a persistent efficacy of IFNβ-1b on disease activity and a positive effect in slowing disability worsening. Furthermore a reduction of relapse rate and a slight positive effect on the progression were demonstrated when IFNβ-1b was administered to still-active secondary progressive MS. IFNβ-1b therapy is well tolerated and relatively free of long-term side effects. In spite of the emergence of new agents for the treatment of MS, IFNβ-1b still remains a first-line therapy with a fundamental role in all stages of the disease.Keywords: interferon beta-1b, relapsing-remitting multiple sclerosis, clinically isolated syndromes, efficacy, safety, neutralizing antibodies

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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. © 2015 The American Society for Clinical Pharmacology and Therapeutics.

  10. Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling.

    Science.gov (United States)

    Wu, Chia-Lun; Buszard, Bree; Teng, Chun-Hung; Chen, Wei-Lin; Warr, Coral G; Tiganis, Tony; Meng, Tzu-Ching

    2011-10-01

    PTP1B (protein tyrosine phosphatase 1B) is a negative regulator of IR (insulin receptor) activation and glucose homoeostasis, but the precise molecular mechanisms governing PTP1B substrate selectivity and the regulation of insulin signalling remain unclear. In the present study we have taken advantage of Drosophila as a model organism to establish the role of the SH3 (Src homology 3)/SH2 adaptor protein Dock (Dreadlocks) and its mammalian counterpart Nck in IR regulation by PTPs. We demonstrate that the PTP1B orthologue PTP61F dephosphorylates the Drosophila IR in S2 cells in vitro and attenuates IR-induced eye overgrowth in vivo. Our studies indicate that Dock forms a stable complex with PTP61F and that Dock/PTP61F associate with the IR in response to insulin. We report that Dock is required for effective IR dephosphorylation and inactivation by PTP61F in vitro and in vivo. Furthermore, we demonstrate that Nck interacts with PTP1B and that the Nck/PTP1B complex inducibly associates with the IR for the attenuation of IR activation in mammalian cells. Our studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR.

  11. Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo*

    Science.gov (United States)

    Lopez-Santiago, Luis F.; Brackenbury, William J.; Chen, Chunling; Isom, Lori L.

    2011-01-01

    Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na+ current (INa) mediated by voltage-gated Na+ channels (VGSCs). In nociceptive DRG neurons, VGSC β2 subunits, encoded by Scn2b, selectively regulate TTX-S α subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by β1 subunits, encoded by Scn1b. Scn1b null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of Scn1b deletion on CNS neurons have been described. In contrast, little is known about the role of Scn1b in peripheral neurons in vivo. Here we demonstrate that Scn1b null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S INa inactivation, reduced persistent TTX-R INa, a prolonged rate of recovery of TTX-R INa from inactivation, and reduced cell surface expression of Nav1.9 compared with their WT littermates. Investigation of action potential firing shows that Scn1b null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K+ current (Ito) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both INa and IK. PMID:21555511

  12. Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico.

    Science.gov (United States)

    Zenteno, Juan Carlos; Hernandez-Merino, Elena; Mejia-Lopez, Herlinda; Matías-Florentino, Margarita; Michel, Norma; Elizondo-Olascoaga, Celia; Korder-Ortega, Vincent; Casab-Rueda, Homero; Garcia-Ortiz, Jose Elias

    2008-01-01

    The frequency of primary congenital glaucoma (PCG)-causing CYP1B1 mutations varies importantly among distinct populations, ranging from 20% in Indonesians and Japanese to about 100% among the Saudi Arabians and Slovakian Gypsies. Thus, the molecular characterization of large groups of PCG from different ethnic backgrounds is important to establish the actual CYP1B1 contribution in specific populations. In this work, the molecular analysis of the CYP1B1 gene in a group of Mexican PCG patients is reported. Thirty unrelated Mexican patients fulfilling the clinical criteria for PCG were included. Two cases were familial and with proven consanguinity, originating from distinct regions of the country. Polymerase chain reaction amplification and direct automated sequencing of the CYP1B1 coding region was performed in each participating subject. An identical pathogenic CYP1B1 mutation was demonstrated in 2 unrelated PCG subjects. The mutation consisted of a homozygous G to A transition at nucleotide position 1505 in exon 3, which predicted a substitution of glutamic acid for lysine at residue 387 of the protein (E387K). In the remaining 28 PCG subjects, no deleterious mutations were identified. Both subjects with the E387K mutation shared a same haplotype for 5 CYP1B1 intragenic single nucleotide polymorphisms, indicating a common origin of the allele. Mexican patients with PCG are rarely (less than 10%) due to CYP1B1 mutations. Available data indicate that most of the non-Brazilian Latin American PCG patients investigated to date are not due to CYP1B1 defects. Populations with low incidence of CYP1B1 mutations are appropriate candidates for the identification of novel PCG-causing genes.

  13. Regulation of brown fat adipogenesis by protein tyrosine phosphatase 1B.

    Directory of Open Access Journals (Sweden)

    Kosuke Matsuo

    2011-01-01

    Full Text Available Protein-tyrosine phosphatase 1B (PTP1B is a physiological regulator of insulin signaling and energy balance, but its role in brown fat adipogenesis requires additional investigation.To precisely determine the role of PTP1B in adipogenesis, we established preadipocyte cell lines from wild type and PTP1B knockout (KO mice. In addition, we reconstituted KO cells with wild type, substrate-trapping (D/A and sumoylation-resistant (K/R PTP1B mutants, then characterized differentiation and signaling in these cells. KO, D/A- and WT-reconstituted cells fully differentiated into mature adipocytes with KO and D/A cells exhibiting a trend for enhanced differentiation. In contrast, K/R cells exhibited marked attenuation in differentiation and lipid accumulation compared with WT cells. Expression of adipogenic markers PPARγ, C/EBPα, C/EBPδ, and PGC1α mirrored the differentiation pattern. In addition, the differentiation deficit in K/R cells could be reversed completely by the PPARγ activator troglitazone. PTP1B deficiency enhanced insulin receptor (IR and insulin receptor substrate 1 (IRS1 tyrosyl phosphorylation, while K/R cells exhibited attenuated insulin-induced IR and IRS1 phosphorylation and glucose uptake compared with WT cells. In addition, substrate-trapping studies revealed that IRS1 is a substrate for PTP1B in brown adipocytes. Moreover, KO, D/A and K/R cells exhibited elevated AMPK and ACC phosphorylation compared with WT cells.These data indicate that PTP1B is a modulator of brown fat adipogenesis and suggest that adipocyte differentiation requires regulated expression of PTP1B.

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

    Science.gov (United States)

    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. Copyright © 2016. Published by Elsevier Ireland Ltd.

  15. Bis(μ-bis{[4-(2-pyridylpyrimidin-2-yl]sulfanyl}methanedisilver(I bis(perchlorate

    Directory of Open Access Journals (Sweden)

    Hai-Bin Zhu

    2010-12-01

    Full Text Available In the macrocyclic centrosymmetric dinuclear complex, [Ag2(C19H14N6S22](ClO42, the AgI atom, bis{[4-(2-pyridylpyrimidin-2-yl]sulfanyl}methane (2-bppt ligand and perchlorate anion each lie on a twofold rotation axis. The 2-bppt ligand chelates two four-coordinated AgI atoms through its two bipyridine-like arms. The O atoms of the perchlorate anion are disordered each over two positions of equal occupancy. Adjacent complex molecules are linked by π–π interactions between the pyridine and pyrimidine rings [centroid–centroid distance = 3.663 (8 Å].

  16. Bis[N,N-bis(diphenylphosphanylpentylamine-κ2P,P′]platinum(II bis(hexafluoridophosphate dichloromethane disolvate

    Directory of Open Access Journals (Sweden)

    Ilana Engelbrecht

    2010-08-01

    Full Text Available The PtII atom in the title compound, [Pt(C29H31NP22](PF62·2CH2Cl2, is coordinated by four P atoms from two bis(diphenylphosphanylpentylamine ligands with an average Pt—P distance of 2.300 (1 Å. The coordination around the PtII atom shows a highly distorted square-planar geometry, as evidenced by the P—Pt—P bite angles of 70.45 (3 and 70.64 (3°. The asymmetric unit contains two hexafluoridophosphate ions, the metal complex and two dichloromethane solvent molecules. One of the chloride atoms of one of the dichloromethane molecules is disordered over two sites in a 0.515 (3:0.485 (3 ratio. C—H...F hydrogen bonds stabilize the crystal packing.

  17. Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling

    DEFF Research Database (Denmark)

    Lund, I K; Hansen, J A; Andersen, H S

    2005-01-01

    Upon leptin binding, the leptin receptor is activated, leading to stimulation of the JAK/STAT signal transduction cascade. The transient character of the tyrosine phosphorylation of JAK2 and STAT3 suggests the involvement of protein tyrosine phosphatases (PTPs) as negative regulators...... PTP1B mediates the cessation of the leptin signal transduction. Leptin-induced activation of a STAT3 responsive reporter was dose-dependently inhibited by co-transfection with PTP1B. No inhibition was observed when a catalytically inactive mutant of PTP1B was used or when other PTPs were co...

  18. CYP1B1 expression in ovarian cancer in the laying hen Gallusdomesticus.

    Science.gov (United States)

    Zhuge, Yan; Lagman, Jo Ann J; Ansenberger, Kristine; Mahon, Cassandra J; Daikoku, Takiko; Dey, Sudhansu K; Bahr, Janice M; Hales, Dale B

    2009-01-01

    Ovarian carcinoma is the most lethal gynecological malignancy. The genetic and molecular mechanisms that cause it still remain largely unknown. CYP1B1 is a cytochrome P450 enzyme that catalyzes the conversion of estrogens to genotoxic catechol estrogens which may cause DNA mutations and initiate ovarian epithelial cancer. Our objectives were to evaluate CYP1B1 expression, distribution and localization in the hen ovary and to determine if there is an increased CYP1B1 expression associated with, and possibly involved in the initiation of ovarian cancer. Two groups of hens were used: 1. young (50 weeks of age; devoid of cancer) and 2. old (165 weeks of age; divided into two groups: age-matched normal and ovarian cancer). CYP1B1 mRNA and protein expression were analyzed in cancerous ovaries, ovaries of age-matched normal and/or young hens by quantitative real-time PCR (qRT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). RNA was extracted from tissue preserved in RNAlater for qRT-PCR. Tissue frozen in liquid nitrogen was used for ISH. Tissue fixed in neutral buffered formalin was subjected to IHC. Higher expression of CYP1B1 mRNA was observed in cancerous ovaries as compared to ovaries of young and age-matched normal hens by qRT-PCR. ISH and IHC confirmed that the expression of CYP1B1 was much higher in ovarian tumors compared to ovaries of age-matched normal hens. CYP1B1 mRNA and protein were distributed extensively throughout the carcinoma, while primarily localized to the granulosa layer surrounding the follicle in age-matched normal hens. IHC also showed nuclear localization of CYP1B1. Highly expressed CYP1B1 was found in POF-3 from young and age-matched normal hens as compared to POF-1 and POF-2 by qRT-PCR. No significant difference was found in the expression of CYP1B1 between the distal (site of rupture) and the proximal (site of attachment to the ovary) of POF-1 from young and age-matched normal hens. High expression of CYP1B1 in the hen ovary

  19. Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1

    DEFF Research Database (Denmark)

    Bassan, Merav; Liu, Hongguang; Madsen, Kenneth L

    2008-01-01

    Synaptic plasticity is implemented by the interaction of glutamate receptors with PDZ domain proteins. Glutamate transporters provide the only known mechanism of clearance of glutamate from excitatory synapses, and GLT1 is the major glutamate transporter. We show here that GLT1 interacts...... expressing PICK1 and GLT1b. In addition, expression of GLT1b in COS7 cells changed the distribution of PICK1, bringing it to the surface. GLT1b and PICK1 co-localized with each other and with synaptic markers in hippocampal neurons in culture. Phorbol ester, an activator of protein kinase C (PKC), a known...

  20. Organic anion transporter 1B1 (SLCO1B1) polymorphism and gallstone formation: High incidence of Exon4 CA genotype in female patients in North India.

    Science.gov (United States)

    Srivastava, Anshika; Srivastava, Anvesha; Srivastava, Neena; Choudhuri, Gourdas; Mittal, Balraj

    2011-01-01

      Gallstone disease is an important cause of abdominal morbidity Organic anion transport protein 1B1 (OATP1B1) (encoded by SLCO1B1) is a major transporter protein for bile salt uptake in enterohepatic circulation of bile salts. Disturbance in this pathway can decrease relative concentration of bile salts in gallbladder and may lead to formation of gallstones. We investigated role of SLCO1B1 polymorphisms [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] in conferring interindividual susceptibility to gallstone disease.   A total of 173 healthy controls and 226 gallstone patients (USG positive) were recruited. Genotyping was done by using standard polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method.   The observed control frequencies of both polymorphisms of SLCO1B1 gene [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] were in agreement with Hardy-Weinberg equilibrium. The frequency CA genotype and A allele of Exon4 C > A polymorphism was higher in gallstones patients (12.4% and 6.2%) as compared to controls (5.2% and 2.6%) which was statistically significant [(P = 0.029; OR = 2.31; 95% CI = 1.1-5.0); (P = 0.034; OR = 2.22; 95% CI = 1.1-4.8)], respectively). However, distribution of genotypes and alleles of Ex6 + 40T > C polymorphism was almost similar between gallstone patients and controls. Haplotype analysis showed frequency of A,T haplotype consisting of was significantly higher in gallstone patients as compared to controls and was imposing risk for the disease (P = 0.036; OR = 2.34; 95% CI = 1.0-5.1).   These results suggest that SLCO1B1 Exon4 C > A polymorphism confers increased risk for gallstone disease in North Indian population. © 2010 The Japan Society of Hepatology.

  1. Atomic layer deposition of molybdenum oxide using bis(tert-butylimido)bis(dimethylamido) molybdenum

    Energy Technology Data Exchange (ETDEWEB)

    Bertuch, Adam, E-mail: abertuch@ultratech.com; Sundaram, Ganesh [Ultratech/Cambridge NanoTech, 130 Turner Street, Waltham, Massachusetts 02453 (United States); Saly, Mark; Moser, Daniel; Kanjolia, Ravi [SAFC Hitech, 1429 Hilldale Avenue, Haverhill, Massachusetts 01832 (United States)

    2014-01-15

    Molybdenum trioxide films have been deposited using thermal atomic layer deposition techniques with bis(tert-butylimido)bis(dimethylamido)molybdenum. Films were deposited at temperatures from 100 to 300 °C using ozone as the oxidant for the process. The Mo precursor was evaluated for thermal stability and volatility using thermogravimetric analysis and static vapor pressure measurements. Film properties were evaluated with ellipsometry, x-ray photoelectron spectroscopy, secondary ion mass spectroscopy, and secondary electron microscopy. The growth rate per cycle was determined to extend from 0.3 to 2.4 Å/cycle with <4% nonuniformity (1-sigma) with-in-wafer across a 150 mm wafer for the investigated temperature range.

  2. Crystal structure of bis[bis(4-azaniumylphenyl sulfone] tetranitrate monohydrate

    Directory of Open Access Journals (Sweden)

    Amani Hind Benahsene

    2017-11-01

    Full Text Available In the title compound, the hydrated tetra(nitrate salt of dapsone (4,4′-diaminodiphenylsulfone, 2C12H14N2O2S2+·4NO3−·H2O {alternative name: bis[bis(4,4′-diazaniumylphenyl sulfone] tetranitrate monohydrate}, the cations are conformationally similar, with comparable dihedral angles between the two benzene rings in each of 70.03 (18 and 69.69 (19°. In the crystal, mixed cation–anion–water molecule layers lying parallel to the (001 plane are formed through N—H...O, O—H...O and C—H...O hydrogen-bonding interactions and these layers are further extended into an overall three-dimensional supramolecular network structure. Inter-ring π–π interactions are also present [minimum ring centroid separation = 3.693 (3 Å].

  3. Bis{N,N-bis[(diphenylphosphanylmethyl]aniline-κ2P,P′}copper(I tetrafluoridoborate

    Directory of Open Access Journals (Sweden)

    Qing-Ling Ni

    2011-01-01

    Full Text Available In the cation of the title compound, [Cu(C32H29NP22]BF4, the CuI atom is four-coordinated in a distorted tetrahedral geometry by four P atoms from two N,N-bis[(diphenylphosphanylmethyl]aniline ligands. In the crystal, the cations are linked by C—H...π interactions, forming chains along the a axis. Intramolecular C—H...N and intermolecular C—H...F hydrogen bonds are also observed.

  4. Bis[N,N'-bis(diphenylmethylene)ethylenediamine-2N,N']copper(I) dichlorocuprate(I)

    NARCIS (Netherlands)

    Mirkhani, Valiollah; Harkema, Sybolt; Kia, Reza

    2004-01-01

    The 1:1 adduct of N,N'-bis(diphenylmethylene)ethylenediamine (bz2en) with copper(I) chloride, viz. [Cu(C28H24N2)2][CuCl2], has been synthesized. The structure contains cationic moieties of CuI ions (Cu on a twofold axis) coordinated to four N atoms of two bz2en molecules (in a distorted tetrahedron)

  5. Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of oatp1b1s

    NARCIS (Netherlands)

    Steeg, E. van de; Greupink, R.; Schreurs, M.; Nooijen, I.H.G.; Verhoeck, K.C.M.; Hanemaaijer, R.; Ripken, D.; Monshouwer, M.; Vlaming, M.L.H.; DeGroot, J.; Verwei, M.; Russel, F.G.M.; Huisman, M.T.; Wortelboer, H.M.

    2013-01-01

    Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with

  6. TES/Aura L1B Spectra Special Observation High Resolution V004

    Data.gov (United States)

    National Aeronautics and Space Administration — A L1B High Resolution granule consists of radiometrically calibrated spectra & associated NESR, observed at 0.025 cm-1 resolution for a Special Observation &...

  7. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 1km V005

    Data.gov (United States)

    National Aeronautics and Space Administration — The MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 36 discrete bands located in the 0.4 to 14.4 micron region of...

  8. Typical radiographic findings of dentin dysplasia type 1b with dental fluorosis

    National Research Council Canada - National Science Library

    Suman, S Venkata; Jayam, Raviraj; Kumar, B Vijay; Dirasantchu, Suresh; Kumar, K Venkata Suneel; Sk, Sameeulla

    2013-01-01

    .... We hereby report a case of dentin dysplasia type 1b with typical radiographic findings: short and blunt roots, pulpal obliteration, horizontal/crescent shaped radiolucencies in pulp chambers, and multiple periapical radiolucencies...

  9. Influence of drug formulation on OATP1B-mediated transport of paclitaxel

    NARCIS (Netherlands)

    A.J.M. Nieuweboer (Annemieke ); S. Hu (Shuiying); C. Gui (Chunshan); B. Hagenbuch (Bruno); I.M.G. Moghaddam-Helmantel; A.A. Gibson; P. de Bruijn (Peter); A.H.J. Mathijssen (Ron); A. Sparreboom (Alex)

    2014-01-01

    textabstractTaxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested

  10. Gfi1 and gfi1b repress rag transcription in plasmacytoid dendritic cells in vitro.

    Directory of Open Access Journals (Sweden)

    Kwan T Chow

    Full Text Available 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.

  11. Water molecule network and active site flexibility of apo protein tyrosine phosphatase 1B

    DEFF Research Database (Denmark)

    Pedersen, A.K.; Peters, Günther H.J.; Møller, K.B.

    2004-01-01

    Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator of insulin and leptin signalling and is therefore considered to be an important molecular target for the treatment of type 2 diabetes and obesity. Detailed structural information about the structure of PTP1B, including...... the conformation and flexibility of active-site residues as well as the water-molecule network, is a key issue in understanding ligand binding and enzyme kinetics and in structure-based drug design. A 1.95 Angstrom apo PTP1B structure has been obtained, showing four highly coordinated water molecules in the active......-site pocket of the enzyme; hence, the active site is highly solvated in the apo state. Three of the water molecules are located at positions that approximately correspond to the positions of the phosphate O atoms of the natural substrate phosphotyrosine and form a similar network of hydrogen bonds. The active...

  12. Deglacial Meltwater Pulse 1B and Younger Dryas Sea Levels Revisited with Boreholes at Tahiti

    National Research Council Canada - National Science Library

    Edouard Bard; Bruno Hamelin; Donane Delanghe-Sabatier

    2010-01-01

    ... changes associated with the Younger Dryas cold event and the meltwater pulse IB (MWP-1B). We used the uranium-thorium method to date shallow-living corals from three new cores drilled onshore in the Tahiti barrier reef...

  13. IceBridge UAF Lidar Profiler L1B Geolocated Surface Elevation Triplets

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA IceBridge UAF Lidar Profiler L1B Geolocated Surface Elevation Triplets data set contains surface profiles of Alaska Glaciers acquired using the airborne...

  14. SAGE III Meteor-3M L1B Solar Event Transmission Data (Native) V003

    Data.gov (United States)

    National Aeronautics and Space Administration — Level 1B pixel group transmission profiles for a single solar event (Suggested Usage: Vertical transmission profiles for input into an inversion algorithm)

  15. ASTER Expedited L1B Registered Radiance at the Sensor V003

    Data.gov (United States)

    National Aeronautics and Space Administration — The Expedited ASTER Level-1B Registered Radiance at the Sensor data set is produced with the express purpose of providing ASTER Science Team members data of their...

  16. Archive of Census Related Products (ACRP): 1990 Summary Tape File (STF1B)

    Data.gov (United States)

    National Aeronautics and Space Administration — The 1990 Summary Tape File (STF1B) portion of the Archive of Census Related Products (ACRP) contains population and housing data, along with additional demographic...

  17. ASTER L1B Registered Radiance at the Sensor V003

    Data.gov (United States)

    National Aeronautics and Space Administration — The ASTER Level-1B Registered Radiance at the Sensor product contains radiometrically calibrated and geometrically co-registered data for the acquired channels of...

  18. GLAS/ICESat L1B Global Waveform-based Range Corrections Data V034

    Data.gov (United States)

    National Aeronautics and Space Administration — The level 1B waveform parameterization data will contain waveform-based range corrections and surface characteristics at the full 40 per second resolution. Data...

  19. IceBridge DMS L1B Geolocated and Orthorectified Images V001

    Data.gov (United States)

    National Aeronautics and Space Administration — This data set contains Level-1B imagery taken from the Digital Mapping System (DMS) over Greenland and Antarctica. The data were collected as part of Operation...

  20. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 1km - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — The MODIS Level 1B Near Real Time (NRT) data set contains calibrated and geolocated at-aperture radiances for 36 discrete bands located in the 0.4 to 14.4 micron...

  1. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 1km

    Data.gov (United States)

    National Aeronautics and Space Administration — The MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 36 discrete bands located in the 0.4 to 14.4 micron region of...

  2. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 1km

    Data.gov (United States)

    National Aeronautics and Space Administration — The MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 36 discrete bands located in the 0.4 to 14.4 micron region of the...

  3. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 1km V006

    Data.gov (United States)

    National Aeronautics and Space Administration — The MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 36 discrete bands located in the 0.4 to 14.4 micron region of...

  4. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 1km V006

    Data.gov (United States)

    National Aeronautics and Space Administration — The MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 36 discrete bands located in the 0.4 to 14.4 micron region of the...

  5. OMI/Aura Level 1B Solar Irradiances V003 (OML1BIRR) at GES DISC

    Data.gov (United States)

    National Aeronautics and Space Administration — The OMI Level 1B solar irradiance product is the radiometrically calibrated and geolocated measurements of the UV and Visible channels of the spectral solar...

  6. AIRS/Aqua Level 1B Infrared (IR) geolocated and calibrated radiances V005

    Data.gov (United States)

    National Aeronautics and Space Administration — The AIRS Infrared (IR) level 1B data set contains AIRS infrared calibrated and geolocated radiances in milliWatts/m^2/cm^-1/steradian. This data set is generated...

  7. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 1km - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — The MODIS Level 1B Near Real Time (NRT) data set contains calibrated and geolocated at-aperture radiances for 36 discrete bands located in the 0.4 to 14.4 micron...

  8. Geometrical criteria for characterizing open and closed states of WPD-loop in PTP1B

    Science.gov (United States)

    Shinde, Ranajit Nivrutti; Elizabeth Sobhia, M.

    2012-06-01

    Distinctive movement of WPD-loop occurs during the catalysis of phosphotyrosine by protein tyrosine phosphatase 1B (PTP1B). This loop is in the "open" state in apo-form whereas it is catalytically competent in the "closed" state. During the closure of this loop, unique hydrogen bond interactions are formed between different residues of the PTP1B. Present study examines such interactions from the available 118 crystal structures of PTP1B. It gives insights into the five novel hydrogen bonds essentially formed in the "closed" loop structures. Additionally, the study provides distance ranges between the atoms involved in the hydrogen bonds. This information can be used as a geometrical criterion in the characterization of conformational state of the WPD-loop especially in the molecular dynamics simulations.

  9. Spectral Properties and Variability of BIS objects

    Science.gov (United States)

    Gaudenzi, S.; Nesci, R.; Rossi, C.; Sclavi, S.; Gigoyan, K. S.; Mickaelian, A. M.

    2017-10-01

    Through the analysis and interpretation of newly obtained and of literature data we have clarified the nature of poorly investigated IRAS point sources classified as late type stars, belonging to the Byurakan IRAS Stars catalog. From medium resolution spectroscopy of 95 stars we have strongly revised 47 spectral types and newly classified 31 sources. Nine stars are of G or K types, four are N carbon stars in the Asymptotic Giant Branch, the others being M-type stars. From literature and new photometric observations we have studied their variability behaviour. For the regular variables we determined distances, absolute magnitudes and mass loss rates. For the other stars we estimated the distances, ranging between 1.3 and 10 kpc with a median of 2.8 kpc from the galactic plane, indicating that BIS stars mostly belong to the halo population.

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

    Directory of Open Access Journals (Sweden)

    Slobodan M Jankovic

    2010-03-01

    Full Text Available Slobodan M JankovicPharmacology Department, Medical Faculty, University of Kragujevac, Kragujevac, SerbiaAbstract: 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

  11. trans-Bis[4-amino-3,5-bis(2-pyridyl-4H-1,2,4-triazole-κN3]diaquacobalt(II bis(3-carboxy-5-nitrobenzoate

    Directory of Open Access Journals (Sweden)

    Cheng-Peng Li

    2011-10-01

    Full Text Available The title complex, [Co(C12H10N62(H2O2](C8H4NO62, is composed of a mononuclear cobalt(II cation and two 3-carboxy-5-nitrobenzoate anions for charge balance. In the cation, the CoII atom is six-coordinated in a distorted octahedral geometry. It bonds to two O atoms of two water molecules, and two pairs of N atoms from two 4-amino-3,5-bis(2-pyridyl-4H-1,2,4-triazole molecules, which behave as bidentate chelating ligands. There are intramolecular N—H...N hydrogen bonds in the cation. In the crystal, there are a number of intermolecular N—H...O and O—H...O hydrogen bonds, as well as intermolecular π–π stacking interactions [centroid–centroid distances = 3.657 (2 and 3.847 (2 Å], that link the molecules into two-dimensional networks lying parallel to the ab plane. The presence of C—H...O interactions leads to the formation of a three-dimensional network.

  12. Protein kinase C affects the internalization and recycling of organic anion transporting polypeptide 1B1.

    Science.gov (United States)

    Hong, Mei; Hong, Weifang; Ni, Chunxu; Huang, Jiujiu; Zhou, Chao

    2015-10-01

    Organic anion-transporting polypeptides are members of the solute carrier (SLC) family and key determinants for the transmembrane transport of a wide variety of compounds. OATP1B1 is predominantly expressed at the basolateral membrane of human hepatocytes and play an important role in drug clearance from the body. It has been demonstrated to be responsible for the hepatic uptake of various drugs. Computer-based hydropathy analysis predicted several putative phosphorylation sites at the amino and carboxyl termini and at intracellular loop 3 of OATP family members. Therefore, their transport functions may be regulated by phosphorylation. Previous studies have demonstrated that uptake function of OATP2B1 and OATP1A2 is regulated by protein kinase C (PKC). In the present study, we treated HEK293 cells stably expressing OATP1B1 with different PKC modulators and measured their transport activity for prototypic substrate estrone-3-sulfate. It was found that OATP1B1 uptake function was reduced upon PKC activation. Further studies indicated that PKC may affect OATP1B1 activity through regulation of the cell surface protein level. Moreover, we found out that PKC activator phorbol 12-myristate 13-acetate (PMA) not only affects the internalization of OATP1B1 but its recycling as well. Immunocytochemistry analysis revealed that internalized OATP1B1 co-localized with early and recycling endosomal markers and the co-localization of OATP1B1 with recycling endosome is dependent on PKC activation. Taken together, our present study demonstrated that PKC regulates the function of OATP1B1 by affecting internalization and recycling of the transporter protein. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Microtubule-associated protein 1b is required for shaping the neural tube.

    Science.gov (United States)

    Jayachandran, Pradeepa; Olmo, Valerie N; Sanchez, Stephanie P; McFarland, Rebecca J; Vital, Eudorah; Werner, Jonathan M; Hong, Elim; Sanchez-Alberola, Neus; Molodstov, Aleksey; Brewster, Rachel M

    2016-01-18

    Shaping of the neural tube, the precursor of the brain and spinal cord, involves narrowing and elongation of the neural tissue, concomitantly with other morphogenetic changes that contribue to this process. In zebrafish, medial displacement of neural cells (neural convergence or NC), which drives the infolding and narrowing of the neural ectoderm, is mediated by polarized migration and cell elongation towards the dorsal midline. Failure to undergo proper NC results in severe neural tube defects, yet the molecular underpinnings of this process remain poorly understood. We investigated here the role of the microtubule (MT) cytoskeleton in mediating NC in zebrafish embryos using the MT destabilizing and hyperstabilizing drugs nocodazole and paclitaxel respectively. We found that MTs undergo major changes in organization and stability during neurulation and are required for the timely completion of NC by promoting cell elongation and polarity. We next examined the role of Microtubule-associated protein 1B (Map1b), previously shown to promote MT dynamicity in axons. map1b is expressed earlier than previously reported, in the developing neural tube and underlying mesoderm. Loss of Map1b function using morpholinos (MOs) or δMap1b (encoding a truncated Map1b protein product) resulted in delayed NC and duplication of the neural tube, a defect associated with impaired NC. We observed a loss of stable MTs in these embryos that is likely to contribute to the NC defect. Lastly, we found that Map1b mediates cell elongation in a cell autonomous manner and polarized protrusive activity, two cell behaviors that underlie NC and are MT-dependent. Together, these data highlight the importance of MTs in the early morphogenetic movements that shape the neural tube and reveal a novel role for the MT regulator Map1b in mediating cell elongation and polarized cell movement in neural progenitor cells.

  14. Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    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.

  15. Anti-Chol-1 antigen, GQ1bα, antibodies are associated with Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Toshio Ariga

    Full Text Available The interaction of amyloid β-proteins (Aβ with membrane gangliosides has been reported to be an early event in Aβ fibril formation in Alzheimer's disease (AD. Neuronal degeneration in AD has been postulated to be associated with the presence of anti-ganglioside antibodies in patient sera. Using an enzyme-linked immunosorbent assay (ELISA and high-performance thin-layer chromatography (HPTLC immunostaining, sera from 27 individuals (10 with AD, 6 with vascular dementia (VD, and 11 non-demented age-matched pathological controls were examined in order to detect anti-glycosphingolipid (GSL antibodies, including anti-cholinergic-specific antigen (Chol-1α; GQ1bα antibodies. All sera had natural antibodies against ganglio-N-tetraosyl gangliosides (brain-type gangliosides. However, sera of demented patients with AD and VD had significantly higher titers of anti-GSL antibodies than those in age-matched pathological controls. Although most serum antibodies, including anti- GM1, -GT1b, -GQ1b, -GQ1bα, were of the IgM type, the presence of the IgG type antibodies was also significantly elevated in the sera of demented patients with AD. Anti-GT1b antibodies of the IgG type were elevated in AD (90%, 9 of 10 cases and VD (100%, respectively. Most surprisingly, anti-GQ1bα antibodies (IgM were found in 90% (9/10 and 100% (6/6 in the sera of patients with AD and VD, respectively. Since GQ1bα is present in the cerebral cortex and hippocampus, the presence of anti-GQ1bα antibodies may play an important role in disrupting cholinergic synaptic transmission and may participate in the pathogenesis of dementia. We conclude that elevated anti-GSL antibody titers may be useful as an aid for clinical diagnosis of those dementias.

  16. Cloning and tissue expression of cytochrome P450 1B1 and 1C1 ...

    African Journals Online (AJOL)

    Cytochrome P450 1 (CYP1) is widely used as an indicator of exposure to environmental contaminants. In the study, two full-length complementary DNAs encode for CYP1B1 and CYP1C1 were cloned from medaka liver exposed to 500 ppb β-naphthoflavone for 24 h. CYP1B1, having 1984 bp, contains an open reading ...

  17. Integrative bioinformatics links HNF1B with clear cell carcinoma and tumor-associated thrombosis.

    Directory of Open Access Journals (Sweden)

    Justin Cuff

    Full Text Available 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.

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

    Directory of Open Access Journals (Sweden)

    Tyler J. Broering

    2015-07-01

    Full Text Available 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.

  19. Unit 1b: A General Approach to the Teaching of Architecture

    DEFF Research Database (Denmark)

    Toft, Anne Elisabeth

    2011-01-01

    The chapter presents the overall academic aims of the teaching at Unit 1b and how these were implemented in the curriculum for 2009/2010. The section includes considerations about learning targets, method, discourse, pedagogy and didactics.......The chapter presents the overall academic aims of the teaching at Unit 1b and how these were implemented in the curriculum for 2009/2010. The section includes considerations about learning targets, method, discourse, pedagogy and didactics....

  20. [Pharmacokinetics (PK) of mAbs].

    Science.gov (United States)

    Paintaud, Gilles

    2009-12-01

    The human Fc portion of humanized monoclonal antibodies (mAb) gives them a half-life of around 21 days, similar to that of endogenous immunoglobulin G (IgG). Neonatal Fc receptor (FcRn) plays a major role in the pharmacokinetics (PK) of mAbs. By protecting them from degradation, it is responsible for their long half-life and by allowing their transcytosis, it influences their absorption and their distribution. After subcutaneous administration, the absorption of mAbs is slow and incomplete. Most of them are still administered intravenously. Their distribution in tissues is poorly known. It seems limited and certain organs, such as the central nervous system, may be protected by FcRn. The elimination of mAbs is partly mediated by binding to their target-antigen, a mechanism that leads to dose-dependent PK. The interindividual variability in mAb PK is clinically relevant and its main known origins are demographic factors, antigen mass and immunization. Complex PK models are needed to describe satisfactorily their fate in the body and their concentration-effect relationship.

  1. Final State Resolved Quantum Predissociation Dynamics of SO2(C̃1B2) and Its Isotopomers via a Crossing with a Singlet Repulsive State.

    Science.gov (United States)

    Xie, Changjian; Jiang, Bin; Kłos, Jacek; Kumar, Praveen; Alexander, Millard H; Poirier, Bill; Guo, Hua

    2017-07-06

    The fragmentation dynamics of predissociative SO2(C̃1B2) is investigated on an accurate adiabatic potential energy surface (PES) determined from high level ab initio data. This singlet PES features non-C2v equilibrium geometries for SO2, which are separated from the SO(X̃3Σ-) + O(3P) dissociation limit by a barrier resulting from a conical intersection with a repulsive singlet state. The ro-vibrational state distribution of the SO fragment is determined quantum mechanically for many predissociative states of several sulfur isotopomers of SO2. Significant rotational and vibrational excitations are found in the SO fragment. It is shown that these fragment internal state distributions are strongly dependent on the predissociative vibronic states, and the excitation typically increases with the photon energy.

  2. UGT1A1, SLCO1B1, and SLCO1B3 polymorphisms vs. neonatal hyperbilirubinemia: is there an association?

    Science.gov (United States)

    Alencastro de Azevedo, Laura; Reverbel da Silveira, Themis; Carvalho, Clarissa Gutierrez; Martins de Castro, Simone; Giugliani, Roberto; Matte, Ursula

    2012-08-01

    Jaundice is a physiological phenomenon; however, severe hyperbilirubinemia occurs in only 5 to 6% of the healthy newborn population. It has been suggested that genetic variation could enhance the risk of hyperbilirubinemia when coexpressed with other icterogenic conditions. The study included newborns with a gestational age of greater than 35 wk and weights greater than 2,000 g with indications for phototherapy. The polymorphisms from UGT1A1 (rs8175347), SLCO1B1 (rs4149056 and rs2306283), and SLCO1B3 (rs17680137 and rs2117032) were analyzed by capillary electrophoresis and hydrolysis probes. A total of 167 hyperbilirubinemic infants and 247 control subjects were enrolled. The gender, ABO incompatibility, birth weight, and gestational age differed between the groups, but the allelic and genotypic frequency of the polymorphisms from SLCO1B genes did not. In logistic regression, the ABO incompatibility, gestational age, and polymorphic T allele of rs2117032 remained in the model. The presence of this polymorphism seemed to provide protection from hyperbilirubinemia. The individuals who were homozygous for the G allele of rs2306283 and who were glucose 6-phosphate-dehydrogenase deficient were more frequent among the cases. Although genetic variation accounts for a good part of this condition, the association between different polymorphisms and environmental factors has yet to be explained.

  3. Polymorphisms in DENND1B gene are associated with asthma and atopy phenotypes in Brazilian children.

    Science.gov (United States)

    Fiuza, Bianca S D; Silva, Milca de J; Alcântara-Neves, Neuza M; Barreto, Maurício L; Costa, Ryan Dos S; Figueiredo, Camila A

    2017-10-01

    Asthma is a heterogeneous disease associated with a complex basis involving environmental factors and individual variabilities. The DENN Domain Containing 1B (DENND1B) gene has an important role on T cell receptor (TCR) down-regulation on Th2 cells and studies have shown that mutations or loss of this factor can be associated with increased Th2 responses and asthma. The aim of this work is to evaluate the association of polymorphisms in the DENND1B with asthma and allergy markers phenotypes in Brazilian children. Genotyping was performed using a commercial panel from Illumina (2.5 Human Omni bead chip) in 1309 participants of SCAALA (Social Change, Asthma, Allergy in Latin American) program. Logistic regressions for asthma and atopy markers were performed using PLINK software 1.9. The analyzes were adjusted for sex, age, helminth infections and ancestry markers. The DENND1B gene was associated with different phenotypes such as severe asthma and atopic markers (specific IgE production, skin prick test and IL-13 production). Among the 166 SNPs analyzed, 72 were associated with asthma and/or allergy markers. In conclusion, polymorphisms in the DENND1B are significantly associated with development of asthma and atopy and these polymorphisms can influence DENND1B expression and consequently, asthma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Jasmonate signalling in Arabidopsis involves SGT1b-HSP70-HSP90 chaperone complexes.

    Science.gov (United States)

    Zhang, Xue-Cheng; Millet, Yves A; Cheng, Zhenyu; Bush, Jenifer; Ausubel, Frederick M

    Plant hormones play pivotal roles in growth, development and stress responses. Although it is essential to our understanding of hormone signalling, how plants maintain a steady state level of hormone receptors is poorly understood. We show that mutation of the Arabidopsis thaliana co-chaperone SGT1b impairs responses to the plant hormones jasmonate, auxin and gibberellic acid, but not brassinolide and abscisic acid, and that SGT1b and its homologue SGT1a are involved in maintaining the steady state levels of the F-box proteins COI1 and TIR1, receptors for jasmonate and auxin, respectively. The association of SGT1b with COI1 is direct and is independent of the Arabidopsis SKP1 protein, ASK1. We further show that COI1 is a client protein of SGT1b-HSP70-HSP90 chaperone complexes and that the complexes function in hormone signalling by stabilizing the COI1 protein. This study extends the SGT1b-HSP90 client protein list and broadens the functional scope of SGT1b-HSP70-HSP90 chaperone complexes.

  5. Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies

    Directory of Open Access Journals (Sweden)

    Marie Jazmín Sarabia-Sánchez

    2017-12-01

    Full Text Available The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in the secretion of insulin and a resistance in its target organs. In the search for new antidiabetic drugs, one of the principal strategies consists in promoting the action of insulin. In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B, a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance. In the present work, a chemical library of 250 compounds was evaluated to determine their inhibition capability on the protein PTP1B. Ten molecules inhibited over the 50% of the activity of the PTP1B, the three most potent molecules were selected for its characterization, reporting Ki values of 5.2, 4.2 and 41.3 µM, for compounds 1, 2, and 3, respectively. Docking and molecular dynamics studies revealed that the three inhibitors made interactions with residues at the secondary binding site to phosphate, exclusive for PTP1B. The data reported here support these compounds as hits for the design more potent and selective inhibitors against PTP1B in the search of new antidiabetic treatment.

  6. Interferon beta-1b reduces black holes in a randomised trial of clinically isolated syndrome.

    Science.gov (United States)

    Nagtegaal, Gijsbert J A; Pohl, Christoph; Wattjes, Mike P; Hulst, Hanneke E; Freedman, Mark S; Hartung, Hans-Peter; Miller, David; Montalban, Xavier; Kappos, Ludwig; Edan, Gilles; Pleimes, Dirk; Beckman, Karola; Stemper, Brigitte; Polman, Christoph H; Sandbrink, Rupert; Barkhof, Frederik

    2014-02-01

    Multiple sclerosis (MS) is characterised by inflammatory lesions of the central nervous system. Interferon beta-1b (IFNB-1b) has been shown to improve clinical and magnetic resonance imaging (MRI) measures for patients with MS. To evaluate whether IFNB-1b in patients presenting with clinically isolated syndromes (CIS) prevented persisting T1 hypointensities on MRI (persistent black holes (PBHs)). In the placebo-controlled phase, patients (n = 468) were initially randomised to IFNB-1b (n = 292) or placebo (n = 176) for two years or clinically definite MS (CDMS). In the open-label phase (n = 418), both groups were offered IFNB-1b for up to five years. Lesions were classified as PBHs if T1 hypointensity persisted throughout the last available scan (minimum time one year). A total of 435 patients were evaluable for analysis. The number of PBHs/patient was lower in the early rather than the delayed treatment arm during both phases (.42 vs .71, p = .0102 and .70 vs 1.17, p = .0121). Exploratory analyses identified baseline characteristics that affected rate of conversion. Although the rate of lesions that converted to PBH showed no significant differences between groups, the numbers of PBHs per patient out of new lesions was significantly lower in IFNB-1b patients compared to patients on placebo. NCT00544037.

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

    Science.gov (United States)

    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 m(2) 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 m(2), only when the simulated fire temperature is larger than 900 K, may the fire be detected. For fire areas about 100 m(2), 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.

  8. Knockdown of Lingo1b protein promotes myelination and oligodendrocyte differentiation in zebrafish.

    Science.gov (United States)

    Yin, Wu; Hu, Bing

    2014-01-01

    Demyelinating diseases include multiple sclerosis, which is a neurodegenerative disease characterized by immune attacks on the central nervous system (CNS), resulting in myelin sheath damage and axonal loss. Leucine-rich repeat and immunoglobulin domain-containing neurite outgrowth inhibitory protein (Nogo) receptor-interacting protein-1 (LINGO-1) have been identified as a negative regulator of oligodendrocytes differentiation. Targeted LINGO-1 inhibition promotes neuron survival, axon regeneration, oligodendrocyte differentiation, and remyelination in diverse animal models. Although studies in rodent models have extended our understanding of LINGO-1, its roles in neural development and myelination in zebrafish (Danio rerio) are not yet clear. In this study, we cloned the zebrafish homolog of the human LINGO-1 and found that lingo1b regulated myelination and oligodendrocyte differentiation. The expression of lingo1b started 1 (mRNA) and 2 (protein) days post-fertilization (dpf) in the CNS. Morpholino oligonucleotide knockdown of lingo1b resulted in developmental abnormalities, including less dark pigment, small eyes, and a curly spinal cord. The lack of lingo1b enhanced myelination and oligodendrocyte differentiation during embryogenesis. Furthermore, immunohistochemistry and movement analysis showed that lingo1b was involved in the axon development of primary motor neurons. These results suggested that Lingo1b protein functions as a negative regulator of myelination and oligodendrocyte differentiation during zebrafish development. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Extracting fields snow coverage information with HJ-1A/B satellites data

    Science.gov (United States)

    Dong, Wenquan; Meng, Jihua

    2015-10-01

    The distribution and change of snow coverage are sensitive factors of climate change. In northeast part of China, farmlands are still covered with snow in spring. Since sowing activity can only be done when the snow melted, fields snow coverage monitoring provides reference for the determination of sowing date. Because of the restriction of the sensors and application requirements, current researches on remote sensing of snow focus more on the study of musicale and large scale, rather than the study of small scale, and especially research on snow melting period is rarely reported.HJ-1A/B satellites are parts of little satellite constellation, focusing on environment and disaster monitoring and meteorological forecast. Compared to other data sources, HJ-1A/B satellites both have comparatively higher temporal and spatial resolution and are more conducive to monitor the variations of melting snow coverage at small watershed. This paper was based on HJ-1A/1B data, taking Hongxing farm of Bei'an, Heilongjiang Province, China as the study area. In this paper, we exploited the methods for extraction of snow cover information on farmland in two cases, both HJ-1A/1B CCD with HJ-1B IRS data and just HJ-1A/1B CCD data. The reason we chose the two cases is that, the two optical satellites HJ-1A/B are capable of providing a whole territory coverage period in visible light spectrum in two days, infrared spectrum in four days. So sometimes we can only obtain CCD image. In this case, the method of normalized snow index cannot be used to extract snow coverage information. Using HJ-1A/1B CCD with HJ-1B IRS data, combined with the theory of snow remote sensing monitoring, this paper analyzed spectral response characteristics of HJ-1A/1B satellites data, then the widely used Normalized Difference Snow Index(NDSI) and S3 Index were quoted to the HJ-1A/1B satellites data. The NDSI uses reflectance values of Red and SWIR spectral bands of HJ-1B, and S3 index uses reflectance values of

  10. Mono- and bis-thiazolium salts have potent antimalarial activity.

    Science.gov (United States)

    Hamzé, Abdallah; Rubi, Eric; Arnal, Pascal; Boisbrun, Michel; Carcel, Carole; Salom-Roig, Xavier; Maynadier, Marjorie; Wein, Sharon; Vial, Henri; Calas, Michèle

    2005-05-19

    Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC(50) values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED(50)

  11. Ab interno trabeculectomy: patient selection and perspectives.

    Science.gov (United States)

    Vinod, Kateki; Gedde, Steven J

    2016-01-01

    Ab interno trabeculectomy is one among several recently introduced minimally invasive glaucoma surgeries that avoid a conjunctival incision and full-thickness sclerostomy involved in traditional glaucoma surgery. Ablation of the trabecular meshwork and inner wall of Schlemm's canal is performed in an arcuate fashion via a clear corneal incision, alone or in combination with phacoemulsification cataract surgery. Intraocular pressure reduction following ab interno trabeculectomy is limited by resistance in distal outflow pathways and generally stabilizes in the mid-to-high teens. Relief of medication burden has been demonstrated by some studies. A very low rate of complications, most commonly transient hyphema and intraocular pressure elevations in the immediate postoperative period, have been reported. However, available data are derived from small retrospective and prospective case series. Randomized, controlled trials are needed to better elucidate the potential merits of ab interno trabeculectomy in the combined setting versus phacoemulsification cataract surgery alone and to compare it with other minimally invasive glaucoma surgeries.

  12. SLCO1B1 *15 haplotype is associated with rifampin-induced liver injury.

    Science.gov (United States)

    Li, Ling-Min; Chen, Lei; Deng, Guo-Hong; Tan, Wen-Ting; Dan, Yun-Jie; Wang, Rong-Quan; Chen, Wen-Sheng

    2012-07-01

    The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n = 118) and without (non-DILI) (n = 155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 *1a, *1b, *5 and *15, with their respective frequencies being 23.44, 66.30, 0.73 and 9.52% in a total of 273 individuals. The logistic regression analysis indicated that the *15 haplotype was associated with susceptibility to DILI (p = 0.03, OR = 2.04, 95% CI 1.05-3.96). The frequency of the *15 haplotype in DILI patients was significantly higher than that in non-DILI patients (p = 0.03). In the subgroup analysis, the *15 haplotype was associated with susceptibility to cholestatic/mixed injury (p = 0.03, OR = 2.31, 95% CI 1.06-5.02). Functional assessment of the OATP1B1 *15 haplotype revealed that the activity of bile acid uptake was markedly reduced compared to the three other haplotypes. In the inhibition study, the inhibition by rifampin in the *15 haplotype was greater compared to that in the other haplotypes. These results suggest that the OATP1B1 *15 haplotype is an important predisposing factor for rifampin-induced liver injury.

  13. Laptop computer--associated erythema ab igne.

    Science.gov (United States)

    Levinbook, Wendy Susser; Mallett, Janelle; Grant-Kels, Jane M

    2007-10-01

    A 40-year-old woman presented with an asymptomatic reticulated eruption on the thighs. After an extensive workup, she was diagnosed with erythema ab igne caused by laptop computer use. The eruption ultimately cleared several months after discontinuation of direct placement of the laptop computer on her thighs. Erythema ab igne is becoming increasingly associated with exposure to modern heat sources. A thorough history of patients with suspicious lesions should include questioning for contact with alternative heat sources to avoid an unnecessary workup for this condition.

  14. Ab initio valence calculations in chemistry

    CERN Document Server

    Cook, D B

    1974-01-01

    Ab Initio Valence Calculations in Chemistry describes the theory and practice of ab initio valence calculations in chemistry and applies the ideas to a specific example, linear BeH2. Topics covered include the Schrödinger equation and the orbital approximation to atomic orbitals; molecular orbital and valence bond methods; practical molecular wave functions; and molecular integrals. Open shell systems, molecular symmetry, and localized descriptions of electronic structure are also discussed. This book is comprised of 13 chapters and begins by introducing the reader to the use of the Schrödinge

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

    Directory of Open Access Journals (Sweden)

    Christine Nießner

    Full Text Available 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.

  16. Melatonin Receptor 1B Gene Polymorphisms, Haplotypes and Susceptibility to Schizophrenia

    Directory of Open Access Journals (Sweden)

    Saravani Ramin

    2017-04-01

    Full Text Available Melatonin has an important role in the regulation of human sleep circadian rhythms. Sleep disturbances commonly exist in schizophrenia (SCZ patients. To begin its performance, melatonin must interact to its receptor. In the present study, Single Nucleotide Polymorphisms (SNPs of melatonin receptor gene 1 B (MTN1B with SCZ development in Iranian population were investigated. The current case-control study was performed on 92 SCZ patients and 92 healthy control (HC subjects. NESTED-PCR and ARMS-PCR modified methods (combination and ARMSPCR method were used on the genotype. The impact of MTN1B rs3781637 (T/C and rs10830963(C/G polymorphism variants on the risk SCZ in the sample of Iranian population was investigated. The findings showed significant association between MTN1B rs10830963(C/G variant and SCZ (OR=2.78, 95%CI=1.25-6.25, P=0.012, GG vs. CC, OR=1.66, 95%CI=1.09-2.51, P=0.021 G vs. C, OR=3.85 95%CI=.89-8.33, P<0.0001, GG vs. CC+CG. There was no association between MTN1B rs3781637 (T/C and SCZ risk. In addition, haplotype analysis revealed that TG and CC haplotype of rs3781637 (T/C and rs10830963 (C/G polymorphisms were associated with SCZ risk (P=0.039 and protective (P<0.0001 effects, respectively. The findings revealed that MTN1B rs10830963 (C/G polymorphism was associated with the risk of SCZ; while another SNP rs3781637 (T/C MTN1B gene did not show any risk/protection association with SCZ. Further studies with larger sample sizes and different ethnicities are required to approve the results.

  17. TRAIL signaling is proinflammatory and proviral in a murine model of rhinovirus 1B infection.

    Science.gov (United States)

    Girkin, Jason L; Hatchwell, Luke M; Collison, Adam M; Starkey, Malcolm R; Hansbro, Philip M; Yagita, Hideo; Foster, Paul S; Mattes, Joerg

    2017-01-01

    the aim of this study is to elucidate the role of TRAIL during rhinovirus (RV) infection in vivo. Naïve wild-type and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-deficient (Tnfsf10(-/-)) BALB/c mice were infected intranasally with RV1B. In separate experiments, Tnfsf10(-/-) mice were sensitized and challenged via the airway route with house dust mite (HDM) to induce allergic airways disease and then challenged with RVIB or UV-RVIB. Airway hyperreactivity (AHR) was invasively assessed as total airways resistance in response to increasing methacholine challenge and inflammation was assessed in bronchoalveolar lavage fluid at multiple time points postinfection. Chemokines were quantified by ELISA of whole lung lysates and viral load was determined by quantitative RT-PCR and tissue culture infective dose (TCID50). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID50 HDM-challenged Tnfsf10(-/-) mice were protected against RV-induced AHR and had suppressed cellular infiltration in the airways upon RV infection. Chemokine C-X-C-motif ligand 2 (CXCL2) production was suppressed in naïve Tnfsf10(-/-) mice infected with RV1B, with less RV1B detected 24 h postinfection. This was associated with reduced apoptotic cell death and a reduction of interferon (IFN)-λ2/3 but not IFN-α or IFN-β. TRAIL stimulation increased, whereas anti-TRAIL antibodies reduced viral replication in RV1B-infected BEAS2B cells in vitro. In conclusion, TRAIL promotes RV-induced AHR, inflammation and RV1B replication, implicating this molecule and its downstream signaling pathways as a possible target for the amelioration of RV1B-induced allergic and nonallergic lung inflammation and AHR. Copyright © 2017 the American Physiological Society.

  18. JARID1B expression in human melanoma and benign melanocytic skin lesions.

    Science.gov (United States)

    Kuźbicki, Lukasz; Lange, Dariusz; Strączyńska-Niemiec, Anita; Chwirot, Barbara W

    2013-02-01

    It has been suggested that dynamically regulated expression of the JARID1B protein is required for the continuous growth of tumors and at the same time downregulated in melanoma. The majority of the data on a role of JARID1B in maintaining tumor growth has come from in-vitro and xenografting experiments, with only one immunohistochemical study involving human tissues. We compared JARID1B expression levels in human melanomas and benign nevi and analyzed patterns of spatial distributions of positive cells among different skin layers of the lesions. The expression of JARID1B was evaluated by immunohistochemistry in formalin-fixed paraffin-embedded samples of 30 nevi, 27 primary melanomas, four lymph node metastases, and one local recurrence of melanoma. Staining for JARID1B protein was stronger in melanomas compared with nevi. We also found a significant difference in the spatial distribution of positive cells in individual skin layers of nevi and melanomas. Staining of melanocytes located in granular and spinous layers of nevi was observed very rarely, whereas for melanomas, the mean percentage fractions of positive cells present in these layers exceeded the maximum values found for nevi. The spatial patterns and expression levels of JARID1B did not change significantly with melanoma progression and were similar for primary, metastatic, and recurrent melanomas. Contrary to earlier reports, this study shows enhanced expression of JARID1B by melanoma cells and indicates that such an enhancement may be an early event in the disease progression, is not correlated with melanoma invasiveness, and therefore may not be a suitable candidate as a prognostic marker.

  19. Phase Curve Observations of the Irradaited Transiting Brown Dwarf KELT-1b

    Science.gov (United States)

    Beatty, Thomas; Colon, Knicole; Fortney, Jonathan; Gaudi, Scott; Marley, Mark; Rodriguez, Joseph; Showman, Adam

    2014-12-01

    We propose to observe full orbit phase curves, at 3.6um and 4.5um, of the transiting brown dwarf KELT-1b. KELT-1b is a 27MJ object on a short 1.2 day (29.2 hour) orbit around a bright (V=10.8) F5V star. This system is unique, in that it contains the only known highly irradiated brown dwarf on which it is possible to perform high precision atmospheric measurements, due to KELT-1b's short orbital period and the brightness of its host star. Future work to observationally and theoretically understand the properties of irradiated brown dwarfs will, therefore, rely on our ability to measure the properties of KELT-1b and its atmosphere. Furthermore, a comparison of KELT-1b's Spitzer phase curves to those of similarly irradiated giant planets offers the best possible test of the role of surface gravity in atmospheric circulation. Besides its one-of-a-kind status as an irradiated brown dwarf, KELT-1b is one of the best possible targets for phase curve observations. There are only seven transiting extrasolar giant planets or brown dwarfs with shorter orbital periods (11.8). Our proposed observations will therefore require a relativity low amount of Spitzer time compared to other phase curve proposals (74.5 hours for both bands), and will give very high signal-to-noise ratio (SNR) detections of the phase modulation (estimated SNR of 56 to 74). Our observations will yield one of the best defined phase curve measurements conducted by Spitzer: we estimate a SNR for the phase curve of KELT-1b similar to that achieved on WASP-18b, and a SNR 4 to 5 times higher than the next highest SNR achieved, for the phase curve of HD189733b.

  20. MELCOR 1.8.2 assessment: Aerosol experiments ABCOVE AB5, AB6, AB7, and LACE LA2

    Energy Technology Data Exchange (ETDEWEB)

    Souto, F.J.; Haskin, F.E. [Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Chemical and Nuclear Engineering; Kmetyk, L.N. [Sandia National Labs., Albuquerque, NM (United States)

    1994-10-01

    The MELCOR computer code has been used to model four of the large-scale aerosol behavior experiments conducted in the Containment System Test Facility (CSTF) vessel. Tests AB5, AB6 and AB7 of the ABCOVE program simulate the dry aerosol conditions during a hypothetical severe accident in an LMFBR. Test LA2 of the LACE program simulates aerosol behavior in a condensing steam environment during a postulated severe accident in an LWR with failure to isolate the containment. The comparison of code results to experimental data show that MELCOR is able to correctly predict most of the thermal-hydraulic results in the four tests. MELCOR predicts reasonably well the dry aerosol behavior of the ABCOVE tests, but significant disagreements are found in the aerosol behavior modelling for the LA2 experiment. These results tend to support some of the concerns about the MELCOR modelling of steam condensation onto aerosols expressed in previous works. During these analyses, a limitation in the MELCOR input was detected for the specification of the aerosol parameters for more than one component. A Latin Hypercube Sampling (LHS) sensitivity study of the aerosol dynamic constants is presented for test AB6. The study shows the importance of the aerosol shape factors in the aerosol deposition behavior, and reveals that MELCOR input/output processing is highly labor intensive for uncertainty and sensitivity analyses based on LHS.

  1. Diode laser surgery. Ab interno and ab externo versus conventional surgery in rabbits.

    Science.gov (United States)

    Karp, C L; Higginbotham, E J; Edward, D P; Musch, D C

    1993-10-01

    Fibroblastic proliferation of subconjunctival tissues remains a primary mechanism of failure in filtration surgery. Minimizing the surgical manipulation of episcleral tissues may reduce scarring. Laser sclerostomy surgery involves minimal tissue dissection, and is gaining attention as a method of potentially improving filter duration in high-risk cases. Twenty-five New Zealand rabbits underwent filtration surgery in one eye, and the fellow eye remained as the unoperated control. Ten rabbits underwent ab externo diode laser sclerostomy surgery, ten underwent ab interno diode sclerostomy surgery, and five had posterior sclerostomy procedures. Filtration failure was defined as a less-than-4-mmHg intraocular pressure (IOP) difference between the operative and control eyes. The mean time to failure for the ab externo, ab interno, and conventional posterior sclerostomy techniques measured 17.4 +/- 11.5, 13.1 +/- 6.7, and 6.0 +/- 3.1 days, respectively. In a comparison of the laser-treated groups with the conventional procedure, the time to failure was significantly longer (P = 0.02) for the ab externo filter. The mean ab interno sclerostomy duration was longer than the posterior lip procedure, but this difference was not statistically significant (P = 0.15). The overall level of IOP reduction was similar in the three groups. These data suggest that diode laser sclerostomy is a feasible technique in rabbits, and the ab externo approach resulted in longer filter duration than the conventional posterior lip procedure in this model.

  2. Distinct Features of Cap Binding by eIF4E1b Proteins

    Science.gov (United States)

    Kubacka, Dorota; Miguel, Ricardo Núñez; Minshall, Nicola; Darzynkiewicz, Edward; Standart, Nancy; Zuberek, Joanna

    2015-01-01

    eIF4E1b, closely related to the canonical translation initiation factor 4E (eIF4E1a), cap-binding protein is highly expressed in mouse, Xenopus and zebrafish oocytes. We have previously characterized eIF4E1b as a component of the CPEB mRNP translation repressor complex along with the eIF4E-binding protein 4E-Transporter, the Xp54/DDX6 RNA helicase and additional RNA-binding proteins. eIF4E1b exhibited only very weak interactions with m7GTP-Sepharose and, rather than binding eIF4G, interacted with 4E-T. Here we undertook a detailed examination of both Xenopus and human eIF4E1b interactions with cap analogues using fluorescence titration and homology modeling. The predicted structure of eIF4E1b maintains the α + β fold characteristic of eIF4E proteins and its cap-binding pocket is similarly arranged by critical amino acids: Trp56, Trp102, Glu103, Trp166, Arg112, Arg157 and Lys162 and residues of the C-terminal loop. However, we demonstrate that eIF4E1b is 3-fold less well able to bind the cap than eIF4E1a, both proteins being highly stimulated by methylation at N7 of guanine. Moreover, eIF4E1b proteins are distinguishable from eIF4E1a by a set of conserved amino acid substitutions, several of which are located near to cap-binding residues. Indeed, eIF4E1b possesses several distinct features, namely, enhancement of cap binding by a benzyl group at N7 position of guanine, a reduced response to increasing length of the phosphate chain and increased binding to a cap separated by a linker from Sepharose, suggesting differences in the arrangement of the protein's core. In agreement, mutagenesis of the amino acids differentiating eIF4E1b from eIF4E1a reduces cap binding by eIF4E1a 2-fold, demonstrating their role in modulating cap binding. PMID:25463438

  3. BisQC: an operational pipeline for multiplexed bisulfite sequencing.

    Science.gov (United States)

    Chen, Gary G; Diallo, Alpha B; Poujol, Raphaël; Nagy, Corina; Staffa, Alfredo; Vaillancourt, Kathryn; Lutz, Pierre-Eric; Ota, Vanessa K; Mash, Deborah C; Turecki, Gustavo; Ernst, Carl

    2014-04-16

    Bisulfite sequencing is the most efficient single nucleotide resolution method for analysis of methylation status at whole genome scale, but improved quality control metrics are needed to better standardize experiments. We describe BisQC, a step-by-step method for multiplexed bisulfite-converted DNA library construction, pooling, spike-in content, and bioinformatics. We demonstrate technical improvements for library preparation and bioinformatic analyses that can be done in standard laboratories. We find that decoupling amplification of bisulfite converted (bis) DNA from the indexing reaction is an advantage, specifically in reducing total PCR cycle number and pre-selecting high quality bis-libraries. We also introduce a progressive PCR method for optimal library amplification and size-selection. At the sequencing stage, we thoroughly test the benefits of pooling non-bis DNA library with bis-libraries and find that BisSeq libraries can be pooled with a high proportion of non-bis DNA libraries with minimal impact on BisSeq output. For informatics analysis, we propose a series of optimization steps including the utilization of the mitochondrial genome as a QC standard, and we assess the validity of using duplicate reads for coverage statistics. We demonstrate several quality control checkpoints at the library preparation, pre-sequencing, post-sequencing, and post-alignment stages, which should prove useful in determining sample and processing quality. We also determine that including a significant portion of non-bisulfite converted DNA with bisulfite converted DNA has a minimal impact on usable bisulfite read output.

  4. Lymphocytes Negatively Regulate NK Cell Activity via Qa-1b following Viral Infection

    Directory of Open Access Journals (Sweden)

    Haifeng C. Xu

    2017-11-01

    Full Text Available NK cells can reduce anti-viral T cell immunity during chronic viral infections, including infection with the lymphocytic choriomeningitis virus (LCMV. However, regulating factors that maintain the equilibrium between productive T cell and NK cell immunity are poorly understood. Here, we show that a large viral load resulted in inhibition of NK cell activation, which correlated with increased expression of Qa-1b, a ligand for inhibitory NK cell receptors. Qa-1b was predominantly upregulated on B cells following LCMV infection, and this upregulation was dependent on type I interferons. Absence of Qa-1b resulted in increased NK cell-mediated regulation of anti-viral T cells following viral infection. Consequently, anti-viral T cell immunity was reduced in Qa-1b- and NKG2A-deficient mice, resulting in increased viral replication and immunopathology. NK cell depletion restored anti-viral immunity and virus control in the absence of Qa-1b. Taken together, our findings indicate that lymphocytes limit NK cell activity during viral infection in order to promote anti-viral T cell immunity.

  5. Adherence to interferon β-1b treatment in patients with multiple sclerosis in Spain.

    Directory of Open Access Journals (Sweden)

    Oscar Fernández

    Full Text Available BACKGROUND: Adherence to interferon β-1b (INFβ-1b therapy is essential to maximize the beneficial effects of treatment in multiple sclerosis (MS. For that reason, the main objectives of this study are to assess adherence to INFβ-1b in patients suffering from MS in Spain, and to identify the factors responsible for adherence in routine clinical practice. METHODOLOGY/PRINCIPAL FINDINGS: This was an observational, retrospective, cross-sectional study including 120 Spanish patients with MS under INFβ-1b treatment. Therapeutic adherence was assessed with Morisky-Green test and with the percentage of doses received. The proportion of adherent patients assessed by Morisky-Green test was 68.3%, being indicative of poor adherence. Nevertheless, the percentage of doses received, which was based on the number of injected medication, was 94.3%. The main reason for missing INFβ-1b injections was forgetting some of the administrations (64%. Therefore, interventions that diminish forgetfulness might have a positive effect in the proportion of adherent patients and in the percentage of doses received. In addition, age and comorbidities had a significant effect in the number of doses injected per month, and should be considered in the management of adherence in MS patients. CONCLUSION/SIGNIFICANCE: Among all the available methods for assessing adherence, the overall consumption of the intended dose has to be considered when addressing adherence.

  6. E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor

    Energy Technology Data Exchange (ETDEWEB)

    Turner, Roberta L. [Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Wilkinson, John C., E-mail: john.wilkinson@ndsu.edu [Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Ornelles, David A., E-mail: ornelles@wakehealth.edu [Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States)

    2014-05-15

    Adenovirus inundates the productively infected cell with linear, double-stranded DNA and an abundance of single-stranded DNA. The cellular response to this stimulus is antagonized by the adenoviral E1B and E4 early genes. A mutant group C adenovirus that fails to express the E1B-55K and E4ORF3 genes is unable to suppress the DNA-damage response. Cells infected with this double-mutant virus display significant morphological heterogeneity at late times of infection and frequently contain fragmented nuclei. Nuclear fragmentation was due to the translocation of apoptosis inducing factor (AIF) from the mitochondria into the nucleus. The release of AIF was dependent on active poly(ADP-ribose) polymerase-1 (PARP-1), which appeared to be activated by viral DNA replication. Nuclear fragmentation did not occur in AIF-deficient cells or in cells treated with a PARP-1 inhibitor. The E1B-55K or E4ORF3 proteins independently prevented nuclear fragmentation subsequent to PARP-1 activation, possibly by altering the intracellular distribution of PAR-modified proteins. - Highlights: • E1B-55K or E4orf3 prevents nuclear fragmentation. • Nuclear fragmentation requires AIF and PARP-1 activity. • Adenovirus DNA replication activates PARP-1. • E1B-55K or E4orf3 proteins alter the distribution of PAR.

  7. Hyperechogenic kidneys and polyhydramnios associated with HNF1B gene mutation.

    Science.gov (United States)

    Gondra, Leire; Décramer, Stéphane; Chalouhi, Gihad E; Muller, Françoise; Salomon, Rémi; Heidet, Laurence

    2016-10-01

    HNF1B mutation is the leading cause of isolated hyperechogenic fetal kidneys with normal or moderately large size. Although most cases have normal amniotic fluid volume, some cases present with early oligohydramnios and renal failure associated with high perinatal mortality. Here we report on seven fetuses from six unrelated families, carrying an HNF1B mutation, and presenting with polyhydramnios during the second or third trimester of pregnancy. Polyhydramnios was transitory in two cases. None of the mothers was presenting gestational diabetes. Bilateral hyperechogenic kidneys with size between -2.5 and +2 SD was the most common renal phenotype at prenatal US. Two patients were born prematurely at 28 and 32 weeks of gestation, respectively. Both presented high urine output the first days of life with urinary salt and potassium loss requiring hydro-electrolytic compensation. All mutations were large deletions removing the whole HNF1B gene. In the absence of maternal diabetes, HNF1B mutation can be associated with polyhydramnios, probably due to fetal polyuria. Thus, HNF1B mutation represents a differential diagnosis of polyhydramnios associated with hyperechogenic (and sometimes enlarged) kidneys.

  8. Association of cytochrome P450 1B1 haplotypes with head and neck cancer risk.

    Science.gov (United States)

    Katiyar, Tridiv; Maurya, Shailendra S; Hasan, Feza; Singh, Arvind P; Khan, Anwar J; Hadi, Rahat; Singh, Sudhir; Bhatt, Madan L B; Parmar, Devendra

    2017-07-01

    Genetic polymorphisms have been reported in several cytochrome P450 (CYP) genes, including CYP1B1 which metabolically activates procarcinogens present in tobacco to carcinogenic intermediates. This study used a case-control approach in North Indian population to determine associations between genetic variants in CYP1B1 and risk of Head and Neck Squamous Cell Carcinoma (HNSCC). We examined the genotype and haplotype frequencies at various single-nucleotide polymorphisms (SNPs), including SNPs previously reported in the promoter region and intron 1 of CYP1B1 in Caucasians. Using cycle sequencing, 9 SNPs were identified in the promoter region, intron 1, and exons 2 and 3. Haplotype analysis revealed that 5 SNPs (those in the promoter region, intron, and Arg48Gly and Ala119Ser in exon 2) were in strong linkage disequilibrium (LD). Cases with the T-A-T-G-T haplotype were significantly associated with increased risk of HNSCC. Interestingly, qRT-PCR studies revealed a significant increase in mRNA expression of CYP1B1 in peripheral blood isolated from cases with the T-A-T-G-T haplotype compared with cases with the C-G-C-C-G haplotype, and in cases compared to controls for both main haplotypes. The data thus provide evidence that CYP1B1 haplotypes could be more effective in predicting HNSCC risk. Environ. Mol. Mutagen. 58:443-450, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  9. Characterization of Protein Tyrosine Phosphatase 1B Inhibition by Chlorogenic Acid and Cichoric Acid.

    Science.gov (United States)

    Lipchock, James M; Hendrickson, Heidi P; Douglas, Bonnie B; Bird, Kelly E; Ginther, Patrick S; Rivalta, Ivan; Ten, Nicholas S; Batista, Victor S; Loria, J Patrick

    2017-01-10

    Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of the insulin and leptin signaling pathways and is an active target for the design of inhibitors for the treatment of type II diabetes and obesity. Recently, cichoric acid (CHA) and chlorogenic acid (CGA) were predicted by docking methods to be allosteric inhibitors that bind distal to the active site. However, using a combination of steady-state inhibition kinetics, solution nuclear magnetic resonance experiments, and molecular dynamics simulations, we show that CHA is a competitive inhibitor that binds in the active site of PTP1B. CGA, while a noncompetitive inhibitor, binds in the second aryl phosphate binding site, rather than the predicted benzfuran binding pocket. The molecular dynamics simulations of the apo enzyme and cysteine-phosphoryl intermediate states with and without bound CGA suggest CGA binding inhibits PTP1B by altering hydrogen bonding patterns at the active site. This study provides a mechanistic understanding of the allosteric inhibition of PTP1B.

  10. Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery.

    Science.gov (United States)

    Choy, Meng S; Li, Yang; Machado, Luciana E S F; Kunze, Micha B A; Connors, Christopher R; Wei, Xingyu; Lindorff-Larsen, Kresten; Page, Rebecca; Peti, Wolfgang

    2017-02-16

    Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop. Furthermore, our data show that PTP1B uses conformational and dynamic allostery to regulate its activity. This shows that both conformational rigidity and dynamics are essential for controlling protein activity. This connection between rigidity and dynamics at different timescales is likely a hallmark of all enzyme function. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. {ital Ab} {ital initio} calculations of biomolecules

    Energy Technology Data Exchange (ETDEWEB)

    Les, A. [Department of Chemistry, University of Warsaw, 02-093 Warsaw (Poland)]|[Department of Chemistry, University of Arizona, Tucson, Arizona 85721 (United States); Adamowicz, L. [Department of Theoretical Chemistry, University of Lund, Lund, S-22100 (Sweden)]|[Department of Chemistry, University of Arizona, Tucson, Arizona 85721 (United States)

    1995-08-01

    {ital Ab} {ital initio} quantum mechanical calculations are valuable tools for interpretation and elucidation of elemental processes in biochemical systems. With the {ital ab} {ital initio} approach one can calculate data that sometimes are difficult to obtain by experimental techniques. The most popular computational theoretical methods include the Hartree-Fock method as well as some lower-level variational and perturbational post-Hartree Fock approaches which allow to predict molecular structures and to calculate spectral properties. We have been involved in a number of joined theoretical and experimental studies in the past and some examples of these studies are given in this presentation. The systems chosen cover a wide variety of simple biomolecules, such as precursors of nucleic acids, double-proton transferring molecules, and simple systems involved in processes related to first stages of substrate-enzyme interactions. In particular, examples of some {ital ab} {ital initio} calculations used in the assignment of IR spectra of matrix isolated pyrimidine nucleic bases are shown. Some radiation-induced transformations in model chromophores are also presented. Lastly, we demonstrate how the {ital ab}-{ital initio} approach can be used to determine the initial several steps of the molecular mechanism of thymidylate synthase inhibition by dUMP analogues.

  12. AB INITIO STUDY, INVESTIGATION OF NMR SHIELDING ...

    African Journals Online (AJOL)

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    Ab initio study, investigation of NMR shielding tensors, NBO and vibrational frequency. Bull. Chem. Soc. Ethiop. 2010, 24(2). 231. Gas phase results. In order to study mechanism of the reactions, structure corresponding to reactants, transition states and products were optimized in level of theory. Figure 1 shows the ...

  13. Synthesis, characterization, ab initio calculations, thermal behaviour ...

    Indian Academy of Sciences (India)

    Administrator

    through titration of the ligands with the metal ions at constant ionic strength (0⋅1 M NaClO4) and at 25°C. According to the thermodynamic studies, as the steric character of the ligand increases, the complexation tendency to VO(IV) center decreases. Also, the ab initio calculations were carried out to determine the structural ...

  14. Ab Initio molecular dynamics with excited electrons

    NARCIS (Netherlands)

    Alavi, A.; Kohanoff, J.; Parrinello, M.; Frenkel, D.

    1994-01-01

    A method to do ab initio molecular dynamics suitable for metallic and electronically hot systems is described. It is based on a density functional which is costationary with the finite-temperature functional of Mermin, with state being included with possibly fractional occupation numbers.

  15. sup 1 sup 1 B nutation NMR study of powdered borosilicates

    CERN Document Server

    Woo, A J; Han, D Y

    1998-01-01

    In this work, we applied the 1D sup 1 sup 1 B nutation NMR method for the analysis of the local structural environments in powdered borosilicates (SiO sub 2 -B sub 2 O sub 3). Spin dynamics during a rf irradiation for spin I=3/2 was analytically calculated with a density matrix formalism. Spectral simulation programs were written in MATLAB on a PC. Two borosilicates prepared by the sol-gel process at different stabilization temperature were used for the 1D sup 1 sup 1 B nutation NMR experiment. The sup 1 sup 1 B NMR parameters, quadrupole coupling constants (e sup 2 qQ/h) and asymmetry parameters (eta), for each borosilicate were extracted from the nonlinear least-squares fitting. The effects of heat treatments on the local structures of boron sites in borosilicates were discussed.

  16. Pea Albumin 1 Subunit b (PA1b, a Promising Bioinsecticide of Plant Origin

    Directory of Open Access Journals (Sweden)

    Corinne Royer

    2011-12-01

    Full Text Available PA1b (Pea Albumin 1, subunit b is a peptide extract from pea seeds showing significant insecticidal activity against certain insects, such as cereal weevils (genus Sitophilus, the mosquitoes Culex pipiens and Aedes aegyptii, and certain species of aphids. PA1b has great potential for use on an industrial scale and for use in organic farming: it is extracted from a common plant; it is a peptide (and therefore suitable for transgenic applications; it can withstand many steps of extraction and purification without losing its activity; and it is present in a seed regularly consumed by humans and mammals without any known toxicity or allergenicity. The potential of this peptide to limit pest damage has stimulated research concerning its host range, its mechanism of action, its three-dimensional structure, the natural diversity of PA1b and its structure–function relationships.

  17. Deglacial meltwater pulse 1B and Younger Dryas sea levels revisited with boreholes at Tahiti.

    Science.gov (United States)

    Bard, Edouard; Hamelin, Bruno; Delanghe-Sabatier, Doriane

    2010-03-05

    Reconstructing sea-level changes during the last deglaciation provides a way of understanding the ice dynamics that can perturb large continental ice sheets. The resolution of the few sea-level records covering the critical time interval between 14,000 and 9,000 calendar years before the present is still insufficient to draw conclusions about sea-level changes associated with the Younger Dryas cold event and the meltwater pulse 1B (MWP-1B). We used the uranium-thorium method to date shallow-living corals from three new cores drilled onshore in the Tahiti barrier reef. No significant discontinuity can be detected in the sea-level rise during the MWP-1B period. The new Tahiti sea-level record shows that the sea-level rise slowed down during the Younger Dryas before accelerating again during the Holocene.

  18. Men with high serotonin 1B receptor binding respond to provocations with heightened amygdala reactivity

    DEFF Research Database (Denmark)

    da Cunha-Bang, Sofi; Fisher, Patrick M; Hjordt, Liv V

    2018-01-01

    Serotonin signalling influences amygdala reactivity to threat-related emotional facial expressions in healthy adults, but in vivo serotonin signalling has never been investigated in the context of provocative stimuli in aggressive individuals. The aim of this study was to evaluate associations...... (LV1B) modelling shared correlation between 5-HT1BR binding across multiple brain regions (neocortex, anterior and posterior cingulate cortex, raphe, amygdala, hippocampus and striatum). We tested whether the LV1B was associated with amygdala, striatal and prefrontal reactivity to provocations......, adjusting for age, injected mass and group. Across participants, LV1B was statistically significantly positively associated with amygdala (p = 0.01) but not with striatal (p = 0.2) or prefrontal reactivity to provocations (p = 0.3). These findings provide novel evidence that 5-HT1BR levels are linked...

  19. A novel CYP1B1 mutation with congenital glaucoma and total aniridia.

    Science.gov (United States)

    Alzuhairy, Sultan; Abu-Amero, Khaled K; Al-Shahwan, Sami; Edward, Deepak P

    2015-03-01

    Primary congenital glaucoma is a common disorder in the Middle East mainly caused by mutations in the the CYP1Bl gene. We report a family with three siblings that presented with recalcitrant childhood glaucoma, aniridia in two siblings with a novel CYP1B1 gene mutation. Review of pedigree, clinical history and clinical course of the family. Genetic testing in the affected family members. Three sisters presented with clinical findings of severe congenital glaucoma and a positive family history. Clinical examination of two of sisters revealed corneal scarring, bilateral aniridia with severe glaucoma that required multiple surgical procedures to control intraocular pressure. The third sibling presented with garden-variety primary congenital glaucoma. Genetic analysis revealed a novel CYP1B1 gene mutation (g.8291 C > T; p.S485F). CYP1B1 mutation related congenital glaucoma can present with an extreme form of anterior segment dysgenesis that includes recalcitrant glaucoma, corneal opacification and aniridia.

  20. Cytokines and adhesion molecules in multiple sclerosis patients treated with interferon-beta1b

    DEFF Research Database (Denmark)

    Jensen, Jakob; Krakauer, Martin; Sellebjerg, Finn

    2005-01-01

    Multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system (CNS), is thought to be caused by a T cell-mediated attack on CNS myelin and axons. Recombinant interferon (IFN)-beta is an established treatment of multiple sclerosis, and is known to reduce the number...... of disease relapses and the development of irreversible symptoms and signs of disease. The mechanism of action of IFN-beta treatment is, however, not completely understood. Previous studies have suggested major effects on mononuclear cell cytokine production and T cell migration, but results have been...... initiated on de novo treatment with IFN-beta1b. We found only minor associations between the different changes induced by IFN-beta1b-treatment. Our findings are consistent with changes in T cell expression of CD49d/VLA-4 and induction of sVCAM-1 as important effects of treatment with IFN-beta1b in multiple...

  1. Molecular dynamics simulation of the interaction between protein tyrosine phosphatase 1B and aryl diketoacid derivatives.

    Science.gov (United States)

    Wang, Qiang; Gao, Jun; Liu, Yongjun; Liu, Chengbu

    2012-09-01

    The protein tyrosine phosphatase 1B (PTP-1B) is acknowledged as an outstanding therapeutic target for the treatment of diabetes, obesity and cancer. In this work, six aryl diketoacid compounds have been studied on the basis of molecular dynamics simulations. Hydrogen bonds, binding energies and conformation changes of the WPD loop have been analyzed. The results indicated that their activation model falls into two parts: the target region of the monomeric aryl diketoacid compounds is the active site, whereas the target region of the dimeric aryl diketoacid compounds is the WPD loop or the R loop. The van der Waals interactions exhibit stronger effects than the short-range electrostatic interactions. The van der Waals interaction energy and the IC50 values exhibit an approximately exponential relationship. Furthermore, the van der Waals interactions cooperate with the hydrogen bond interactions. This study provides a more thorough understanding of the PTP-1B inhibitor binding processes. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. {3-[Bis(2-pyridylmethyl-κNamino-κN]propanol}bis(nitrato-κOcopper(II

    Directory of Open Access Journals (Sweden)

    Kil Sik Min

    2011-01-01

    Full Text Available In the title compound, [Cu(NO32(C15H19N3O], the CuII ion is coordinated by the N atoms of the tetradentate 3-[bis(2-pyridylmethylamino]propanol ligand and two O atoms from two monodentate nitrate anions, resulting in a distorted square-pyramidal environment. An intermolecular O—H...O hydrogen-bonding interaction between the free hydroxy group of the ligand and a nitrate O atom of an adjacent complex unit, gives a chain structure which extends across the (101 planes.

  3. Synthesis of the bis-spiroacetal C25-C40 moiety of the antimitotic agent spirastrellolide B using a bis-dithiane deprotection/spiroacetalisation sequence.

    Science.gov (United States)

    Chen, Jack Li-Yang; Brimble, Margaret A

    2010-06-14

    Use of a bis-dithiane deprotection-tandem bis-spiroacetalisation sequence was key to the successful synthesis of the [5,6,6]-bis-spiroacetal of the antimitotic agent spirastrellolide B, achieved in a highly convergent fashion involving successive dithiane alkylations.

  4. A review on bis-hydrazonoyl halides: Recent advances in their synthesis and their diverse synthetic applications leading to bis-heterocycles of biological interest

    Directory of Open Access Journals (Sweden)

    Ahmad Sami Shawali

    2016-11-01

    Full Text Available This review covers a summary of the literature data published on the chemistry of bis-hydrazonoyl halides over the last four decades. The biological activities of some of the bis-heterocyclic compounds obtained from these bis-hydrazonoyl halides are also reviewed and discussed.

  5. STAR and AKR1B10 are down-regulated in high-grade endometrial cancer.

    Science.gov (United States)

    Sinreih, Maša; Štupar, Saša; Čemažar, Luka; Verdenik, Ivan; Frković Grazio, Snježana; Smrkolj, Špela; Rižner, Tea Lanišnik

    2017-07-01

    Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential of STAR and AKR1B10 as

  6. Protein 4.1B contributes to the organization of peripheral myelinated axons.

    Directory of Open Access Journals (Sweden)

    Carmen Cifuentes-Diaz

    Full Text Available Neurons are characterized by extremely long axons. This exceptional cell shape is likely to depend on multiple factors including interactions between the cytoskeleton and membrane proteins. In many cell types, members of the protein 4.1 family play an important role in tethering the cortical actin-spectrin cytoskeleton to the plasma membrane. Protein 4.1B is localized in myelinated axons, enriched in paranodal and juxtaparanodal regions, and also all along the internodes, but not at nodes of Ranvier where are localized the voltage-dependent sodium channels responsible for action potential propagation. To shed light on the role of protein 4.1B in the general organization of myelinated peripheral axons, we studied 4.1B knockout mice. These mice displayed a mildly impaired gait and motility. Whereas nodes were unaffected, the distribution of Caspr/paranodin, which anchors 4.1B to the membrane, was disorganized in paranodal regions and its levels were decreased. In juxtaparanodes, the enrichment of Caspr2, which also interacts with 4.1B, and of the associated TAG-1 and Kv1.1, was absent in mutant mice, whereas their levels were unaltered. Ultrastructural abnormalities were observed both at paranodes and juxtaparanodes. Axon calibers were slightly diminished in phrenic nerves and preterminal motor axons were dysmorphic in skeletal muscle. βII spectrin enrichment was decreased along the axolemma. Electrophysiological recordings at 3 post-natal weeks showed the occurrence of spontaneous and evoked repetitive activity indicating neuronal hyperexcitability, without change in conduction velocity. Thus, our results show that in myelinated axons 4.1B contributes to the stabilization of membrane proteins at paranodes, to the clustering of juxtaparanodal proteins, and to the regulation of the internodal axon caliber.

  7. Protein 4.1B contributes to the organization of peripheral myelinated axons.

    Science.gov (United States)

    Cifuentes-Diaz, Carmen; Chareyre, Fabrice; Garcia, Marta; Devaux, Jérôme; Carnaud, Michèle; Levasseur, Grégoire; Niwa-Kawakita, Michiko; Harroch, Sheila; Girault, Jean-Antoine; Giovannini, Marco; Goutebroze, Laurence

    2011-01-01

    Neurons are characterized by extremely long axons. This exceptional cell shape is likely to depend on multiple factors including interactions between the cytoskeleton and membrane proteins. In many cell types, members of the protein 4.1 family play an important role in tethering the cortical actin-spectrin cytoskeleton to the plasma membrane. Protein 4.1B is localized in myelinated axons, enriched in paranodal and juxtaparanodal regions, and also all along the internodes, but not at nodes of Ranvier where are localized the voltage-dependent sodium channels responsible for action potential propagation. To shed light on the role of protein 4.1B in the general organization of myelinated peripheral axons, we studied 4.1B knockout mice. These mice displayed a mildly impaired gait and motility. Whereas nodes were unaffected, the distribution of Caspr/paranodin, which anchors 4.1B to the membrane, was disorganized in paranodal regions and its levels were decreased. In juxtaparanodes, the enrichment of Caspr2, which also interacts with 4.1B, and of the associated TAG-1 and Kv1.1, was absent in mutant mice, whereas their levels were unaltered. Ultrastructural abnormalities were observed both at paranodes and juxtaparanodes. Axon calibers were slightly diminished in phrenic nerves and preterminal motor axons were dysmorphic in skeletal muscle. βII spectrin enrichment was decreased along the axolemma. Electrophysiological recordings at 3 post-natal weeks showed the occurrence of spontaneous and evoked repetitive activity indicating neuronal hyperexcitability, without change in conduction velocity. Thus, our results show that in myelinated axons 4.1B contributes to the stabilization of membrane proteins at paranodes, to the clustering of juxtaparanodal proteins, and to the regulation of the internodal axon caliber.

  8. The Xenograft Antigen Bound to Griffonia simplicifolia Lectin 1-B4

    Science.gov (United States)

    Tempel, Wolfram; Tschampel, Sarah; Woods, Robert J.

    2006-01-01

    The shortage of organs for transplantation into human patients continues to be a driving force behind research into the use of tissues from non-human donors, particularly pig. The primary barrier to such xenotrans-plantation is the reaction between natural antibodies present in humans and Old World monkeys and the Galα(1–3)Gal epitope (xenograft antigen, xenoantigen) found on the cell surfaces of the donor organ. This hyperacute immune response leads ultimately to graft rejection. Because of its high specificity for the xenograft antigen, isolectin 1-B4 from Griffonia simplicifolia (GS-1-B4) has been used as an immunodiagnostic reagent. Furthermore, haptens that inhibit natural antibodies also inhibit GS-1-B4 from binding to the xenoantigen. Here we report the first x-ray crystal structure of the xenograft antigen bound to a protein (GS-1-B4). The three-dimensional structure was determined from orthorhombic crystals at a resolution of 2.3 Å. To probe the influence of binding on ligand properties, we report also the results of molecular dynamics (MD) simulations on this complex as well as on the free ligand. The MD simulations were performed with the AMBER force-field for proteins augmented with the GLYCAM parameters for glycosides and glycoproteins. The simulations were performed for up to 10 ns in the presence of explicit solvent. Through comparison with MD simulations performed for the free ligand, it has been determined that GS-1-B4 recognizes the lowest energy conformation of the disaccharide. In addition, the x-ray and modeling data provide clear explanations for the reported specificities of the GS-1-B4 lectin. It is anticipated that a further under-standing of the interactions involving the xenograft antigen will help in the development of therapeutic agents for application in the prevention of hyperacute xenograft rejection. PMID:11714721

  9. Alcohol dehydrogenase 1B and Aldehyde dehydrogenase 2 Polymorphisms in Uzbekistan.

    Science.gov (United States)

    Ahn, Keun Soo; Abdiev, Shavkat; Rahimov, Bakhodir; Malikov, Yusuf; Bahramov, Saidkarim; Okada, Rieko; Naito, Mariko; Hamajima, Nobuyuki

    2009-01-01

    The alcohol dehydrogenase 1B (ADH1B) -2 (47His) allele and the aldehyde dehydrogenase 2 (ALDH2) - 2 (487Lys) alleles are seen among some Asian peoples, but rare among other ethnic groups. This study examined the allele frequencies in the Uzbekistan Republic, which is located in Central Asia. Subjects were derived from a case-control study on peptic ulcer disease, which included 161 Uzbeks and 23 Russians. They were enrolled at the Republic Research Center of Emergency Medicine located in the capital, Tashkent City. Genotyping was performed for ADH1B Arg47His and ALDH2 Glu487Lys with a polymerase chain reaction using confronting two-pair primers. The frequency for the ADH1B- 2 allele was similar among cases and controls. The ALDH2 -2 allele was rare in both. Among 161 Uzbeks, the ADH1B -2 allele frequency was 0.286 (95% confidence interval, 0.237-0.338) and for the ALDH2 -2 allele was 0.016 (0.005-0.036), while among the 23 Russians the figures were 0.083 (0.024-0.208) and 0.000 (0.000-0.077), respectively. There were no significant differences in drinking habits among individuals with different genotypes, although the ALDH2 -2-2 genotype was not observed. The present study demonstrated that the ADH1B -2 allele frequency among Uzbeks was closer to that among Caucasians than East Asians, some Uzbeks also demonstrating the ALDH2 -2 allele.

  10. 5-HT(1B) receptors, ventral orbitofrontal cortex, and aggressive behavior in mice.

    Science.gov (United States)

    De Almeida, R M M; Rosa, M M; Santos, D M; Saft, D M; Benini, Q; Miczek, K A

    2006-05-01

    Systemic injections of 5-HT(1B) receptor agonists have been shown to have specific anti-aggressive effects in aggressive individuals. One site of action for these drugs is the 5-HT(1B) receptors in the ventral orbitofrontal cortex (VO PFC), an area that has been implicated in the inhibitory control of behavior and is a terminal region for 5-HT projections. To assess the anti-aggressive effects of the 5-HT(1B) receptor agonist CP-94,253 when microinjected into the VO PFC (0.1, 0.56, and 1.0 microg/0.2 microl) or into the infralimbic prefrontal cortex (IL PFC; 1.0 microg/0.2 microl) in separate groups of aggressive resident male mice. To confirm the 5-HT(1B) receptor as the critical site of action for the anti-aggressive effects, the 5-HT(1B/D) antagonist GR-127,935 was microinjected at 10.0 microg/0.2 microl into the VO PFC. After recovery from surgery, the anti-aggressive effects of microinjected CP-94,253 were studied during 5-min resident-intruder confrontations that were recorded and analyzed. Microinjections of CP-94,253 (0.56 and 1.0 microg/0.2 microl) dose-dependently reduced the frequency of attack bites and sideways threats. This effect was behaviorally specific because non-aggressive motor activities were not significantly altered by the drug. In the IL vmPFC or in an area lateral to the VO PFC, CP-94,253 (1.0 microg/0.2 microl) did not have significant behavioral effects. The results highlight the 5-HT(1B) receptors in the VO PFC as a particularly important site for the inhibition of species-typical aggressive behavior in male mice.

  11. Subcellular localization and internalization of the vasopressin V1B receptor.

    Science.gov (United States)

    Kashiwazaki, Aki; Fujiwara, Yoko; Tsuchiya, Hiroyoshi; Sakai, Nobuya; Shibata, Katsushi; Koshimizu, Taka-aki

    2015-10-15

    Only limited information is available on agonist-dependent changes in the subcellular localization of vasopressin V1B receptors. Our radioligand binding study of membrane preparations and intact cells revealed that a large fraction of the V1B receptor is located in the cytoplasm in unstimulated CHO cells, which is in contrast to the plasma membrane localization of the V1A and V2 receptors. Moreover, when the affinity of radiolabeled arginine-vasopressin ([3H]AVP) was compared between membrane preparations and intact cells, the affinity of [3H]AVP to the cell surface V1B receptors, but not the V1A receptors, was significantly reduced. Although the number and affinity of cell surface V1B receptors decreased, they became extensively internalized upon binding with [3H]AVP. Approximately 87% of cell surface-bound [3H]AVP was internalized and became resistant to acid wash during incubation with 1 nM [3H]AVP. By contrast, less ligand (35%) was internalized in the cells expressing the V1A receptor. Extensive internalization of the V1B receptors was partially attenuated by inhibitors of cytoskeletal proteins, siRNA against β-arrestin 2, or the removal of sodium chloride from the extracellular buffer, indicating that this internalization involves clathrin-coated pits. Together, these results indicate that the mechanism that regulates the number and affinity of V1B receptors in the plasma membrane is markedly distinct from the corresponding mechanisms for the V1A and V2 receptors and plays a critical role under stress conditions, when vasopressin release is augmented. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Safety assessment of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics.

    Science.gov (United States)

    Fiume, Monice M; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2013-01-01

    The Cosmetic Ingredient Review Expert Panel assessed the safety of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics, finding that these ingredients are safe in cosmetic formulations in the present practices of use and concentration. Both ingredients are lanolin substitutes and are reported to function in cosmetics as skin-conditioning agents--emollients. The Panel reviewed available animal and clinical data in making its determination of safety.

  13. Anthrax lethal toxin induced lysosomal membrane permeabilization and cytosolic cathepsin release is Nlrp1b/Nalp1b-dependent.

    Directory of Open Access Journals (Sweden)

    Kathleen M Averette

    2009-11-01

    Full Text Available NOD-like receptors (NLRs are a group of cytoplasmic molecules that recognize microbial invasion or 'danger signals'. Activation of NLRs can induce rapid caspase-1 dependent cell death termed pyroptosis, or a caspase-1 independent cell death termed pyronecrosis. Bacillus anthracis lethal toxin (LT, is recognized by a subset of alleles of the NLR protein Nlrp1b, resulting in pyroptotic cell death of macrophages and dendritic cells. Here we show that LT induces lysosomal membrane permeabilization (LMP. The presentation of LMP requires expression of an LT-responsive allele of Nlrp1b, and is blocked by proteasome inhibitors and heat shock, both of which prevent LT-mediated pyroptosis. Further the lysosomal protease cathepsin B is released into the cell cytosol and cathepsin inhibitors block LT-mediated cell death. These data reveal a role for lysosomal membrane permeabilization in the cellular response to bacterial pathogens and demonstrate a shared requirement for cytosolic relocalization of cathepsins in pyroptosis and pyronecrosis.

  14. Enzymes of the AKR1B and AKR1C subfamilies and uterine diseases

    Directory of Open Access Journals (Sweden)

    Tea eLanisnik Rizner

    2012-03-01

    Full Text Available Endometrial and cervical cancers, uterine myoma, and endometriosis are very common uterine diseases. Worldwide, more than 800,000 women are affected annually by gynecological cancers, as a result of which, more than 360,000 die. During their reproductive age, about 70% of women develop uterine myomas, 10% to 15% suffer from endometriosis, and 35% to 50% from infertility associated with endometriosis. Uterine diseases are associated with aberrant inflammatory responses and concomitant increased production of prostaglandins (PG. They are also related to decreased differentiation, due to low levels of protective progesterone and retinoic acid, and to enhanced proliferation, due to high local concentrations of estrogens. The pathogenesis of these diseases can thus be attributed to disturbed PG, estrogen and retinoid metabolism and actions. Five human members of the aldo-keto reductase 1B (AKR1B and 1C (AKR1C superfamilies, i.e., AKR1B1, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, have roles in these processes and can thus be implicated in uterine diseases. AKR1B1 and AKR1C3 catalyze the formation of PGF2alpha which stimulates cell proliferation. AKR1C3 converts PGD2 to 9alpha,11beta-PGF2, and thus counteracts the formation of 15deoxy-PGJ2, which can activate pro-apoptotic peroxisome-proliferator-activated receptor beta. AKR1B10 catalyzes the reduction of retinal to retinol, and in thus lessens the formation of retinoic acid, with potential pro-differentiating actions. The AKR1C1-AKR1C3 enzymes also act as 17-keto- and 20-ketosteroid reductases to varying extents, and are implicated in increased estradiol and decreased progesterone levels. This review comprises a short introduction to uterine diseases, followed by an overview of the current literature on the AKR1B and AKR1C expression in the uterus and in uterine diseases. The potential implications of the AKR1B and AKR1C enzymes and their pathophysiologies are then discussed, followed by conclusions and

  15. Minimal gauged U(1) B-L model with spontaneous R parity violation.

    Science.gov (United States)

    Barger, Vernon; Pérez, Pavel Fileviez; Spinner, Sogee

    2009-05-08

    We study the minimal gauged U(1) B-L supersymmetric model and show that it provides an attractive theory for spontaneous R-parity violation. Both U(1) B-L and R parity are broken by the vacuum expectation value of the right-handed sneutrino (proportional to the soft supersymmetry masses), thereby linking the B-L and soft SUSY scales. In this context we find a consistent mechanism for generating neutrino masses and a realistic mass spectrum, all without extending the Higgs sector of the minimal supersymmetry standard model. We discuss the most relevant collider signals and the connection between the Z' gauge boson and R-parity violation.

  16. Screening selected Vietnamese plants used to treat diabetes for PTP1B inhibitory activity

    DEFF Research Database (Denmark)

    Trinh, Thi Dieu Binh; Staerk, D; Jäger, A K

    2016-01-01

    Type-2 diabetes is affecting 246 million people worldwide [1]. Patients with type-2 diabetes suffer from complications such as high blood pressure, blindness, kidney failure, lower limb amputation, heart disease and stroke. In this study, 18 medicinal plants traditionally used in Vietnam...... for treatment of diabetes were investigated for inhibition of human recombinant protein-tyrosine phosphatase 1B enzyme (PTP1B) based on a recently developed microplate-based assay [2]. This enzyme is a key negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic...

  17. Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

    DEFF Research Database (Denmark)

    Fork, Christian; Gu, Lunda; Hitzel, Juliane

    2015-01-01

    OBJECTIVE: Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. APPROACH AND RESULTS...... outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C...

  18. Coexistence of ferromagnetism and superconductivity in CeO_{0.3}F_{0.7}BiS_{2}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jooseop [ORNL; Demura, S [National Institute for Materials Science, Tsukuba, Japan; Stone, Matthew B [ORNL; Iida, Kazuki [ORNL; Ehlers, Georg [ORNL; Dela Cruz, Clarina R [ORNL; Matsuda, Masaaki [ORNL; Deguchi, K [National Institute for Materials Science, Tsukuba, Japan; Mizuguchi, Y [National Institute for Materials Science, Tsukuba, Japan; Miura, O [Tokyo Metropolican University; Louca, Despina [University of Virginia; Lee, Seung-Hun [ORNL

    2014-01-01

    Bulk magnetization, transport and neutron scattering measurements were performed to investigate the electronic and magnetic properties of a polycrystalline sample of the newly discovered ferromagnetic superconductor, CeO0:3F0:7BiS2. Ferromagnetism develops below TFM = 6.54(8) K and superconductivity is found to coexist with the ferromagnetic state below TSC 4.5 K. Inelastic neutron scattering measurements reveal a very weakly dispersive magnetic excitation at 1.8 meV that can be explained by an Ising-like spin Hamiltonian. Under application of an external magnetic eld, the direction of the magnetic moment changes from the c-axis to the ab-plane and the 1.8 meV excitation splits into two modes. A possible mechanism for the unusual magnetism and its relation to superconductivity is discussed.

  19. Crystal Structure of Ruthenium Phthalocyanine with Diaxial Monoatomic Ligand: Bis(TriphenylphosphineIminium Dichloro(Phthalocyaninato(2-Ruthenium(III

    Directory of Open Access Journals (Sweden)

    Derrick Ethelbhert Yu

    2013-01-01

    Full Text Available Axially-ligated iron phthalocyanines have been found to be good molecular conductors with giant negative magnetoresistance (GNMR which originates from a strong intramolecular π-d interaction between the metal and phthalocyanine. Ab initio theoretical calculations showed that substitution of ruthenium into the phthalocyanine complex would result in a significant increase in the π-d interaction of the system, potentially intensifying GNMR. This paper presents the crystal preparation and X-ray structural characterization of bis(triphenylphosphineiminium dichloro(phthalocyaninato(2-ruthenium(III, PNP [RuIII(Pc2−Cl2]. It is observed that [RuIII(Pc2−Cl2] system has a symmetric planar RuPc unit with perpendicular axial ligands which results in a unidirectional and uniform solid-state arrangement, suitable for π-d interaction-based molecular conductors with potentially exceptional GNMR.

  20. Upper critical magnetic field of LnO{}_{0.5}F{}_{0.5}BiS2 (Ln = La, Nd) superconductors at ambient and high pressure

    Science.gov (United States)

    Fang, Y.; Wolowiec, C. T.; Breindel, A. J.; Yazici, D.; Ho, P.-C.; Maple, M. B.

    2017-11-01

    The upper critical fields H c2 of polycrystalline samples of LnO{}0.5F{}0.5BiS2 (Ln = La, Nd) at ambient pressure (tetragonal structure) and high pressure (HP) (monoclinic structure) have been investigated via electrical resistivity measurements at various magnetic fields up to 8.5 T. The H c2(T) curves for all the samples show an uncharacteristic concave upward curvature at temperatures below T c , which cannot be described by the conventional one-band Werthamer-Helfand-Hohenberg theory. For the LaO{}0.5F{}0.5BiS2 sample under HP, as temperature is decreased, the upper critical field H onset, estimated from the onset of the superconducting transitions, increases slowly between 4.9 and 5.8 T compared with the slope of H onset(T) below 4.9 T and above 5.8 T. This anomalous behavior reveals a remarkable similarity in superconductivity between LaO{}0.5F{}0.5BiS2 samples measured under HP and synthesized under HP, although the crystal structures of the two samples were reported to be different. A reasonable explanation is that local atomic environment, which can be tuned by applying external pressure, is essential to the enhancement of T c for BiS2-based superconductors. On the other hand, such anomalous behavior is very subtle in the case of NdO{}0.5F{}0.5BiS2 under HP, suggesting that the anisotropy of the upper critical field in the ab-plane and the possible lattice deformation induced by external pressure is weak. This explains why the pressure-induced enhancement of T c for NdO{}0.5F{}0.5BiS2 is not as large as that for LaO{}0.5F{}0.5BiS2.

  1. o-Nitroaryl-bis(5-methylfur-2-ylmethanes as Versatile Synthons for the Synthesis of Nitrogen-Containing Heterocycles

    Directory of Open Access Journals (Sweden)

    Andrey V. Gutnov

    1997-04-01

    Full Text Available 2-Nitroaryldifurylmethanes 1a and 1b, readily available by condensation of 2-nitrobenzaldehyde and 6-nitroveratraldehyde with 2-methylfuran, were transformed into indole, cinnoline and benzothiazine-3,1 derivatives. The reduction of 2-nitroaryldifurylmethanes gave the corresponding anilines 2a,b or indole 3 depending on the reaction conditions. A plausible mechanism for the last reaction involving intramolecular heterocyclic addition between a nitroso-group and a furan ring is proposed. Diazotisation of the amine 2b gave a cinnoline derivative - a product of intramolecular oxidative furan ring opening. Treatment of isothiocyanates 7a,b with perchloric acid resulted in a new rearrangement with furan ring migration leading to the 4-Hbenzothiazine-3,1 derivatives.

  2. Involvement of endocrine system in a patient affected by glycogen storage disease 1b: speculation on the role of autoimmunity.

    Science.gov (United States)

    Melis, Daniela; Della Casa, Roberto; Balivo, Francesca; Minopoli, Giorgia; Rossi, Alessandro; Salerno, Mariacarolina; Andria, Generoso; Parenti, Giancarlo

    2014-03-19

    Glycogen storage disease type 1b (GSD1b) is an inherited metabolic defect of glycogenolysis and gluconeogenesis due to mutations of the SLC37A4 gene and to defective transport of glucose-6-phosphate. The clinical presentation of GSD1b is characterized by hepatomegaly, failure to thrive, fasting hypoglycemia, and dyslipidemia. Patients affected by GSD1b also show neutropenia and/or neutrophil dysfunction that cause increased susceptibility to recurrent bacterial infections. GSD1b patients are also at risk for inflammatory bowel disease. Occasional reports suggesting an increased risk of autoimmune disorders in GSD1b patients, have been published. These complications affect the clinical outcome of the patients. Here we describe the occurrence of autoimmune endocrine disorders including thyroiditis and growth hormone deficiency, in a patient affected by GSD1b. This case further supports the association between GSD1b and autoimmune diseases.

  3. IceBridge Geometrics 823A Cesium Magnetometer L1B Time-Tagged Magnetic Field, Version 1

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA IceBridge Geometrics 823A Cesium Magnetometer L1B Time-Tagged Magnetic Field (IMGEO1B) data set contains magnetic field strength measurements taken over...

  4. SAGE III Meteor-3M L1B Solar Event Transmission Data (HDF-EOS) V004

    Data.gov (United States)

    National Aeronautics and Space Administration — SAGE III Meteor-3M L1B Solar Event Transmission Data are Level 1B pixel group transmission profiles for a single solar event. The Stratospheric Aerosol and Gas...

  5. Discovery and evaluation of the hybrid of bromophenol and saccharide as potent and selective protein tyrosine phosphatase 1B inhibitors.

    Science.gov (United States)

    Zhang, Renshuai; Yu, Rilei; Xu, Qi; Li, Xiangqian; Luo, Jiao; Jiang, Bo; Wang, Lijun; Guo, Shuju; Wu, Ning; Shi, Dayong

    2017-07-07

    Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway. Inhibition of PTP1B is expected to improve insulin action. Appropriate selectivity and permeability are the gold standard for excellent PTP1B inhibitors. In this work, molecular hybridization-based screening identified a selective competitive PTP1B inhibitor. Compound 10a has IC50 values of 199 nM against PTP1B, and shows 32-fold selectivity for PTP1B over the closely related phosphatase TCPTP. Molecule docking and molecular dynamics studies reveal the reason of selectivity for PTP1B over TCPTP. Moreover, the cell permeability and cellular activity of compound 10a are demonstrated respectively. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Iliopsoas abscess as a complication of glycogen storage disease 1b

    Directory of Open Access Journals (Sweden)

    Marcos Prada-Arias

    2017-01-01

    Full Text Available We present a case of iliopsoas abscess secondary to inflammatory bowel disease associated to glycogen storage disease 1b in a 12-year-old boy. To the best of our knowledge, a similar case has not been reported in medical literature.

  7. Data of evolutionary structure change: 1AIRA-2QY1B [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AIRA-2QY1B 1AIR 2QY1 A B ATDTGGYAA-TAGGNVTGAVSKTATSMQDIVNIIDAARLDANGKKVKGGAYPLVIT...1AIR A 1AIRA SSSDT---GRNIT...1AIR A 1AIRA STGTF-PTVAY ...1AIR A 1AIRA IKEFTKGITII ...1AIR A 1AIRA CDGTPDNDTTFE

  8. Fragile X mental retardation protein interactions with the microtubule associated protein 1B RNA.

    Science.gov (United States)

    Menon, Lakshmi; Mader, Samantha Ann; Mihailescu, Mihaela-Rita

    2008-08-01

    Fragile X mental retardation syndrome, the most common form of inherited mental retardation, is caused by the absence of the fragile X mental retardation protein (FMRP). FMRP has been shown to use its arginine-glycine-glycine (RGG) box to bind to a subset of RNA targets that form a G quadruplex structure. We performed a detailed analysis of the interactions between the FMRP RGG box and the microtubule associated protein 1B (MAP1B) mRNA, a relevant in vivo FMRP target. We show that MAP1B RNA forms an intramolecular G quadruplex structure, which is bound with high affinity and specificity by the FMRP RGG box. We determined that hydrophobic interactions are important in the FMRP RGG box-MAP1B RNA association, with minor contributions from electrostatic interactions. Our findings that at low protein:RNA ratios the RNA G quadruplex structure is slightly stabilized, whereas at high ratios is unfolded, suggest a mechanism by which the FMRP concentration variation in response to a neurotransmitter stimulation event could act as a regulatory switch for the protein function, from translation repressor to translation activator.

  9. Data Bank 1B - Ticket Dollar Value Origin and Destination - Public Version : second quarter.

    Science.gov (United States)

    2012-01-01

    This CD presents the same data as Data Bank 1B and also includes dual codes for the operating and ticketed carrier and incorporates data as reported each quarter by participating air carriers from the continuous 10% sample of airline tickets. It incl...

  10. Data Bank 1B - Ticket Dollar Value Origin and Destination - Public Version : third quarter.

    Science.gov (United States)

    2010-01-01

    This CD presents the same data as Data Bank 1B and also includes dual codes for the operating and ticketed carrier and incorporates data as reported each quarter by participating air carriers from the continuous 10% sample of airline tickets. It incl...

  11. Data Bank 1B - Ticket Dollar Value Origin and Destination - Public Version : first quarter.

    Science.gov (United States)

    2014-01-01

    This CD presents the same data as Data Bank 1B and also includes dual codes for the operating and ticketed carrier and incorporates data as reported each quarter by participating air carriers from the continuous 10% sample of airline tickets. It incl...

  12. Data Bank 1B - Ticket Dollar Value Origin and Destination - Public Version : fourth quarter.

    Science.gov (United States)

    2010-01-01

    This CD presents the same data as Data Bank 1B and also includes dual codes for the operating and ticketed carrier and incorporates data as reported each quarter by participating air carriers from the continuous 10% sample of airline tickets. It incl...

  13. Human CRISP-3 binds serum alpha(1)B-glycoprotein across species

    DEFF Research Database (Denmark)

    Udby, Lene; Johnsen, Anders H; Borregaard, Niels

    2010-01-01

    CRISP-3 was previously shown to be bound to alpha(1)B-glycoprotein (A1BG) in human serum/plasma. All mammalian sera are supposed to contain A1BG, although its presence in rodent sera is not well-documented. Since animal sera are often used to supplement buffers in experiments, in particular...

  14. Data of evolutionary structure change: 1ASMA-2AY1B [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1ASMA-2AY1B 1ASM 2AY1 A B MFENITAAPADPILGLADLFRADERPGKINLGIGVYKDE...H HHHHHHHH EEEE EEEEEGG HHHHHHHHHHHHH 0 1ASM... A 1ASMA DFSFI---I... THR CA 475 LEU CA 494 1ASM A 1ASMA GSALINDKRARTA

  15. PTP1B triggers integrin-mediated repression of myosin activity and modulates cell contractility

    Directory of Open Access Journals (Sweden)

    Ana E. González Wusener

    2016-01-01

    Full Text Available Cell contractility and migration by integrins depends on precise regulation of protein tyrosine kinase and Rho-family GTPase activities in specific spatiotemporal patterns. Here we show that protein tyrosine phosphatase PTP1B cooperates with β3 integrin to activate the Src/FAK signalling pathway which represses RhoA-myosin-dependent contractility. Using PTP1B null (KO cells and PTP1B reconstituted (WT cells, we determined that some early steps following cell adhesion to fibronectin and vitronectin occurred robustly in WT cells, including aggregation of β3 integrins and adaptor proteins, and activation of Src/FAK-dependent signalling at small puncta in a lamellipodium. However, these events were significantly impaired in KO cells. We established that cytoskeletal strain and cell contractility was highly enhanced at the periphery of KO cells compared to WT cells. Inhibition of the Src/FAK signalling pathway or expression of constitutive active RhoA in WT cells induced a KO cell phenotype. Conversely, expression of constitutive active Src or myosin inhibition in KO cells restored the WT phenotype. We propose that this novel function of PTP1B stimulates permissive conditions for adhesion and lamellipodium assembly at the protruding edge during cell spreading and migration.

  16. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia

    NARCIS (Netherlands)

    Georgitsi, Marianthi; Raitila, Anniina; Karhu, Auli; van der Luijt, Rob B.; Aalfs, Cora M.; Sane, Timo; Vierimaa, Outi; Mäkinen, Markus J.; Tuppurainen, Karoliina; Paschke, Ralph; Gimm, Oliver; Koch, Christian A.; Gündogdu, Sadi; Lucassen, Anneke; Tischkowitz, Marc; Izatt, Louise; Aylwin, Simon; Bano, Gul; Hodgson, Shirley; de Menis, Ernesto; Launonen, Virpi; Vahteristo, Pia; Aaltonen, Lauri A.

    2007-01-01

    Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two

  17. Pharmacological characterization of the cloned kappa opioid receptor as a kappa 1b subtype.

    Science.gov (United States)

    Lai, J; Ma, S W; Zhu, R H; Rothman, R B; Lentes, K U; Porreca, F

    1994-10-27

    Substantial pharmacological evidence in vitro and in vivo has suggested the existence of subtypes of the kappa opioid receptor. Quantitative radioligand binding techniques resolved the presence of two high affinity binding sites for the kappa 1 ligand [3H]U69,593 in mouse brain membranes, termed kappa 1a and kappa 1b, respectively. Whereas the kappa 1a site has high affinity for fedotozine and oxymorphindole and low affinity for bremazocine and alpha-neoendorphin, site kappa 1b has high affinity for bremazocine and alpha-neoendorphin and low affinity for fedotozine and oxymorphindole. CI-977 and U69,593 bind equally well at both sites. To determine the relationship between these kappa 1 receptor subtypes and the recently cloned mouse kappa 1 receptor (KOR), we examined [3H]U69,593 binding to the KOR in stably transfected cells (KORCHN-8). Competition of [3H]U69,593 binding to the KOR by bremazocine, alpha-neoendorphin, fedotozine and oxymorphindole resolved a single class of binding sites at which these agents had binding affinities similar to that of the kappa 1b site present in mouse brain. These results suggest that the cloned KOR corresponds to the kappa 1 site in mouse brain defined as kappa 1b.

  18. Mirror Advanced Reactor Study (MARS). Final report. Volume 1-B. Commercial fusion electric plant

    Energy Technology Data Exchange (ETDEWEB)

    Donohue, M.L.; Price, M.E. (eds.)

    1984-07-01

    Volume 1-B contains the following chapters: (1) blanket and reflector; (2) central cell shield; (3) central cell structure; (4) heat transport and energy conversion; (5) tritium systems; (6) cryogenics; (7) maintenance; (8) safety; (9) radioactivity, activation, and waste disposal; (10) instrumentation and control; (11) balance of plant; (12) plant startup and operation; (13) plant availability; (14) plant construction; and (15) economic analysis.

  19. 10522 ASSESSMENT OF AFLATOXINS B1, B2, G1 AND G2 ...

    African Journals Online (AJOL)

    user

    2013-04-13

    Apr 13, 2013 ... Aflatoxins belong to a group of naturally occurring toxins which contaminate foodstuffs under favourable conditions. Aspergillus flavus and Aspergillus parasiticus produce aflatoxins; the four major aflatoxins which contaminate foodstuffs are B1, B2,. G1 and G2. Maize, groundnuts, rice, wheat and other ...

  20. Data of evolutionary structure change: 1B06E-2CDYD [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available nce>QIMGQ--GQANQ >H -- > ATOM 55...Chain>E 1B06E NNMAPAGKGGGK re>H ...IDChain>2CDYD LVVKD--GKLDV ture...>EEEE -- EEEE> ATOM 5896 CA LEU D 136 10.194 35.852 6.892 1.0...IDChain> LYYDNESGNLQI >E EE>

  1. A complex selection signature at the human AVPR1B gene.

    Science.gov (United States)

    Cagliani, Rachele; Fumagalli, Matteo; Pozzoli, Uberto; Riva, Stefania; Cereda, Matteo; Comi, Giacomo P; Pattini, Linda; Bresolin, Nereo; Sironi, Manuela

    2009-06-01

    The vasopressin receptor type 1b (AVPR1B) is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses. Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg) in this region has been subjected to directional selection. Although the underlying selective pressure(s) remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution.

  2. Comparative docking studies of CYP1b1 and its PCG-associated ...

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    to be involved in the metabolism of the endogenous steroid oestradiol (E2), the metabolites of which have ... Further, hydroxylation of E2 is considered to be the characteristic reaction catalysed by CYP1b1 (Murray et ..... of side-chains of aromatic amino acids, which stack with the ligand molecules. The hydrophobic nature of ...

  3. A complex selection signature at the human AVPR1B gene

    Directory of Open Access Journals (Sweden)

    Cagliani Rachele

    2009-06-01

    Full Text Available Abstract Background The vasopressin receptor type 1b (AVPR1B is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses. Results Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg in this region has been subjected to directional selection. Conclusion Although the underlying selective pressure(s remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution.

  4. miR-200b mediates post-transcriptional repression of ZFHX1B

    DEFF Research Database (Denmark)

    Christoffersen, Nanna Rønbjerg; Silahtaroglu, Asli; Ørom, Ulf Lupo Andersson

    2007-01-01

    MicroRNAs have important functions during animal development and homeostasis through post-transcriptional regulation of their cognate mRNA targets. ZFHX1B is a transcriptional repressor involved in the TGFbeta signaling pathway and in processes of epithelial to mesenchymal transition via regulation...

  5. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 500m V005

    Data.gov (United States)

    National Aeronautics and Space Administration — The 500 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 7 discrete bands located in the 0.45 to 2.20 micron region of the...

  6. [From gene to disease; the nail-patella syndrome and the LMX1B gene

    NARCIS (Netherlands)

    Bongers, M.H.F.; Knoers, N.V.A.M.

    2003-01-01

    Nail-patella syndrome (NPS) is an autosomal dominant hereditary disorder characterised by nail dysplasia, patellar apoplasia/hypoplasia, iliac horns, elbow dysplasia, and frequently primary open angle glaucoma and progressive nephropathy. The gene underlying NPS, LMX1B on chromosome 9q34.1, is a

  7. A case of neonatal HPA-1b allo-immune thrombocytopenia

    NARCIS (Netherlands)

    van der Vlugt, AH; Hepkema, BG; Tamminga, RYJ

    1999-01-01

    We present a case of a newborn with neonatal alloimmune thrombocytopenia (NAIT) due to fete-maternal incompatibility for the thrombocyte allo-antigen HPA-1b. We discuss the policy of platelet transfusions and suggest to treat NAIT early on with thrombocytes transfusions from selected compatible

  8. Tissue-specific alternative splicing and expression of ATP1B2 gene ...

    African Journals Online (AJOL)

    The Na+-K+-ATPase is an essential transport enzyme expressed in all animal tissues, where it generates ion gradients to maintain membrane potential and drive the transport of other solutes. It also balances metabolism and body temperature. In this study, the characterization of three novel bovine ATP1B2 splice variants, ...

  9. Radical (Wertheim) hysterectomy for early stages (1B and 2A ...

    African Journals Online (AJOL)

    A review of cases of early stages (1B & 2A) cancer of the cervix, managed by radical hysterectomy at Olabisi Onabanjo University Teaching Hospital Sagamu Nigeria between 1997 and 2004 was carried out to appraise the outcome in terms of the success and safety of the operation. Seventeen cases were so treated, and ...

  10. Determining the frequencies of B1, B2, B3 and E alleles of the ...

    African Journals Online (AJOL)

    The aim of the study was to determine the frequencies of B1, B2, B3 and E alleles of the CSN1S1 gene and their effects on milk yield and composition in the Saanen goat breed. Milk samples were collected to identify milk composition with Fourier transform ınfrared (FTIR) spectroscopy. The polymerase chain ...

  11. 76 FR 54143 - Airworthiness Directives; Turbomeca Arriel 1B Turboshaft Engines

    Science.gov (United States)

    2011-08-31

    ... Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of proposed rulemaking...-TU 148 standard Arriel 1B engines. This non compliance may only be found on post-TU 76 standard 2nd... damage of the gas generator turbine, which could result in an uncommanded in-flight engine shutdown, and...

  12. PEGylation of proteins in organic solution: a case study for interferon beta-1b.

    Science.gov (United States)

    Peng, Fei; Wang, Yinjue; Sun, Lijing; Liu, Yongdong; Hu, Tao; Zhang, Guifeng; Ma, Guanghui; Su, Zhiguo

    2012-09-19

    Conventional protein PEGylation is carried out in aqueous solution. However, some hydrophobic proteins seem to be stable in organic solution. In this study, a novel approach of PEGylating IFN-β-1b in an organic solution of 2-butanol (2-BuOH) was investigated. Compared with protein PEGylation in aqueous solution, the overall modification yields increased more than 37%, while the yield of mono-PEGylated products could be increased by 36%. Furthermore, the PEGylated IFN-β-1b, which was obtained in organic solution, demonstrated 18% more antiviral potency than those derived from aqueous solution. The PEGylation step could be directly connected to the previous protein separation step for process integration. Dynamic light scattering (DLS) and atomic force microscope (AFM) analysis revealed that IFN-β-1b formed aggregates both in water and in 2-BuOH solutions. However, the aggregates were much smaller and more homogeneous in 2-BuOH than those in aqueous solution, thereby providing larger solvent accessible protein surfaces, which resulted in a more productive PEGylation process. In addition, the results of circular dichroism (CD), fluorescence spectra, and peptide mapping suggested that the increased bioactivity came from the difference in PEGylation site distribution due to solution environment that induced conformational discrepancy. The results of this study show that PEGylation of IFN-β-1b in organic solution is a facile and efficient process, which might find applications for other hydrophobic proteins.

  13. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Mahmoud R. Fassad

    2016-08-09

    Aug 9, 2016 ... CYP1B1 and myocilin gene mutations in Egyptian patients with primary congenital glaucoma. Mahmoud R. Fassad a. , Asmaa K. Amin a. , Heba A. Morsy a. , Noha M. Issa a. ,. Nader H. Bayoumi b. , Sahar A. El Shafei a. , Soha F. Kholeif a,. * a Department of Human Genetics, Medical Research Institute, ...

  14. Archaeal remains dominate marine organic matter from the early Albian oceanic anoxic event 1b

    NARCIS (Netherlands)

    Sinninghe Damsté, J.S.; Kuypers, M.M.M.; Blokker, P.; Hopmans, E.C.; Kinkel, H.; Pancost, R.D.; Schouten, S.

    2002-01-01

    The sources for both soluble and insoluble organic matter of the early Albian (~112 Myr) oceanic anoxic event (OAE) 1b black shales of the Ocean Drilling Program (ODP) site 1049C (North Atlantic Ocean off the coast of Florida) and the Ravel section of the Southeast France Basin (SEFB) were

  15. Data of evolutionary structure change: 1ASDA-2AY1B [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1ASDA-2AY1B 1ASD 2AY1 A B MFENITAAPADPILGLADLFRADERPGKINLGIGVYKDE...H HHHHHHHH EEEE EEEEEGG HHHHHHHHHHHHH 0 1ASD... A 1ASDA DFSFI---I...ine> ALA CA 413 THR CA 475 LEU CA 494 1ASD... A 1ASDA GSALINDKRARTA

  16. DEPDC1B Coordinates De-adhesion Events and Cell-Cycle Progression at Mitosis

    Science.gov (United States)

    Marchesi, Stefano; Montani, Francesca; Deflorian, Gianluca; D’Antuono, Rocco; Cuomo, Alessandro; Bologna, Serena; Mazzoccoli, Carmela; Bonaldi, Tiziana; Di Fiore, Pier Paolo; Nicassio, Francesco

    2014-01-01

    Summary Cells entering mitosis become rounded, lose attachment to the substrate, and increase their cortical rigidity. Pivotal to these events is the dismantling of focal adhesions (FAs). How mitotic reshaping is linked to commitment to divide is unclear. Here, we show that DEPDC1B, a protein that accumulates in G2, coordinates de-adhesion events and cell-cycle progression at mitosis. DEPDC1B functions as an inhibitor of a RhoA-based signaling complex, which assembles on the FA-associated protein tyrosine phosphatase, receptor type, F (PTPRF) and mediates the integrity of FAs. By competing with RhoA for the interaction with PTPRF, DEPDC1B promotes the dismantling of FAs, which is necessary for the morphological changes preceding mitosis. The circuitry is relevant in whole organisms, as shown by the control exerted by the DEPDC1B/RhoA/PTPRF axis on mitotic dynamics during zebrafish development. Our results uncover an adhesion-dependent signaling mechanism that coordinates adhesion events with the control of cell-cycle progression. PMID:25458010

  17. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood blindness in Egypt. The identification of disease causing mutations has not been extensively investigated. We aimed to examine the frequency of CYP1B1 and MYOC mutations in PCG Egyptian patients, and study a possible ...

  18. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Mahmoud R. Fassad

    2016-08-09

    Aug 9, 2016 ... Abstract Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood blind- ness in Egypt. The identification of disease causing mutations has not been extensively investigated. We aimed to examine the frequency of CYP1B1 and MYOC mutations in PCG Egyptian patients, and study a ...

  19. Syntaxin 1B suppresses macropinocytosis and semaphorin 3A-induced growth cone collapse.

    Science.gov (United States)

    Kabayama, Hiroyuki; Takeuchi, Makoto; Taniguchi, Masahiko; Tokushige, Naoko; Kozaki, Shunji; Mizutani, Akihiro; Nakamura, Takeshi; Mikoshiba, Katsuhiko

    2011-05-18

    Growth cone collapse is a crucial process for repulsive axon guidance and is accompanied by a reduction in growth cone surface area. This process of reduction may be regulated by endocytosis; however, its molecular mechanism is unclear. Macropinocytosis is a clathrin-independent form of endocytosis in which large areas of plasma membrane can be engulfed. We have reported previously that macropinocytosis is induced in growth cones of chick dorsal root ganglion neurons by semaphorin 3A (Sema3A), a repulsive axon guidance cue, and that Sema3A-induced reduction in growth cone surface area and macropinocytic vacuole area were correlated, suggesting a positive role for macropinocytosis in Sema3A-induced growth cone collapse. In the present study, we found that syntaxin 1B (Syx1B), a membrane trafficking protein, is a negative regulator of macropinocytosis, and its expression is downregulated by Sema3A signaling. Macropinocytosis inhibitor ethylisopropylamiloride or Syx1B overexpression suppressed Sema3A-induced macropinocytosis and growth cone collapse. These results indicate that Syx1B couples macropinocytosis-mediated massive internalization of the plasma membrane to Sema3A-induced growth cone collapse.

  20. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 250m

    Data.gov (United States)

    National Aeronautics and Space Administration — The 250 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 2 discrete bands located in the 0.62 to 0.88 micron region of the...

  1. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 250m V005

    Data.gov (United States)

    National Aeronautics and Space Administration — The 250 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 2 discrete bands located in the 0.62 to 0.88 micron region of the...

  2. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 250m

    Data.gov (United States)

    National Aeronautics and Space Administration — The 250 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 2 discrete bands located in the 0.62 to 0.88 micron region of the...

  3. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 500m

    Data.gov (United States)

    National Aeronautics and Space Administration — The 500 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 7 discrete bands located in the 0.45 to 2.20 micron region of the...

  4. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 500m

    Data.gov (United States)

    National Aeronautics and Space Administration — The 500 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 7 discrete bands located in the 0.45 to 2.20 micron region of the...

  5. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 500m - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — The 500 meter MODIS Level 1B Near Real Time (NRT) data set contains calibrated and geolocated at-aperture radiances for 7 discrete bands located in the 0.45 to 2.20...

  6. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 500m - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — The 500 meter MODIS Level 1B Near Real Time (NRT) data set contains calibrated and geolocated at-aperture radiances for 7 discrete bands located in the 0.45 to 2.20...

  7. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 500m V006

    Data.gov (United States)

    National Aeronautics and Space Administration — The 500 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 7 discrete bands located in the 0.45 to 2.20 micron region of the...

  8. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 250m V006

    Data.gov (United States)

    National Aeronautics and Space Administration — The 250 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 2 discrete bands located in the 0.62 to 0.88 micron region of the...

  9. Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

    Directory of Open Access Journals (Sweden)

    Jianqiang Wu

    2016-03-01

    Full Text Available To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1 neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs and Schwann cells (SCs prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b to increase β-catenin. Knockdown of Arid1b or Gsk3β in Stat3fl/fl;Nf1fl/fl;DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials.

  10. Data of evolutionary structure change: 1B04B-3BACA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available yIDChain>1B04B QEVGE----AAYVC ...>HHH ---- EEEE> ATOM 3301 CA GLN B 102 33.953 75.885 40.45...ntryIDChain>3BACA DRLILLPKPLTFCC >HH EEEEE...hain> ERKAR--ELFAN >HHHH -- > HHH ture> ATOM 933 CA TYR A 188 74.4

  11. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 1km Subsetted V006

    Data.gov (United States)

    National Aeronautics and Space Administration — This data type (MOD02SSH) is a subsample from the MODIS Level 1B 1-km data. Every fifth pixel is taken from the MOD021KM product and written out to MOD02SSH. The...

  12. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 1km subsetted V006

    Data.gov (United States)

    National Aeronautics and Space Administration — This data type (MYD02SSH) is a subsample from the MODIS Level 1B 1-km data. Every fifth pixel is taken from the MYD021KM product and written out to MYD02SSH. The...

  13. MODIS/Terra Level 1B Subsampled Calibrated Radiance 5Km - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — This Near Real Time (NRT) data type (MOD02SSH) is a subsample from the MODIS Level 1B 1-km data. Every fifth pixel is taken from the MOD021KM product and written out...

  14. MODIS/Terra Near Real Time (NRT) Level 1B Subsampled Calibrated Radiance 5Km

    Data.gov (United States)

    National Aeronautics and Space Administration — This Near Real Time (NRT) data type (MOD02SSH) is a subsample from the MODIS Level 1B 1-km data. Every fifth pixel is taken from the MOD021KM product and written out...

  15. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 1km Subsetted V005

    Data.gov (United States)

    National Aeronautics and Space Administration — This data type (MOD02SSH) is a subsample from the MODIS Level 1B 1-km data. Every fifth pixel is taken from the MOD021KM product and written out to MOD02SSH. The...

  16. MODIS/Aqua Near Real Time (NRT) Level 1B Subsampled Calibrated Radiance 5Km

    Data.gov (United States)

    National Aeronautics and Space Administration — This Near Real Time (NRT) data type (MYD02SSH) is a subsample from the MODIS Level 1B 1-km data. Every fifth pixel is taken from the MYD021KM product and written out...

  17. Allele mining across DREB1A and DREB1B in diverse rice ...

    Indian Academy of Sciences (India)

    Allele mining across DREB1A and DREB1B in diverse rice genotypes suggest a highly conserved pathway inducible by low temperature. Clarissa Challam, Tapu Ghosh, Mayank Rai and Wricha Tyagi. J. Genet. 94, 231–238. Table 1. Low temperature screening scores for rice genotypes used in the present study. Relative.

  18. 20 CFR 655.736 - What are H-1B-dependent employers and willful violators?

    Science.gov (United States)

    2010-04-01

    ....g., copies of H-1B petitions; payroll records described in § 655.731(b)(1)). (6) Change in corporate structure or identity of employer. If an employer which experiences a change in its corporate structure as... this section). (See § 655.730(e), regarding change in corporate structure or identity of employer.) In...

  19. Functions of OATP1a/1b transporters in vivo: insights from mouse models

    NARCIS (Netherlands)

    Steeg, E. van de; Lusuf, D.; Schinkel, A.H.

    2011-01-01

    Organic anion-transporting polypeptides (OATPs) are a superfamily of uptake transporters that mediate the cellular uptake of a broad range of endogenous and exogenous compounds. Of these OATP transporters, members of the 1A and 1B subfamilies have broad substrate specificities. Because they are

  20. MODIS/Aqua Level 1B Subsampled Calibrated Radiance 5Km - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — This Near Real Time (NRT) data type (MYD02SSH) is a subsample from the MODIS Level 1B 1-km data. Every fifth pixel is taken from the MYD021KM product and written out...

  1. A spontaneous smc1b mutation causes cohesin protein dysfunction and sterility in mice.

    Science.gov (United States)

    Takabayashi, Shuji; Yamauchi, Yumika; Tsume, Mami; Noguchi, Motoko; Katoh, Hideki

    2009-08-01

    In this paper, we describe a novel spontaneous mutation of the Smc1b gene coding a cohesin component, which causes female and male sterility. We have discovered an ICR male mouse with a novel autosomal recessive gene that causes small gonads and sterility in both sexes. Mutant female and male mice homozygous for the novel sterility gene had normal body weights and showed normal mating behavior, but did not produce any offspring. Histological examination showed that Sertoli cells and spermatogonia were present in the testicular seminiferous tubules in 8-week-old mutant male mice, but no spermatids or spermatozoa were observed. Mutant females showed a markedly reduced number of oocytes with age. The novel sterility gene mapped between D15Mit105 (47.9 cM) and D15Mit171 (54.5 cM) on chromosome 15. Sequences of three candidate sterility genes, Dmc1, Mei1 and Smc1b, which are closely linked to these microsatellite markers, were compared between normal and mutant mice. The Dmc1 and Mei1 genes showed the same sequences in both normal and mutant mice, but the Smc1b gene had a deletion of 16 nucleotides in exon 5, in the mutant mice. We concluded that this deletion led to a frame-shift, which generated a stop codon at position 761 (amino acid 247) of the Smc1b cDNA in mutant mice.

  2. Structural basis for midbody targeting of spastin by the ESCRT-III protein CHMP1B

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Dong; Rimanchi, Neggy; Renvoise, Benoit; Lippincott-Schwartz, Jennifer; Blackstone, Craig; Hurley, James H. (NIH)

    2009-01-15

    The endosomal sorting complex required for transport (ESCRT) machinery, including ESCRT-III, localizes to the midbody and participates in the membrane-abscission step of cytokinesis. The ESCRT-III protein charged multivesicular body protein 1B (CHMP1B) is required for recruitment of the MIT domain-containing protein spastin, a microtubule-severing enzyme, to the midbody. The 2.5-{angstrom} structure of the C-terminal tail of CHMP1B with the MIT domain of spastin reveals a specific, high-affinity complex involving a noncanonical binding site between the first and third helices of the MIT domain. The structural interface is twice as large as that of the MIT domain of the VPS4-CHMP complex, consistent with the high affinity of the interaction. A series of unique hydrogen-bonding interactions and close packing of small side chains discriminate against the other ten human ESCRT-III subunits. Point mutants in the CHMP1B binding site of spastin block recruitment of spastin to the midbody and impair cytokinesis.

  3. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 250m - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — The 250 meter MODIS Level 1B Near Real Time (NRT) data set contains calibrated and geolocated at-aperture radiances for 2 discrete bands located in the 0.62 to 0.88...

  4. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 250m V006

    Data.gov (United States)

    National Aeronautics and Space Administration — The 250 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 2 discrete bands located in the 0.62 to 0.88 micron region of the...

  5. MODIS/Terra Calibrated Radiances 5-Min L1B Swath 250m - NRT

    Data.gov (United States)

    National Aeronautics and Space Administration — The 250 meter MODIS Level 1B Near Real Time (NRT) data set contains calibrated and geolocated at-aperture radiances for 2 discrete bands located in the 0.62 to 0.88...

  6. MODIS/Aqua Calibrated Radiances 5-Min L1B Swath 500m V006

    Data.gov (United States)

    National Aeronautics and Space Administration — The 500 meter MODIS Level 1B data set contains calibrated and geolocated at-aperture radiances for 7 discrete bands located in the 0.45 to 2.20 micron region of the...

  7. Comparative docking studies of CYP1b1 and its PCG-associated ...

    Indian Academy of Sciences (India)

    Molecular docking has been used to compare and contrast the binding modes of oestradiol with the wild-type and some disease-associated mutant forms of the human CYP1b1 protein. The receptor structures used for docking were derived from molecular dynamics simulations of homology-modelled structures. Earlier ...

  8. Binding and discerning interactions of PTP1B allosteric inhibitors: novel insights from molecular dynamics simulations.

    Science.gov (United States)

    Shinde, Ranajit Nivrutti; Sobhia, M Elizabeth

    2013-09-01

    The α7 helix is either disordered or missing in the three co-crystal structures of allosteric inhibitors with protein tyrosine phosphatase 1B (PTP1B). It was modeled in each complex using the open form of PTP1B structure and studied using molecular dynamics (MD) simulations for 25 ns. B-factor analysis of the residues sheds light on its disordered nature in the co-crystal structures. Further, the ability of inhibitors to act as allosteric inhibitor was studied and established using novel hydrogen bond criteria. The MD simulations were utilized to determine the relative importance of electrostatic and hydrophobic component in to the binding of inhibitors. It was revealed that the hydrophobic interactions predominantly drive the molecular recognition of these inhibitors. Per residue energy decomposition analysis attributed dissimilar affinities of three inhibitors to the several hydrogen bonds and non-bonded interactions. Among the secondary structure elements that surround the allosteric site, helices α6, α7 and loop α6-α7 were notorious in providing variable affinities to the inhibitors. A novel hydrophobic pocket lined by the α7 helix residues Val287, Asn289 and Trp291 was identified in the allosteric site. This study provides useful insights for the rational design of high affinity PTP1B allosteric inhibitors. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. cis-Bis(butylamine-κNbis[sulfadiazine(1−-κ2N,N′]copper(II pentahydrate

    Directory of Open Access Journals (Sweden)

    Orhan Büyükgüngör

    2008-09-01

    Full Text Available In the title compound {systematic name: cis-bis[4-amino-N-(pyrimidin-2-ylbenzenesulfonamidato-κ2N,N′]bis(butylamine-κNcopper(II pentahydrate}, [Cu(C10H9N4O2S2(C4H11N2]·5H2O or [Cu(sdz2(ba2]·5H2O [ba is butylamine and sdz = sulfadiazine(1−], the copper(II cation is six-coordinated by four N atoms of two sulfadiazine ligands and two N atoms of butylamine ligands. The copper(II ion and one of the water molecules lie on twofold rotation axes. One of the butyl groups is disordered over two sites, with occupancies of 0.395 (8 and 0.605 (8. The geometry around the S atom is distorted tetrahedral. The crystal structure involves intermolecular N—H...N and N—H...O hydrogen bonds. N—H...N hydrogen bonds between sdz ligands lead to a sheet structure parallel to the ab plane.

  10. A functional polymorphism in the promoter region of the IL1B gene is associated with risk of multiple myeloma

    DEFF Research Database (Denmark)

    Vangsted, Annette Juul; Nielsen, Kaspar Renÿ; Klausen, Tobias Wirenfeldt

    2012-01-01

    The cytokine interleukin-1β (IL1B) is important for anti-tumour immune response. Genetic variation may modify the expression of IL1B and thereby influence the risk of disease. We investigated genetic variations with functional importance in the IL1B and NFKB1 genes in 348 population-based samples...

  11. Macrosomia, obesity, and macrocephaly as first clinical presentation of PHP1b caused by STX16 deletion

    NARCIS (Netherlands)

    de Lange, Iris M|info:eu-repo/dai/nl/413919986; Verrijn Stuart, Annemarie A|info:eu-repo/dai/nl/304817589; van der Luijt, Rob B|info:eu-repo/dai/nl/153170824; Ploos van Amstel, Hans Kristian|info:eu-repo/dai/nl/079641202; van Haelst, Mieke M|info:eu-repo/dai/nl/33889392X

    Pseudohypoparathyroidism (PHP) is a genetic disorder with resistance to parathyroid hormone (PTH) as most important feature. Main subtypes of the disease are pseudohypoparathyroidism 1b (PHP1b) and pseudohypoparathyroidism 1a (PHP1a). PHP1b is characterized by PTH resistance of the renal cortex due

  12. A functional polymorphism in the IL1B gene promoter, IL1B -31C>T, is not associated with cerebral malaria in Thailand

    OpenAIRE

    Tangpukdee Noppadon; Hananantachai Hathairad; Patarapotikul Jintana; Doi Akihiro; Naka Izumi; Ohashi Jun; Looareesuwan Sornchai; Tokunaga Katsushi

    2005-01-01

    Abstract Background IL-1β and IL-1RA levels are higher in the serum of cerebral malaria patients than in patients with mild malaria. Recently, the level of IL1B expression was reported to be influenced by a polymorphism in the promoter of IL1, IL1B -31C>T. Methods To examine whether polymorphisms in IL1B and IL1RA influence the susceptibility to cerebral malaria, IL1B -31C>T, IL1B 3953C>T, and IL1RA variable number of tandem repeat (VNTR) were analysed in 312 Thai patients with malaria (109 c...

  13. The co-existence of spread spectrum ranging signal in Indian National Satellite-1B (INSAT-1B) with TV or SCPC channels

    Science.gov (United States)

    Lal, P. M. C.; Palsule, V. S.; Kumar, Pramod

    Spread Spectrum Systems have the potential of sharing the frequency spectrum with broadcasting, telephony, and data communications services due to their low power density signalling. A study of the feasibility of co-existence of Direct Sequence Spread Spectrum ranging signal with TV or SCPC carriers in a common satellite transponder is presented in this paper. The suitability of this type of ranging for Indian National Satellite-1B system from Master Control Facility, Hassan, India has been examined. The mutual interference effects between spread spectrum ranging signal and TV or SCPC services through various sizes of earth stations in INSAT network have been calculated. The study indicates that simultaneous accurate range measurement by spread spectrum technique from control earth station is possible without any significant degradation in signal quality of TV or SCPC services.

  14. Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.

    Science.gov (United States)

    Lane, Jacqueline M; Chang, Anne-Marie; Bjonnes, Andrew C; Aeschbach, Daniel; Anderson, Clare; Cade, Brian E; Cain, Sean W; Czeisler, Charles A; Gharib, Sina A; Gooley, Joshua J; Gottlieb, Daniel J; Grant, Struan F A; Klerman, Elizabeth B; Lauderdale, Diane S; Lockley, Steven W; Munch, Miriam; Patel, Sanjay; Punjabi, Naresh M; Rajaratnam, Shanthakumar M W; Rueger, Melanie; St Hilaire, Melissa A; Santhi, Nayantara; Scheuermaier, Karin; Van Reen, Eliza; Zee, Phyllis C; Shea, Steven A; Duffy, Jeanne F; Buxton, Orfeu M; Redline, Susan; Scheer, Frank A J L; Saxena, Richa

    2016-06-01

    The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  15. Should Level V Be Routinely Dissected in N1b Papillary Thyroid Carcinoma?

    Science.gov (United States)

    Kim, Seo Ki; Park, Inhye; Hur, Nayoon; Lee, Jun Ho; Choe, Jun-Ho; Kim, Jung-Han; Kim, Jee Soo

    2017-02-01

    For N1b papillary thyroid carcinoma (PTC) patients, modified radical neck dissection (MRND) encompassing levels II-V is generally recommended. However, routine level V dissection is controversial because of the low incidence of metastasis/recurrence in level V and the increased morbidities associated with level V dissection. This study retrospectively reviewed 646 N1b PTC patients who underwent unilateral MRND between January 1997 and June 2015. Specifically, to assess surgery-related outcomes of level V dissection, outcomes from N1b PTC patients who underwent unilateral MRND (levels II-V) were compared with those who underwent unilateral selective neck dissection (SND; levels II-IV) using propensity score matching. Overall and occult level V metastases were observed in 13.9% and 8.6% of patients, respectively. Level V recurrences were observed in only 2.26 (7.7%) recurred N1b PTC patients who underwent unilateral MRND. In multivariate analysis, three-level (II, III, and IV) simultaneous metastasis (adjusted odds ratio = 3.079, p = 0.003) was an independent predictor for level V metastasis. Under a matched condition, "shoulder syndrome" encompassing shoulder dysfunction and pain (9.1% vs. 2.7%, p = 0.002) was significantly more frequent in the MRND group than it was in the SND group. Because of the low incidence of metastasis/recurrence in level V and the clear evidence of increased morbidities, level V dissection in N1b PTC patients may be reserved for those with three-level simultaneous metastasis or clinically/radiologically evident level V metastasis.

  16. Relationship of interleukin-1B gene promoter region polymorphism with Helicobacter pylori infection and gastritis.

    Science.gov (United States)

    Ramis, Ivy Bastos; Vianna, Júlia Silveira; Halicki, Priscila Cristina Bartolomeu; Lara, Caroline; Tadiotto, Thássia Fernanda; da Silva Maciel, João Batista; Gonçalves, Carla Vitola; von Groll, Andrea; Dellagostin, Odir Antônio; da Silva, Pedro Eduardo Almeida

    2015-09-29

    Helicobacter pylori infection is associated with gastritis, peptic ulcer disease and gastric carcinoma. The severity of damage is determined by the interplay between environmental/behavioral factors, bacterial pathogenicity genes and host genetic polymorphisms that can influence the secretion levels of inflammatory cytokines. Accordingly, this study aimed to identify polymorphisms in the IL-1B and IL-1RN genes and their associations with H. pylori infection, cagA gene of H. pylori, and gastroduodenal diseases. Gastric biopsy samples from 151 patients infected with H. pylori and 76 uninfected individuals were analyzed. H. pylori infection was diagnosed by histology and PCR. Polymorphisms at positions -511, -31 and +3954 of the IL-1B gene were detected by PCR-RFLP, and an analysis of the VNTR polymorphism of the IL-1RN gene was performed by PCR. It was observed that the presence of the T/T genotype at position -511 and the C/C genotype at position -31 were associated with H. pylori infection and with an increased risk of gastritis in H. pylori-positive patients. Additionally, strains from patients H. pylori-positive carrying the cagA gene was significantly related with the T/T genotype at position -511 of IL-1B.  No association of polymorphisms at position +3954 of IL-1B and in the IL-1RN with H. pylori infection and with risk of severe gastric diseases was found. We demonstrated that polymorphisms in the promoter region of the IL-1B gene (at positions -511 and -31) are associated with an enhanced risk of H. pylori infection as well as gastritis in H. pylori-positive patients.

  17. Criteria for HNF1B analysis in patients with congenital abnormalities of kidney and urinary tract.

    Science.gov (United States)

    Raaijmakers, Anke; Corveleyn, Anniek; Devriendt, Koen; van Tienoven, Theun Pieter; Allegaert, Karel; Van Dyck, Mieke; van den Heuvel, Lambertus; Kuypers, Dirk; Claes, Kathleen; Mekahli, Djalila; Levtchenko, Elena

    2015-05-01

    Congenital anomalies of kidneys and urinary tract (CAKUT) are the most predominant developmental disorders comprising ∼20-30% of all anomalies identified in the prenatal period. Mutations in hepatocyte nuclear factor 1-beta (HNF-1β) involved in the development of kidneys, liver, pancreas and urogenital tract are currently the most frequent monogenetic cause of CAKUT found in 10-30% of patients depending on screening policy and study design. We aimed to validate criteria for analysis of HNF1B in a prospective cohort of paediatric and adult CAKUT patients. We included CAKUT patients diagnosed in our paediatric and adult nephrology departments from January 2010 until April 2013 based on predefined screening criteria. Subjects presenting with at least one major renal criterion or one minor renal criterion combined with one or more extra-renal criteria in the personal history or a familial history of renal or extra-renal manifestations were considered eligible. We prospectively screened 205 patients and detected HNF1B mutations in 10% [n = 20, 12 children, median age 4.2 (range 0-13.1) years and 8 adults, median age 34.8 (range 16.6-62) years]. We observed that bilateral renal anomaly, renal cysts from unknown origin, a combination of two major renal anomalies and hypomagnesaemia were predictive for finding HNF1B mutations (P < 0.001; P < 0.001; P = 0.004; P = 0.008, respectively). We demonstrated that HNF1B mutations are responsible for ∼10% of CAKUT cases, both in children and in adults. Based on our results we propose adapted criteria for HNF1B analysis to reduce the screening costs without missing affected patients. These criteria should be reaffirmed in a larger validation cohort. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  18. Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy.

    Science.gov (United States)

    Danik, Jacqueline S; Chasman, Daniel I; MacFadyen, Jean G; Nyberg, Fredrik; Barratt, Bryan J; Ridker, Paul M

    2013-06-01

    Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy. In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol rs4149056 in SLCO1B1, which encodes organic anion-transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia. Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio [HR] 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism. There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1. Copyright © 2013 Mosby, Inc. All rights reserved.

  19. Reductions in brain 5-HT1B receptor availability in primarily cocaine-dependent humans.

    Science.gov (United States)

    Matuskey, David; Bhagwagar, Zubin; Planeta, Beata; Pittman, Brian; Gallezot, Jean-Dominique; Chen, Jason; Wanyiri, Jane; Najafzadeh, Soheila; Ropchan, Jim; Geha, Paul; Huang, Yiyun; Potenza, Marc N; Neumeister, Alexander; Carson, Richard E; Malison, Robert T

    2014-11-15

    Preclinical evidence implicates the serotonin receptor 5-hydroxytryptamine 1B (5-HT1B) in the effects of cocaine. This study explores 5-HT1B in humans by examining receptor availability in vivo in subjects whose primary addiction is cocaine dependence (CD) using positron emission tomography. Study participants included 14 medically healthy subjects with CD (mean age = 41 ± 6 years) who were compared with 14 age-matched healthy control subjects (mean age = 41 ± 8 years) with no past or current history of cocaine or other illicit substance abuse. Participants underwent magnetic resonance imaging followed by positron emission tomography with the highly selective 5-HT1B tracer, [(11)C]P943, for purposes of quantifying regional binding potential. Voxel-based morphometry and gray matter masking also were employed to control for potential partial volume effects. The [(11)C]P943 positron emission tomography imaging data in nine candidate regions (amygdala, anterior cingulate cortex, caudate, frontal cortex, hypothalamus, pallidum, putamen, thalamus, and ventral striatum) showed significant or nearly significant reductions of regional binding potential in subjects with CD in three regions: anterior cingulate (-16%, p < .01), hypothalamus (-16%, p = .03), and frontal cortex (-7%, p = .08). Voxel-based morphometry showed significant gray matter reductions in the frontal cortex of subjects with CD. After gray matter masking, statistically significant reductions in the [(11)C]P943 regional binding potential were either retained (anterior cingulate, -14%, p = .01; hypothalamus, -20%, p < .01) or achieved (frontal cortex, -14%, p < .01). Whole-brain voxel-wise parameter estimation confirmed these results. Secondary analyses were also significant in some regions for years of cocaine and daily tobacco use. The reductions found in this study suggest that 5-HT1B receptors may contribute to the etiology or expression of CD and potentially represent a target for medication

  20. Crystal structures of bis-[(9S,13S,14S)-3-meth-oxy-17-methyl-morphinanium] tetra-chlorido-cobaltate and tetra-chlorido-cuprate.

    Science.gov (United States)

    Gauchat, Eric; Nazarenko, Alexander Y

    2017-01-01

    (9S,13S,14S)-3-Meth-oxy-17-methyl-morphinan (dextromethorphan) forms two isostructural salts with (a) tetra-chlorido-cobaltate, namely bis-[(9S,13S,14S)-3-meth-oxy-17-methyl-morphinanium] tetra-chlorido-cobaltate, (C18H26NO)2[CoCl4], and (b) tetra-chlorido-cuprate, namely bis-[(9S,13S,14S)-3-meth-oxy-17-methyl-morphinanium] tetra-chlorido-cuprate, (C18H26NO)2[CuCl4]. The distorted tetra-hedral anions are located on twofold rotational axes. The dextromethorphan cation can be described as being composed of two ring systems, a tetra-hydro-naphthalene system A+B and a deca-hydro-isoquinolinium subunit C+D, that are nearly perpendicular to one another: the angle between mean planes of the A+B and C+D moieties is 78.8 (1)° for (a) and 79.0 (1)° for (b). Two symmetry-related cations of protonated dextromethorphan are connected to the tetra-chlorido-cobaltate (or tetra-chlorido-cuprate) anions via strong N-H⋯Cl hydrogen bonds, forming neutral ion associates. These associates are packed in the (001) plane with no strong attractive bonding between them. Both compounds are attractive crystalline forms for unambiguous identification of the dextromethorphan and, presumably, of its optical isomer, levomethorphan.

  1. CCD Measurement of STT 547AB

    Science.gov (United States)

    Priest, Allen; Smith, Kent

    2017-10-01

    The AB component of the multi-star system STT 547 was observed during the summer of 2016. The position angle was 190° and the separation was 5.99". These values are consistent with historical data. A typographical error was found in the position angle for epoch 2011.8016 in the historical data maintained in the Washington Double Star database. The corrected value was used in our data analysis. Two orbits have been proposed for STT 547AB and our measurements do not provide enough additional data to prefer one orbit or the other. Additional measurements over the next few years should allow the confirmation of one of the orbits.

  2. Astrometry Observations of STF 1321AB

    Science.gov (United States)

    Bush, Mitchell; Del Medico, Eric; Boulais, Hunter; Lang, Christina; Escalante, Jesus Segura; D'ambrosia, Sara; Rowe, David; Freed, Rachel; Genet, Russell

    2018-01-01

    The double star STF 1321AB (WDS 09144+5241) was observed April 12th, 2017 using a CDK-17 robotic telescope at Sierra Remote Observatories (SRO). Through the use of Astro Image J astrometry software, we determined an average arclength of 17.17" (arc seconds) with a position angle of 98.17° (degrees). Our measurements from this observation showed a statistically significant deviation from the projected orbital motion of this binary.

  3. Erythema Ab Igne Caused By Laptop Computer.

    Science.gov (United States)

    Guarneri, Claudio; Tchernev, Georgi; Wollina, Uwe; Lotti, Torello; Vaccaro, Mario

    2017-07-25

    Erythema ab igne (EAI) represents the stereotype of a modern technology induced disease. Originally produced by repeated exposure of the skin to a heat source, more often because of habits related to the job or personal activities, this condition now tends to occur more frequently, being associated with a variety of modern instruments. The aim of our report is to discuss this strange medical condition with a focus on clinical features, possible confounding differential diagnoses and recommendations for prevention.

  4. Ab interno trabeculectomy: patient selection and perspectives

    Science.gov (United States)

    Vinod, Kateki; Gedde, Steven J

    2016-01-01

    Ab interno trabeculectomy is one among several recently introduced minimally invasive glaucoma surgeries that avoid a conjunctival incision and full-thickness sclerostomy involved in traditional glaucoma surgery. Ablation of the trabecular meshwork and inner wall of Schlemm’s canal is performed in an arcuate fashion via a clear corneal incision, alone or in combination with phacoemulsification cataract surgery. Intraocular pressure reduction following ab interno trabeculectomy is limited by resistance in distal outflow pathways and generally stabilizes in the mid-to-high teens. Relief of medication burden has been demonstrated by some studies. A very low rate of complications, most commonly transient hyphema and intraocular pressure elevations in the immediate postoperative period, have been reported. However, available data are derived from small retrospective and prospective case series. Randomized, controlled trials are needed to better elucidate the potential merits of ab interno trabeculectomy in the combined setting versus phacoemulsification cataract surgery alone and to compare it with other minimally invasive glaucoma surgeries. PMID:27574396

  5. Highly scalable Ab initio genomic motif identification

    KAUST Repository

    Marchand, Benoit

    2011-01-01

    We present results of scaling an ab initio motif family identification system, Dragon Motif Finder (DMF), to 65,536 processor cores of IBM Blue Gene/P. DMF seeks groups of mutually similar polynucleotide patterns within a set of genomic sequences and builds various motif families from them. Such information is of relevance to many problems in life sciences. Prior attempts to scale such ab initio motif-finding algorithms achieved limited success. We solve the scalability issues using a combination of mixed-mode MPI-OpenMP parallel programming, master-slave work assignment, multi-level workload distribution, multi-level MPI collectives, and serial optimizations. While the scalability of our algorithm was excellent (94% parallel efficiency on 65,536 cores relative to 256 cores on a modest-size problem), the final speedup with respect to the original serial code exceeded 250,000 when serial optimizations are included. This enabled us to carry out many large-scale ab initio motiffinding simulations in a few hours while the original serial code would have needed decades of execution time. Copyright 2011 ACM.

  6. Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2

    OpenAIRE

    Sun, Su-Xia; Li, Xiao-Bo; Liu, Wen-Bo; Ma, Ying; Wang, Run-Ling; Cheng, Xian-Chao; Wang, Shu-Qing; Liu, Wei

    2013-01-01

    Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steri...

  7. Apoptosis and survivability of human dental pulp cells under exposure to Bis-GMA

    Directory of Open Access Journals (Sweden)

    Junya Yano

    2011-06-01

    Full Text Available OBJECTIVE: In the present study, we examined whether 2, 2-bis [4-(2-hydroxy-3-methacryloxypropoxy phenyl] propane (Bis-GMA has effects on LSC2 cells, human dental pulp cell line. MATERIAL AND METHODS: The viability, cell cycle, and morphology of LSC2 cells were analyzed after exposure to several different concentrations of Bis-GMA. The recovery of viability of Bis-GMA exposed cells was also analyzed in the condition without Bis-GMA. Further, penetration of Bis-GMA to dentin disc was examined using isocratic high-performance liquid chromatography. RESULTS: There was a concentration-dependent decrease in cell proliferation and an increase in cell number in the sub-G1 population after exposure to Bis-GMA. Furthermore, the cells showed typical characteristics of apoptotic cells after the exposure to high concentration of Bis-GMA. In contrast, cells exposed to lower concentrations of Bis-GMA recovered their viability after being cultured without Bis-GMA. We also found that Bis-GMA is capable of penetrating 1-mm-thick dentin discs, though the penetrated concentration was lower than that showing cytotoxicity. CONCLUSION: These results suggest that Bis-GMA has cytotoxic effects, though dental pulp exposed to lower concentrations is able to recover their viability when Bis-GMA is removed.

  8. Data and Analysis of the Double Stars STFA 10AB and STFA 1744AB

    Science.gov (United States)

    Arcilla, Marisa; Bowden, Sam; DeBlase, Jacqueline; Hall, Anthony; Hall, Corielyn; Hernandez, Alyssa; Renna, Danielle; Rodriguez, Fatima; Salazar, Cassandra; Sanchez, Andres; Teeter, Dayton; Brewer, Mark; Funk, Benjamin; Gillette, Travis; Sharpe, Scott

    2017-04-01

    Eighth grade students at Vanguard Preparatory School measured the double stars STFA 10AB and STFA 1744AB. A 22-inch Newtonian Alt/Az telescope and a 14-inch Celestron Schmidt Cassegrain telescope were used. The star Bellatrix was used as the calibration star to determine the scale constant of the 22-inch telescope to be 7.8 “/tick marks. The double star STFA 1744AB was used as the calibration star to determine the scale constant of the 14-inch telescope to be 5.1 “/tick marks. The separation and position angle of STFA 10AB was determined by the 22-inch telescope to be 347.9” and 339.3°. The separation and position angle of STFA 1744AB was determined by the 14-inch telescope to be 3.6” and 158.1°. The measurements that were calculated were compared to the most recent measurements listed in the Washington Double Star Catalog.

  9. [1,4-Bis(diphenylphosphanylbutane-κ2P,P′]dibromidopalladium(II

    Directory of Open Access Journals (Sweden)

    Kwang Ha

    2014-02-01

    Full Text Available In the title complex, [PdBr2(C28H28P2], the PdII ion has a distorted cis-Br2P2 square-planar coordination geometry defined by two P atoms from the chelating 1,4-bis(diphenylphosphanylbutane ligand and two Br− anions. The four phenyl rings are inclined to the least-squares plane of the PdBr2P2 unit [maximum deviation = 0.1294 (7 Å], making dihedral angles of 66.3 (2, 87.2 (2, 68.8 (2 and 86.8 (2°. The butylene chain is in a gauche conformation, with a C—C—C—C torsion angle of 57.0 (8°. Intermolecular C—H...Br hydrogen bonds link the complex molecules into supramolecular layers in the ab plane. Weak π–π interactions, both intra- and intermolecular [shortest inter-centroid distance = 4.598 (5 Å], are also noted in the three-dimensional architecture.

  10. The mouse NKR-P1B:Clr-b recognition system is a negative regulator of innate immune responses.

    Science.gov (United States)

    Rahim, Mir Munir A; Chen, Peter; Mottashed, Amelia N; Mahmoud, Ahmad Bakur; Thomas, Midhun J; Zhu, Qinzhang; Brooks, Colin G; Kartsogiannis, Vicky; Gillespie, Matthew T; Carlyle, James R; Makrigiannis, Andrew P

    2015-04-02

    NKR-P1B is a homodimeric type II transmembrane C-type lectinlike receptor that inhibits natural killer (NK) cell function upon interaction with its cognate C-type lectin-related ligand, Clr-b. The NKR-P1B:Clr-b interaction represents a major histocompatibility complex class I (MHC-I)-independent missing-self recognition system that monitors cellular Clr-b levels. We have generated NKR-P1B(B6)-deficient (Nkrp1b(-/-)) mice to study the role of NKR-P1B in NK cell development and function in vivo. NK cell inhibition by Clr-b is abolished in Nkrp1b(-/-) mice, confirming the inhibitory nature of NKR-P1B(B6). Inhibitory receptors also promote NK cell tolerance and responsiveness to stimulation; hence, NK cells expressing NKR-P1B(B6) and Ly49C/I display augmented responsiveness to activating signals vs NK cells expressing either or none of the receptors. In addition, Nkrp1b(-/-) mice are defective in rejecting cells lacking Clr-b, supporting a role for NKR-P1B(B6) in MHC-I-independent missing-self recognition of Clr-b in vivo. In contrast, MHC-I-dependent missing-self recognition is preserved in Nkrp1b(-/-) mice. Interestingly, spontaneous myc-induced B lymphoma cells may selectively use NKR-P1B:Clr-b interactions to escape immune surveillance by wild-type, but not Nkrp1b(-/-), NK cells. These data provide direct genetic evidence of a role for NKR-P1B in NK cell tolerance and MHC-I-independent missing-self recognition. © 2015 by The American Society of Hematology.

  11. Protein tyrosine phosphatase 1B deficiency potentiates PERK/eIF2α signaling in brown adipocytes.

    Directory of Open Access Journals (Sweden)

    Ahmed Bettaieb

    Full Text Available Protein-tyrosine phosphatase 1B (PTP1B is a physiological regulator of glucose homeostasis and body mass, and has been implicated in endoplasmic reticulum (ER stress. Herein, we assess the role of PTP1B in ER stress in brown adipocytes, which are key regulators of thermogenesis and metabolic response.To determine the role of PTP1B in ER stress, we utilized brown adipose tissue (BAT from mice with adipose-specific PTP1B deletion, and brown adipocytes deficient in PTP1B and reconstituted with PTP1B wild type (WT or the substrate-trapping PTP1B D181A (D/A mutant. PTP1B deficiency led to upregulation of PERK-eIF2α phosphorylation and IRE1α-XBP1 sub-arms of the unfolded protein response. In addition, PTP1B deficiency sensitized differentiated brown adipocytes to chemical-induced ER stress. Moreover, PERK activation and tyrosine phosphorylation were increased in BAT and adipocytes lacking PTP1B. Increased PERK activity resulted in the induction of eIF2α phosphorylation at Ser51 and better translatability of ATF4 mRNA in response to ER stress. At the molecular level, we demonstrate direct interaction between PTP1B and PERK and identify PERK Tyr615 as a mediator of this association.Collectively, the data demonstrate that PTP1B is a physiologically-relevant modulator of ER stress in brown adipocytes and that PTP1B deficiency modulates PERK-eIF2α phosphorylation and protein synthesis.

  12. Synthesis and biological study of novel methylene-bis-benzofuranyl-

    Directory of Open Access Journals (Sweden)

    Sanjeeva R. Cherkupally

    2008-12-01

    Full Text Available A series of novel methylene-bis-[1,5]-benzothiazepines 4 and methylene-bis-benzofuranyl-[1,5]-benzothiazepines 5 were prepared by the reaction of methylene-bis-chalcones 3 with 2-aminothiophenolfollowed by the condensation with -bromoacetophenone. The structures of the synthesized compounds wereconfirmed by their IR, 1H, 13C NMR and Mass spectral analyses. All the synthesized compounds were tested fortheir antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. Among the synthesizedcompounds, the compounds 4f, 4g, 5f and 5g were found to be the most active against Bacillus subtilis, Bacillussphaericus, Staphylococcus aureus, Klebsiella aerogenes and Chromobacterium violaceum. Similarly thesecompounds showed potent antifungal effect against Candida albicans, Aspergillus fumigatus, Trichophytonrubrum, and Trichophyton mentagrophytes. It is interesting to note that the compounds with heterocyclic ringsubstituents at the 4th position of benzothiazepine system displayed notable antibacterial activity, almost equalto that of streptomycin and penicillin.

  13. Bis(N-{bis[methyl(phenylamino]phosphoryl}-2,2,2-trichloroacetamidedinitratodioxidouranium(VI

    Directory of Open Access Journals (Sweden)

    Vladimir M. Amirkhanov

    2010-03-01

    Full Text Available In the title compound, [UO2L2(NO32] {L = N-{bis[methyl(phenylamino]phosphoryl}-2,2,2-trichloroacetamide, C16H17Cl3N3O2P}, the UVI ions are eight-coordinated by axial oxido ligands and six equatorial O atoms from the phosphoryl and nitrate groups in a distorted hexagonal–bipyramidal geometry. There are disordered fragments in the two coordinating L ligands: the trichloromethyl group is rotationally disordered between two orientations [occupancy ratio 0.567 (15:0.433 (15] in one ligand, and a methyl(phenylamine fragment is disordered over two conformations [occupancy ratio 0.60 (4:0.40 (4] in the other ligand. In the crystal structure, intramolecular N—H...O hydrogen bonds between the amine and nitrate groups are observed.

  14. Bis[μ-N-(tert-butyldimethylsilyl-N-(pyridin-2-ylmethylamido]bis[methylcobalt(II

    Directory of Open Access Journals (Sweden)

    Astrid Malassa

    2012-09-01

    Full Text Available The green title complex, [Co2(CH32(C12H21N2Si2], was obtained from bis{[μ-N-tert-butyldimethylsilyl-N-(pyridin-2-ylmethylamido]chloridocobalt(II} and methyllithium in diethyl ether at 195 K via a metathesis reaction. The dimeric cobalt(II complex exhibits a crystallographic center of inversion in the middle of the Co2N2 ring (average Co—N = 2.050 Å. The CoII atom shows a distorted tetrahedral coordination sphere. The exocyclic Co—N bond length to the pyridyl group shows a similar value of 2.045 (4 Å. The exocyclic methyl group has a rather long Co—C bond length of 2.019 (5 Å.

  15. Bis{2,6-bis[(2-hydroxy-5-methylphenyliminomethyl]pyridine} monohydrate

    Directory of Open Access Journals (Sweden)

    Muhammet Kose

    2011-12-01

    Full Text Available The title compound, 2C21H19N3O2·H2O, was synthesized by a Schiff base condensation of 2,6-diformylpyridine with 2-amino-4-methylphenol in ethanol. In the crystal, two molecules of 2,6-bis[(2-hydroxy-5-methylphenyliminomethyl]pyridine dimerize via hydrogen bonding to a water molecule, which lies on a twofold axis. There are also intramolecular phenol–imine hydrogen bonds. The dimers are further linked via π–π (phenyl–pyridine [centroid–centroid distance = 3.707 (2 Å] and π–π edge-to-edge [3.392 (2 Å] interactions. The dihedral angles between the central ring and the two pendant rings are 11.46 (8 and 2.06 (8° while the pendant rings make a dihedral angle of 10.14 (8°.

  16. Mixed adenosquamous histology is associated with poorer survival of cervical cancer stage 1b

    DEFF Research Database (Denmark)

    Lauszus, Finn; Tjessem, Ingvild; Al-Far, Hanine M

    2016-01-01

    Background: Evaluation of histopathological factors for women with radical hysterectomy a.m. Okabayashi for cervical cancer in stage 1bwith similar pre- and postoperative treatment Methods: Data on 141 women with cervical cancer stage 1b were revised. The local patient registry, data charts, and ......, while survival was found to be 89 % (83-95 %) and 86 % (79-93 %), respectively. The women’s age at diagnosis showed no association with histology type or survival......., and post mortem sections provided follow-up on survival, relapse, and re-admittance. Histopathological evaluation was performed by the same pathologist. Results: Histological evaluation showed that adenosquamous cervical cancer in stage 1b was associated with poorer survival than the pure squamous...... and adenomatous type (passociated with glandular metastasis (p

  17. INHIBITORY POTENTIAL OF POLYHYDROXYLATED FULLERENES AGAINST PROTEIN TYROSINE PHOSPHATASE 1B.

    Science.gov (United States)

    Kobzar, O L; Trush, V V; Tanchuk, V Yu; Vovk, A I

    2015-01-01

    Inhibition of PTP1B by polyhydroxylated fullerenes was studied in silico and in vitro. The enzyme kinetics in the presence of polyhydroxy small gap fullerenes showed that reciprocal value of maximum velocity non-linearly increases with increasing the inhibitor concentration. Analysis of the dose-dependent curve of PTP1B inhibition suggests an apparent positive cooperativity with involvement of at least two binding sites for the hydroxylated fullerene cages. Molecular docking calculations indicated that highly hydroxylated fullerene C60 may occupy the active site and additional allosteric binding site with similar affinity. In silico analysis of a number of fullerenols with 6, 12, 18, 24, 30, and 36 hydroxyl groups showed that the inhibitory activity may depend on the degree of hydroxylation of the nanoparticles surface. These data provide some understanding of the mechanisms of inhibitory action of fullerenols on activity of protein tyrosine phosphatases.

  18. Fructophilic behaviour of Gordonia alkanivorans strain 1B during dibenzothiophene desulfurization process.

    Science.gov (United States)

    Alves, Luís; Paixão, Susana M

    2014-01-25

    Biodesulfurization (BDS) aims at the removal of recalcitrant sulfur from fossil fuels at mild operating conditions with the aid of microorganisms. These microorganisms can remove sulfur from dibenzothiphene (DBT), a model compound, or other polycyclic aromatic used as sulfur source, making BDS an easy and environmental friendly process. Gordonia alkanivorans strain 1B has been described as a desulfurizing bacterium, able to desulfurize DBT to 2-hydroxybiphenyl (2-HBP), the final product of the 4S pathway, using d-glucose as carbon source. However, both cell growth and desulfurization can be largely affected by the nutrient composition of the growth medium, due to cofactor requirements of many enzymes involved in the BDS biochemical pathway. In this study, the main goal was to investigate the influence of several sugars, as carbon source, on the growth and DBT desulfurization ability of G. alkanivorans strain 1B. The results of desulfurization tests showed that the lowest values for the growth rate (0.025 hour(-1)) and for the overall 2-HBP production rate (1.80 μm/hour) by the strain 1B were obtained in glucose grown cultures. When using sucrose, the growth rate increase exhibited by strain 1B led to a higher biomass productivity, which induced a slightly increase in the 2-HBP production rate (1.91 μm/hour), conversely in terms of 2-HBP specific production rate (q2-HBP) the value obtained was markedly lower (0.718 μmol/g/hour in sucrose versus 1.22 μmol/g/hour in glucose). When a mixture of glucose and fructose was used as carbon source, strain 1B reached a value of q2-HBP=1.90 μmol/g/hour, close to that in fructose (q2-HBP=2.12 μmol/g/hour). The highest values for both cell growth (μ=0.091 hour(-1)) and 2-HPB production (9.29μm/hour) were obtained when strain 1B was desulfurizing DBT in the presence of fructose as the only carbon source, indicating a fructophilic behaviour by this bacterium. This fact is in agreement with the highest value of biomass

  19. [A snow depth inversion method for the HJ-1B satellite data].

    Science.gov (United States)

    Dong, Ting-Xu; Jiang, Hong-Bo; Chen, Chao; Qin, Qi-Ming

    2011-10-01

    The importance of the snow is self-evident, while the harms caused by the snow have also received more and more attention. At present, the retrieval of snow depth mainly focused on the use of microwave remote sensing data or a small amount of optical remote sensing data, such as the meteorological data or the MODIS data. The small satellites for environment and disaster monitoring of China are quite different form the meteorological data and MODIS data, both in the spectral resolution or spatial resolution. In this paper, aimed at the HJ-1B data, snow spectral of different underlying surfaces and depths were surveyed. The correlation between snow cover index and snow depth was also analyzed to establish the model for the snow depth retrieval using the HJ-1B data. The validation results showed that it can meet the requirements of real-time monitoring the snow depth on the condition of conventional snow depth.

  20. Isolation of pathogenic Yersinia enterocolitica 1B/O:8 from Apodemus mice in Japan.

    Science.gov (United States)

    Oda, Shinya; Kabeya, Hidenori; Sato, Shingo; Shimonagane, Ai; Inoue, Kai; Hayashidani, Hideki; Takada, Nobuhiro; Fujita, Hiromi; Kawabata, Hiroki; Maruyama, Soichi

    2015-01-01

    Yersinia enterocolitica was isolated from 15.7% (88/560) of wild rodents captured in 15 prefectures in Japan. Prevalences by rodent species were 18.0% (70/388) in Japanese field mice (Apodemus speciosus), 20% (14/71) in small Japanese field mice (Apodemus argenteus), and 11% (4/38) in gray red-backed vole (Myodes rufocanus bedfordiae), suggesting that these rodent species are important reservoirs of Y. enterocolitica. Although most of the isolates were identified as biotype 1A, the pathogenic bioserotype 1B/O:8 was detected in one of the A. speciosus and in three of the A. argenteus captured in Aomori Prefecture. It is suggested that Apodemus mice may be an important reservoir of Y. enterocolitica, and that there are foci of the pathogenic bioserotype 1B/O:8 in Aomori Prefecture, because human sporadic cases by the serotype have been reported in this prefecture.

  1. Ab initio-based approach to structural change of compound semiconductor surfaces during MBE growth

    Science.gov (United States)

    Ito, Tomonori; Akiyama, Toru; Nakamura, Kohji

    2009-01-01

    Phase diagrams of GaAs and GaN surfaces are systematically investigated by using our ab initio-based approach in conjunction with molecular beam epitaxy (MBE). The phase diagrams are obtained as a function of growth parameters such as temperature and beam equivalent pressure (BEP). The versatility of our approach is exemplified by the phase diagram calculations for GaAs(0 0 1) surfaces, where the stable phases and those phase boundaries are successfully determined as functions of temperature and As 2 and As 4 BEPs. The initial growth processes are clarified by the phase diagram calculations for GaAs(1 1 1)B-(2×2). The calculated results demonstrate that the As-trimer desorption on the GaAs(1 1 1)B-(2×2) with Ga adatoms occurs beyond 500-700 K while the desorption without Ga adatoms does beyond 800-1000 K. This self-surfactant effect induced by Ga adsorption crucially affects the initial growth of GaAs on the GaAs(1 1 1)B-(2×2). Furthermore, the phase diagram calculations for GaN(0 0 0 1) suggests that Ga adsorption or desorption during GaN MBE growth can easily change the pseudo-(1×1) to the (2×2)-Ga via newly found (1×1) and vice versa. On the basis of this finding, the possibility of ghost island formation during MBE growth is discussed.

  2. Behavioral pharmacology of AR-A000002, a novel, selective 5-hydroxytryptamine(1B) antagonist.

    Science.gov (United States)

    Hudzik, T J; Yanek, M; Porrey, T; Evenden, J; Paronis, C; Mastrangelo, M; Ryan, C; Ross, S; Stenfors, C

    2003-03-01

    The present review summarizes the behavioral pharmacology conducted to profile the anxiolytic and antidepressant potential of the selective 5-hydroxytryptamine (HT)(1B) antagonist (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (AR-A000002). AR-A000002 functions as a 5-HT(1B) antagonist in vivo, which was shown by the antagonism of the discriminative stimulus effects in the guinea pig of the 5-HT(1B) agonist 3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole (CP135,807). Anxiolytic activity of AR-A000002 was demonstrated in the separation-induced vocalization paradigm in guinea pig pups, and in a suppressed responding procedure in pigeons and guinea pigs, but only a weak trend was noted in a suppressed responding procedure in squirrel monkeys. Antidepressant efficacy was shown in a number of paradigms. In pigeons and guinea pigs responding under a differential reinforcement of low rates schedule of reinforcement (DRL), AR-A000002 increased the number of reinforcers earned without altering the number of responses made. In guinea pigs trained under a response duration differentiation paradigm, AR-A000002 increased mean lever-press duration. Finally, AR-A000002 was shown to block escape failures in guinea pigs submitted to a learned helplessness paradigm. Taken together, these data suggest utility for 5-HT(1B) antagonists in the treatment of both anxiety and affective disorders.

  3. Melatonin receptor 1 B polymorphisms associated with the risk of gestational diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Yang Jae-Hyug

    2011-06-01

    Full Text Available Abstract Backgrounds Two SNPs in melatonin receptor 1B gene, rs10830963 and rs1387153 showed significant associations with fasting plasma glucose levels and the risk of Type 2 Diabetes Mellitus (T2DM in previous studies. Since T2DM and gestational diabetes mellitus (GDM share similar characteristics, we suspected that the two genetic polymorphisms in MTNR1B may be associated with GDM, and conducted association studies between the polymorphisms and the disease. Furthermore, we also examined genetic effects of the two polymorphisms with various diabetes-related phenotypes. Methods A total of 1,918 subjects (928 GDM patients and 990 controls were used for the study. Two MTNR1B polymorphisms were genotyped using TaqMan assay. The allele distributions of SNPs were evaluated by x2 models calculating odds ratios (ORs, 95% confidence intervals (CIs, and corresponding P values. Multiple regressions were used for association analyses of GDM-related traits. Finally, conditional analyses were also performed. Results We found significant associations between the two genetic variants and GDM, rs10830963, with a corrected P value of 0.0001, and rs1387153, with the corrected P value of 0.0008. In addition, we also found that the two SNPs were associated with various phenotypes such as homeostasis model assessment of beta-cell function and fasting glucose levels. Further conditional analyses results suggested that rs10830963 might be more likely functional in case/control analysis, although not clear in GDM-related phenotype analyses. Conclusion There have been studies that found associations between genetic variants of other genes and GDM, this is the first study that found significant associations between SNPs of MTNR1B and GDM. The genetic effects of two SNPs identified in this study would be helpful in understanding the insight of GDM and other diabetes-related disorders.

  4. SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells.

    Science.gov (United States)

    Redd, Priscilla S; Ibrahim, Mohammed L; Klement, John D; Sharman, Sarah K; Paschall, Amy V; Yang, Dafeng; Nayak-Kapoor, Asha; Liu, Kebin

    2017-06-01

    Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b(+)Gr1(-) and immature CD11b(+)Gr1(+) myeloid cells in vivo Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834-43. ©2017 AACR. ©2017 American Association for Cancer Research.

  5. Free Fatty Acids Inhibit Protein Tyrosine Phosphatase 1B and Activate Akt

    Directory of Open Access Journals (Sweden)

    Eisuke Shibata

    2013-09-01

    Full Text Available Background/Aims: Accumulating evidence has suggested that free fatty acids (FFAs interact with protein kinases and protein phosphatases. The present study examined the effect of FFAs on protein phosphatases and Akt. Methods: Activities of protein phosphatase 1 (PP1, protein phosphatase 2A (PP2A, and protein tyrosine phosphatase 1B (PTP1B were assayed under the cell-free conditions. Phosphorylation of Akt was monitored in MSTO-211H human malignant pleural mesothelioma cells without and with knocking-down phosphatidylinositol 3 kinase (PI3K or 3-phosphoinositide-dependent protein kinase-1 (PDK1. Results: In the cell-free assay, unsaturated FFAs (uFFAs such as oleic, linoleic and linolenic acid and saturated FFAs (sFFAs such as stearic, palmitic, myristic, and behenic acid markedly reduced PTP1B activity, with the potential for uFFAs greater than that for sFFAs. All the investigated sFFAs inhibited PP2A activity, but otherwise no inhibition was obtained with uFFAs. Both uFFAs and sFFAs had no effect on PP1 activity. Oleic acid phosphorylated Akt both on Thr308 and Ser473, while stearic acid phosphorylated Akt on Thr308 alone. The effects of oleic and stearic acid on Akt phosphorylation were abrogated by the PI3K inhibitor wortmannin or the PDK1 inhibitor BX912 and also by knocking-down PI3K or PDK1. Conclusion: The results of the present study indicate that uFFAs and sFFAs could activate Akt through a pathway along a PI3K/PDK1/Akt axis in association with PTP1B inhibition.

  6. The vasopressin V1b receptor modulates plasma corticosterone responses to dehydration-induced stress.

    Science.gov (United States)

    Roberts, E M; Pope, G R; Newson, M J F; Lolait, S J; O'Carroll, A-M

    2011-01-01

    Vasopressin V1b receptor knockout (V1b⁻/⁻) mice were used to investigate a putative role for the V1b receptor (V1bR) in fluid regulation and in the hypothalamic-neurohypophysial system (HNS) and hypothalamic-pituitary-adrenal (HPA) axis responses to osmotic stress induced by water deprivation (WD). Male wild-type and V1b⁻/⁻ mice were housed in metabolic cages to allow determination of water intake and urine volume and osmolality. When provided with food and water ad lib., spontaneous urine volume and urine osmolality did not differ between genotypes. Similarly, WD for 24 h caused comparable decreases in urine volume and increases in urine osmolality irrespective of genotype. WD resulted in an increase in plasma corticosterone concentration in wild-type animals; however, this WD-induced increase in plasma corticosterone was significantly attenuated in V1b⁻/⁻ mice. Comparable increases in neuronal activation, indicated by increased c-fos mRNA expression, and in vasopressin mRNA expression occurred in both the supraoptic nucleus and paraventricular nucleus (PVN) of wild-type and V1b⁻/⁻ mice following WD; however, the WD-induced decrease in corticotrophin-releasing hormone mRNA expression seen in the PVN of wild-type mice was not observed in the PVN of V1b⁻/⁻ mice. These data suggest that, although the vasopressin V1bR is not required for normal HNS function, it is necessary for a full HPA-axis response to the osmotic stress of WD. © 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.

  7. Mixed Adenosquamous Histology is Associated with Poorer Survival of Cervical Cancer Stage 1b

    OpenAIRE

    Lauszus, Finn; Tjessem, Ingvild; Al-Far, Hanine M; Jensen, Trine D; Vetner, Max Ove

    2016-01-01

    Background: Evaluation of histopathological factors for women with radical hysterectomy a.m. Okabayashi for cervical cancer in stage 1bwith similar pre- and postoperative treatment Methods: Data on 141 women with cervical cancer stage 1b were revised. The local patient registry, data charts, and post mortem sections provided follow-up on survival, relapse, and re-admittance. Histopathological evaluation was performed by the same pathologist. Results: Histological evaluation showed that adenos...

  8. [Ataxia with ophthalmoplegia: Miller-Fisher syndrome with anti-GQ1b antibody positivity].

    Science.gov (United States)

    Guilloton, L; Camarasa, C; Agard, E; Tondeur, G; Dot, C; Drouet, A

    2014-02-01

    Miller-Fisher syndrome is defined as ophthalmoplegia, ataxia and areflexia. Considered as a variant of Guillain-Barré syndrome, it differs in its clinical presentation and by anti-GQ1b antibody positivity. The authors report a case of Miller-Fisher syndrome characterized by ataxia and complete ophthalmoplegia. Through this example, the range of ophthalmologic clinical manifestations are discussed. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. Antimicrobial Resistance of Shigella flexneri Serotype 1b Isolates in China.

    Directory of Open Access Journals (Sweden)

    Xianyan Cui

    Full Text Available Shigella flexneri serotype 1b is among the most prominent serotypes in developing countries, followed by serotype 2a. However, only limited data is available on the global phenotypic and genotypic characteristics of S. flexneri 1b. In the present study, 40 S. flexneri 1b isolates from different regions of China were confirmed by serotyping and biochemical characterization. Antimicrobial susceptibility testing showed that 85% of these isolates were multidrug-resistant strains and antibiotic susceptibility profiles varied between geographical locations. Strains from Yunnan were far more resistant than those from Xinjiang, while only one strain from Shanghai was resistant to ceftazidime and aztreonam. Fifteen cephalosporin resistant isolates were identified in this study. ESBL genes (blaSHV, blaTEM, blaOXA, and blaCTX-M and ampC genes (blaMOX, blaFOX, blaMIR(ACT-1, blaDHA, blaCIT and blaACC were subsequently detected among the 15 isolates. The results showed that these strains were positive only for blaTEM, blaOXA, blaCTX-M, intI1, and intI2. Furthermore, pulsed-field gel electrophoresis (PFGE analysis showed that the 40 isolates formed different profiles, and the PFGE patterns of Xinjiang isolates were distinct from Yunnan and Shanghai isolates by one obvious, large, missing band. In summary, similarities in resistance patterns were observed in strains with the same PFGE pattern. Overall, the results supported the need for more prudent selection and use of antibiotics in China. We suggest that antibiotic susceptibility testing should be performed at the start of an outbreak, and antibiotic use should be restricted to severe Shigella cases, based on resistance pattern variations observed in different regions. The data obtained in the current study might help to develop a strategy for the treatment of infections caused by S. flexneri 1b in China.

  10. A Novel Germline CDKN1B Mutation Causing Multiple Endocrine Tumors: Clinical, Genetic and Functional Characterization

    OpenAIRE

    Molatore, Sara; Marinoni, Ilaria; Lee, Misu; Pulz, Elke; Ambrosio, Maria Rosaria; Degli Uberti, Ettore; Zatelli, Maria Chiara; Pellegata, Natalia

    2010-01-01

    Abstract Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving two or more endocrine glands. Two MEN syndromes have long been known: MEN1 and MEN2, caused by germline mutations in MEN1 or RET, respectively. Recently, mutations in CDKN1B, encoding the cyclin dependent kinase (Cdk) inhibitor p27, were identified in patients having a MEN1-like phenotype but no MEN1 gene mutations. Currently, the molecular mechanisms mediating the role of p27 in tumor predi...

  11. Polygonumnolides A1-B3, minor dianthrone derivatives from the roots of Polygonum multiflorum Thunb.

    Science.gov (United States)

    Yang, Jianbo; Yan, Zheng; Ren, Jin; Dai, Zhong; Ma, Shuangcheng; Wang, Aiguo; Su, Yalun

    2017-07-05

    Seven new dianthrone glycosides, named polygonumnolides A1-B3 (1-7), were isolated from the 70 % EtOH extract of the dried roots of Polygonum multiflorum Thunb. using column chromatography and preparative high-performance liquid chromatography. Their structures were determined by 1D and 2D NMR and mass spectroscopy. The isolated compounds were evaluated for their cytotoxic effects against KB tumor cell lines and compounds 1-4 showed moderate cytotoxicity.

  12. Seasonality of Yersinia enterocolitica bioserotype 1B/O:8 infections in Poland.

    Science.gov (United States)

    Rastawicki, W; Szych, J; Rokosz, N; Zacharczuk, K; Gierczyński, R

    2013-10-01

    Both serological and bacteriological investigations revealed a cyclic, seasonal pattern of Yersinia enterocolitica 1B/O8 infections in Poland during the years 2008–2011. A large increase in incidence was observed in the second quarter and a decrease in the third quarter of each year. Such seasonal changes were not seen in the case of infections caused by the other enteropathogenic Yersinia bioserotypes.

  13. cadmium(II) coordination polymers based on semi-rigid/flexible bis ...

    Indian Academy of Sciences (India)

    flexible bis-pyridyl-bis-amide ligands and. 5-aminoisophthalate: Syntheses, structures and properties. HONGYAN LINa, HUIZHE LUb, MAO LEa, JIAN LUANa, XIULI WANGa,∗ and. GUOCHENG LIUa. aDepartment of Chemistry, Bohai University, ...

  14. Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis

    Science.gov (United States)

    Žigman, Mihaela; Laumann-Lipp, Nico; Titus, Tom; Postlethwait, John; Moens, Cecilia B.

    2014-01-01

    Hox genes are classically ascribed to function in patterning the anterior-posterior axis of bilaterian animals; however, their role in directing molecular mechanisms underlying morphogenesis at the cellular level remains largely unstudied. We unveil a non-classical role for the zebrafish hoxb1b gene, which shares ancestral functions with mammalian Hoxa1, in controlling progenitor cell shape and oriented cell division during zebrafish anterior hindbrain neural tube morphogenesis. This is likely distinct from its role in cell fate acquisition and segment boundary formation. We show that, without affecting major components of apico-basal or planar cell polarity, Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish. This function correlates with a non-cell-autonomous requirement for Hoxb1b in regulating microtubule plus-end dynamics in progenitor cells in interphase. We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo. PMID:24449840

  15. GOES-R L1b Readiness Implementation and Management Plan

    Science.gov (United States)

    Kunkee, David; Farley, Robert; Kwan, Betty; Walterscheid, Richard; Hecht, James; Claudepierre, Seth.; De Luccia, Frank

    2017-01-01

    A complement of Readiness, Implementation and Management Plans (RIMPs) to facilitate management of post-launch product test activities for the official Geostationary Operational Environmental Satellite (GOES-R) Level 1b (L1b) products have been developed and documented. Separate plans have been created for each of the GOES-R sensors including: the Advanced Baseline Imager (ABI), the Extreme ultraviolet and X-ray Irradiance Sensors (EXIS), Geostationary Lightning Mapper (GLM), GOES-R Magnetometer (MAG), the Space Environment In-Situ Suite (SEISS), and the Solar Ultraviolet Imager (SUVI). The GOES-R program has implemented these RIMPs in order to address the full scope of CalVal activities required for a successful demonstration of GOES-R L1b data product quality throughout the three validation stages: Beta, Provisional and Full Validation. For each product maturity level, the RIMPs include specific performance criteria and required artifacts that provide evidence a given validation stage has been reached, the timing when each stage will be complete, a description of every applicable Post-Launch Product Test (PLPT), roles and responsibilities of personnel, upstream dependencies, and analysis methods and tools to be employed during validation. Instrument level Post-Launch Tests (PLTs) are also referenced and apply primarily to functional check-out of the instruments.

  16. HNF1B-associated clinical phenotypes: the kidney and beyond.

    Science.gov (United States)

    Bockenhauer, Detlef; Jaureguiberry, Graciana

    2016-05-01

    Mutations in HNF1B, the gene encoding hepatocyte nuclear factor 1β are the most commonly identified genetic cause of renal malformations. HNF1B was first identified as a disease gene for diabetes (MODY5) in 1997, and its involvement in renal disease was subsequently noted through clinical observations in pedigrees affected by MODY5. Since then, a whole spectrum of associated phenotypes have been reported, including genital malformations, autism, epilepsy, gout, hypomagnesaemia, primary hyperparathyroidism, liver and intestinal abnormalities and a rare form of kidney cancer. The most commonly identified mutation, in approximately 50 % of patients, is an entire gene deletion occurring in the context of a 17q12 chromosomal microdeletion that also includes several other genes. Some of the associated phenotypes, especially the neurologic ones, appear to occur only in the context of this microdeletion and thus may not be directly linked to HNF1B. Here we review the spectrum of associated phenotypes and discuss potential implications for clinical management.

  17. CD1a and CD1b surface expression is independent from de novo synthesized glycosphingolipids.

    Science.gov (United States)

    Manolova, Vania; Hirabayashi, Yoshio; Mori, Lucia; De Libero, Gennaro

    2003-01-01

    CD1 molecules resemble classical MHC molecules in structure, bind self and bacterial glycolipids and present them to T cells. Whether the CD1 antigen-binding groove becomes filled during maturation and traffic to the cell surface is an important and still unsolved biological question. As most cell types synthesize complex glycosphingolipids (GSL), which also stimulate CD1-restricted T cells, it could be possible that these ligands associate with nascent CD1 molecules. Here, we show that treatment of cells with drugs blocking at different levels the de novo and salvage pathways of GSL synthesis does not prevent surface expression of CD1a and CD1b. Furthermore, transfection of CD1A and CD1B genes in a mutant cell line unable to synthesize glucosylceramides and galactosylceramides showed normal surface expression of both CD1 molecules. Lack of GSL did not induce intracellular CD1 accumulation as indicated by confocal microscopy. The same results were obtained by transfecting the Lec series of mutants, which are deficient in sugar addition to glycolipids and glycoproteins. These findings demonstrate that endogenous de novo synthesized GSL are not mandatory for CD1a and CD1b negotiating surface expression.

  18. Clathrin adaptor AP1B controls adenovirus infectivity of epithelial cells.

    Science.gov (United States)

    Diaz, Fernando; Gravotta, Diego; Deora, Ami; Schreiner, Ryan; Schoggins, John; Falck-Pedersen, Erik; Rodriguez-Boulan, Enrique

    2009-07-07

    Adenoviruses invading the organism via normal digestive or respiratory routes require the Coxsackie-adenovirus receptor (CAR) to infect the epithelial barrier cells. Because CAR is a component of tight junctions and the basolateral membrane and is normally excluded from the apical membrane, most epithelia are resistant to adenoviruses. However, we discovered that a specialized epithelium, the retinal pigment epithelium (RPE), anomalously expressed CAR at the apical surface and was highly susceptible to adenovirus infection. These properties of RPE cells correlated with the absence of the epithelial-specific clathrin adaptor AP1B. Furthermore, knockdown of this basolateral sorting adaptor in adenovirus-resistant MDCK cells promoted apical localization of CAR and increased dramatically Adenovirus infectivity. Targeting assays showed that AP1B is required for accurate basolateral recycling of CAR after internalization. AP1B knock down MDCK cells missorted CAR from recycling endosomes to the apical surface. In summary, we have characterized the cellular machinery responsible for normal sorting of an adenovirus receptor and illustrated how tissue-specific variations in such machinery result in drastic changes in tissue-susceptibility to adenoviruses.

  19. [Validation of HJ-1B thermal infrared channels onboard radiometric calibration based on spectral response differences].

    Science.gov (United States)

    Liu, Li; Fu, Qiao-yan; Shi, Ting-ting; Wang, Ai-chun; Zhang, Xue-wen

    2014-08-01

    Since HJ-1B was launched, 7 sets of blackbody data have been used to calculate onboard calibration coefficients, but the research work on the validation of coefficients is rare. According to the onboard calibration principle, calibration coefficients of HJ-1B thermal infrared channel on Sep 14th, 2009 were calculated with the half-width, moments and look-up table methods. MODIS was selected for the reference sensor, and algorithms of spectral match were improved between the HJ-1B thermal infrared channel and MODIS 31, 32 channels based on the spectral response divergence. The relationship of top of atmosphere (TOA) radiance between the remote sensors was calculated, based on which the surface leaving brightness temperature was calculated by Planck function to validate the brightness temperature calculated through the onboard calibration coefficients. The equivalent brightness temperature calculated by spectral response divergence method is 285.97 K, and the inversion brightness temperature calculated by half-width, moments and look-up table methods is 288.77, 274.52 and 285.97 K respectively. The difference between the inversion brightness temperature and the equivalent brightness temperature is 2.8, -11.46 and 0.02 K, respectively, which demonstrate that onboard calibration coefficients calculated by the look-up table method has better precision and feasibility.

  20. Possible gene-gender interaction between the SLCO1B1 polymorphism and statin treatment efficacy.

    Science.gov (United States)

    Hubacek, Jaroslav A; Dlouha, Dana; Adámkova, Vera; Lanska, Vera; Ceska, Richard; Vrablik, Michal

    2012-01-01

    A significant inter-individual variability in statin treatment efficacy is likely to have a strong genetic background. A candidate gene with the potential to influence statin treatment efficacy is SLCO1B1. This gene codes for the solute carrier organic anion transporter, which has been shown to regulate the hepatic uptake of statins and some other drugs. The SLCO1B1 rs4149056 (T>C) polymorphism was successfully analysed in a group of 253 patients with dyslipidemia (treated with simvastin or atorvastatin, 10 or 20 mg per day) and 470 healthy normolipidemic controls. The polymorphism was analysed using nested PCR-RFLP. Lipid levels (total, LDL and HDL cholesterol; triglycerides) were analysed before and after 10-13 weeks of treatment. After treatment, as expected, there was a significant decrease both in the total cholesterol (7.60±1.36 → 5.37±1.12 mmol/L, prs4149056 variant within the SLCO1B1 gene on statin treatment efficacy.

  1. Distinct circuits underlie the effects of 5-HT1B receptors on aggression and impulsivity

    Science.gov (United States)

    Nautiyal, Katherine M.; Tanaka, Kenji F.; Barr, Mary M.; Tritschler, Laurent; Le Dantec, Yannick; David, Denis J.; Gardier, Alain M.; Blanco, Carlos; Hen, René; Ahmari, Susanne E.

    2015-01-01

    Summary Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs, and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulate impulsive behavior during adulthood. PMID:25892302

  2. Neutrino mass, leptogenesis and FIMP dark matter in a U(1)_{B-L} model

    Science.gov (United States)

    Biswas, Anirban; Choubey, Sandhya; Khan, Sarif

    2017-12-01

    The Standard Model (SM) is inadequate to explain the origin of tiny neutrino masses, the dark matter (DM) relic abundance and the baryon asymmetry of the Universe. In this work, to address all three puzzles, we extend the SM by a local U(1)_{B-L} gauge symmetry, three right-handed (RH) neutrinos for the cancellation of gauge anomalies and two complex scalars having non-zero U(1)_{B-L} charges. All the newly added particles become massive after the breaking of the U(1)_{B-L} symmetry by the vacuum expectation value (VEV) of one of the scalar fields φ _H. The other scalar field, φ _DM, which does not have any VEV, becomes automatically stable and can be a viable DM candidate. Neutrino masses are generated using the Type-I seesaw mechanism, while the required lepton asymmetry to reproduce the observed baryon asymmetry can be attained from the CP violating out of equilibrium decays of the RH neutrinos in TeV scale. More importantly within this framework, we study in detail the production of DM via the freeze-in mechanism considering all possible annihilation and decay processes. Finally, we find a situation when DM is dominantly produced from the annihilation of the RH neutrinos, which are at the same time also responsible for neutrino mass generation and leptogenesis.

  3. Elevated lipoprotein(a) levels and homozygous human platelet antigen 1b (HPA-1b) genotype are risk factors for intrauterine growth restriction (IUGR).

    Science.gov (United States)

    Gerhardt, Andrea; Howe, Nadja; Krüssel, Jan Steffen; Scharf, Ruediger Eberhard; Zotz, Rainer Bernd

    2014-01-01

    The risk of premature manifestation of cardiovascular disease is higher in women after a maternal placental syndrome, especially with a history of fetal IUGR. Aim of the study was to assess hereditary risk factors for arterial thrombosis as risk factors for IUGR. 183 women with fetal IUGR birth weight below the 10th percentile for gestational age and 300 control women were evaluated using a case-control design. In 121 of the 183 women, the newborns' birth weight was below the 5th percentile for gestational age. A risk association could be shown for homozygous human platelet antigen 1b genotype (OR 3.2, P = 0.038) in women with a history for a newborn's birth weight below the 5th percentile. Elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 2.9, P = 0.048) also represent a risk association in the same group of subjects. So did elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 3.4, P = 0.015) in women with a history for a newborn's birth weight below the 10th percentile. Risk factors of arterial thrombosis such as platelet receptor genotypes associated with platelet thrombogenicity and elevated levels of lipoprotein(a) might be of importance in the pathogenesis of IUGR.

  4. Synthesis of bis(indolyl)methanes Catalyzed by Triethylborane

    Science.gov (United States)

    Merinos, J. Pablo García; Ruíz, Heraclio López; López, Yliana; Lima, Susana Rojas

    2015-01-01

    Triethylborane (TEB) was found to be a mild, efficient, and acid catalyst in electrophilic substitution reaction of indoles with aldehydes compounds to afford the corresponding bis(indolyl)methanes. Vibrindole A (5) and bis(indolyl)methanes derivatives 16 and 18 were synthesized using this methodology. Compound 16 is an intermediary in the synthesis of the natural bisindoles arsindoline B (2) and streptindole (6). The structure of vibrindole A (5) was unequivocally confirmed by a single crystal X-ray diffraction analysis. PMID:26120289

  5. Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1.

    Science.gov (United States)

    Nies, Anne T; Niemi, Mikko; Burk, Oliver; Winter, Stefan; Zanger, Ulrich M; Stieger, Bruno; Schwab, Matthias; Schaeffeler, Elke

    2013-01-01

    Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates. Expression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin (n = 82). Expression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A > G (rs2306283) even after correction for multiple testing (P = 0.00034). This held true for haplotypes harboring c.388A > G but not the functional variant c.521T > C (rs4149056) associated with statin-related myopathy. c.388A > G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression. Our results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A > G is the major determinant with additional consequences on atorvastatin plasma levels.

  6. Enhanced expression of Pafah1b1 causes over-migration of cerebral cortical neurons into the marginal zone.

    Science.gov (United States)

    Katayama, Kei-Ichi; Hayashi, Kanehiro; Inoue, Seika; Sakaguchi, Kazushige; Nakajima, Kazunori

    2017-12-01

    Mutations of PAFAH1B1 cause classical lissencephaly in humans. In addition, duplications and triplications of PAFAH1B1 are found in individuals with intellectual disability and other neurological disorders suggesting that proper brain development is highly sensitive to the PAFAH1B1 dosage. To examine the effect of PAFAH1B1 over-dosage in neural development, especially in migration of neurons and layer formation during cerebral cortical development, we overexpressed Pafah1b1 in migrating neurons in the mouse embryonic cortex using in utero electroporation. Enhanced expression of Pafah1b1 in radially-migrating neurons resulted in their over-migration into the marginal zone. Neurons that invaded the marginal zone were oriented abnormally. Layer distribution of Pafaha1b1-overexpressing neurons shifted more superficially than control neurons. Some of the Pafaha1b1-overexpressing future layer 4 neurons changed their positions to layers 2/3. Furthermore, they also changed their layer marker expression from layer 4 to layers 2/3. These results suggest that overexpression of Pafah1b1 affects the migration of neurons and disrupts layer formation in the developing cerebral cortex, and further support the idea that appropriate dosage of Pafah1b1 is crucial for the proper development of the brain.

  7. Association of IL1A and IL1B loci with primary open angle glaucoma

    Directory of Open Access Journals (Sweden)

    Mukhopadhyay Indranil

    2010-06-01

    Full Text Available Abstract Background Recent studies suggest that glaucoma is a neurodegenerative disease in which secondary degenerative losses occur after primary insult by raised Intraocular pressure (IOP or by other associated factors. It has been reported that polymorphisms in the IL1A and IL1B genes are associated with Primary Open Angle Glaucoma (POAG. The purpose of our study was to investigate the role of these polymorphisms in eastern Indian POAG patients. Methods The study involved 315 unrelated POAG patients, consisting of 116 High Tension Glaucoma (HTG patients with intra ocular pressure (IOP > 21 mmHg and 199 non-HTG patients (presenting IOP IL1A (-889C/T; rs1800587, IL1B (-511C/T; rs16944 and IL1B (3953C/T; rs1143634. Haplotype frequency was determined by Haploview 4.1 software. The association of individual SNPs and major haplotypes was evaluated using chi-square statistics. The p-value was corrected for multiple tests by Bonferroni method. Results No significant difference was observed in the allele and genotype frequencies for IL1A and IL1B SNPs between total pool of POAG patients and controls. However, on segregating the patient pool to HTG and non-HTG groups, weak association was observed for IL1A polymorphism (-889C/T where -889C allele was found to portray risk (OR = 1.380; 95% CI = 1.041-1.830; p = 0.025 for non-HTG patients. Similarly, 3953T allele of IL1B polymorphism (+3953C/T was observed to confer risk to HTG group (OR = 1.561; 95% CI = 1.022-2.385; p = 0.039. On haplotype analysis it was observed that TTC was significantly underrepresented in non-HTG patients (OR = 0.538; 95% CI = 0.356- 0.815; p = 0.003 while TCT haplotype was overrepresented in HTG patients (OR = 1.784; 95% CI = 1.084- 2.937; p = 0.022 compared to control pool. However, after correction for multiple tests by Bonferroni method, an association of only TTC haplotype with non-HTG cases sustained (pcorrected = 0.015 and expected to confer protection. Conclusion The study

  8. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.

    Science.gov (United States)

    Niemi, Mikko; Pasanen, Marja K; Neuvonen, Pertti J

    2011-03-01

    The importance of membrane transporters for drug pharmacokinetics has been increasingly recognized during the last decade. Organic anion transporting polypeptide 1B1 (OATP1B1) is a genetically polymorphic influx transporter expressed on the sinusoidal membrane of human hepatocytes, and it mediates the hepatic uptake of many endogenous compounds and xenobiotics. Recent studies have demonstrated that OATP1B1 plays a major, clinically important role in the hepatic uptake of many drugs. A common single-nucleotide variation (coding DNA c.521T>C, protein p.V174A, rs4149056) in the SLCO1B1 gene encoding OATP1B1 decreases the transporting activity of OATP1B1, resulting in markedly increased plasma concentrations of, for example, many statins, particularly of active simvastatin acid. The variant thereby enhances the risk of statin-induced myopathy and decreases the therapeutic indexes of statins. However, the effect of the SLCO1B1 c.521T>C variant is different on different statins. The same variant also markedly affects the pharmacokinetics of several other drugs. Furthermore, certain SLCO1B1 variants associated with an enhanced clearance of methotrexate increase the risk of gastrointestinal toxicity by methotrexate in the treatment of children with acute lymphoblastic leukemia. Certain drugs (e.g., cyclosporine) potently inhibit OATP1B1, causing clinically significant drug interactions. Thus, OATP1B1 plays a major role in the hepatic uptake of drugs, and genetic variants and drug interactions affecting OATP1B1 activity are important determinants of individual drug responses. In this article, we review the current knowledge about the expression, function, substrate characteristics, and pharmacogenetics of OATP1B1 as well as its role in drug interactions, in parts comparing with those of other hepatocyte-expressed organic anion transporting polypeptides, OATP1B3 and OATP2B1.

  9. Aldo-keto reductase 1b7, a novel marker for renin cells, is regulated by cyclic AMP signaling.

    Science.gov (United States)

    Lin, Eugene E; Pentz, Ellen S; Sequeira-Lopez, Maria Luisa S; Gomez, R Ariel

    2015-09-01

    We previously identified aldo-keto reductase 1b7 (AKR1B7) as a marker for juxtaglomerular renin cells in the adult mouse kidney. However, the distribution of renin cells varies dynamically, and it was unknown whether AKR1B7 maintains coexpression with renin in response to different developmental, physiological, and pathological situations, and furthermore, whether similar factor(s) simultaneously regulate both proteins. We show here that throughout kidney development, AKR1B7 expression-together with renin-is progressively restricted in the kidney arteries toward the glomerulus. Subsequently, when formerly renin-expressing cells reacquire renin expression, AKR1B7 is reexpressed as well. This pattern of coexpression persists in extreme pathological situations, such as deletion of the genes for aldosterone synthase or Dicer. However, the two proteins do not colocalize within the same organelles: renin is found in the secretory granules, whereas AKR1B7 localizes to the endoplasmic reticulum. Interestingly, upon deletion of the renin gene, AKR1B7 expression is maintained in a pattern mimicking the embryonic expression of renin, while ablation of renin cells resulted in complete abolition of AKR1B7 expression. Finally, we demonstrate that AKR1B7 transcription is controlled by cAMP. Cultured cells of the renin lineage reacquire the ability to express both renin and AKR1B7 upon elevation of intracellular cAMP. In vivo, deleting elements of the cAMP-response pathway (CBP/P300) results in a stark decrease in AKR1B7- and renin-positive cells. In summary, AKR1B7 is expressed within the renin cell throughout development and perturbations to homeostasis, and AKR1B7 is regulated by cAMP levels within the renin cell. Copyright © 2015 the American Physiological Society.

  10. Overexpression of protein tyrosine phosphatase 1B impairs glucose-stimulated insulin secretion in INS-1 cells.

    Science.gov (United States)

    Lu, Bin; Gu, Ping; Xu, Yixin; Ye, Xiaozhen; Wang, Yingzhijie; DU, Hong; Shao, Jiaqing

    2016-03-01

    Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin signaling. We reported previously that impaired glucose-stimulated insulin secretion (GSIS) in rats fed high-fat diet was associated with higher PTP1B protein levels in islets. The aim of the present study was to investigate the effect of increasing PTP1B on insulin secretion in β-cells. INS-1 cells were transduced with recombinant adenoviruses containing human PTP1B cDNA (Ad-PTP1B), or no exogenous gene (Ad-ctrl). The expression levels of PTP1B, insulin receptor (IR), insulin receptor substrate-1(IRS-1), glucokinase and glucose transporter-2 were evaluated by Western blot. Then insulin-stimulated IR and IRS tyrosine phosphorylation, and Akt pathway activation were measured. GSIS was also performed to evaluate INS-1 cells function. PTP1B expression level was increased 5.9-fold at 48h post-transduction. The overexpression of PTP1B had no effect on proliferation and apoptosis of INS-1 cells. Compared with control cells, INS-1 cells overexpressing PTP1B showed decrease in insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate-1(IRS-1) by 56.4% and 53.1%, respectively. In addition, Akt phosphorylation was reduced 59.6%. Moreover, in Ad-PTP1B-transduced cells, 16.7mM glucose caused a 1.6±0.2 fold increase (vs. 3.9±0.7 fold in nontransduced cells) in insulin secretion relative to secretion at 2.8mM glucose. Further analysis determined that overexpression of PTP1B induced down-regulated expression of glucokinase (42%) and glucose transporter-2 (48%). Our findings suggested that overexpression of PTP1B can inhibit GSIS in INS-1 cells through negatively regulating insulin signaling.

  11. Bis(4-hydroxybenzoato-κ2O,O′bis(pyridine-κNcopper(II

    Directory of Open Access Journals (Sweden)

    Lailatun Nazirah Ozair

    2011-07-01

    Full Text Available In the title compound, [Cu(C7H5O32(C5H5N2], the Cu atom is located on an inversion center and is coordinated by the N atoms of the two pyridine ligands, trans to each other, and to the carboxylate O atoms of two bidentate 4-hydroxybenzoate ligands [Cu—O = 1.9706 (10 and 2.5204 (11 Å]. Hydrogen bonding between hydroxy H and carboxylate O atoms results in a layer structure parallel to the ab plane.

  12. A novel and facile synthesis of 3-(2-benzofuroyl- and 3,6-bis(2-benzofuroylcarbazole derivatives

    Directory of Open Access Journals (Sweden)

    Wentao Gao

    2011-11-01

    Full Text Available A facile synthesis of hitherto unreported 3-(2-benzofuroylcarbazoles 3a–k, 3,6-bis(2-benzofuroylcarbazoles 5a–k, and naphtho[2,1-b]furoylcarbazoles 3l and 5l is described. The synthesis mainly relies on the ultrasound-assisted Rap–Stoermer reaction of 3-chloroacetyl- (1 or 3,6-dichloroacetyl-9-ethyl-9H-carbazole (4 with various salicylaldehydes 2a–k as well as 2-hydroxy-1-naphthaldehyde (2l in CH3CN with the presence of PEG-400 as catalyst. The procedure offers easy access to benzofuroylcarbazoles in short reaction times and the products are obtained in moderate to good yields.

  13. 40 CFR 721.10096 - Benzene, 1,4-bis (methoxymethyl)-.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzene, 1,4-bis (methoxymethyl)-. 721... Substances § 721.10096 Benzene, 1,4-bis (methoxymethyl)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, 1,4-bis (methoxymethyl)- (PMN P-03...

  14. The triazine-based azo-azomethine dyes; synthesis, characterization, spectroscopy, solvatochromism and biological properties of 2,2'-(((6-methoxy-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)bis(2,1-phenylene))bis(azanylylidene)bis(methanylylidene))bis(4-(phenyldiazenyl)phenol).

    Science.gov (United States)

    Ghasemian, Motaleb; Kakanejadifard, Ali; Azarbani, Farideh; Zabardasti, Abedin; Shirali, Somayeh; Saki, Zeinab; Kakanejadifard, Sahar

    2015-03-05

    The macrocyclic azo-azomethine dyes 2,2'-(((6-methoxy-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)bis(2,1-phenylene))bis(azanylylidene)bis(methanylylidene))bis(4-(phenyldiazenyl)phenol) and its derivatives were synthesized and characterized by elemental analysis, mass, FT-IR, UV-vis and NMR spectroscopy. The solvatochromism as well as effects of substitutions on the electronic absorption of these compounds have been studied in the DMSO, DMF, THF, CH3CN, CH3OH and CH3COOH as solvents. Also they positive solvatochromism behaviors are explained on the basis of intramolecular hydrogen bonding, enol-keto tautomeric and dipole moment changes. Compounds having electron donating substituent on the phenyl ring showed good antioxidant activity. However, none of them has a considerable antibacterial activity. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. The triazine-based azo-azomethine dyes; synthesis, characterization, spectroscopy, solvatochromism and biological properties of 2,2‧-(((6-methoxy-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)bis(2,1-phenylene))bis(azanylylidene)bis(methanylylidene))bis(4-(phenyldiazenyl)phenol)

    Science.gov (United States)

    Ghasemian, Motaleb; Kakanejadifard, Ali; Azarbani, Farideh; Zabardasti, Abedin; Shirali, Somayeh; Saki, Zeinab; Kakanejadifard, Sahar

    2015-03-01

    The macrocyclic azo-azomethine dyes 2,2‧-(((6-methoxy-1,3,5-triazine-2,4-diyl)bis(sulfanediyl)bis(2,1-phenylene))bis(azanylylidene)bis(methanylylidene))bis(4-(phenyldiazenyl)phenol) and its derivatives were synthesized and characterized by elemental analysis, mass, FT-IR, UV-vis and NMR spectroscopy. The solvatochromism as well as effects of substitutions on the electronic absorption of these compounds have been studied in the DMSO, DMF, THF, CH3CN, CH3OH and CH3COOH as solvents. Also they positive solvatochromism behaviors are explained on the basis of intramolecular hydrogen bonding, enol-keto tautomeric and dipole moment changes. Compounds having electron donating substituent on the phenyl ring showed good antioxidant activity. However, none of them has a considerable antibacterial activity.

  16. Effektivare ytterbelysning inom Karlstads Bostads AB :  

    OpenAIRE

    Lenz, Mikaela

    2008-01-01

    This report is an inventory of the street lighting in half of the residential estates owned by Karlstad Bostads AB, a public housing company. The inventory was made to reduce the environmental impact of the street lighting. From the inventory an estimation of the total installed power and the energy consumption was made. The total estimated power of the street lighting was 125 kW and the energy consumption was 500 000 kWh/year with an estimated running time of 4 000 h/year. The dominating sou...

  17. Simulation and Robust Contol of Antilock Braking System ABS

    Directory of Open Access Journals (Sweden)

    David Jordan DELICHRISTOV

    2009-06-01

    Full Text Available This paper deals with simulation and robust control of Antilock Braking System ABS. The briefly are described the main parts of ABS hydraulic system and control algorithm of ABS. Hydraulic system described here is BOSCH ABS 5.x series. The goal of ABS system is vehicle stability and vehicle steering response when braking. If during the braking occurred slip at one or more wheels from any reason, ABS evaluates this by “brake slip” controller. At this moment ABS is trying to use maximal limits of adhesion between tire and road. It means that is necessary control the differences between braking torque and friction torque , which reacts to the wheel via friction reaction tire-road surface. This is realized through the solenoid valves, which are controls (triggered by on the base of PID controller described further in chapter 4. Presented concept is more or less standard for most of the existing ABS systems. The issue should be applied concept of robust ABS control algorithm, which is specific for every type of ABS.

  18. Bis[tetraaqua(1,10-phenanthroline-κ2N,N′cobalt(II] hexaaquacobalt(II bis[3,5-bis(carboxylatomethoxybenzoate] tetrahydrate

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    Hui-Ying Song

    2010-12-01

    Full Text Available The title compound, [Co(C12H8N2(H2O4]2[Co(H2O6](C11H7O82·4H2O, was obtanied by the reaction of cobalt acetate with 3,5-bis(carboxymethoxybenzoic acid and 1,10-phenanthroline. The asymmetric unit contains one tetraaqua(1,10-phenanthrolinecobalt(II cation, one half of a hexaaquacobalt(II cation that is completed by inversion symmetry, one 3,5-bis(carboxylatomethoxybenzoate trianion and two lattice water molecules. The two CoII atoms each show a slightly distorted octahedral coordination (CoO6 and CoO4N2. The cations, anions and lattice water molecules are linked by an intricate network of O—H...O hydrogen bonds into a three-dimensional structure.

  19. MYELOMA CELL CKS1B EXPRESSION IN 171 NEWLY DIAGNOSED PATIENTS IS NOT ASSOCIATED WITH INFERIOR SURVIVAL

    DEFF Research Database (Denmark)

    Christensen, Jacob Haaber; Abildgaard, Niels; Meldgaard Knudsen, Lene

    2007-01-01

    DNA were generated and finally amplified by PCR using a sequence independent X-(dT)24 primer. Gene expression of CSK1B and the housekeeping gene ß-actin were analysed by RQ-PCR and CKS1B expression levels were normalized to ß-actin. Expression of CKS1B was observed in 52% of the patients. Results......Introduction. In recent years global gene expression profiling studies introduce several new potential prognostic markers in multiple myeloma (MM). Up-regulation and amplification of the gene CKS1B in myeloma cells has lately been associated with a poor prognosis in MM patients. The CKS1B gene...... is located on chromosome 1q and is involved in the induction of cell proliferation by inhibiting the cyclin-dependent kinase inhibitor p27(kip1). Materials and Methods. We investigated the prognostic value of CKS1B expression by real time quantitative polymerase chain reaction techniques in purified myeloma...

  20. Protein tyrosine phosphatase 1B deficiency ameliorates murine experimental colitis via the expansion of myeloid-derived suppressor cells.

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    Jing Zhang

    Full Text Available Protein tyrosine phosphatase 1B (PTP1B is a key molecule in modulating low-degree inflammatory conditions such as diabetes. The role of PTP1B in other chronic inflammations, however, remains unknown. Here, we report that PTP1B deficiency ameliorates Dextran Sulfate Sodium (DSS-induced murine experimental colitis via expanding CD11b(+Gr-1(+ myeloid-derived suppressor cells (MDSCs. Employing DSS-induced murine experimental colitis as inflammatory animal model, we found that, compared with wild-type littermates, PTP1B-null mice demonstrated greater resistance to DSS-induced colitis, as reflected by slower weight-loss, greater survival rates and decreased PMN and macrophage infiltration into the colon. The evidence collectively also demonstrated that the resistance of PTP1B-null mice to DSS-induced colitis is based on the expansion of MDSCs. First, PTP1B-null mice exhibited a greater frequency of MDSCs in the bone marrow (BM, peripheral blood and spleen when compared with wild-type littermates. Second, PTP1B levels in BM leukocytes were significantly decreased after cells were induced into MDSCs by IL-6 and GM-CSF, and the MDSC induction occurred more rapidly in PTP1B-null mice than in wild-type littermates, suggesting PTP1B as a negative regulator of MDSCs. Third, the adoptive transfer of MDSCs into mice with DSS-colitis significantly attenuated colitis, which accompanies with a decreased serum IL-17 level. Finally, PTP1B deficiency increased the frequency of MDSCs from BM cells likely through enhancing the activities of signal transducer and activator of transcription 3 (STAT3 and Janus kinase 2 (JAK2. In conclusion, our study provides the first evidences that PTP1B deficiency ameliorates murine experimental colitis via expanding MDSCs.