Science.gov

Sample records for 2b holzpellets und

  1. Fit 2-B FATHERS.

    ERIC Educational Resources Information Center

    Maiorano, Joseph J.

    2001-01-01

    Fit 2-B FATHERS is a parenting-skills education program for incarcerated adult males. The goals of this program are for participants to have reduced recidivism rates and a reduced risk of their children acquiring criminal records. These goals are accomplished by helping participants become physically, practically, and socially fit for the demands…

  2. Boeing XF2B-1 (F2B-1)

    NASA Technical Reports Server (NTRS)

    1931-01-01

    Boeing XF2B-1 (F2B-1): Serving as the prototype for the F2B-1 shipboard fighter, the XF2B-1 differed visually in having a pointed spinner and an unbalanced rudder. Like many aircraft of its day, the Boeing model 69 was powered by a Pratt & Whitney Wasp radial engine.

  3. SACALC2B

    2007-02-08

    SACALC2B calculates the average solid angle subtended by a rectangular or circular detector window to a coaxial or non-coaxial rectangular, circular or point source, including where the source and detector planes are not parallel. SACALC_CYL calculates the average solid angle subtended by a cylinder to a rectangular or circular source, plane or thick, at any location and orientation. This is needed, for example, in calculating the intrinsic gamma efficiency of a detector such as amore » GM tube. The program also calculates the number of hits on the cylinder side and on each end, and the average path length through the detector volume (assuming no scattering or absorption). Point sources can be modelled by using a circular source of zero radius.« less

  4. Pancreatic Cancer Stage 2B

    MedlinePlus

    ... 2B Description: Stage IIB pancreatic cancer; drawing shows cancer in the pancreas and in nearby lymph nodes. Also shown are the bile duct, pancreatic duct, and duodenum. Stage IIB pancreatic cancer. Cancer has spread to nearby lymph nodes and ...

  5. Branchen und Unternehmensbereiche

    NASA Astrophysics Data System (ADS)

    Kramer, Regine

    Dieses Kapitel gibt einen Überblick über die Haupteinsatzgebiete von Mathematikern, Informatikern, Naturwissenschaftlern und Ingenieuren in den wichtigsten Wirtschaftsbranchen und Unternehmensbereichen. Dabei werden ausbildungsnahe Aufgabenbereiche ebenso beschrieben wie eher fachferne Tätigkeiten und neben den klassischen Branchen und Berufsbildern auch neue Tätigkeitsfelder für MINT-Fachkräfte beschrieben.

  6. Information und Kommunikation

    NASA Astrophysics Data System (ADS)

    Wesoly, Michael; Ohlhausen, Peter; Bucher, Michael; Hichert, Rolf; Korge, Gabriele; Schnabel, Ulrich; Gairola, Arun; Reichwald, Ralf; Habicht, Hagen; Möslein, Kathrin; Schwarz, Torsten; Schönsleben, Paul; Scherer, Eric; Schloske, Alexander; Adlbrecht, Gerald; Federhen, Jens

    Wissen ist mittlerweile unverzichtbar für den entscheidenden Vorsprung auf dem Markt. Unabhängig davon, ob sich das Wissen in Innovationen, neuen Produkten und Dienstleistungen oder in der Verbesserung interner Unternehmensprozesse manifestiert: Wissen ist Treiber von Innovation, Wissen bringt Schnelligkeit und Wissen ist die Voraussetzung für Problemlösungen [40]. Wissensmanagement ist daher der Schlüssel für Unternehmenserfolg und bezeichnet den "bewussten und systematischen Umgang mit der Ressource Wissen und den zielgerichteten Einsatz von Wissen in der Organisation“ [6]. In dieser umfassenden Sichtweise ist Wissensmanagement ein Begriff, der Konzepte, Strategien und Methoden umfasst.

  7. Peginterferon Alfa-2b (PEG-Intron)

    MedlinePlus

    ... powder at room temperature and away from excess heat and moisture (not in the bathroom).It is best to inject peginterferon alfa-2b solution in vials or injection pens immediately after mixing. If necessary, vials or injection pens containing prepared peginterferon alfa-2b solution may be stored ...

  8. Welt und Wirkungsprinzip

    NASA Astrophysics Data System (ADS)

    Landgraf, Werner

    1997-05-01

    Modell einer kausalen Bewirkung der Welt, und logische, geometrische, physikalische Interprätation dieser Kausalmenge und Fortwirkung der frühsten ihrer sukzessiv als echt Neues bewirkten und durch Vorhandenes oder Späteres nicht darstellbaren oder widerrufbaren Ereignisse als Dimensionen und sie verkörpernde primäre Naturkräfte, mit Korrespondenz zur beobachteten Welt und ihrer grundlegendsten Eigenschaften. Wirklich ist nur was wirkt, wo und wie. Entsprechend ist im Bogenelement statt der Eigenzeit die variante Anzahl Wirkungen relevant, 0 ≈ 1/h2 dS2 - 1/tpl2 (dt2 - 1/c2 {dq12 + G02/G2 [dq2,32 - ...]}) mit G0 = c4lpl/Epl ≈ G. Die heutigen Dimensionen und Naturkräfte entstanden in dieser Reihenfolge, haben 'komplementäre' aber gleichwertige statische und dynamische Aspekte, entsprechend ihren Termen in Bogenelement bzw. Vierervektor, aus derem Vergleich sowie mit denen ihrer Nachbarn folgen Grundgleichungen bzw. Erhaltungssätze. Jeweils individuelle Eigenschaften wie ihre Naturkonstante konkretisieren sie und tragen zu gattungsmäßigen wie globale Affinität und Äquivalenzen bei. Ältestes Gebiet oder räumlicher Rand jeder Dimension sind die ersten vom Vorgänger bewirkten Ereignisse, selbst raumzeitlicher Ursprung des Nachfolgers, dort einmalig und ewig maximal rotverschoben fortwirkend und nicht lokalisierbar, um neue Elementareinheiten verschieden und lichtartig mit deren Verhältnis oder dem ihrer globalen Zustandsgrößen als konstanten Anfangsimpuls, Expansion, Längen- oder Ereignisdichte zueinander. Der Übergang vom diskreten Modell weniger Informationen zum Kontinuum und die Korrespondenz zur Physik ist problemlos, Details wie ein kontinuierlicher, abrupter oder ganz fehlender Abfall der Metrik beim ältesten Gebiet sind aber nur durch Beobachtungen entscheidbar. Erörtert werden allgemeine und individuelle Eigenschaften und ihre Konsequenzen der Dimensionen mit ihren Kräften, selbst und im Verhältnis zueinander, etwa ihrer begrenzten

  9. Lymph- und Immunsystem

    NASA Astrophysics Data System (ADS)

    Perry, Steven F.

    Alle Lebewesen müssen sich gegen Eindringlinge wehren. Ihre Abwehrmechanismen wirken auf verschiedenen Ebenen, von übergeordneten Feindvermeidungsstrategien und Putzverhalten bis hin zu molekularen Erkennungs- und Tötungsmechanismen. Da Eindringlinge über Kontaktflächen mit der Außenwelt, wie z.B. Körperoberfläche, Darmwand und Atmungsoberflächen, in den Organismus gelangen, sind an diesen Stellen immer primäre Abwehrmechanismen zu finden. Dazu zählen (1) Schleimabsonderung (Schleimhäute bei allen Schädeltieren, Fischkiemen, epidermale Schleimdrüsen (Fische, Amphibien)), (2) Stoffwechselgifte und antibakteriell wirkende Substanzen in der Haut (Fische, Amphibien) und im Speichel (Amnioten), (3) Flimmerepithelien zum Abtransport von Eindringlingen und (4) starke Keratinbildung in der mehrschichtigen Epidermis und schützende Strukturen wie Schuppen, Federn und Haare (Amnioten) (S. 20). Auch die starke Säurebildung im Magen kann als Schutz gegen Eindringlinge betrachtet werden.

  10. Investigation of Class 2b Trucks

    SciTech Connect

    Davis, S.C.

    2002-04-03

    The popularity of trucks in the class 2 category--that is, those with a 6,000 to 10,000 pounds (lbs) gross vehicle weight rating (GVWR)--has increased since the late 1970s/early 1980s. The purpose of this research is to identify and examine vehicles in the upper portion of the class 2 weight range (designated as vehicle class 2b) and to assess their impact. Vehicles in class 2b (8,500-10,000 lbs GVWR) include pickup trucks, sport utility vehicles (SUVs), and large vans (i.e., not minivans). Oak Ridge National Laboratory researched each individual truck model to determine which models were class 2b trucks and arrived at four methodologies to derive sales volumes. Two methods--one for calendar year and one for model year sales--were recommended for producing believable and reliable results. The study indicates that 521,000 class 2b trucks were sold in calendar year 1999--6.4% of sales of all trucks under 10,000 lbs. Eighty-two percent of class 2b trucks sold in 1999 were pickups; one third of class 2b trucks sold in 1999 were diesel. There were 5.8 million class 2b trucks on the road in 2000, which amounts to 7.8% of all trucks under 10,000 lbs. Twenty-four percent of the class 2b truck population is diesel. Estimates show that class 2b trucks account for 8% of annual miles traveled by trucks under 10,000 lbs and 9% of fuel use. Data on class 2b trucks are scarce. As the Tier 2 standards, which apply to passenger vehicles in the 8,500-10,000 lb GVWR category, become effective, additional data on class 2b trucks may become available--not only emissions data, but data in all areas. At the moment, distinguishing class 2b trucks from class 2 trucks in general is a substantial task requiring data on an individual model level.

  11. Peginterferon Alfa-2b Injection (Sylatron)

    MedlinePlus

    ... is also available as a different product (PEG-Intron) that is used to treat chronic hepatitis C ( ... to remove it. If you are using Peg-Intron, read the monograph entitled Peginterferon alfa-2b (PEG- ...

  12. Membrane Integration of Poliovirus 2B Viroporin▿

    PubMed Central

    Martínez-Gil, Luis; Bañó-Polo, Manuel; Redondo, Natalia; Sánchez-Martínez, Silvia; Nieva, José Luis; Carrasco, Luis; Mingarro, Ismael

    2011-01-01

    Virus infections can result in a variety of cellular injuries, and these often involve the permeabilization of host membranes by viral proteins of the viroporin family. Prototypical viroporin 2B is responsible for the alterations in host cell membrane permeability that take place in enterovirus-infected cells. 2B protein can be localized at the endoplasmic reticulum (ER) and the Golgi complex, inducing membrane remodeling and the blockade of glycoprotein trafficking. These findings suggest that 2B has the potential to integrate into the ER membrane, but specific information regarding its biogenesis and mechanism of membrane insertion is lacking. Here, we report experimental results of in vitro translation-glycosylation compatible with the translocon-mediated insertion of the 2B product into the ER membrane as a double-spanning integral membrane protein with an N-/C-terminal cytoplasmic orientation. A similar topology was found when 2B was synthesized in cultured cells. In addition, the in vitro translation of several truncated versions of the 2B protein suggests that the two hydrophobic regions cooperate to insert into the ER-derived microsomal membranes. PMID:21835803

  13. Geoinformation und Staat

    NASA Astrophysics Data System (ADS)

    Zypries, Brigitte

    2002-09-01

    Geoinformationen besaßen als Grundlage militärischer Interventionen schon immer einen hohen Stellenwert für den Staat. Im Zeitalter der modernen Informations- und Kommunikationstechnologien wächst in demokratischen Staaten die Bedeutung von Geodaten weit über den Verteidigungsbereich hinaus. Brigitte Zypries, Staatssekretärin im Bundesministerium des Innern (BMI) und Vorsitzende des Interministeriellen Ausschusses für Geoinformationswesen (IMAGI), sprach mit Dipl.-Geogr. Ute C. Bauerüber die Anwendung und Koordinierung von Geodaten in Politik und Staat.

  14. Integument und Anhangsorgane

    NASA Astrophysics Data System (ADS)

    Schliemann, Harald

    Das Integument umhüllt den Wirbeltierkörper lückenlos. In der embryonalen Mundbucht (Stomodaeum) und der Afterbucht (Proctodaeum) grenzt es an die Auskleidung des Darmrohres. Über die generelle Bedeutung einer Haut als Abgrenzung zwischen Körperinnenraum und Außenmedium hinaus hat es bei Schädeltieren ein breites Spektrum von Funktionen. Die wichtigsten sind: Mechanischer Schutz durch Verhornungen und Verknöch erungen; Wundheilung; Schutz vor Wasserverlust; Schutz vor Infektionen durch bakterizide Drüsensekrete und immunkompetente Zellen; Schutz vor kurzwelliger Strahlung durch Pigmente; Schutz vor Überwärmung durch Schweißdrüsensekrete und Schutz vor Wärmeverlust durch Federn und Haare; Ausbildung lokomotorisch wichtiger Strukturen wie Federn, Flug- und Schwimmhäute, Krallen und Hufe; Redukt ion des Strömungswiderstandes durch Dämpfungshaut; Abgabe von Sekreten zur Ernährung (Milch); Ausbildung von Strukturen zu Nahrungserwerb und_-bearbeitung, z. B. Zähne, Barten;

  15. ADORA2b Signaling in Cardioprotection

    PubMed Central

    Gile, Jennifer; Eckle, Tobias

    2016-01-01

    Cardiovascular disease is the number one cause of death worldwide. A powerful strategy for cardioprotection would be to identify specific molecules or targets that mimic ischemic preconditioning (IP), where short non-lethal episodes of ischemia and reperfusion prior to myocardial infarction result in dramatic reduction of infarct sizes. Since 1960 researchers believed that adenosine has a strong cardio-protective potential. In fact, with the discovery of cardiac IP in 1986 by Murry et al., adenosine was the first identified molecule that was used in studying the underlying mechanism of IP. Today we know, based on genetic studies, that adenosine is crucial for IP mediated cardio-protection and that the adenosine receptors ADORA1, ADORA2a and ADORA2b play an important role. However, the ADORA2b receptor is the only receptor so far which has been found to play a role in human and murine myocardial ischemia. With recent advances using tissue specific mice for the ADORA2b, we were able to uncover cardiomyocytes and endothelia as the responsible cell type for cardiac IP. Using a wide search for ADORA2b downstream targets, our group identified the circadian rhythm protein, Period 2 (PER2), as a novel target for IP mediated cardioprotection. Mechanistic studies on PER2 mediated cardioprotection revealed an important role for PER2 in optimizing cardiac metabolism through activation of oxygen saving pathways. Thus, cardiomyocyte or endothelial expressed ADORA2b or the downstream circadian rhythm protein PER2 are key targets for cardiac IP and could represent novel strategies to treat or prevent MI.

  16. Milch, Milchprodukte, Analoge und Speiseeis

    NASA Astrophysics Data System (ADS)

    Coors, Ursula

    Die Produktpalette Milch und Erzeugnisse aus Milch beinhaltet Konsummilch, die aus Milch oder Bestandteilen der Milch hergestellten Milcherzeugnisse wie Sauermilch-, Joghurt-, Kefir-, Buttermilch-, Sahne-, Kondensmilch-, Trockenmilch- und Molkenerzeugnisse, Milchmisch- und Molkenmischprodukte (Produkte mit beigegebenen Lebensmitteln), Milchzucker, Milcheiweißerzeugnisse, Milchfette und Käse.

  17. Neuausrichtung und Konsolidierung

    NASA Astrophysics Data System (ADS)

    Grohmann, Heinz

    Mit der Wahl von Wolfgang Wetzel zum Vorsitzenden der Deutschen Statistischen Gesellschaft im Jahre 1972 begann eine 32jährige Ära, in der die praktische und die theoretische Statistik in einem ausgewogenen Verhältnis gepflegt wurden. Ein regelmäßiger vierjähriger Wechsel im Vorsitz stärkte die Gemeinschaft und die praktische wie die wissenschaftliche Arbeit gleichermaßen. Die jährlichen Hauptversammlungen behandelten gesellschaftlich aktuelle wie zukunftsorientierte Themen, und die Ausschüsse sowie weitere Veranstaltungen gaben Gelegenheit zur Förderung und Pflege einer Vielzahl von Arbeitsgebieten der Statistik. Darüber wird nicht nur in diesem Kapitel, sondern auch in den Teilen II und III des Bandes berichtet.

  18. Falten und fliegen: Papierflieger und ihre Physik

    NASA Astrophysics Data System (ADS)

    Gruber, Werner

    2004-09-01

    Mit Papierfliegern können wichtige Eigenschaften der Aerodynamik anschaulich vermittelt werden: ein Blatt Papier, ein paar Faltungen und schon kann man experimentieren. Allerdings sind beim Trimmen des Fliegers einige Punkte zu beachten. Besonders wichtig ist die Y-Stellung der Flügel, die ihm Flugstabilität verleiht. Ist der Flieger fertig, dann gilt es, die dem Modell am besten angepasste Wurftechnik herauszufinden. Dazu variiert man Wurfgeschwindigkeit und Abwurfwinkel. Den Boden kann ein Papierflieger auf vier prinzipiell verschiedenen Flugkurven erreichen: Optimal ist die Gerade, dann fliegt er am weitesten.

  19. What Happened with Spectrometer Magnet 2B

    SciTech Connect

    Green, Michael A

    2010-05-27

    The spectrometer solenoid is supposed to be the first magnets installed in MICE [1]-[4]. This report described what happened during the test of the MICE spectrometer solenoid 2B. First, the report describes the temperatures in the magnet, the cooler top plate and the shield during the run where the magnet quenched at 258 A. During this quench, a lead between the bottom of the HTS leads and the diode bank burned out causing the magnet to quench. Second, three methods for measuring the net heat flow into the cold mass are described. Third, there is a discussion of possible resistive heating in the HTS leads between liquid helium temperature and the copper plate, which is at about 50 K. Fourth, there is a discussion of the measured first stage heat loads in the magnet, when there is no current in the magnet. The first stage heat load calculations are based on knowing the first stage temperatures of the three two-stage pulse tube coolers and the single stage GM cooler. Fifth, the estimated heat load to the first stage when the magnet has current in it is discussed. Sixth, there is a comparison of the stage 1 heat loads in magnet 1A [5], magnet 2A [6], and magnet 2B [7]. Finally there is a discussion of recommended changes for improving the spectrometer solenoids so that the coolers can keep them cold.

  20. Messung und Analyse

    NASA Astrophysics Data System (ADS)

    Bathelt, Hartmut; Scheinhardt, Michael; Sell, Hendrik; Sottek, Roland; Guidati, Sandro; Helfer, Martin

    Für die Beurteilung von Akustik und Fahrkomfort eines Fahrzeugs gilt in der Fahrzeugentwicklung immer noch der alte Grundsatz: "Der Kunde fährt nicht am Prüfstand, sondern auf der Straße“. Daher werden Gesamtbeurteilungen des Entwicklungsstandes und Konkurrenzvergleiche (Benchmarking) nach wie vor auf der Straße durchgeführt, meist auf ausgewählten Fahrbahnen am Prüfgelände oder im Rahmen der regelmäßigen Winter- und Sommererprobungen unter extremen Witterungsverhältnissen.

  1. Getreide, Brot und Feine Backwaren

    NASA Astrophysics Data System (ADS)

    von Grabowski, Hans-Uwe; Rolfe, Birgit

    Getreide und Getreideerzeugnisse sind ebenso wie Brot und Feine Backwaren nach dem Lebensmittel- und Futtermittel-Gesetzbuch (LFGB) [1] Lebensmittel im Sinne des Artikels 2 der VO (EG) Nr. 178/2002 (BasisVO) (s. auch Kap. 1.6/2.4.1/3.2). Gesetzlich festgelegte Begriffsbestimmungen gibt es für diese Lebensmittel nicht. Man muss sich daher allgemeiner Verkehrsauffassungen bedienen, wie sie von der Deutschen Lebensmittelbuch-Kommission in Form von Leitsätzen erarbeitet und veröffentlicht wurden [2]. Der Gesundheitsschutz und der Schutz des Verbrauchers vor Täuschung sind in der Basis-VO und dem LFGB geregelt.

  2. Telecom 2-B and 2-C (TC2B and TC2C)

    NASA Technical Reports Server (NTRS)

    Dulac, J.; Alvarez, H.

    1991-01-01

    The DSN (Deep Space Network) mission support requirements for Telecom 2-B and 2-C (TC2B and TC2C) are summarized. These Telecom missions will provide high-speed data link applications, telephone, and television service between France and overseas territories as a follow-on to TC2A. Mission objectives are outlined and the DSN support requirements are defined through the presentation of tables and narratives describing the spacecraft flight profile; DSN support coverage; frequency assignments; support parameters for telemetry, command and support systems; and tracking support responsibility.

  3. Unternehmens- und Marktstatistik

    NASA Astrophysics Data System (ADS)

    Grömling, Michael; Scheinost, Ulrich

    Deutschland verfügt über ein gut ausgebautes System amtlicher und nicht amtlicher Unternehmens- und Marktstatistiken, das sich in einem fortwährenden Wandel befindet. Wird es sinnvoll genutzt, können für einzelne Marktteilnehmer wie für die gesamte Gesellschaft kostspielige Fehlentwicklungen vermieden werden. Dazu bedarf es eines sachkundigen Überblicks über die Vielfalt der Statistiken und der zwischen ihnen bestehenden Beziehungen sowie einer ständigen Anpassung an die wirtschaftliche Entwicklung. Als eine mögliche Orientierung kann der auf der Güter- und Faktorebene zu beobachtende Wandel dienen. Einer adäquaten Abbildung der ökonomischen Realität stehen in Deutschland mit seiner starken Verrechtlichung der Statistik jedoch mancherlei Schwierigkeiten im Wege. Teilweise tiefgreifende Reformbestrebungen sind vor allem auf europäischer Ebene im Gange. Als eine ergebnisorientierte Innovation für das Gesamtsystem der Unternehmens- und Marktstatistik wird ein modular aufgebautes System vorgestellt, das auch bei unterschiedlichen und sich wandelnden Rahmenbedingungen schrittweise realisiert werden kann.

  4. Datenintegration und Deduplizierung

    NASA Astrophysics Data System (ADS)

    Bleiholder, Jens; Schmid, Joachim

    In Unternehmen liegen viele Daten heutzutage immer seltener vollständig an einem einzigen physikalischen Ort vor, sondern sind weltweit verteilt. Dies liegt zum einen an der immer besser gewordenen Infrastruktur, die eine solche Verteilung auf einfache Art und Weise ermöglicht, und zum anderen an der Tatsache, dass viele Unternehmen weltweit tätig sind. So fallen Daten weltweit an, werden aber jeweils lokal - vor Ort - gespeichert. Daher müssen oft mehrere Datenquellen genutzt werden, um einen aktuellen, vollständigen und genauen Überblick über die vorhandenen Daten zu gewinnen. Datenintegration hilft, indem sie Daten aus mehreren Quellen zusammenführt und einheitlich darstellt. Diese integrierten Daten können genutzt werden, um sich einen Überblick über das Unternehmen zu verschaffen, z.B. wenn Unternehmen fusionieren und nur noch eine Kundendatenbank bestehen bleiben soll, oder wenn zu einem Kunden die Daten aus den verschiedenen Fachabteilungen zusammengeführt werden sollen. Anhand eines solchen Beispiels, der Integration von Kundendaten zu Kfz- und Lebensversicherungen erläutern wir im Folgenden einzelne Techniken.

  5. Mikrostrukturtechnik und Biomaterialien

    NASA Astrophysics Data System (ADS)

    Guber, Andreas E.; Saile, Volker; Weibezahn, Karl-Friedrich

    In der Biomedizintechnik zeichnet sich derzeit ein Trend zu einer verstärkten Miniaturisierung des operativen Instrumentariums und der Peripheriegeräte ab, da zur sicheren Durchführung vieler minimal invasiv auszuführender chirurgischer Eingriffe sehr kleine Instrumente und Zusatzgeräte benötigt werden. Weiterhin werden für verschiedene Anwendungen im Life-Sciences-Bereich, wie z. B. innerhalb der klinischen Diagnostik und der pharmazeutischen Chemie, in zunehmendem Masse Komponenten mit eingearbeiteten Mikrostrukturen benötigt. Mit den inzwischen verfügbaren mikrotechnischen Herstellungsverfahren (siehe Kapitel 40.2) ist man in der Lage, unterschiedliche geometrische Formen von kleinen dreidimensionalen Bauteilen und Baugruppen im Mikrometerbereich zu fertigen. Für spezielle Anwendungen können aber auch Strukturen im Bereich von einigen 100 nm erzeugt werden. Mikrostrukturierte Komponenten und Baugruppen können entweder in Form von Implantaten in den menschlichen Körper gelangen oder in extrakorporal einsetzbaren Geräten zum Einsatz kommen (siehe Kapitel 40.3). Dabei ist zwischen Kurzzeit- und Langzeitimplantaten zu unterscheiden. Typische Kurzzeitimplantate sind beispielsweise Operationsinstrumente während eines operativen Eingriffes und für kurze Zeiträume gelegte Spezialkatheter zur gezielten Entnahme von Körpersäften oder zur temporären Medikamentenapplikation. Zur Kategorie der Langzeitimplantate gehören beispielsweise auf Dauer eingesetzte Gefässendoprothesen (Stents), Herzschrittmacher, Cochleaimplantate, miniaturisierte Medikamentendosiersysteme auf Basis mikrofluidischer Baugruppen (Mikropumpen, Mikrokanäle, etc.), implantierbare Arrays von Mikroelektroden, welche innerhalb der Neurobionik verstärkt Anwendung finden werden, sowie in der Zukunft auch künstliche Organe.

  6. Synthesis and Electrochemical Properties of Nano-VO2 (B).

    PubMed

    Yang, Yun; Lu, Yong; Wang, Wei; Feng, Chuanqi; Yang, Shuijin

    2016-03-01

    The nano-VO2 (B) has been self-assembly synthesized by hydrothermal method using different templates, which may give them some interesting properties. The as-prepared samples were characterized by X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The electrochemical properties of the samples were investigated. The results show that the hexadecyltrimethyl ammonium bromide (CTAB) (soft template) was used to obtain the VO2 (B1) nanobelts. The flake graphite (hard template) was taken to get the VO2 (B2) nanosheets. The VO2 (B1) nanobelts have higher initial capacity to compare with VO2 (B2). But the VO2 (B2) nanosheets showed better cycling performance than that of VO2 (B1) nanobelts. The nano VO2 (B2) is a promising anode material for lithium ion battery application. PMID:27455666

  7. Karamell und Schokolade optimal

    NASA Astrophysics Data System (ADS)

    Eichhorn, Andreas

    In verschiedenen Situationen in Technik, Wirtschaft oder Politik ist man daran interessiert unter einer Anzahl von möglichen Entscheidungen die jeweils beste auszuwählen, also die optimale Entscheidung zu treffen, die den größtmöglichen Nutzen bringt. In den meisten Fällen sind Nutzen und Entscheidungsalternativen nicht exakt gegeben, Entscheidungen werden dann entweder sprachlichargumentativ ausgewählt und begründet oder gar aus dem Bauch heraus gefällt. In manchen Fällen ist es aber möglich, Entscheidungsalternativen und Nutzen in Zahlen und Formeln so auszudrücken, dass über diese Beschreibung im Prinzip die optimalen Entscheidungen und der maximale Nutzen festgelegt sind. Dabei ist zu beachten, dass bei mehreren (gleichzeitig oder hintereinander) zu treffenden Entscheidungen gewisse Abhängigkeiten zu berücksichtigen sind, bezüglich der möglichen Alternativen. Wenn beispielsweise die Umsetzung einer bestimmten (Teil-)Entscheidung mit bestimmten Kosten verbunden wäre, so stünde dieser Geldbetrag für andere Entscheidungen nicht mehr zur Verfügung.

  8. Technikwissenschaft - Erfinden und Entdecken

    NASA Astrophysics Data System (ADS)

    Linnemann, Gerhard

    Umrissen wird das allgemeine Ziel der Technikwissenschaft, konstruktiv zu verwerten und nicht-natürlich Entdeckbares zu erfinden. Wir befinden uns in einer Umwälzung der Technik im Verlauf der wissenschaftlich-technischen Revolution, auf dem Wege zu einem neuen Techniktyp. Dieser schafft und nutzt die künstliche Intelligenz. Dazu benötigt der in der Technik tätige Mensch spezielle Kenntnisse und Erfahrungen in kreativ-konstruktiver, -gestalterischer und erfinderischer Sicht mit dem Einsatz spezieller Strukturen und Sprachen. Vorschläge zur Arbeitsweise in der Technik werden gegeben.Translated AbstractTechnological Science-Invent and DiscoverThe general aim of engineering science is outlined to utilize results constructively and to invent something that cannot be discovered in nature. We are now in a period of transformation of technology in the course of scientific-technological revolution, on the way to a new type of technology. This new type creates and utilizes artificial intelligence. For this, man acitive in this field requires special knowledge and experiences in a creative, constructive, design-oriented and ultimately inventive way by deploying special structures and languages. There are also made some proposals concerning the method of working in the field of technology.

  9. Patentierung und Patentlage

    NASA Astrophysics Data System (ADS)

    Herrmann, Uwe

    Gewerbliche Schutzrechte nehmen in der nationalen Rechts- und Wirtschaftsordnung sowie auch auf internationaler Ebene stetig an Bedeutung zu. Sie dienen dem Schutz geistigen Eigentums und sind für jeden Gewerbetreibenden nicht nur im Hinblick darauf von Bedeutung, eigene Rechte zu sichern, sondern auch insofern von Relevanz, dass ein Verstoß gegen Rechte Dritter zu vermeiden ist. Zu den gewerblichen Schutzrechten gehören unter anderem Kennzeichenrechte, Geschmacksmusterrechte sowie die sogenannten technischen Schutzrechte in Form des Patents sowie des Gebrauchsmusters. Die folgenden Ausführungen befassen sich ausschließlich mit den technischen Schutzrechten und geben eine kurze Einführung in die Voraussetzungen, das Entstehen und den Wegfall sowie in die Wirkungen technischer Schutzrechte. Beleuchtet wird die Situation im Wesentlichen im Hinblick auf nationale technische Schutzrechte, d. h. auf Deutsche Patente und Gebrauchsmuster sowie auf Europäische Patente, die Schutz in Deutschland entfalten. Die Möglichkeit der Erlangung von Schutzrechten im außereuropäischen Ausland wird nur am Rande gestreift.

  10. 7 CFR 301.85-2b - Exempted articles. 1

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 5 2011-01-01 2011-01-01 false Exempted articles. 1 301.85-2b Section 301.85-2b... § 301.85-2b Exempted articles. 1 1 The articles hereby exempted remain subject to applicable restrictions under other quarantines and other provisions of this subpart. (a) The following articles...

  11. 7 CFR 301.85-2b - Exempted articles. 1

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 5 2012-01-01 2012-01-01 false Exempted articles. 1 301.85-2b Section 301.85-2b... § 301.85-2b Exempted articles. 1 1 The articles hereby exempted remain subject to applicable restrictions under other quarantines and other provisions of this subpart. (a) The following articles...

  12. 7 CFR 301.85-2b - Exempted articles. 1

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 5 2010-01-01 2010-01-01 false Exempted articles. 1 301.85-2b Section 301.85-2b... § 301.85-2b Exempted articles. 1 1 The articles hereby exempted remain subject to applicable restrictions under other quarantines and other provisions of this subpart. (a) The following articles...

  13. 7 CFR 301.85-2b - Exempted articles. 1

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 5 2014-01-01 2014-01-01 false Exempted articles. 1 301.85-2b Section 301.85-2b... § 301.85-2b Exempted articles. 1 1 The articles hereby exempted remain subject to applicable restrictions under other quarantines and other provisions of this subpart. (a) The following articles...

  14. 7 CFR 301.85-2b - Exempted articles. 1

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 5 2013-01-01 2013-01-01 false Exempted articles. 1 301.85-2b Section 301.85-2b... § 301.85-2b Exempted articles. 1 1 The articles hereby exempted remain subject to applicable restrictions under other quarantines and other provisions of this subpart. (a) The following articles...

  15. PHOX2B is a suppressor of neuroblastoma metastasis

    PubMed Central

    Naftali, Osnat; Maman, Shelly; Meshel, Tsipi; Sagi-Assif, Orit; Ginat, Ravit; Witz, Isaac P.

    2016-01-01

    Paired like homeobox 2B (PHOX2B) is a minimal residual disease (MRD) marker of neuroblastoma. The presence of MRD, also referred to as micro-metastases, is a powerful marker of poor prognosis in neuroblastoma. Lung metastasis is considered a terminal event in neuroblastoma. Lung micro-metastatic neuroblastoma (MicroNB) cells show high expression levels of PHOX2B and possess a less malignant and metastatic phenotype than lung macro metastatic neuroblastoma (MacroNB) cells, which hardly express PHOX2B. In vitro assays showed that PHOX2B knockdown in MicroNB cells did not affect cell viability; however it decreased the migratory capacity of the MicroNB-shPHOX2B cells. An orthotopic inoculation of MicroNB-shPHOX2B cells into the adrenal gland of nude mice resulted in significantly larger primary tumors and a heavier micro-metastatic load in the lungs and bone-marrow, than when control cells were inoculated. PHOX2B expression was found to be regulated by methylation. The PHOX2B promoter in MacroNB cells is significantly more methylated than in MicroNB cells. Demethylation assays using 5-azacytidine demonstrated that methylation can indeed inhibit PHOX2B transcription in MacroNB cells. These pre-clinical data strongly suggest that PHOX2B functions as a suppressor of neuroblastoma progression. PMID:26840262

  16. Hepatic SH2B1 and SH2B2 Regulate Liver Lipid Metabolism and VLDL Secretion in Mice

    PubMed Central

    Sheng, Liang; Liu, Yan; Jiang, Lin; Chen, Zheng; Zhou, Yingjiang; Cho, Kae Won; Rui, Liangyou

    2013-01-01

    SH2B1 is an SH2 and PH domain-containing adaptor protein. Genetic deletion of SH2B1 results in obesity, type 2 diabetes, and fatty liver diseases in mice. Mutations in SH2B1 are linked to obesity in humans. SH2B1 in the brain controls energy balance and body weight at least in part by enhancing leptin sensitivity in the hypothalamus. SH2B1 in peripheral tissues also regulates glucose and lipid metabolism, presumably by enhancing insulin sensitivity in peripheral metabolically-active tissues. However, the function of SH2B1 in individual peripheral tissues is unknown. Here we generated and metabolically characterized hepatocyte-specific SH2B1 knockout (HKO) mice. Blood glucose and plasma insulin levels, glucose tolerance, and insulin tolerance were similar between HKO, albumin-Cre, and SH2B1f/f mice fed either a normal chow diet or a high fat diet (HFD). Adult-onset deletion of SH2B1 in the liver either alone or in combination with whole body SH2B2 knockout also did not exacerbate HFD-induced insulin resistance and glucose intolerance. Adult-onset, but not embryonic, deletion of SH2B1 in the liver attenuated HFD-induced hepatic steatosis. In agreement, adult-onset deletion of hepatic SH2B1 decreased the expression of diacylglycerol acyltransferase-2 (DGAT2) and increased the expression of adipose triglyceride lipase (ATGL). Furthermore, deletion of liver SH2B1 in SH2B2 null mice attenuated very low-density lipoprotein (VLDL) secretion. These data indicate that hepatic SH2B1 is not required for the maintenance of normal insulin sensitivity and glucose metabolism; however, it regulates liver triacylglycerol synthesis, lipolysis, and VLDL secretion. PMID:24358267

  17. PTK2b function during fertilization of the mouse oocyte

    SciTech Connect

    Luo, Jinping; McGinnis, Lynda K.; Carlton, Carol; Beggs, Hilary E.; Kinsey, William H.

    2014-08-01

    Highlights: • PTK2b is expressed in oocytes and is activated following fertilization. • PTK2b suppression in oocytes prevents fertilization, but not parthenogenetic activation. • PTK2b suppression prevents the oocyte from fusing with or incorporating bound sperm. • PTK2b suppressed oocytes that fail to fertilize do not exhibit calcium oscillations. - Abstract: Fertilization triggers rapid changes in intracellular free calcium that serve to activate multiple signaling events critical to the initiation of successful development. Among the pathways downstream of the fertilization-induced calcium transient is the calcium-calmodulin dependent protein tyrosine kinase PTK2b or PYK2 kinase. PTK2b plays an important role in fertilization of the zebrafish oocyte and the objective of the present study was to establish whether PTK2b also functions in mammalian fertilization. PTK2b was activated during the first few hours after fertilization of the mouse oocyte during the period when anaphase resumption was underway and prior to the pronuclear stage. Suppression of PTK2b kinase activity in oocytes blocked sperm incorporation and egg activation although sperm-oocyte binding was not affected. Oocytes that failed to incorporate sperm after inhibitor treatment showed no evidence of a calcium transient and no evidence of anaphase resumption suggesting that egg activation did not occur. The results indicate that PTK2b functions during the sperm-egg fusion process or during the physical incorporation of sperm into the egg cytoplasm and is therefore critical for successful development.

  18. Tipps und Tricks

    NASA Astrophysics Data System (ADS)

    Häger, Wolfgang; Bauermeister, Dirk

    Hier wollen wir einige uns nützlich erscheinende Hinweise zur Arbeit mit dem Inventor geben. Dabei geht es vor allem darum, das Arbeiten mit dem Inventor zu vereinfachen. Die Beispiele stellen eine unvollständige Aufzählung dar und sollen dazu anregen, nach alternativen Vorgehensweisen zu suchen (hier sei noch einmal ausdrücklich auf das Internet verwiesen).

  19. Kometen und Asteroiden

    NASA Astrophysics Data System (ADS)

    Borgeest, Ulf; Staude, Jakob; Hahn, Gerhard; Harris, Alan W.; Jaumann, Ralf; Köhler, Ulrich; Kührt, Ekkehard; Schulz, Rita; Neukum, Gerhard; Arnold, Gabriele; Keller, Horst Uwe; Denk, Tilmann; Müller, Thomas; Wulff, André; Maruhn, Nicolaus; Fischer, Daniel; Trieloff, Mario; Althaus, Tilmann

    Contents: Die Kleinkörper des Sonnensystems. Kern, Koma und Schweife. Ziele der Planetenforschung. ROSETTA: Naherkundung von Kometen. Asteroiden: Trümmer aus planetarer Urzeit. Kleinkörper im Infrarotweltall. Selbs beobachten! Apocalypse - not now! Meteoriten - Boten aus der Urzeit des Sonnensystems.

  20. Knockdown of the sodium-dependent phosphate co-transporter 2b (NPT2b) suppresses lung tumorigenesis.

    PubMed

    Hong, Seong-Ho; Minai-Tehrani, Arash; Chang, Seung-Hee; Jiang, Hu-Lin; Lee, Somin; Lee, Ah-Young; Seo, Hwi Won; Chae, Chanhee; Beck, George R; Cho, Myung-Haing

    2013-01-01

    The sodium-dependent phosphate co-transporter 2b (NPT2b) plays an important role in maintaining phosphate homeostasis. In previous studies, we have shown that high dietary inorganic phosphate (Pi) consumption in mice stimulated lung tumorigenesis and increased NPT2b expression. NPT2b has also been found to be highly expressed in human lung cancer tissues. The association of high expression of NPT2b in the lung with poor prognosis in oncogenic lung diseases prompted us to test whether knockdown of NPT2b may regulate lung cancer growth. To address this issue, aerosols that contained small interfering RNA (siRNA) directed against NPT2b (siNPT2b) were delivered into the lungs of K-ras (LA1) mice, which constitute a murine model reflecting human lung cancer. Our results clearly showed that repeated aerosol delivery of siNPT2b successfully suppressed lung cancer growth and decreased cancer cell proliferation and angiogenesis, while facilitating apoptosis. These results strongly suggest that NPT2b plays a role lung tumorigenesis and represents a novel target for lung cancer therapy. PMID:24194864

  1. Structure, functional regulation and signaling properties of Rap2B

    PubMed Central

    QU, DEBAO; HUANG, HUI; DI, JIEHUI; GAO, KEYU; LU, ZHENG; ZHENG, JUNNIAN

    2016-01-01

    The Ras family small guanosine 5′-triphosphate (GTP)-binding protein Rap2B is is a member of the Ras oncogene family and a novel target of p53 that regulates the p53-mediated pro-survival function of cells. The Rap2B protein shares ~90% homology with Rap2A, and its sequence is 70% identical to other members of the Rap family such as RaplA and RaplB. As a result, Rap2B has been theorized to have similar signaling effectors to the GTPase-binding protein Rap, which mediates various biological functions, including the regulation of sterile 20/mitogen-activated proteins. Since its identification in the early 1990s, Rap2B has elicited a considerable interest. Numerous studies indicate that Rap2B exerts specific biological functions, including binding and stimulating phospholipase C-ε and interferon-γ. In addition, downregulation of Rap2B affects the growth of melanoma cells. The present review summarizes the possible effectors and biological functions of Rap2B. Increasing evidence clearly supports the association between Rap2B function and tumor development. Therefore, it is conceivable that anticancer drugs targeting Rap2B may be generated as novel therapies against cancer. PMID:27073477

  2. Presence of histone H2B in Trypanosoma cruzi chromatin.

    PubMed

    Toro, G C; Wernstedt, C; Hellman, U; Galanti, N

    1993-01-01

    The organization of chromatin in protists presents some characteristic features. In Trypanosoma cruzi, no condensation of chromatin into chromosomes is observed during cell division. A systematic characterization of histones should provide information on this peculiar behaviour. Histone H2B from this parasite was characterized by selective dissociation from chromatin in 0.8 M NaCl, by its elution pattern in narrow-bore reversed phase high performance liquid chromatography, by polyacrylamide gel electrophoresis and by partial sequencing of its amino terminal domain. This chromosomal protein differs from histone H2B of other species. The first 12 amino acids are missing which explains its lower molecular weight when compared to human histone H2B. Correspondingly, the amino terminal domain of T. cruzi histone H2B is 25-30% shorter than other histones H2B. Moreover, three out of four acetylation sites present in human histone H2B are missing in T. cruzi histone H2B. The differences in size and in acceptor sites for acetylation of T. cruzi histone H2B when compared to human histone H2B may represent a functional feature to consider for the understanding of the chromatin cycle of condensation in this parasite.

  3. Wirkstoffe, Medikamente und Mathematische Bildverarbeitung

    NASA Astrophysics Data System (ADS)

    Bauer, Günter J.; Lorenz, Dirk A.; Maaß, Peter; Preckel, Hartwig; Trede, Dennis

    Die Entwicklung neuer Medikamente ist langwierig und teuer. Der erste Schritt ist hierbei die Suche nach neuen Wirkstoffkandidaten, die für die Behandlung bislang schwer therapierbarer Krankheiten geeignet sind. Hierfür stehen der Pharma- und Biotechnologieindustrie riesige Substanzbibliotheken zur Verfügung. In diesen Bibliotheken werden die unterschiedlichsten Substanzen gesammelt, die entweder synthetisch hergestellt oder aus Pilzen, Bakterienkulturen und anderen Lebewesen gewonnen werden können.

  4. Scientific core hole Valles caldera No. 2b (VC-2b), New Mexico

    SciTech Connect

    Garner, J.N.; Hulen, J.B.; Lysne, P.; Jacobson, R.; Goff, F.; Nielson, D.L.; Pisto, L.; Criswell, C.W.; Gribble, R.; Utah Univ. Research Inst., Salt Lake City, UT; Sandia National Labs., Albuquerque, NM; Los Alamos National Lab., NM; Utah Univ. Research Inst., Salt Lake City, UT; Tonto Drilling Services, Inc., Salt Lake City, UT; Los Alamo

    1989-01-01

    Research core hole was continuously cored to 1.762 km on the western flank of the caldera's resurgent dome in 1988. Bottom hole temperature is about 295{degree}C within Precambrian (1.5 Ga) quartz monzonite, deep within the liquid-dominated portions of the Sulphur Springs hydrothermal system. VC-2b may be the deepest, hottest, continuously cored hole in North America. Core recovery was 99.2%. The only major drilling problems encountered were when temperatures at the bit exceeded 225{degree}C below depths of about 1000 m. The result of these conditions was loss of viscosity and/or lubricity in the mud, apparently caused by breakdown of the high temperature polymers. Lithologies in caldera-fill indicate the drill site may be proximal to ignimbrite vents and that an intracaldera lake with temperatures approaching boiling formed soon after the caldera itself. Structural correlations between VC-2b and the 528-m-deep companion hole VC-2a indicate the earlier Toledo caldera (1.45 Ma; Otowi Member tuffs) and even older Lower Tuffs caldera experienced no structural resurgence similar to the 1.12 million year old Valles caldera. The hydrothermal system penetrated by these bores, consists of a shallow vapor-rich cap, which has evolved from an earlier 200{degree}C liquid-dominated system, overlying stacked, liquid-dominated zones up to about 300{degree}C. Geochemistry of mud returns collected during drilling suggests chloride-rich geothermal fluids were entering the bore and mixing with the drilling fluids in the fractured lower Paleozoic and Precambrian sections. 23 refs., 5 figs., 1 tab.

  5. In silico analysis of Brucella abortus Omp2b and in vitro expression of SOmp2b

    PubMed Central

    2016-01-01

    Purpose At present, there is no vaccine available for the prevention of human brucellosis. Brucella outer membrane protein 2b (Omp2b) is a 36 kD porin existed in common Brucella pathogens and it is considered as priority antigen for designing a new subunit vaccine. Materials and Methods In the current study, we aimed to predict and analyze the secondary and tertiary structures of the Brucella abortus Omp2b protein, and to predict T-cell and B-cell epitopes with the help of bioinformatics tools. Subsequently, cloning and expression of the short form of Omp2b (SOmp2b) was performed using pET28a expression vector and Escherichia coli BL21 host, respectively. The recombinant SOmp2b (rSOmp2b) was purified with Ni-NTA column. Results The recombinant protein was successfully expressed in E. coli host and purified under denaturation conditions. The yield of the purified rSOmp2b was estimated by Bradford method and found to be 220 µg/mL of the culture. Conclusion Our results indicate that Omp2b protein has a potential to induce both B-cell– and T-cell–mediated immune responses and it can be evaluated as a new subunit vaccine candidate against brucellosis. PMID:26866027

  6. Building Customized University-to-Business (U2B) Partnerships

    ERIC Educational Resources Information Center

    Irvine, George; Verma, Lisa

    2013-01-01

    Continuing education (CE) units throughout the United States have successfully built University-to-Business (U2B) partnerships to provide greater value to their community partners and to increase revenue for the university. Our experience in building U2B partnerships and feedback from our partners--businesses, corporations, state agencies, and…

  7. Slow epidemic of lymphogranuloma venereum L2b strain.

    PubMed

    Spaargaren, Joke; Schachter, Julius; Moncada, Jeanne; de Vries, Henry J C; Fennema, Han S A; Peña, A Salvador; Coutinho, Roel A; Morré, Servaas A

    2005-11-01

    We traced the Chlamydia trachomatis L2b variant in Amsterdam and San Francisco. All recent lymphogranuloma venereum cases in Amsterdam were caused by the L2b variant. This variant was also present in the 1980s in San Francisco. Thus, the current "outbreak" is most likely a slowly evolving epidemic.

  8. Monoclonal Antibodies Against NS2B of Japanese Encephalitis Virus.

    PubMed

    Dong, Qian; Xu, Qiuping; Ruan, Xindi; Huang, Shaomei; Cao, Shengbo

    2015-04-01

    Japanese encephalitis (JE) is one of the most important viral encephalitis, caused by the Japanese encephalitis virus (JEV). The function of non-structural protein 2B (NS2B) mostly remains unclear. In our study, NS2B of Japanese encephalitis virus (JEV) was expressed in Escherichia coli and purified by dialysis. After fusing mouse myeloma cell line SP2/0 with spleen lymphocytes from NS2B protein immunized mice, three clones of monoclonal antibodies (MAbs), named 1B9, 3E12, and 4E6, were generated. The specificity and sensitivity of MAbs were demonstrated by ELISA, indirect immunofluorescence assay, and Western blot. These MAbs will be useful in further exploration of the functions of NS2B and the pathogenesis of Japanese encephalitis virus. PMID:25897607

  9. Substrate- and pH-Specific Antifolate Transport Mediated by Organic Anion-Transporting Polypeptide 2B1 (OATP2B1-SLCO2B1)

    PubMed Central

    Visentin, Michele; Chang, Min-Hwang; Romero, Michael F.; Zhao, Rongbao

    2012-01-01

    Human organic anion-transporting polypeptide (OATP) 2B1 (OATP-B; SLCO2B1) is expressed in the apical membrane of the small intestine and the hepatocyte basolateral membrane and transports structurally diverse organic anions with a wide spectrum of pH sensitivities. This article describes highly pH-dependent OATP2B1-mediated antifolate transport and compares this property with that of sulfobromophthalein (BSP), a preferred OATP2B1 substrate. At pH 5.5 and low substrate concentrations (∼2.5 μM), only [3H]pemetrexed influx [in contrast to methotrexate (MTX), folic acid, and reduced folates] could be detected in OATP2B1-transfected HeLa R1-11 cells that lack endogenous folate-specific transporters. Influx was optimal at pH 4.5 to 5.5, falling precipitously with an increase in pH >6.0; BSP influx was independent of pH. Influx of both substrates at low pH was markedly inhibited by the proton ionophore 4-(trifluoromethoxy)phenylhydrazone; BSP influx was also suppressed at pH 7.4. At 300 μM MTX, influx was one-third that of pemetrexed; influx of folic acid, (6S)5-methyltetrahydrofolate, or (6S)5-formyltetrahydrofolate was not detected. There were similar findings in OATP2B1-expressing Xenopus laevis oocytes. The pemetrexed influx Km was ∼300 μM; the raltitrexed influx Ki was ∼70 μM at pH 5.5. Stable expression of OAPT2B1 in HeLa R1-11 cells resulted in substantial raltitrexed, but modest pemetrexed, growth inhibition consistent with their affinities for this carrier. Hence, OATP2B1 represents a low-affinity transport route for antifolates (relative affinities: raltitrexed > pemetrexed > MTX) at low pH. In contrast, the high affinity of this transporter for BSP relative to antifolates seems to be intrinsic to its binding site and independent of the proton concentration. PMID:22021325

  10. Pyropheophorbide und a as a catabolite of ethylene-induced chlorophyll und a degradation

    SciTech Connect

    Shimokawa, Keishi; Hashizume, Akihito ); Shioi, Yuzo )

    1990-05-01

    An enzyme extract prepared from ethylene-induced degreening Citrus fruits contains chlorophyll (Chl) degrading enzymes. The fate of Chl carbons during an enzymatic degradation was investigated using Chl {und a}-{sup 14}C. Accompanying the disappearance of labelled Chl {und a}, pheophorbide {und a} and pyropheophorbide {und a} appeared and accumulation of pyropheophorbide {und a} was observed. HydroxyChl {und a} was also detected, but this is thought to be an artifact during chromatography. Unlike ethylene-induced Citrus fruits (in vivo), further degradation of pyropheophorbide {und a} did not occur in vitro enzyme system. This suggests that there is a lack of enzyme(s) and/or cofactor(s) for further degradation. It is concluded that Chl {und a} degraded enzymatically by the following order: Chl {und a}, chlorophyllide {und a}, pheophorbide {und a} and pyropheophorbide {und a}.

  11. Bildanalyse in Medizin und Biologie

    NASA Astrophysics Data System (ADS)

    Athelogou, Maria; Schönmeyer, Ralf; Schmidt, Günther; Schäpe, Arno; Baatz, Martin; Binnig, Gerd

    Heutzutage sind bildgebende Verfahren aus medizinischen Untersuchungen nicht mehr wegzudenken. Diverse Methoden - basierend auf dem Einsatz von Ultraschallwellen, Röntgenstrahlung, Magnetfeldern oder Lichtstrahlen - werden dabei spezifisch eingesetzt und liefern umfangreiches Datenmaterial über den Körper und sein Inneres. Anhand von Mikroskopieaufnahmen aus Biopsien können darüber hinaus Daten über die morphologische Eigenschaften von Körpergeweben gewonnen werden. Aus der Analyse all dieser unterschiedlichen Arten von Informationen und unter Konsultation weiterer klinischer Untersuchungen aus diversen medizinischen Disziplinen kann unter Berücksichtigung von Anamnesedaten ein "Gesamtbild“ des Gesundheitszustands eines Patienten erstellt werden. Durch die Flut der erzeugten Bilddaten kommt der Bildverarbeitung im Allgemeinen und der Bildanalyse im Besonderen eine immer wichtigere Rolle zu. Gerade im Bereich der Diagnoseunterstützung, der Therapieplanung und der bildgeführten Chirurgie bilden sie Schlüsseltechnologien, die den Forschritt nicht nur auf diesen Gebieten maßgeblich vorantreiben.

  12. Rf2a and rf2b transcription factors

    DOEpatents

    Beachy, Roger N.; Petruccelli, Silvana; Dai, Shunhong

    2007-10-02

    A method of activating the rice tungro bacilliform virus (RTBV) promoter in vivo is disclosed. The RTBV promoter is activated by exposure to at least one protein selected from the group consisting of Rf2a and Rf2b.

  13. Secretion of human interferon alpha 2b by Streptomyces lividans.

    PubMed

    Pimienta, E; Fando, R; Sánchez, J C; Vallin, C

    2002-02-01

    Biologically active human interferon alpha 2b (HuIFNalpha-2b) was secreted into the culture medium by Streptomyces lividans transformed with recombinant plasmids coding for HuIFNalpha-2b fused to the Streptomyces exfoliatus M11 lipase A signal sequence. Levels were low, 15 or 100 ng/ml, depending on the plasmid used. Neither processed nor unprocessed HuIFNalpha-2b was detected in cell lysates of the transformants secreting the recombinant product. However, the secreted recombinant product was found to partially degrade when cultures reached the stationary phase by the action of an, as yet, unidentified mycelium-associated factor. Experimental evidence suggests that the degrading factor is related to mycelium-associated proteolytic activity.

  14. Crystal structure of eukaryotic translation initiation factor 2B.

    PubMed

    Kashiwagi, Kazuhiro; Takahashi, Mari; Nishimoto, Madoka; Hiyama, Takuya B; Higo, Toshiaki; Umehara, Takashi; Sakamoto, Kensaku; Ito, Takuhiro; Yokoyama, Shigeyuki

    2016-03-01

    Eukaryotic cells restrict protein synthesis under various stress conditions, by inhibiting the eukaryotic translation initiation factor 2B (eIF2B). eIF2B is the guanine nucleotide exchange factor for eIF2, a heterotrimeric G protein consisting of α-, β- and γ-subunits. eIF2B exchanges GDP for GTP on the γ-subunit of eIF2 (eIF2γ), and is inhibited by stress-induced phosphorylation of eIF2α. eIF2B is a heterodecameric complex of two copies each of the α-, β-, γ-, δ- and ε-subunits; its α-, β- and δ-subunits constitute the regulatory subcomplex, while the γ- and ε-subunits form the catalytic subcomplex. The three-dimensional structure of the entire eIF2B complex has not been determined. Here we present the crystal structure of Schizosaccharomyces pombe eIF2B with an unprecedented subunit arrangement, in which the α2β2δ2 hexameric regulatory subcomplex binds two γε dimeric catalytic subcomplexes on its opposite sides. A structure-based in vitro analysis by a surface-scanning site-directed photo-cross-linking method identified the eIF2α-binding and eIF2γ-binding interfaces, located far apart on the regulatory and catalytic subcomplexes, respectively. The eIF2γ-binding interface is located close to the conserved 'NF motif', which is important for nucleotide exchange. A structural model was constructed for the complex of eIF2B with phosphorylated eIF2α, which binds to eIF2B more strongly than the unphosphorylated form. These results indicate that the eIF2α phosphorylation generates the 'nonproductive' eIF2-eIF2B complex, which prevents nucleotide exchange on eIF2γ, and thus provide a structural framework for the eIF2B-mediated mechanism of stress-induced translational control.

  15. Final report on EUROMET PR-K2.b: Comparison on spectral responsivity (300 nm to 1000 nm)

    NASA Astrophysics Data System (ADS)

    Campos, Joaquin; Pons, Alicia; Blattner, Peter; Dubard, Jimmy; Bastie, Jean; Litwiniuk, Lukasz; Pietrzykowski, Jerzy; Smid, Marek; Mihai, Sim; Bos, Daniel; Gran, Jarle; Bazkir, Ozcan; Fäldt, Anne A.

    2013-01-01

    This report contains the results of the regional comparison EUROMET PR-K2.b (registered in the KCDB under the identifier EURAMET.PR-K2.b). Ten laboratories took part in it, including the pilot. In general the results are consistent, with a few exceptions as explained in the report. The comparison gives international linkage in spectral responsivity from 300 nm to 1000 nm to seven European laboratories: Bundesamt für Metrologie und Akkreditierung (METAS), Norwegian Metrology and Accreditation Service (Justervesenet), Central Office of Measures (GUM), National Institute of Metrology (INM-Romania), Optics Laboratory of TUBITAK-UME (UME), Czech Metrology Institute (CMI) and Swedish National Testing and Research Institute (SP). Three laboratories provided the link to CCPR-K2.b: Bureau National de Metrologie (BNM-INM/CNAM), Instituto de Optica 'Daza de Valdés' (IO-CSIC, acting as pilot) and NMi Van Swinden Laboratorium BV (NMi-VSL). Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCPR, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  16. PTK2b function during fertilization of the mouse oocyte.

    PubMed

    Luo, Jinping; McGinnis, Lynda K; Carlton, Carol; Beggs, Hilary E; Kinsey, William H

    2014-08-01

    Fertilization triggers rapid changes in intracellular free calcium that serve to activate multiple signaling events critical to the initiation of successful development. Among the pathways downstream of the fertilization-induced calcium transient is the calcium-calmodulin dependent protein tyrosine kinase PTK2b or PYK2 kinase. PTK2b plays an important role in fertilization of the zebrafish oocyte and the objective of the present study was to establish whether PTK2b also functions in mammalian fertilization. PTK2b was activated during the first few hours after fertilization of the mouse oocyte during the period when anaphase resumption was underway and prior to the pronuclear stage. Suppression of PTK2b kinase activity in oocytes blocked sperm incorporation and egg activation although sperm-oocyte binding was not affected. Oocytes that failed to incorporate sperm after inhibitor treatment showed no evidence of a calcium transient and no evidence of anaphase resumption suggesting that egg activation did not occur. The results indicate that PTK2b functions during the sperm-egg fusion process or during the physical incorporation of sperm into the egg cytoplasm and is therefore critical for successful development.

  17. Expression of zebrafish nos2b surrounds oral cavity.

    PubMed

    Poon, Kar-Lai; Richardson, Michael; Korzh, Vladimir

    2008-06-01

    Inducible nitric oxide synthase (NOS2) catalyzes the production of nitric oxide (NO), and is one of the factors establishing innate immunity. In zebrafish, Nos2 is represented by nos2a and nos2b. Here, we report the cloning and expression pattern of the zebrafish nos2b gene, which does not seem to participate in induced immune response. nos2b was mapped to zebrafish linkage group 15. The spatial and temporal expression pattern of nos2b in embryonic zebrafish was analyzed by whole-mount in situ hybridization. nos2b is expressed constitutively in two primordia located along the ventral midline. The first group of cells contributes to the neurohypophysis. Initially at the level of the ventral hindbrain, the second group of cells migrates closely with the thyroid primordium to its final position at the basihyal by 3 dpf. Thus, the analysis of expression pattern of nos2b reveals complex morphogenetic movements resulting in its expression surrounding the oral cavity.

  18. Beschallungstechnik, Beschallungsplanung und Simulation

    NASA Astrophysics Data System (ADS)

    Ahnert, Wolfgang; Goertz, Anselm

    Die primäre Aufgabe einer Lautsprecheranlage ist es, Musik, Sprache oder auch Signaltöne und Geräusche wiederzugeben. Diese können von einem Tonträger kommen (CD, Sprachspeicher), von einem anderen Ort übertragen (Zuspielung über Radio, TV, Telefon) oder vor Ort erzeugt werden. Letzteres umfasst Konzerte, Ansprachen, Durchsagen oder künstlerische Darbietungen, bei denen es meist darum geht, eine bereits vorhandene Quelle einer größeren oder weiter verteilten Anzahl von Personen zugänglich zu machen.

  19. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

    PubMed Central

    Zanger, Ulrich M.; Klein, Kathrin

    2013-01-01

    Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4–12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems. PMID

  20. Antagonistic effects of extracts from Artemisia rupetris L. and Leontopodium leontopodioides to CC chemokine receptor 2b (CCR2b).

    PubMed

    Yu, Qin-Wei; Hu, Jie; Wang, Hao; Chen, Xin; Zhao, Fang; Gao, Peng; Yang, Qiu-Bin; Sun, Dan-Dan; Zhang, Lu-Yong; Yan, Ming

    2016-05-01

    The present study was designed to establish a suitable assay to explore CCR2b receptor antagonists from the natural products of Artemisia rupetris and Leontopodium leontopodioides. An aequorin assay was developed as a cell-based assay suitable for 384-well microplate and used for screening CCR2b receptor antagonists from natural products. Through establishing suitable conditions, the assay was shown to be suitable for screening of CCR2b receptor antagonists. Seven compounds were identified in preliminary screening. Five of them showed evident dose-response relationship in secondary screening. The structure-activity relationship study suggested that 7-position hydroxyl group of flavonoids was necessary, a polar group should be introduced on the 3-position, and the substituents on 2-position benzene ring of flavonoids have little influence on the potentency of the inhibition activity on CCR2b receptor. The ortho-position dihydroxyl structure in quinic acid compounds may be important. In conclusion, Compounds HR-1, 5, 7, and AR-20, 35 showed activity as antagonist of CCR2b receptor, which shed lights on the development of novel drugs as CCR2b receptor antagonists for preventing inflammation related diseases. PMID:27478099

  1. Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension

    PubMed Central

    Schroer, Alison K.; Chen, Peter; Ryzhova, Larisa M.; Gladson, Santhi; Shay, Sheila; Hutcheson, Joshua D.; Merryman, W. David

    2016-01-01

    Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice. PMID:26863209

  2. Lithium insertion in nanostructured TiO(2)(B) architectures.

    PubMed

    Dylla, Anthony G; Henkelman, Graeme; Stevenson, Keith J

    2013-05-21

    Electric vehicles and grid storage devices have potentialto become feasible alternatives to current technology, but only if scientists can develop energy storage materials that offer high capacity and high rate capabilities. Chemists have studied anatase, rutile, brookite and TiO2(B) (bronze) in both bulk and nanostructured forms as potential Li-ion battery anodes. In most cases, the specific capacity and rate of lithiation and delithiation increases as the materials are nanostructured. Scientists have explained these enhancements in terms of higher surface areas, shorter Li(+) diffusion paths and different surface energies for nanostructured materials allowing for more facile lithiation and delithiation. Of the most studied polymorphs, nanostructured TiO2(B) has the highest capacity with promising high rate capabilities. TiO2(B) is able to accommodate 1 Li(+) per Ti, giving a capacity of 335 mAh/g for nanotubular and nanoparticulate TiO2(B). The TiO2(B) polymorph, discovered in 1980 by Marchand and co-workers, has been the focus of many recent studies regarding high power and high capacity anode materials with potential applications for electric vehicles and grid storage. This is due to the material's stability over multiple cycles, safer lithiation potential relative to graphite, reasonable capacity, high rate capability, nontoxicity, and low cost (Bruce, P. G.; Scrosati, B.; Tarascon, J.-M. Nanomaterials for Rechargeable Lithium Batteries. Angew. Chem., Int. Ed.2008, 47, 2930-2946). One of the most interesting properties of TiO2(B) is that both bulk and nanostructured forms lithiate and delithiate through a surface redox or pseudocapacitive charging mechanism, giving rise to stable high rate charge/discharge capabilities in the case of nanostructured TiO2(B). When other polymorphs of TiO2 are nanostructured, they still mainly intercalate lithium through a bulk diffusion-controlled mechanism. TiO2(B) has a unique open crystal structure and low energy Li

  3. Faszination Weltall. Sehen und Verstehen.

    NASA Astrophysics Data System (ADS)

    Humphrey, C.

    This book is a German translation, by T. Bührke, of the English original "The amateur astronomer's pathfinder" published in 1992. Contents: 1. Die Erde im Universum. 2. Der Nachthimmel. 3. Die Erforschung von Raum und Zeit.

  4. Renaturierung und Management von Heiden

    NASA Astrophysics Data System (ADS)

    Härdtle, Werner; Assmann, Thorsten; van Diggelen, Rudy; von Oheimb, Goddert

    Heiden zählen zu den ältesten und besonders reizvollen Kulturlandschaften Nordwesteuropas. Sie sind bezeichnend für nährstoffarme Böden in wintermilden Gebieten mit hohen Sommerniederschlägen. Während Heiden vor wenigen Jahrhunderten noch weit verbreitet und für manche Landschaften sogar prägend waren, hat sich ihr Areal heute auf wenige, meist in Naturschutzgebieten gelegene Restbestände verkleinert. Zu diesem Rückgang haben maßgeblich Änderungen der Landnutzung, aber auch Nährstoffeinträge aus umgebenden Agrarflächen und atmogene Depositionen beigetragen. In den meisten Ländern der Europäischen Union sind Heiden heute gesetzlich geschützte Ökosysteme, da diese, neben ihrem Erholungswert für den Menschen, Pflanzen- und Tierarten beherbergen, die außerhalb von Heiden nicht oder kaum überlebensfähig sind.

  5. Komet Halley: Bahnelemente und Perihelzeiten

    NASA Astrophysics Data System (ADS)

    Landgraf, Werner

    1985-02-01

    Verbesserte Bahnelemente und Perihelzeiten -2316 bis 2284 für Komet Halley. Zusammenfassung der für ein breiteres Publikum relevantesten Ergebnisse von "On the Motion of Comet Halley". ESTEC EP/14.7/6184 Final Report

  6. Flow Simulation of N2B Hybrid Wing Body Configuration

    NASA Technical Reports Server (NTRS)

    Kim, Hyoungjin; Liou, Meng-Sing

    2012-01-01

    The N2B hybrid wing body aircraft was conceptually designed to meet environmental and performance goals for the N+2 generation transport set by the subsonic fixed wing project. In this study, flow fields around the N2B configuration is simulated using a Reynolds-averaged Navier-Stokes flow solver using unstructured meshes. Boundary conditions at engine fan face and nozzle exhaust planes are provided by response surfaces of the NPSS thermodynamic engine cycle model. The present flow simulations reveal challenging design issues arising from boundary layer ingestion offset inlet and nacelle-airframe interference. The N2B configuration can be a good test bed for application of multidisciplinary design optimization technology.

  7. ORM-Based Semantics of B2B Transactions

    NASA Astrophysics Data System (ADS)

    Balsters, H.; van Blommestein, F.

    After widespread implementation of Enterprise Resource Planning and Personal Information Management, the next wave in the application of ICT is headed towards business to business (B2B) communication. B2B has a number of specific aspects, one of them being negotiation. This aspect has been largely neglected by present implementations of standard EDI- or XML-messaging and by B2B webservice implementations. In this paper a precise model is given of the negotiation process. The requirements of a potential Buyer and the offer of a potential Seller are matched and, if the negotiation is successful, a contract is concluded. The negotiation process model is represented in ORM, extended with dynamic constraints. Our model may be implemented in the databases of the trading partners and in message- or service definitions.

  8. Expanding Interprofessional EHR Data in i2b2

    PubMed Central

    Westra, Bonnie L.; Christie, Beverly; Johnson, Steven G.; Pruinelli, Lisiane; LaFlamme, Anne; Park, Jung In; Sherman, Suzan G.; Byrne, Matthew D.; Ranallo, Piper; Speedie, Stuart

    2016-01-01

    Emerging issues of team-based care, precision medicine, and big data science underscore the need for health information technology (HIT) tools for integrating complex data in consistent ways to achieve the triple aims of improving patient outcomes, patient experience, and cost reductions. The purpose of this study was to demonstrate the feasibility of creating a hierarchical flowsheet ontology in i2b2 using data-derived information models and determine the underlying informatics and technical issues. This study is the first of its kind to use information models that aggregate team-based care across time, disciplines, and settings into 14 information models that were integrated into i2b2 in a hierarchical model. In the process of successfully creating a hierarchical ontology for flowsheet data in i2b2, we uncovered a variety of informatics and technical issues described in this paper. PMID:27570680

  9. Expanding Interprofessional EHR Data in i2b2.

    PubMed

    Westra, Bonnie L; Christie, Beverly; Johnson, Steven G; Pruinelli, Lisiane; LaFlamme, Anne; Park, Jung In; Sherman, Suzan G; Byrne, Matthew D; Ranallo, Piper; Speedie, Stuart

    2016-01-01

    Emerging issues of team-based care, precision medicine, and big data science underscore the need for health information technology (HIT) tools for integrating complex data in consistent ways to achieve the triple aims of improving patient outcomes, patient experience, and cost reductions. The purpose of this study was to demonstrate the feasibility of creating a hierarchical flowsheet ontology in i2b2 using data-derived information models and determine the underlying informatics and technical issues. This study is the first of its kind to use information models that aggregate team-based care across time, disciplines, and settings into 14 information models that were integrated into i2b2 in a hierarchical model. In the process of successfully creating a hierarchical ontology for flowsheet data in i2b2, we uncovered a variety of informatics and technical issues described in this paper. PMID:27570680

  10. Substrate Recognition of Histone H2B by DUBm

    NASA Astrophysics Data System (ADS)

    Henderson, Elizabeth; Berndsen, Christopher; Wolberger, Cynthia

    2011-03-01

    The SAGA complex is a transcriptional coactivator that regulates gene expression in eukaryotes via histone acetylation and deubiquitination, which are crucial for transcription. Our lab is investigating the SAGA-dependent deubiquitination of histone H2B. The deubiquitinating module (DUBm) of SAGA is comprised of a ubiquitin-specific protease, Ubp8, and three other proteins. It is known that Ubp8 cleaves ubiquitin from histone H2B, however, the specific way in which the enzyme binds to the substrate remains elusive. In order to unravel this mechanism, we attempted to determine the crystal structure of the substrate binding complex. We obtained this substrate by exploiting the techniques of intein chemistry to artificially ubiquitinate a histone H2B peptide, which we then co-crystallized with DUBm. Additionally, we synthesized Ub-K63R-linked chains and Ub-K48-linked chains and co-crystallized them with DUBm.

  11. Welt und Wirkungsprinzip (2nd Aufl.)

    NASA Astrophysics Data System (ADS)

    Landgraf, Werner

    2010-03-01

    Modell einer kausalen Bewirkung der Welt, und logische, geometrische, physikalische Interprätation dieser Kausalmenge und Fortwirkung der frühsten ihrer sukzessiv als echt Neues bewirkten und durch Vorhandenes oder Späteres nicht darstellbaren oder widerrufbaren Ereignisse als Dimensionen und sie verkörpernde primäre Naturkräfte, mit Korrespondenz zur beobachteten Welt und ihrer grundlegendsten Eigenschaften. Wirklich ist nur was wirkt, wo und wie. Entsprechend ist im Bogenelement statt der Eigenzeit die variante Anzahl Wirkungen relevant, 0 ≈ 1/h2 dS2 - 1/tpl2 (dt2 - 1/c2 {dq12 + G02/G2 [dq2,32 - ...]}) mit G0 = c4lpl/Epl ≈ G. Die heutigen Dimensionen und Naturkräfte entstanden in dieser Reihenfolge, haben 'komplementäre' aber gleichwertige statische und dynamische Aspekte, entsprechend ihren Termen in Bogenelement bzw. Vierervektor, aus derem Vergleich sowie mit denen ihrer Nachbarn folgen Grundgleichungen bzw. Erhaltungssätze. Jeweils individuelle Eigenschaften wie ihre Naturkonstante konkretisieren sie und tragen zu gattungsmäßigen wie globale Affinität und Äquivalenzen bei. Ältestes Gebiet oder räumlicher Rand jeder Dimension sind die ersten vom Vorgänger bewirkten Ereignisse, selbst raumzeitlicher Ursprung des Nachfolgers, dort einmalig und ewig maximal rotverschoben fortwirkend und nicht lokalisierbar, um neue Elementareinheiten verschieden und lichtartig mit deren Verhältnis oder dem ihrer globalen Zustandsgrößen als konstanten Anfangsimpuls, Expansion, Längen- oder Ereignisdichte zueinander. Der Übergang vom diskreten Modell weniger Informationen zum Kontinuum und die Korrespondenz zur Physik ist problemlos, Details wie ein kontinuierlicher, abrupter oder ganz fehlender Abfall der Metrik beim ältesten Gebiet sind aber nur durch Beobachtungen entscheidbar. Erörtert werden allgemeine und individuelle Eigenschaften und ihre Konsequenzen der Dimensionen mit ihren Kräften, selbst und im Verhältnis zueinander, etwa ihrer begrenzten

  12. DNA encoding an. alpha. sub 2B -adrenergic receptor

    SciTech Connect

    Weinshank, R.L.; Hartig, P.R.

    1991-10-01

    This paper describes an isolated nucleic acid molecule encoding a human alpha 2B-adrenergic receptor. This patent also describes an isolated nucleic acid molecule, wherein the isolated nucleic acid molecule is a DNA molecule and a mammalian cell comprising the DNA molecule.

  13. Kernspaltung und Westintegration Beispiel österreich

    NASA Astrophysics Data System (ADS)

    Forstner, Christian

    Während des Kalten Krieges erreichte in Europa sowohl die Verflechtung physikalischer Forschung mit Staat, Politik und Industrie als auch deren öffentliche Verhandlung und Bewertung eine qualitativ neuartige Dimension. Dieser Aspekt tritt am schärfsten in der Geschichte der Kernphysik und Kerntechnik hervor.

  14. [Evidenzbasierte Leitlinien, Anspruch und Wirklichkeit].

    PubMed

    Gutsch, Johannes; Reif, Marcus; Müller-Hübenthal, Boris; Matthiessen, Peter F

    2016-01-01

    Mit der Konzeption der «Evidenzbasierten Medizin» und den «Evidenzbasierten Leitlinien» soll mithilfe von Formalisierungsprozeduren die ärztliche Irrtumsanfälligkeit kalkulierbar gemacht werden. Quantifizierte objektive Aussagen über die therapeutische Wirksamkeit einer Behandlung sollen die individuelle ärztliche Beurteilung der therapeutischen Wirksamkeit überflüssig machen. Damit kommt der Befolgung von formalen Regeln die entscheidende Rolle bei der Beantwortung der Frage nach dem Wahrheitsgehalt und dem Wirklichkeitsbezug zu. Im Rahmen evidenzbasierter Leitlinien werden vorrangig die Ergebnisse randomisierter kontrollierter Studien (RCT) oder Meta-Analysen solcher Studien herangezogen. Am Beispiel der S3-Leitlinie «Malignes Melanom» wird hier eine evidenzbasierte Urteilsbildung zur Wirksamkeit einer unkonventionellen Therapie - hier mit einem Mistelpräparat - analytisch nachvollzogen. Die für die Beurteilung dieser unkonventionellen Therapie herangezogene randomisierte Studie wird genauer methodisch analysiert. Obwohl sie keine statistisch basierte Aussage zulässt, wurde eine Leitlinienempfehlung auf Basis dieser Studie abgeleitet. Es wird gezeigt, dass 1) allein die Existenz einer einzigen RCT mit hoher Evidenz gleichgesetzt wird, 2) die Ergebnisse trotz beträchtlicher Fehlinterpretationen in eine S3-Leitlinie einfließen und 3) Meinungen anstelle kritischer wissenschaftlicher Analysen verarbeitet werden. Unsere Untersuchung zeigt, dass noch so ausgefeilte epistemologische und methodologische Formalien den Arzt nicht von der Pflicht entbinden, auf Basis seiner ärztlichen Erfahrung und professionellen Kompetenz den Realitätswert der ihm zur Verfügung stehenden Information zu beurteilen. PMID:27161555

  15. [Vegetarische und vegane Ernährung bei Kindern - Stand der Forschung und Forschungsbedarf].

    PubMed

    Keller, Markus; Müller, Stine

    2016-01-01

    Die Praxis vegetarischer Ernährungsformen ist in Deutschland im letzten Jahrzehnt deutlich angestiegen. Allerdings ist der Anteil vegetarischer und veganer Kinder dabei unbekannt. Studien mit Erwachsenen zeigen das präventive Potenzial, aber auch potenzielle Schwachstellen pflanzenbasierter Kostformen. Die Vorteile und Risiken einer vegetarischen bzw. veganen Ernährung im Kindesalter wurden bisher jedoch relativ selten untersucht. Außerdem lassen das unterschiedliche Alter der Kinder, das heterogene Studiendesign sowie die teilweise geringe Probandenzahl der Studien keine verbindlichen Aussagen zu. In dieser Übersichtsarbeit werden die Ergebnisse der wenigen Studien zu vegetarisch und vegan ernährten Kindern (< 12 Jahren) in Nordamerika und Europa zusammengefasst. Demnach lag die Zufuhr von Nahrungsenergie und Makronährstoffen vegetarischer und veganer Kinder meist näher an den Empfehlungen der Fachgesellschaften als die Ernährung gleichaltriger Mischkostkinder. Ebenso wiesen vegetarisch und vegan ernährte Kinder eine höhere Zufuhr von und bessere Versorgung mit verschiedenen Vitaminen und Mineralstoffen auf. Häufiger zeigten sich jedoch Defizite bei Vitamin B12, Zink, Kalzium, Eisen und Vitamin D. Das Wachstum und die Entwicklung vegetarisch und vegan ernährter Kinder entsprachen weitgehend den Referenzstandards, wobei sie dazu tendierten, leichter, schlanker und (< 5 Jahren) auch kleiner zu sein. Aufgrund der unzureichenden Studienlage besteht erheblicher Forschungsbedarf zu den Auswirkungen einer vegetarischen und veganen Ernährung im Kindesalter.

  16. [Vegetarische und vegane Ernährung bei Kindern - Stand der Forschung und Forschungsbedarf].

    PubMed

    Keller, Markus; Müller, Stine

    2016-01-01

    Die Praxis vegetarischer Ernährungsformen ist in Deutschland im letzten Jahrzehnt deutlich angestiegen. Allerdings ist der Anteil vegetarischer und veganer Kinder dabei unbekannt. Studien mit Erwachsenen zeigen das präventive Potenzial, aber auch potenzielle Schwachstellen pflanzenbasierter Kostformen. Die Vorteile und Risiken einer vegetarischen bzw. veganen Ernährung im Kindesalter wurden bisher jedoch relativ selten untersucht. Außerdem lassen das unterschiedliche Alter der Kinder, das heterogene Studiendesign sowie die teilweise geringe Probandenzahl der Studien keine verbindlichen Aussagen zu. In dieser Übersichtsarbeit werden die Ergebnisse der wenigen Studien zu vegetarisch und vegan ernährten Kindern (< 12 Jahren) in Nordamerika und Europa zusammengefasst. Demnach lag die Zufuhr von Nahrungsenergie und Makronährstoffen vegetarischer und veganer Kinder meist näher an den Empfehlungen der Fachgesellschaften als die Ernährung gleichaltriger Mischkostkinder. Ebenso wiesen vegetarisch und vegan ernährte Kinder eine höhere Zufuhr von und bessere Versorgung mit verschiedenen Vitaminen und Mineralstoffen auf. Häufiger zeigten sich jedoch Defizite bei Vitamin B12, Zink, Kalzium, Eisen und Vitamin D. Das Wachstum und die Entwicklung vegetarisch und vegan ernährter Kinder entsprachen weitgehend den Referenzstandards, wobei sie dazu tendierten, leichter, schlanker und (< 5 Jahren) auch kleiner zu sein. Aufgrund der unzureichenden Studienlage besteht erheblicher Forschungsbedarf zu den Auswirkungen einer vegetarischen und veganen Ernährung im Kindesalter. PMID:27160086

  17. "IARC group 2B Carcinogens" reported in cigarette mainstream smoke.

    PubMed

    Smith, C J; Perfetti, T A; Mullens, M A; Rodgman, A; Doolittle, D J

    2000-09-01

    In the third and final part of a series surveying the international literature on the "IARC carcinogens" in cigarette mainstream smoke, the "IARC Group 2B carcinogens" are reviewed. A search of the published literature shows that of 227 chemical components classified as Group 2B, that is, "possible carcinogens," by the International Agency for Research on Cancer (IARC), 48 have previously been reported in cigarette mainstream smoke. Owing to its highly interactive molecular nature, removal from or inhibition of a given mutagenic or carcinogenic chemical within the complex aerosol mixture cannot reliably be predicted to reduce either the overall mutagenicity or carcinogenicity. However, in the absence of experimental data demonstrating an increase in adverse biological activity resulting from removal or inhibition of a potentially carcinogenic constituent, negation of the activity of the potential carcinogen may be considered as a desirable circumstance.

  18. Structural stability of W2B5 under high pressure

    NASA Astrophysics Data System (ADS)

    Kumar, N. R. Sanjay; Shekar, N. V. Chandra; Sahu, P. Ch.

    2015-05-01

    High-pressure structural stability studies have been carried out on tungsten boride W2B5 up to maximum pressure of 36 GPa using a Mao-Bell diamond-anvil cell at beamline BR-12 of the ELETTRA synchrotron facility (λ = 0.68881 Å). The hexagonal phase (S.G:P63/mmc) of W2B5 is stable up to the maximum pressure studied. The bulk modulus is estimated to be ~347 GPa using the Birch-Murnaghan equation of state. The variation of lattice parameters and bond lengths B-B and W-B have been studied and the c-axis is seen to be marginally more compressible than the a-axis.

  19. Chemical Reactivity Perspective into the Group 2B Metals Halides.

    PubMed

    Özen, Alimet Sema; Akdeniz, Zehra

    2016-06-30

    Chemical reactivity descriptors within the conceptual density functional theory can be used to understand the nature of the interactions between two monomers of the Group 2B metal halides. This information might be valuable in the development of adequate force law parameters for simulations in the liquid state. In this study, MX2 monomers and dimers, where M = Zn, Cd, Hg and X = F, Cl, Br, I, were investigated in terms of chemical reactivity descriptors. Relativistic effects were taken into account using the effective core potential (ECP) approach. Correlations were produced between global and local reactivity descriptors and dimerization energies. Results presented in this work represent the first systematic investigation of Group 2B metal halides in the literature from a combined point of view of both relativistic effects and chemical reactivity descriptors. Steric effects were found to be responsible for the deviation from the chemical reactivity principles. They were introduced into the chemical reactivity descriptors such as local softness.

  20. Agent-based services for B2B electronic commerce

    NASA Astrophysics Data System (ADS)

    Fong, Elizabeth; Ivezic, Nenad; Rhodes, Tom; Peng, Yun

    2000-12-01

    The potential of agent-based systems has not been realized yet, in part, because of the lack of understanding of how the agent technology supports industrial needs and emerging standards. The area of business-to-business electronic commerce (b2b e-commerce) is one of the most rapidly developing sectors of industry with huge impact on manufacturing practices. In this paper, we investigate the current state of agent technology and the feasibility of applying agent-based computing to b2b e-commerce in the circuit board manufacturing sector. We identify critical tasks and opportunities in the b2b e-commerce area where agent-based services can best be deployed. We describe an implemented agent-based prototype system to facilitate the bidding process for printed circuit board manufacturing and assembly. These activities are taking place within the Internet Commerce for Manufacturing (ICM) project, the NIST- sponsored project working with industry to create an environment where small manufacturers of mechanical and electronic components may participate competitively in virtual enterprises that manufacture printed circuit assemblies.

  1. Restaurierung von Seen und Renaturierung von Seeufern

    NASA Astrophysics Data System (ADS)

    Grüneberg, Björn; Ostendorp, Wolfgang; Leßmann, Dieter; Wauer, Gerlinde; Nixdorf, Brigitte

    Süßwasserseen haben als ökosysteme und Lebensraum für Pflanzen und Tiere eine herausragende Bedeutung für die Artenvielfalt auf der Erde und prägen als Landschaftselemente unsere natürliche Umwelt. Seen fungieren als natürliche Stoffsenken, vor allem für Kohlenstoff und Nährstoffe, aber auch als Senken für in ihren Einzugsgebieten emittierte gelöste und feste Schadstoffe. Darüber hinaus ist Wasser eine wichtige Naturressource. Süßwasserseen stellen in den meisten Regionen der Erde lebenswichtige Quellen für die Versorgung mit Trinkwasser und tierischem Eiweiß (Fischfang) dar. Sie dienen als Wasserspeicher für die landwirtschaftliche und industrielle Nutzung. Auch für Erholungsaktivitäten des Menschen kommt ihnen eine große Bedeutung zu.

  2. Bewegungsapparat: Postcraniales Skelett und Muskulatur

    NASA Astrophysics Data System (ADS)

    Fischer, Martin S.

    Der Bewegungsapparat bestimmt die Form des Wirbeltierkörpers. So lässt sich z. B. aus der Gestalt eines Fisches auf seine bevorzugt e Schwimmweise schließen (S. 61). Bei den aquatisch en Schädeltieren dominiert die Fortbewegung mit axialem Antrieb; bei den meisten Tetrapoda findet sich eine Kombination aus axialem Antrieb und Bewegung durch Gliedmaßen. Selbst beim höchst spezialisierten Gang, der bipeden Bewegung des Menschen, sind Torsionsbewegungen des Rumpfes noch maßgeblich und bestimmen auch die Grundform des menschlichen Körpers (z. B. die Taille). Obwohl die verschiedenen Antriebsmechanismen eine funktionelle Einheit bilden, werden im Folgenden das Axialskelett sowie der Schulter- und Beckengürtel mit den zugehörigen Extremitäten getrennt besprochen.

  3. Kosmologie und Teilchenphysik.

    NASA Astrophysics Data System (ADS)

    Appenzeller, I.

    This book is a selection of 17 articles published in the journal "Spektrum der Wissenschaft". The original English versions of the papers were first published in "Scientific American". Contents: 1. Einführung (I. Appenzeller). 2. Sehr große Strukturen im Universum (J. O. Burns). 3. Die großräumigen Eigenbewegungen der Galaxien (A. Dressler). 4. Dunkle Materie im Universum (L. M. Krauss). 5. Der doppelte Beta-Zerfall (M. K. Moe, S. P. Rosen). 6. Quark-Lepton Familien (D. B. Cline). 7. Beschleunigerexperimente testen kosmologische Theorien (D. N. Schramm, G. Steigman). 8. Das Rätsel der kosmologischen Konstanten (L. Abbott). 9. Das Higgs-Boson (M. J. G. Veltman). 10. Die Suche nach dem Protonenzerfall (J. M. LoSecco, F. Reines, D. Sinclair). 11. Das inflationäre Universum (A. H. Guth, P. J. Steinhardt). 12. Die fünfte Dimension (E. Schmutzer). 13. Die verborgenen Dimensionen der Raumzeit (D. Z. Freedman, P. van Nieuwenhuizen). 14. Ist die Natur supersymmetrisch? (H. E. Haber, G. L. Kane). 15. Schwerkraft und Antimaterie (T. Goldman, R. J. Hughes, M. M. Nieto). 16. Superstrings (M. B. Green). 17. Kosmische Strings (A. Vilenkin).

  4. The ISS 2B PVTCS Ammonia Leak: An Operational History

    NASA Technical Reports Server (NTRS)

    Vareha, Anthony

    2014-01-01

    In 2006, the Photovoltaic Thermal Control System (PVTCS) for the International Space Station's 2B power channel began leaking ammonia at a rate of approximately 1.5lbm/year (out of a starting approximately 53lbm system ammonia mass). Initially, the operations strategy was "feed the leak," a strategy successfully put into action via Extra Vehicular Activity during the STS-134 mission. During this mission the system was topped off with ammonia piped over from a separate thermal control system. This recharge was to have allowed for continued power channel operation into 2014 or 2015, at which point another EVA would have been required. Without these periodic EVAs to refill the 2B coolant system, the channel would eventually leak enough fluid as to risk pump cavitation and system failure, resulting in the loss of the 2B power channel - the most critical of the Space Station's 8 power channels. In mid-2012, the leak rate increased to approximately 5lbm/year. Once discovered, an EVA was planned and executed within a 5 week timeframe to drastically alter the architecture of the PVTCS via connection to a dormant thermal control system not intended to be utilized as anything other than spare components. The purpose of this rerouting of the TCS was to increase system volume and to isolate the photovoltaic radiator, thought to be the likely leak source. This EVA was successfully executed on November 1st, 2012 and left the 2B PVTCS in a configuration where the system was now being adequately cooled via a totally different radiator than what the system was designed to utilize. Unfortunately, data monitoring over the next several months showed that the isolated radiator was not leaking, and the system itself continued to leak steadily until May 9th, 2013. It was on this day that the ISS crew noticed the visible presence of ammonia crystals escaping from the 2B channel's truss segment, signifying a rapid acceleration of the leak from 5lbm/year to 5lbm/day. Within 48 hours of the

  5. Anisotropic elastic and vibrational properties of Ru2B3 and Os2B3: a first-principles investigation

    NASA Astrophysics Data System (ADS)

    Ozisik, Haci; Deligoz, Engin; Surucu, Gokhan; Bogaz Ozisik, Havva

    2016-07-01

    The structural, mechanical and lattice dynamical properties of Ru2B3 and Os2B3 have been investigated by using a first-principles method based on the density functional theory within the generalized gradient approximation. The single crystal elastic constants are numerically estimated using strain–stress approach. The polycrystalline aggregate elastic parameters are calculated from the single elastic constants via the Voigt–Reuss–Hill approximations. Subsequently, the ductility and brittleness are characterized with the estimation from Pugh’s rule (B/G) and Cauchy pressure. Additionally, the Debye temperature is calculated from the average elastic wave velocity obtained from bulk and shear moduli. The calculated parameters are consistent with the previous experimental and theoretical data. These borides are both mechanically and dynamically stable in the considered structure.

  6. Magnetospheric Multiscale Mission (MMS) Phase 2B Navigation Performance

    NASA Technical Reports Server (NTRS)

    Scaperoth, Paige Thomas; Long, Anne; Carpenter, Russell

    2009-01-01

    The Magnetospheric Multiscale (MMS) formation flying mission, which consists of four spacecraft flying in a tetrahedral formation, has challenging navigation requirements associated with determining and maintaining the relative separations required to meet the science requirements. The baseline navigation concept for MMS is for each spacecraft to independently estimate its position, velocity and clock states using GPS pseudorange data provided by the Goddard Space Flight Center-developed Navigator receiver and maneuver acceleration measurements provided by the spacecraft's attitude control subsystem. State estimation is performed onboard in real-time using the Goddard Enhanced Onboard Navigation System flight software, which is embedded in the Navigator receiver. The current concept of operations for formation maintenance consists of a sequence of two maintenance maneuvers that is performed every 2 weeks. Phase 2b of the MMS mission, in which the spacecraft are in 1.2 x 25 Earth radii orbits with nominal separations at apogee ranging from 30 km to 400 km, has the most challenging navigation requirements because, during this phase, GPS signal acquisition is restricted to less than one day of the 2.8-day orbit. This paper summarizes the results from high-fidelity simulations to determine if the MMS navigation requirements can be met between and immediately following the maintenance maneuver sequence in Phase 2b.

  7. Abdichtungen im Verbund mit Fliesen und Platten

    NASA Astrophysics Data System (ADS)

    Platts, Thomas

    Abdichtungen im Verbund mit Fliesen und Platten, im Folgenden auch als Verbundabdichtungen oder mit Kurzzeichen als AIV bezeichnet, haben sich in der Baupraxis insbesondere in Innenräumen wegen des vereinfachten konstruktiven Aufbaus gegenüber Bahnenabdichtungen nach DIN 18195-5 [14.1] in der Mehrzahl der Ausführungen durchgesetzt und bewährt. Sie können im Innen- und Außenbereich angeordnet werden und sind dadurch gekennzeichnet, dass die Nutzschicht in Boden- und Wandbereichen im Dünnbettverfahren unmittelbar auf die Abdichtung aufgebracht wird. Aufwändige Zwischenschichten oder Einbauteile wie armierter Putz, Telleranker etc. entfallen (Bild 14.1) und es lassen sich geringere Aufbauhöhen realisieren.

  8. The cyclotron energization through auroral wave experiments (CENTAUR 2B)

    NASA Technical Reports Server (NTRS)

    Winningham, J. D.

    1992-01-01

    The CENTAUR 2B mission, a dual payload program, is in many aspects the same as the previous missions from Cape Perry and Norway in 1985. It was planned that these payloads would be launched from Andoya, Norway, Nov. 1989 from the Universal II launcher. The payloads are identical, but would have been launched at different azimuths as far north and as far west as possible. Particle experiments include the angular resolving energy analyzer (AREA), the fast ion mass spectrometer (FIMS), the spectrographic particle images (SPI), and finally, the differential ion flux probe (DIFP). SwRI was responsible for the scientific payload, which includes the power supplies, the power supply interfacing, the manipulating of the data from the instruments to format it for the telemetry system, all mechanical structure and restraint mechanisms, and the payload subskin. The status of the various components of this program is given.

  9. Semantic ETL into i2b2 with Eureka!

    PubMed Central

    Post, Andrew R.; Krc, Tahsin; Rathod, Himanshu; Agravat, Sanjay; Mansour, Michel; Torian, William; Saltz, Joel H.

    Clinical phenotyping is an emerging research information systems capability. Research uses of electronic health record (EHR) data may require the ability to identify clinical co-morbidities and complications. Such phenotypes may not be represented directly as discrete data elements, but rather as frequency, sequential and temporal patterns in billing and clinical data. These patterns’ complexity suggests the need for a robust yet flexible extract, transform and load (ETL) process that can compute them. This capability should be accessible to investigators with limited ability to engage an IT department in data management. We have developed such a system, Eureka! Clinical Analytics. It extracts data from an Excel spreadsheet, computes a broad set of phenotypes of common interest, and loads both raw and computed data into an i2b2 project. A web-based user interface allows executing and monitoring ETL processes. Eureka! is deployed at our institution and is available for deployment in the cloud. PMID:24303265

  10. Semantic ETL into i2b2 with Eureka!

    PubMed

    Post, Andrew R; Krc, Tahsin; Rathod, Himanshu; Agravat, Sanjay; Mansour, Michel; Torian, William; Saltz, Joel H

    2013-01-01

    Clinical phenotyping is an emerging research information systems capability. Research uses of electronic health record (EHR) data may require the ability to identify clinical co-morbidities and complications. Such phenotypes may not be represented directly as discrete data elements, but rather as frequency, sequential and temporal patterns in billing and clinical data. These patterns' complexity suggests the need for a robust yet flexible extract, transform and load (ETL) process that can compute them. This capability should be accessible to investigators with limited ability to engage an IT department in data management. We have developed such a system, Eureka! Clinical Analytics. It extracts data from an Excel spreadsheet, computes a broad set of phenotypes of common interest, and loads both raw and computed data into an i2b2 project. A web-based user interface allows executing and monitoring ETL processes. Eureka! is deployed at our institution and is available for deployment in the cloud. PMID:24303265

  11. Study of Subsonic Flow Over a TOW 2B Missile

    NASA Astrophysics Data System (ADS)

    Goudarzi, Koorosh; Jamali, Mehdi

    2016-01-01

    The objective of this investigation is to study the subsonic flow over a missile. In this paper, a model of TOW 2B missile is studied. Two computational approaches are being explored, namely solutions based on the Reynolds-averaged compressible Navier-Stokes equations and solutions based on the inviscid flow (small disturbance theory). The simulations are performed at the Mach number of 0.6, 0.7, 0.8, 0.9 and 1.0 at four angles of attack of 2, 4, 6 and 8 degree. Results obtained from analytical simulation are compared with numerical data. It is found that lift and drag coefficients would go up by increasing of the angle of attack and the Mach number. Trend of changes of the results that obtained from the small disturbance theory is roughly as same as the numeric solution.

  12. Semantic ETL into i2b2 with Eureka!

    PubMed

    Post, Andrew R; Krc, Tahsin; Rathod, Himanshu; Agravat, Sanjay; Mansour, Michel; Torian, William; Saltz, Joel H

    2013-01-01

    Clinical phenotyping is an emerging research information systems capability. Research uses of electronic health record (EHR) data may require the ability to identify clinical co-morbidities and complications. Such phenotypes may not be represented directly as discrete data elements, but rather as frequency, sequential and temporal patterns in billing and clinical data. These patterns' complexity suggests the need for a robust yet flexible extract, transform and load (ETL) process that can compute them. This capability should be accessible to investigators with limited ability to engage an IT department in data management. We have developed such a system, Eureka! Clinical Analytics. It extracts data from an Excel spreadsheet, computes a broad set of phenotypes of common interest, and loads both raw and computed data into an i2b2 project. A web-based user interface allows executing and monitoring ETL processes. Eureka! is deployed at our institution and is available for deployment in the cloud.

  13. Integrated Product and Process Data for B2B Collaboration

    SciTech Connect

    Kulvatunyou, Boonserm; Ivezic, Nenad; Jones, Albert; Wysk, Richard A.

    2003-09-01

    Collaborative development of engineered products in a business-to-business (B2B) environment will require more than just the selection of components from an on-line catalogue. It will involve the electronic exchange of product, process, and production engineering information during both design and manufacturing. While the state-of-the-practice does include a variety of ways to exchange product data electronically, it does not extend to the exchange of manufacturing process data. The reason is simple; process data is usually tied to specific manufacturing resources. These resources are not known typically at product development time. This paper proposes an approach, called an Integrated Product and Process Data (IPPD), where manufacturing process data is considered during product development. This approach replaces traditional process plans, which are resource specific, with a resource-independent process representation. Such a representation will allow a much wider collaboration among business partners and provide the necessary base for collaborative product development.

  14. Structure of human nucleosome containing the testis-specific histone variant TSH2B

    SciTech Connect

    Urahama, Takashi; Horikoshi, Naoki; Osakabe, Akihisa; Tachiwana, Hiroaki; Kurumizaka, Hitoshi

    2014-03-25

    The crystal structure of human nucleosome containing the testis-specific TSH2B variant has been determined. The TSH2B Ser85 residue does not interact with H4 in the nucleosome, and induces a local structural difference between TSH2B and H2B in nucleosomes. The human histone H2B variant TSH2B is highly expressed in testis and may function in the chromatin transition during spermatogenesis. In the present study, the crystal structure of the human testis-specific nucleosome containing TSH2B was determined at 2.8 Å resolution. A local structural difference between TSH2B and canonical H2B in nucleosomes was detected around the TSH2B-specific amino-acid residue Ser85. The TSH2B Ser85 residue does not interact with H4 in the nucleosome, but in the canonical nucleosome the H2B Asn84 residue (corresponding to the TSH2B Ser85 residue) forms water-mediated hydrogen bonds with the H4 Arg78 residue. In contrast, the other TSH2B-specific amino-acid residues did not induce any significant local structural changes in the TSH2B nucleosome. These findings may provide important information for understanding how testis-specific histone variants form nucleosomes during spermatogenesis.

  15. SH2B1 regulation of energy balance, body weight, and glucose metabolism

    PubMed Central

    Rui, Liangyou

    2014-01-01

    The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo- or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuron-specific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans. PMID:25126397

  16. Physik gestern und heute Das Eiskalorimeter

    NASA Astrophysics Data System (ADS)

    Heering, P.

    2003-07-01

    Kalorimetrische Messungen gehören heute zum experimentellen Standardrepertoire im Bereich der Thermodynamik und der physikalischen Chemie. Das erste Gerät für derartige Messungen entwickelten Ende des 18. Jahrhunderts die französischen Wissenschaftler Antoine Laurent Lavoisier und Pierre Simon de Laplace.

  17. Natural releases from contaminated groundwater, Example Reference Biosphere 2B.

    PubMed

    Simón, I; Naito, M; Thorne, M C; Walke, R

    2005-01-01

    Safety assessment is a tool which, by means of an iterative procedure, allows the evaluation of the performance of a disposal system and its potential impact on human health and the environment. Radionuclides from a deep geological disposal facility may not reach the surface environment until many tens of thousands of years after closure of the facility. The BIOMASS Programme on BIOsphere Modelling and ASSessment developed Examples of "Reference Biospheres" to illustrate the use of the methodology and to demonstrate how biosphere models can be developed and justified as being fit for purpose. The practical examples are also intended to be useful in their own right. The Example Reference Biosphere 2B presented here involves the consideration of alternative types of geosphere-biosphere interfaces and calculation of doses to members of hypothetical exposure groups arising from a wide range of exposure pathways within agricultural and semi-natural environments, but without allowing for evolution of the corresponding biosphere system. The example presented can be used as a generic analysis in some situations although it was developed around a relatively specific conceptual model. It should be a useful practical example, but the above numerical results are not intended to be understood as prescribed biosphere 'conversion factors'.

  18. BRI2 (ITM2b) Inhibits Aβ Deposition in Vivo

    PubMed Central

    Kim, Jungsu; Miller, Victor M.; Levites, Yona; West, Karen Jansen; Zwizinski, Craig W.; Moore, Brenda D.; Troendle, Fredrick J.; Bann, Maralyssa; Verbeeck, Christophe; Price, Robert W.; Smithson, Lisa; Sonoda, Leilani; Wagg, Kayleigh; Rangachari, Vijayaraghavan; Zou, Fanggeng; Younkin, Steven G.; Graff-Radford, Neill; Dickson, Dennis; Rosenberry, Terrone; Golde, Todd E.

    2008-01-01

    Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid β precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer’s disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Aβ1-40 transgenes in amyloid β protein precursor (APP) mouse models. Expression of BRI2-Aβ1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild type human BRI2 reduces cerebral Aβ deposition in an AD mouse model. Additional data indicate that the 23 amino acid peptide, Bri23, released from BRI2 by normal processing is present in human cerebrospinal fluid (CSF), inhibits Aβ aggregation in vitro, and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Aβ deposition in vivo. PMID:18524908

  19. Molecular characterization of an. alpha. sub 2B -adrenergic receptor

    SciTech Connect

    Harrison, J.K.; Dewan Zeng; D'Angelo, D.D.; Tucker, A.L.; Zhihong Lu; Barber, C.M.; Lynch, K.R. )

    1990-02-26

    {alpha}{sub 2}-Adrenergic receptors comprise a heterogeneous population based on pharmacologic and molecular evidence. The authors have isolated a cDNA clone (pRNG{alpha}2) encoding a previously undescribed third subtype of an {alpha}{sub 2}-adrenergic receptor from a rat kidney cDNA library. The library was screened with an oligonucleotide encoding a highly conserved region found in all biogenic amine receptors described to date. The deduced amino acid sequence displays many features of G-protein coupled receptors with exception of the absence of the consensus N-linked glycosylation site at the amino terminus. Membranes prepared from COS-1 cells transfected with pRNG{alpha}2 display high affinity and saturable binding to {sup 3}H-rauwolscine (K{sub d}=2 nM).Competition curve data analysis shows that pRNG{alpha}2 protein binds to a variety of adrenergic drugs with the following rank order of potency: yohimbine {ge} cholorpromazine > prazosin {ge} clonidine > norepinephrine {ge} oxymetazoline. pRNG{alpha}2 RNA accumulates in both adult rat kidney and rat neonatal lung (predominant species is 4.0 kb). They conclude that pRNG{alpha}2 likely represents a cDNA for the {alpha}{sub 2B}-adrenergic receptor.

  20. Remission of liver fibrosis by interferon-alpha 2b.

    PubMed

    Moreno, M G; Muriel, P

    1995-08-01

    Fibrosis is a dynamic process associated with the continuous deposition and resorption of connective tissue, mainly collagen. Therapeutic strategies are emerging by which this dynamic process can be modulated. Since interferons are known to inhibit collagen production, the aim of this study was to investigate if the administration of interferon-alpha 2b (IFN-alpha) can restore the normal hepatic content of collagen in rats with established fibrosis. Fibrosis was induced by prolonged bile duct ligation. IFN-alpha (100,000 IU/rat/day; s.c.) was administered to fibrotic rats for 15 days. Bile duct ligation increased liver collagen content 6-fold. In addition, serum and liver markers of hepatic injury increased significantly; liver histology showed an increase in collagen deposition, and the normal architecture was lost, with large zones of necrosis being observed frequently. IFN-alpha administration reversed to normal the values of all the biochemical markers measured and restored the normal architecture of the liver. Our results demonstrated that IFN-alpha is useful in reversing fibrosis and liver damage induced by biliary obstruction in the rat. However, further investigations are required to evaluate the therapeutic relevance of interferons on non-viral fibrosis and cholestasis. PMID:7646558

  1. Molecular evolution of the mammalian alpha 2B adrenergic receptor.

    PubMed

    Madsen, Ole; Willemsen, Diederik; Ursing, Björn M; Arnason, Ulfur; de Jong, Wilfried W

    2002-12-01

    The alpha 2B adrenergic receptor (A2AB) is a heptahelical G protein-coupled receptor for catecholamines. We compared the almost complete coding region (about 1,175 bp) of the A2AB gene from 48 mammalian species, including eight newly determined sequences, representing all the 18 eutherian and two marsupial orders. Comparison of the encoded proteins reveals that residues thought to be involved in agonist binding are highly conserved, as are the regions playing a role in G protein-coupling. The three extracellular loops are generally more variable than the transmembrane domains and two of the intracellular loops, indicating a lower functional constraint. However, the greatest variation is observed in the very long, third intracellular loop, where only a few residues and a polyglutamyl tract are preserved. Although this polyglutamyl domain displays a great variation in length, its presence in all described A2ABs confirms its proposed role in agonist-dependent phosphorylation of the third intracellular loop. Phylogenetic analyses of the A2AB data set, including Bayesian methods, recognized the superordinal clades Afrotheria, Laurasiatheria, and Euarchontoglires, in agreement with recent molecular evidence, albeit with lower support. Within Afrotheria, A2AB strongly supports the paenungulate clade and the association of the continental African otter shrew with Malagasy tenrecs. Among Laurasiatheria, A2AB confirms the nesting of whales within the artiodactyls, as a sister group to hippopotamus. Within the Euarchontoglires, there is constant support for rodent monophyly. PMID:12446807

  2. Beyond the exchange--the future of B2B.

    PubMed

    Wise, R; Morrison, D

    2000-01-01

    Using the Internet to facilitate business-to-business commerce promises many benefits, such as dramatic cost reductions and greater access to buyers and sellers. Yet little is known about how B2B e-commerce will evolve. The authors argue that changes in the financial services industry over the past two decades provide important clues. Exchanges, they say, are not the primary source of value in information-intensive markets; value tends to accumulate among a diverse group of specialists that focus on such tasks as packaging, standard setting, arbitrage, and information management. Because scale and liquidity are vitally important to efficient trading, today's exchanges will consolidate into a relatively small set of mega-exchanges. Originators will handle the origination and aggregation of complex transactions before sending them on to mega-exchanges for execution. E-speculators, seeking to capitalize on an abundance of market information, will tend to concentrate where relatively standardized products can be transferred easily among a large group of buyers. In many markets, a handful of independent solution providers with well-known brand names and solid reputations will thrive alongside mega-exchanges. Sell-side asset exchanges will create the networks and provide the tools to allow suppliers to trade orders among themselves, sometimes after initial transactions with customers are made on the mega-exchanges. For many companies, traditional skills in such areas as product development, manufacturing, and marketing may become relatively less important, while the ability to understand and capitalize on market dynamics may become considerably more important. PMID:11184979

  3. The resurgence of A2B adenosine receptor signaling

    PubMed Central

    Aherne, Carol M.; Kewley, Emily M.; Eltzschig, Holger K.

    2010-01-01

    Since its discovery as a low-affinity adenosine receptor (AR), the A2B receptor (A2BAR), has proven enigmatic in its function. The previous discovery of the A2AAR, which shares many similarities with the A2BAR but demonstrates significantly greater affinity for its endogenous ligand, led to the original perception that the A2BAR was not of substantial physiologic relevance. In addition, lack of specific pharmacological agents targeting the A2BAR made its initial characterization challenging. However, the importance of this receptor was reconsidered when it was observed that the A2BAR is highly transcriptionally regulated by factors implicated in inflammatory hypoxia. Moreover, the notion that during ischemia or inflammation extracellular adenosine is dramatically elevated to levels sufficient for A2BAR activation, indicated that A2BAR signaling may be important to dampen inflammation particularly during tissue hypoxia. In addition, the recent advent of techniques for murine genetic manipulation along with development of pharmacological agents with enhanced A2BAR specificity has provided invaluable tools for focused studies on the explicit role of A2BAR signaling in different disease models. Currently, studies performed with combined genetic and pharmacological approaches have demonstrated that A2BAR signaling plays a tissue protective role in many models of acute diseases e.g. myocardial ischemia, or acute lung injury. These studies indicate that the A2BAR is expressed on a wide variety of cell types and exerts tissue/cell specific effects. This is an important consideration for future studies where tissue or cell type specific targeting of the A2BAR may be used as therapeutic approach. PMID:20546702

  4. Maintenance therapy with interferon alfa 2b in Hodgkin's disease.

    PubMed

    Avilés, A; Díaz-Maqueo, J C; Talavera, A; Nambo, M J; García, E L

    1998-08-01

    We performed a randomized clinical trial to assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with advanced Hodgkin's disease in complete remission (CR) after conventional chemotherapy. One hundred and thirty-five patients (stage IIIB-IV B) were initially treated with EBVD (epirubicin, bleomycin, vinblastine, dacarbazine). IF CR was achieved they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU three times a week for one year or no further treatment (control group). Clinical and laboratory characteristics at diagnosis were quite similar in both groups. After a median follow-up of 74.3 months (range 49 to 108), 61 out of 68 patients (91%; 95% confidence interval (CI): 76% to 97%) remain in first complete remission in the IFN-treated group compared to 38 out of 67 (58%; 95% CI: 49% to 71%) in the control group (p<.01). Overall survival was also better in the IFN treated group: 62 patients (92%; 95% CI: 82% to 97%) are alive free of disease at 7-years compared to 40 patients (67%, 95%: 55% to 76%) in the control group (p<.01). Toxicity secondary to IFN administration was mild and no dose modification was necessary during treatment. All patients received the planned dose of IFN. This was not an intent-to treat analysis. IFN administration as maintenance therapy was appears to be the only cause of improvement in outcome in these patients. We feel that IFN should be considered as maintenance therapy in patients with advanced Hodgkin's disease because this treatment improves the final outcome without the excessive toxicities of more aggressive therapeutic approaches such as bone marrow transplantation during first CR. We hope that IFN will be considered in future randomized clinical trials in order to define it's role in the treatment of Hodgkin's disease. PMID:9711927

  5. Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida

    PubMed Central

    Wilderman, P. Ross; Jang, Hyun-Hee; Malenke, Jael R.; Salib, Mariam; Angermeier, Elizabeth; Lamime, Sonia; Dearing, M. Denise; Halpert, James R.

    2014-01-01

    Mammalian detoxification processes have been the focus of intense research, but little is known about how wild herbivores process plant secondary compounds, many of which have medicinal value or are drugs. cDNA sequences that code for three enzymes of the cytochrome P450 (CYP) 2B subfamily, here termed 2B35, 2B36, and 2B37 have been recently identified from a wild rodent, the desert woodrat (Malenke et al., 2012). Two variant clones of each enzyme were engineered to increase protein solubility and to facilitate purification, as reported for CYP2B enzymes from multiple species. When expressed in E. coli each of the woodrat proteins gave the characteristic maximum at 450 nm in a reduced carbon monoxide difference spectrum but generally expressed at lower levels than rat CYP2B1. Two enzymes, 2B36 and 2B37, showed dealkylation activity with the model substrates 7-ethoxy-4-(trifluoromethyl)coumarin and 7-benzyloxyresorufin, whereas 2B35 was inactive. Binding of the monoterpene (+)-α-pinene produced a Type I shift in the absorbance spectrum of each enzyme. Mutation of 2B37 at residues 114, 262, or 480, key residues governing ligand interactions with other CYP2B enzymes, did not significantly change expression levels or produce the expected functional changes. In summary, two catalytic and one ligand-binding assay are sufficient to distinguish among CYP2B35, 2B36, and 2B37. Differences in functional profiles between 2B36 and 2B37 are partially explained by changes in substrate recognition site residue 114, but not 480. The results advance our understanding of the mechanisms of detoxification in wild mammalian herbivores and highlight the complexity of this system. PMID:24361551

  6. Archaeal aIF2B interacts with eukaryotic translation initiation factors eIF2α and eIF2Bα: implications for aIF2B function and eIF2B regulation

    PubMed Central

    Dev, Kamal; Santangelo, Thomas J.; Rothenburg, Stefan; Neculai, Dante; Dey, Madhusudan; Sicheri, Frank; Dever, Thomas E.; Reeve, John N.; Hinnebusch, Alan G.

    2009-01-01

    Translation initiation is down-regulated in eukaryotes by phosphorylation of the α subunit of eIF2, which inhibits its guanine nucleotide exchange factor eIF2B. The N-terminal S1 domain of phosphorylated eIF2α interacts with a subcomplex of eIF2B formed by the three regulatory subunits, α/GCN3, β/GCD7, and δ/GCD2, blocking the GDP-GTP exchange activity of the catalytic ε-subunit of eIF2B. These regulatory subunits have related sequences and also have sequences in common with many archaeal proteins, some of which are involved in methionine salvage and CO2 fixation. Our sequence analyses predicted however that members of one phylogenetically distinct and coherent group of these archaeal proteins (designated aIF2Bs) are functional homologues of the α, β and δ subunits of eIF2B. Three of these proteins, from different Archaea, have been shown to bind in vitro to the α subunit of the archaeal aIF2 from the cognate Archaeon. In once case, the aIF2B protein was shown further to bind to the S1 domain of the α subunit of yeast eIF2 in vitro and to interact with eIF2Bα/GCN3 in vivo in yeast. The aIF2B-eIF2α interaction was however independent of eIF2α phosphorylation. Mass spectrometry has identified several proteins that copurify with aIF2B from Thermococcus kodakaraensis and these include aIF2α, a sugar-phosphate nucleotidyltransferase with sequence similarity to eIF2Bε, and several large subunit (50S) ribosomal proteins. Based on this evidence that aIF2B has functions in common with eIF2B, the crystal structure established for an aIF2B was used to construct a model of the eIF2B regulatory subcomplex. In this model, the evolutionarily conserved regions and sites of regulatory mutations in the three eIF2B subunits in yeast are juxtaposed in one continuous binding surface for phosphorylated eIF2α. PMID:19616556

  7. [Medullary thyroid carcinoma in a 10-month-old child with multiple endocrine neoplasia 2B].

    PubMed

    Mathiesen, Jes Sloth; Døssing, Helle; Bender, Lars; Godballe, Christian

    2014-01-27

    In infants at risk of multiple endocrine neoplasia type 2B (MEN2B) the American Thyroid Association recommends genetic testing as soon as possible after birth and that thyroidectomy should be performed in MEN2B RET-mutation positive individuals as soon as possible and if possible within the first year of life. We present a ten-month-old girl with MEN2B who had prophylactic thyroidectomy. The surgical specimen showed medullary thyroid carcinoma. This case emphasizes the need for early diagnosis and prophylactic thyroidectomy in MEN2B patients. PMID:27498810

  8. A 12p13 GRIN2B deletion is associated with developmental delay and macrocephaly.

    PubMed

    Morisada, Naoya; Ioroi, Tomoaki; Taniguchi-Ikeda, Mariko; Juan Ye, Ming; Okamoto, Nobuhiko; Yamamoto, Toshiyuki; Iijima, Kazumoto

    2016-01-01

    N-methyl D-aspartate receptor subtype 2B (GluN2B), encoded by GRIN2B, is one of the components of the N-methyl D-aspartate receptor protein. Aberrations in GRIN2B have been reported to be responsible for various types of neurodevelopmental disorders. We report a Japanese boy with an ~2 Mb interstitial deletion in 12p13 involving the entire GRIN2B gene, who presented with intellectual disability, motor developmental delay and marked macrocephaly. PMID:27656287

  9. A 12p13 GRIN2B deletion is associated with developmental delay and macrocephaly

    PubMed Central

    Morisada, Naoya; Ioroi, Tomoaki; Taniguchi-Ikeda, Mariko; Juan Ye, Ming; Okamoto, Nobuhiko; Yamamoto, Toshiyuki; Iijima, Kazumoto

    2016-01-01

    N-methyl D-aspartate receptor subtype 2B (GluN2B), encoded by GRIN2B, is one of the components of the N-methyl D-aspartate receptor protein. Aberrations in GRIN2B have been reported to be responsible for various types of neurodevelopmental disorders. We report a Japanese boy with an ~2 Mb interstitial deletion in 12p13 involving the entire GRIN2B gene, who presented with intellectual disability, motor developmental delay and marked macrocephaly.

  10. A 12p13 GRIN2B deletion is associated with developmental delay and macrocephaly

    PubMed Central

    Morisada, Naoya; Ioroi, Tomoaki; Taniguchi-Ikeda, Mariko; Juan Ye, Ming; Okamoto, Nobuhiko; Yamamoto, Toshiyuki; Iijima, Kazumoto

    2016-01-01

    N-methyl D-aspartate receptor subtype 2B (GluN2B), encoded by GRIN2B, is one of the components of the N-methyl D-aspartate receptor protein. Aberrations in GRIN2B have been reported to be responsible for various types of neurodevelopmental disorders. We report a Japanese boy with an ~2 Mb interstitial deletion in 12p13 involving the entire GRIN2B gene, who presented with intellectual disability, motor developmental delay and marked macrocephaly. PMID:27656287

  11. Postsynaptic density protein 95-regulated NR2B tyrosine phosphorylation and interactions of Fyn with NR2B in levodopa-induced dyskinesia rat models

    PubMed Central

    Ba, Maowen; Kong, Min; Ma, Guozhao

    2015-01-01

    Context Abnormality in interactions between N-methyl-d-aspartate (NMDA) receptor and its signaling molecules occurs in the lesioned striatum in Parkinson’s disease (PD) and levodopa-induced dyskinesia (LID). It was reported that Fyn-mediated NR2B tyrosine phosphorylation, can enhance NMDA receptor function. Postsynaptic density protein 95 (PSD-95), one of the synapse-associated proteins, regulates interactions between receptor and downstream-signaling molecules. In light of the relationship between PSD-95, NR2B, and Fyn kinases, does PSD-95 contribute to the overactivity of NMDA receptor function induced by dopaminergic treatment? To further prove the possibility, the effects of regulating the PSD-95 expression on the augmented NR2B tyrosine phosphorylation and on the interactions of Fyn and NR2B in LID rat models were evaluated. Methods In the present study, parkinsonian rat models were established by injecting 6-hydroxydopamine. Subsequently, valid PD rats were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily) intraperitoneally for 22 days to create LID rat models. Then, the effect of pretreatment with an intrastriatal injection of the PSD-95mRNA antisense oligonucleotides (PSD-95 ASO) on the rotational response to levodopa challenge was assessed. The effects of pretreatment with an intrastriatal injection of PSD-95 ASO on the augmented NR2B tyrosine phosphorylation and interactions of Fyn with NR2B in the LID rat models were detected by immunoblotting and immunoprecipitation. Results Levodopa administration twice daily for 22 days to parkinsonian rats shortened the rotational duration and increased the peak turning responses. The altered rotational responses were attenuated by PSD-95 ASO pretreatment. Meanwhile, PSD-95 ASO pretreatment decreased the level of PSD-95 protein expression and reduced both the augmented NR2B tyrosine phosphorylation and interactions of Fyn with NR2B triggered during the levodopa administration in the

  12. Homo- and hetero-dimerization of human UDP-glucuronosyltransferase 2B7 (UGT2B7) wild type and its allelic variants affect zidovudine glucuronidation activity.

    PubMed

    Yuan, Lingmin; Qian, Sainan; Xiao, Yongsheng; Sun, Hongying; Zeng, Su

    2015-05-01

    Most human UDP-glucuronosyltransferase (UGT; EC 2.4.1.17) genes contain non-synonymous single nucleotide polymorphisms (nsSNPs) which cause amino acid substitutions. Allelic variants caused by nsSNPs may exhibit absent or reduced enzyme activity. UGT2B7 is one of the most important UGTs that glucuronidates abundant endobiotics and xenobiotics, such as estriol, morphine, and anticancer drugs. Three nsSNPs, UGT2B7*71S (211G>T), UGT2B7*2 (802C>T) and UGT2B7*5 (1192G>A) are observed in the UGT2B7 gene, and they code for allozymes UGT2B7*71S (A71S), UGT2B7*2 (H268Y), and UGT2B7*5 (D398N). UGT2B7 has been observed to form oligomers that affect its enzymatic activity and in this study, we investigated protein-protein interactions among UGT2B7 allozymes wild type (WT), A71S, H268Y and D398N, by performing a systematic quantitative fluorescence resonance energy transfer (FRET) analysis in combination with co-immunoprecipitation assay. Quantitative FRET analysis revealed that UGT2B7 allozymes formed homo- and hetero-dimers and showed distinct features in donor-acceptor distances. Both codon 71 and codon 268 in the N-terminal domain were involved in the dimeric interaction. Co-immunoprecipitation experiments also proved that UGT2B7 allozymes formed stable dimers. The glucuronidation activities of homo- and hetero-dimers were further tested with zidovudine as the substrate. An increase in activity was observed when WT hetero-dimerized with A71S compared with homo-dimers, while both H268Y and D398N impaired the activity of WT and A71S by forming hetero-dimers. In addition, zidovudine glucuronidation activity is associated with FRET distance. These findings provide insights into the consequences of amino acid substitution in UGT2B7 on zidovudine glucuronidation and the association between protein-protein interaction and glucuronidation activity. PMID:25770680

  13. Copy Number Variation of UGT 2B Genes in Indian Families Using Whole Genome Scans

    PubMed Central

    Veerappa, Avinash M.; Padakannaya, Prakash; Ramachandra, Nallur B.

    2016-01-01

    Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B) is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs) status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes. Methods. We investigated the presence of CNVs in UGT2B genes in 31 members from eight Indian families using Affymetrix Genome-Wide Human SNP Array 6.0 chip. Results. Our data revealed >50% of the study members carried CNVs in UGT2B genes, of which 76% showed deletion polymorphism. CNVs were observed more in UGT2B17 (76.4%) than in UGT2B15 (17.6%). Molecular network and pathway analysis found enrichment related to steroid metabolic process, carboxylesterase activity, and sequence specific DNA binding. Interpretation and Conclusion. We report the presence of UGT2B gene deletion and duplication polymorphisms in Indian families. Network analysis indicates the substitutive role of other possible genes in the UGT activity. The CNVs of UGT2B genes are very common in individuals indicating that the effect is neutral in causing any suspected diseases. PMID:27092269

  14. Copy Number Variation of UGT 2B Genes in Indian Families Using Whole Genome Scans.

    PubMed

    Veerappa, Avinash M; Padakannaya, Prakash; Ramachandra, Nallur B

    2016-01-01

    Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B) is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs) status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes. Methods. We investigated the presence of CNVs in UGT2B genes in 31 members from eight Indian families using Affymetrix Genome-Wide Human SNP Array 6.0 chip. Results. Our data revealed >50% of the study members carried CNVs in UGT2B genes, of which 76% showed deletion polymorphism. CNVs were observed more in UGT2B17 (76.4%) than in UGT2B15 (17.6%). Molecular network and pathway analysis found enrichment related to steroid metabolic process, carboxylesterase activity, and sequence specific DNA binding. Interpretation and Conclusion. We report the presence of UGT2B gene deletion and duplication polymorphisms in Indian families. Network analysis indicates the substitutive role of other possible genes in the UGT activity. The CNVs of UGT2B genes are very common in individuals indicating that the effect is neutral in causing any suspected diseases. PMID:27092269

  15. Symmetriebrechung und Emergenz in der Kosmologie.

    NASA Astrophysics Data System (ADS)

    Mainzer, K.

    Seit der Antike wird der Aufbau des Universums mit einfachen und regulären (symmetrischen) Grundstrukturen verbunden. Diese Annahme liegt selbst noch den Standardmodellen der relativistischen Kosmologie zugrunde. Demgegenüber läßt sich die Emergenz neuer Strukturen von den Elementarteilchen über Moleküle bis zu den komplexen Systemen des Lebens als Symmetriebrechung verstehen. Symmetriebrechung und strukturelle Komplexität bestimmen die kosmische Evolution. Damit zeichnet sich ein fachübergreifendes Forschungsprogramm von Physik, Chemie und Biologie ab, in dem die Evolution des Universums untersucht werden kann.

  16. Mutations of the human interferon alpha-2b (hIFNα-2b) gene in low-dose natural terrestrial ionizing radiation exposed dwellers.

    PubMed

    Shahid, Saman; Mahmood, Nasir; Chaudhry, Muhammad Nawaz; Ahmad, Nauman

    2015-12-01

    Natural terrestrial ionizing radiations emerge from uranium deposits and can impact human tissues by affecting DNA bases which constitute genes. Human interferon alpha-2b (hIFNα-2b) gene synthesizes a protein which exhibits anticancerous, immunomodulatory, anti-proliferative and antiviral properties. This research aimed to find out hIFNα-2b gene mutations for those residents who were chronically exposed to low-dose natural terrestrial ionizing radiations. The gene amplifications was done through PCR technique and gene mutations were identified by bioinformatics in order to conclude as to how mutations identified in hIFNα-2b gene sequences will lead to alterations in the hIFNα-2b protein in radiation exposed residents. The range of radiation dose exposure was 0.4383-4.55832 (mSv/y) for the selected radiation exposed locations which were having uranium mineralization. Mutations (24%) in hIFNα-2b gene shows that some of the radiation exposed inhabitants were having a modulated immune response. The CBC (Complete Blood Count) parameters: WBC (White Blood Cells), MCH (Mean Corpuscular Hemoglobin), MCHC (MCH Concentration) and PLT (Platelets) on average were below the normal range in 24% radiation exposed subjects who were having hIFNα-2b gene mutations. Immunomodulation is observed by the mixed trend of either lymphocytosis or lymphopenia and neutropenia or neutrophilia in the exposed population. Thus, a radioactive exposure from uranium can affect the immune system and can induce mutations.

  17. Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida

    SciTech Connect

    Wilderman, P. Ross; Jang, Hyun-Hee; Malenke, Jael R.; Salib, Mariam; Angermeier, Elisabeth; Lamime, Sonia; Dearing, M. Denise; Halpert, James R.

    2014-02-01

    Mammalian detoxification processes have been the focus of intense research, but little is known about how wild herbivores process plant secondary compounds, many of which have medicinal value or are drugs. cDNA sequences that code for three enzymes of the cytochrome P450 (CYP) 2B subfamily, here termed 2B35, 2B36, and 2B37 have been recently identified from a wild rodent, the desert woodrat (Malenke et al., 2012). Two variant clones of each enzyme were engineered to increase protein solubility and to facilitate purification, as reported for CYP2B enzymes from multiple species. When expressed in Escherichia coli each of the woodrat proteins gave the characteristic maximum at 450 nm in a reduced carbon monoxide difference spectrum but generally expressed at lower levels than rat CYP2B1. Two enzymes, 2B36 and 2B37, showed dealkylation activity with the model substrates 7-ethoxy-4-(trifluoromethyl)coumarin and 7-benzyloxyresorufin, whereas 2B35 was inactive. Binding of the monoterpene (+)-α-pinene produced a Type I shift in the absorbance spectrum of each enzyme. Mutation of 2B37 at residues 114, 262, or 480, key residues governing ligand interactions with other CYP2B enzymes, did not significantly change expression levels or produce the expected functional changes. In summary, two catalytic and one ligand-binding assay are sufficient to distinguish among CYP2B35, 2B36, and 2B37. Differences in functional profiles between 2B36 and 2B37 are partially explained by changes in substrate recognition site residue 114, but not 480. The results advance our understanding of the mechanisms of detoxification in wild mammalian herbivores and highlight the complexity of this system. - Highlights: • Three CYP2B enzymes from Neotoma lepida were cloned, engineered, and expressed. • A mix of catalytic and binding assays yields unique results for each enzyme. • Mutational analysis indicates CYP{sub 2}B substrate recognition remains to be clarified. • Reported N. lepida gene

  18. Nrk2b-mediated NAD+ production regulates cell adhesion and is required for muscle morphogenesis in vivo: Nrk2b and NAD+ in muscle morphogenesis.

    PubMed

    Goody, Michelle F; Kelly, Meghan W; Lessard, Kevin N; Khalil, Andre; Henry, Clarissa A

    2010-08-15

    Cell-matrix adhesion complexes (CMACs) play fundamental roles during morphogenesis. Given the ubiquitous nature of CMACs and their roles in many cellular processes, one question is how specificity of CMAC function is modulated. The clearly defined cell behaviors that generate segmentally reiterated axial skeletal muscle during zebrafish development comprise an ideal system with which to investigate CMAC function during morphogenesis. We found that Nicotinamide riboside kinase 2b (Nrk2b) cell autonomously modulates the molecular composition of CMACs in vivo. Nrk2b is required for normal Laminin polymerization at the myotendinous junction (MTJ). In Nrk2b-deficient embryos, at MTJ loci where Laminin is not properly polymerized, muscle fibers elongate into adjacent myotomes and are abnormally long. In yeast and human cells, Nrk2 phosphorylates Nicotinamide Riboside and generates NAD+ through an alternative salvage pathway. Exogenous NAD+ treatment rescues MTJ development in Nrk2b-deficient embryos, but not in laminin mutant embryos. Both Nrk2b and Laminin are required for localization of Paxillin, but not beta-Dystroglycan, to CMACs at the MTJ. Overexpression of Paxillin in Nrk2b-deficient embryos is sufficient to rescue MTJ integrity. Taken together, these data show that Nrk2b plays a specific role in modulating subcellular localization of discrete CMAC components that in turn plays roles in musculoskeletal development. Furthermore, these data suggest that Nrk2b-mediated synthesis of NAD+ is functionally upstream of Laminin adhesion and Paxillin subcellular localization during MTJ development. These results indicate a previously unrecognized complexity to CMAC assembly in vivo and also elucidate a novel role for NAD+ during morphogenesis. PMID:20566368

  19. The Brain-Specific Neural Zinc Finger Transcription Factor 2b (NZF-2b/7ZFMyt1) Suppresses Cocaine Self-Administration in Rats

    PubMed Central

    Chandrasekar, Vijay; Dreyer, Jean-Luc

    2009-01-01

    Brain-specific neural-zinc-finger transcription factor-2b (NZF2b/7ZFMyt1) is induced in the mesolimbic dopaminergic region after chronic cocaine exposure and lentiviral-mediated expression of NZF2b/7ZFMyt1 in the nucleus accumbens results in decreased locomotor activity (Chandrasekar and Dreyer, 2010). In this study the role of NZF2b/7ZFMyt1 in active cocaine seeking and of its interaction with histone deacetylase on the altered behavior has been observed. Localized expression of NZF2b/7ZFMyt1 in the nucleus accumbens resulted in attenuated cocaine self-administration, whereas silencing this transcription factor with lentiviruses expressing siRNAs increased the animal′s motivation to self-infuse cocaine. Low doses of sodium butyrate, a potent inhibitor of histone deacetylase, were sufficient to reverse the NZF2b/7ZFMyt1-mediated decrease in cocaine self-administration. NZF2b/7ZFMyt1 expression resulted in strong induction of transcription factors REST1 and NAC1 and of the dopamine D2 receptor, with concomitant inhibition of BDNF and its receptor TrkB. We show that NZF2b/7ZFMyt1 colocalizes with histone deacetylase-2 (HDAC2), probably overcoming the suppression of transcriptional activity caused by Lingo1. These findings show that molecular adaptations mediated by NZF2b/7ZFMyt1 expression possibly lead to decreased responsiveness to the reinforcing properties of cocaine and play a prominent role in affecting the behavioral changes induced by the drug. PMID:20407577

  20. NR2B antagonist CP-101,606 inhibits NR2B phosphorylation at tyrosine-1472 and its interactions with Fyn in levodopa-induced dyskinesia rat model.

    PubMed

    Kong, Min; Ba, Maowen; Liu, Chuanyu; Zhang, Yanxiang; Zhang, Hongli; Qiu, Haiyan

    2015-04-01

    The augmented tyrosine phosphorylation of NR2B subunit of N-methyl-d-aspartate receptors (NMDAR) dependent on Fyn kinase has been associated with levodopa (l-dopa)-induced dyskinesia (LID). CP-101,606, one selective NR2B subunit antagonist, can improve dyskinesia. Yet, the accurate action mechanism is less well understood. In the present study, the evidences were investigated. Valid 6-hydroxydopamine-lesioned parkinsonian rats were treated with l-dopa intraperitoneally for 22 days to induce LID rat model. On day 23, rats received either CP-101,606 (0.5mg/kg) or vehicle with each l-dopa dose. On the day of 1, 8, 15, 22, and 23 during l-dopa treatment, we determined abnormal involuntary movements (AIMs) in rats. The levels of NR2B phosphorylation at tyrosine-1472 (pNR2B-Tyr1472) and interactions of NR2B with Fyn in LID rat model were detected by immunoblotting and immunoprecipitation. Results showed that CP-101,606 attenuated l-dopa-induced AIMs. In agreement with behavioral analysis, CP-101,606 reduced the augmented pNR2B-Tyr1472 and its interactions with Fyn triggered during the l-dopa administration in the lesioned striatum of parkinsonian rats. Moreover, CP-101,606 also decreased the level of Ca(2+)/calmodulin-dependent protein kinase II at threonine-286 hyperphosphorylation (pCaMKII-Thr286), which was the downstream signaling amplification molecule of NMDAR overactivation and closely associated with LID. However, the protein level of NR2B and Fyn had no difference under the above conditions. These data indicate that the inhibition of the interactions of NR2B with Fyn and NR2B tyrosine phosphorylation may contribute to the CP-101,606-induced downregulation of NMDAR function and provide benefit for the therapy of LID.

  1. Fascin 2b Is a Component of Stereocilia that Lengthens Actin-Based Protrusions

    PubMed Central

    Gomez, Gustavo; Fernando, Carol A.; West, Megan C.; Pollock, Lana M.; Lin-Jones, Jennifer; Burnside, Beth; McDermott, Brian M.

    2011-01-01

    Stereocilia are actin-filled protrusions that permit mechanotransduction in the internal ear. To identify proteins that organize the cytoskeleton of stereocilia, we scrutinized the hair-cell transcriptome of zebrafish. One promising candidate encodes fascin 2b, a filamentous actin-bundling protein found in retinal photoreceptors. Immunolabeling of zebrafish hair cells and the use of transgenic zebrafish that expressed fascin 2b fused to green fluorescent protein demonstrated that fascin 2b localized to stereocilia specifically. When filamentous actin and recombinant fusion protein containing fascin 2b were combined in vitro to determine their dissociation constant, a Kd≈0.37 µM was observed. Electron microscopy showed that fascin 2b-actin filament complexes formed parallel actin bundles in vitro. We demonstrated that expression of fascin 2b or espin, another actin-bundling protein, in COS-7 cells induced the formation of long filopodia. Coexpression showed synergism between these proteins through the formation of extra-long protrusions. Using phosphomutant fascin 2b proteins, which mimicked either a phosphorylated or a nonphosphorylated state, in COS-7 cells and in transgenic hair cells, we showed that both formation of long filopodia and localization of fascin 2b to stereocilia were dependent on serine 38. Overexpression of wild-type fascin 2b in hair cells was correlated with increased stereociliary length relative to controls. These findings indicate that fascin 2b plays a key role in shaping stereocilia. PMID:21625653

  2. Satellitenbewegung, band III: Natiirliche und gesteuerte bewegung.

    NASA Astrophysics Data System (ADS)

    Jochim, E. F.

    2014-12-01

    Im dritten Band der Satellitenbewegung werden in fortlaufender Nummerierung einige für Untersuchungen der Bewegung der künstlichen Satelliten wichtige Grundlagen der Astrodynamik mit ausführlichen mathematischen Formelsystemen behandelt. Dazu zählen die unterschiedlichen Aspekte der Bewegung der natürlichen Himmelskörper, die Steuerung und Kontrolle von künstlichen Objekten, und insbesondere die für eine Satellitenbahnanalyse wichtigen physikalischen Beeinflussungen einer Satellitenbewegung. Mathematisch entscheidend ist die Wahl geeigneter Bahnparameter, die ein bestimmtes Bewegungsproblem widerspruchsfrei und singularitätenfrei zu behandeln gestatten. Für die Behandlung routinemäßiger Aufgabenstellungen der Satellitenbewegung, in erster Linie einer präzisen Bahnbestimmung und Bahnverbesserung, kann auf eine Fülle von lehrbuchartigen Monographien verwiesen werden, so dass diese Problematik in der vorliegenden Arbeit nur angedeutet werden soll.

  3. Simulation und virtuelle Realität

    NASA Astrophysics Data System (ADS)

    von Estorff, Otto; Markiewicz, Marian; Özkan, Ali; Zaleski, Olgierd; Blumrich, Reinhard; Genuit, Klaus; Fiebig, André

    Mit Hilfe akustischer Berechnungen ist es möglich, aufwendige Messungen an Fahrzeugprototypen deutlich zu reduzieren. Dieses Kapitel gibt einen kurzen Überblick über die wichtigsten derzeit verfügbaren Methoden. Dabei wird zunächst auf Elementverfahren, wie die Finite-Elemente-Methode (FEM) und die Boundary-Elemente-Methode (BEM), näher eingegangen. Während diese vor allem im tieffrequenten Bereich eingesetzt werden, kommen bei höheren Frequenzen vermehrt Verfahren zum Einsatz, die auf Energieformulierungen beruhen. Exemplarisch wird hier die Funktionsweise und der Einsatz der Statistischen-Energie-Analyse (SEA) erläutert. Anhand von repräsentativen Beispielen werden die Einsatzmöglichkeiten und Grenzen der verschiedenen Verfahren aufgezeigt, wobei vor allem auch auf Vergleiche zwischen Rechnung und Messung eingegangen wird.

  4. Hochschule fur Film und Fernsehen (Babelsberg).

    ERIC Educational Resources Information Center

    Neumann, Roland

    1992-01-01

    Describes the Hochschule fur Film und Fernsehen, an institution of higher education for the study of film and television production in Babelsberg, Germany (formerly the German Democratic Republic). Discusses the major reorientations in the school caused by Germany's reunification. (SR)

  5. Kosmische Katastrophen und der Ursprung der Religion.

    NASA Astrophysics Data System (ADS)

    Hoyle, F.

    This book is a German translation, by V. Delavre, from the English original "The origin of the Universe and the origin of religion", published in 1993. Contents: E. Sens: Die unterbrochene Musikstunde. Einleitung zur deutschen Ausgabe. C. Ryskamp: Einführung. R. N. Anshen: Vorwort. F. Hoyle: Kosmische Katastrophen und der Ursprung der Religion - Die Folgen der Respektabilität; Eiszeiten und Kometen; Die allgemeine Situation in den Nacheiszeiten; Kometen und der Ursprung der Religionen; Der Übergang zu Mittelalter und Neuzeit. Diskussionsbeiträge: Ruth Nanda Anshen, Freeman Dyson, Paul Oscar Kristeller, John Archibald Wheeler, James Schwartz, Roger Shinn, Milton Gatch, Philip Solomon, Norman Newell. F. Hoyle: Schlußwort. A. Tollmann: Nachwort zur deutschen Ausgabe.

  6. Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients

    PubMed Central

    Romero-Lorca, Alicia; Novillo, Apolonia; Gaibar, María; Bandrés, Fernando; Fernández-Santander, Ana

    2015-01-01

    Tamoxifen is used to prevent and treat estrogen-dependent breast cancer. It is described as a prodrug since most of its antiestrogen effects are exerted through its hydroxylated metabolites 4-OH-tamoxifen and endoxifen. In prior work, we correlated optimal plasma levels of these metabolites with certain genotypes of CYP2D6 and SULT1A2. This descriptive study examines correlations between concentrations of tamoxifen's glucuronide metabolites and genotypes UGT1A4 Pro24Thr, UGT1A4 Leu48Val, UGT2B7 His268Tyr, UGT2B15 Asp85YTyr UGT2B15 Lys523Thr and UGT2B17del in 132 patients with estrogen receptor-positive breast cancer under treatment with tamoxifen. Patients were genotyped by real-time and conventional PCR-RFLP. The glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide were isolated from blood plasma and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Individuals who were homozygous for UGT1A448VAL showed significantly lower mean concentrations of both glucuronide metabolites compared to subjects genotyped as wt/wt plus wt/48Val (p=0.037 and p=0.031, respectively). Women homozygous for UGT2B7268Tyr also showed mean substrate/product ratios of 4-OH-tamoxifen/4-OH-tamoxifen-O-glucuronide and 4-OH-tamoxifen/4-OH-tamoxifen-N-glucuronide indicative of reduced glucuronidase activity compared to wt homozygotes or to heterozygotes for the polymorphism (p=0.005 and p=0.003, respectively). In contrast, UGT2B15 Lys523Thr and UGT2B17del were associated with possibly increased enzyme activity. Patients with at least one variant allele UGT2B15523Thr showed significantly higher 4-OH-tamoxifen-O-glucuronide and endoxifen-glucuronide levels (p=0.023 and p=0.025, respectively) indicating a variant gene-dose effect. Higher 4-OH-tamoxifen-N-glucuronide levels observed in UGT2B17del genotypes (p=0.042) could be attributed to a mechanism that compensates for the greater expression of other genes in UGT2B

  7. Solution structure of the isolated histone H2A-H2B heterodimer.

    PubMed

    Moriwaki, Yoshihito; Yamane, Tsutomu; Ohtomo, Hideaki; Ikeguchi, Mitsunori; Kurita, Jun-Ichi; Sato, Masahiko; Nagadoi, Aritaka; Shimojo, Hideaki; Nishimura, Yoshifumi

    2016-01-01

    During chromatin-regulated processes, the histone H2A-H2B heterodimer functions dynamically in and out of the nucleosome. Although detailed crystal structures of nucleosomes have been established, that of the isolated full-length H2A-H2B heterodimer has remained elusive. Here, we have determined the solution structure of human H2A-H2B by NMR coupled with CS-Rosetta. H2A and H2B each contain a histone fold, comprising four α-helices and two β-strands (α1-β1-α2-β2-α3-αC), together with the long disordered N- and C-terminal H2A tails and the long N-terminal H2B tail. The N-terminal αN helix, C-terminal β3 strand, and 310 helix of H2A observed in the H2A-H2B nucleosome structure are disordered in isolated H2A-H2B. In addition, the H2A α1 and H2B αC helices are not well fixed in the heterodimer, and the H2A and H2B tails are not completely random coils. Comparison of hydrogen-deuterium exchange, fast hydrogen exchange, and {(1)H}-(15)N hetero-nuclear NOE data with the CS-Rosetta structure indicates that there is some conformation in the H2A 310 helical and H2B Lys11 regions, while the repression domain of H2B (residues 27-34) exhibits an extended string-like structure. This first structure of the isolated H2A-H2B heterodimer provides insight into its dynamic functions in chromatin. PMID:27181506

  8. Solution structure of the isolated histone H2A-H2B heterodimer

    PubMed Central

    Moriwaki, Yoshihito; Yamane, Tsutomu; Ohtomo, Hideaki; Ikeguchi, Mitsunori; Kurita, Jun-ichi; Sato, Masahiko; Nagadoi, Aritaka; Shimojo, Hideaki; Nishimura, Yoshifumi

    2016-01-01

    During chromatin-regulated processes, the histone H2A-H2B heterodimer functions dynamically in and out of the nucleosome. Although detailed crystal structures of nucleosomes have been established, that of the isolated full-length H2A-H2B heterodimer has remained elusive. Here, we have determined the solution structure of human H2A-H2B by NMR coupled with CS-Rosetta. H2A and H2B each contain a histone fold, comprising four α-helices and two β-strands (α1–β1–α2–β2–α3–αC), together with the long disordered N- and C-terminal H2A tails and the long N-terminal H2B tail. The N-terminal αN helix, C-terminal β3 strand, and 310 helix of H2A observed in the H2A-H2B nucleosome structure are disordered in isolated H2A-H2B. In addition, the H2A α1 and H2B αC helices are not well fixed in the heterodimer, and the H2A and H2B tails are not completely random coils. Comparison of hydrogen-deuterium exchange, fast hydrogen exchange, and {1H}-15N hetero-nuclear NOE data with the CS-Rosetta structure indicates that there is some conformation in the H2A 310 helical and H2B Lys11 regions, while the repression domain of H2B (residues 27–34) exhibits an extended string-like structure. This first structure of the isolated H2A-H2B heterodimer provides insight into its dynamic functions in chromatin. PMID:27181506

  9. Emotional disorders in adult mice heterozygous for the transcription factor Phox2b.

    PubMed

    Bollen, Bieke; Ramanantsoa, Nelina; Naert, Arne; Matrot, Boris; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

    2015-03-15

    Phox2b is an essential transcription factor for the development of the autonomic nervous system. Mice carrying one invalidated Phox2b allele (Phox2b(+/-)) show mild autonomic disorders including sleep apneas, and impairments in chemosensitivity and thermoregulation that recover within 10days of postnatal age. Because Phox2b is not expressed above the pons nor in the cerebellum, this mutation is not expected to affect brain development and cognitive functioning directly. However, the transient physiological disorders in Phox2b(+/-) mice might impair neurodevelopment. To examine this possibility, we conducted a behavioral test battery of emotional, motor, and cognitive functioning in adult Phox2b(+/-) mice and their wildtype littermates (Phox2b(+/+)). Adult Phox2b(+/-) mice showed altered exploratory behavior in the open field and in the elevated plus maze, both indicative of anxiety. Phox2b(+/-) mice did not show cognitive or motor impairments. These results suggest that also mild autonomic control deficits may disturb long-term emotional development. PMID:25582512

  10. Emotional disorders in adult mice heterozygous for the transcription factor Phox2b.

    PubMed

    Bollen, Bieke; Ramanantsoa, Nelina; Naert, Arne; Matrot, Boris; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

    2015-03-15

    Phox2b is an essential transcription factor for the development of the autonomic nervous system. Mice carrying one invalidated Phox2b allele (Phox2b(+/-)) show mild autonomic disorders including sleep apneas, and impairments in chemosensitivity and thermoregulation that recover within 10days of postnatal age. Because Phox2b is not expressed above the pons nor in the cerebellum, this mutation is not expected to affect brain development and cognitive functioning directly. However, the transient physiological disorders in Phox2b(+/-) mice might impair neurodevelopment. To examine this possibility, we conducted a behavioral test battery of emotional, motor, and cognitive functioning in adult Phox2b(+/-) mice and their wildtype littermates (Phox2b(+/+)). Adult Phox2b(+/-) mice showed altered exploratory behavior in the open field and in the elevated plus maze, both indicative of anxiety. Phox2b(+/-) mice did not show cognitive or motor impairments. These results suggest that also mild autonomic control deficits may disturb long-term emotional development.

  11. Beyond Cohort Selection: An Analytics-Enabled i2b2.

    PubMed

    Gabetta, Matteo; Malovini, Alberto; Bucalo, Mauro; Zini, Elisa; Tibollo, Valentina; Priori, Silvia G; Vettoretti, Simone; Larizza, Cristiana; Bellazzi, Riccardo; Barbarini, Nicola

    2016-01-01

    The i2b2 software is a widely adopted solution for secondary use of clinical data for clinical research, specifically designed for cohort identification. i2b2 is still lacking functionalities for data analysis. The aim of this work is to empower the i2b2 framework enabling clinical researchers to perform statistical analyses for accelerating the process of hypothesis testing. To this aim we have developed a flexible extension of i2b2 able to exploit different statistical engines. We have implemented some first applications for basic statistics and survival analyses, exploiting this extension and accessible through suitable user interfaces designed with a special consideration for usability.

  12. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain.

    PubMed

    Miksys, Sharon; Lerman, Caryn; Shields, Peter G; Mash, Deborah C; Tyndale, Rachel F

    2003-07-01

    CYP2B6 metabolizes drugs such as nicotine and bupropion, and many toxins and carcinogens. Nicotine induces CYP2B1 in rat brain and in humans polymorphic variation in CYP2B6 affects smoking cessation rates. The aim of this study was to compare CYP2B6 expression in brains of human smokers and non-smokers and alcoholics and non-alcoholics (n=26). CYP2B6 expression was brain region-specific, and was observed in both neurons and astrocytes. CYP2B6 levels were higher in brains of smokers and alcoholics, particularly in cerebellar Purkinje cells and hippocampal pyramidal neurons, cells known to be damaged in alcoholics. Significantly more (p<0.05) CYP2B6 protein was seen in four brain regions of smoking alcoholics compared to non-smoking non-alcoholics: hippocampus (5.8-fold), caudate nucleus (3.3-fold), putamen (3.0-fold) and cerebellar hemisphere (1.6-fold). The genetic variant C1459T (R487C) has been associated with reduced hepatic enzyme levels, stability and activity. Preliminary genotyping of this small sample (n=24) suggested that individuals with the CC genotype had higher brain CYP2B6 than those with the CT or TT genotype. Higher brain CYP2B6 activity in smokers and alcoholics may cause altered sensitivity to centrally acting drugs, increased susceptibility to neurotoxins and carcinogenic xenobiotics and contribute to central tolerance to nicotine.

  13. Untethered 4,1,2-MC2B10 supraicosahedral metallacarboranes, their C,C'-dimethyl 4,1,6-, 4,1,8- and 4,1,12-MC2B10 analogues, and DFT study of the (4,)1,2- to (4,)1,6-isomerisations of C2B11 carboranes and MC2B10 metallacarboranes.

    PubMed

    McAnaw, Amelia; Lopez, Maria Elena; Scott, Greig; Ellis, David; McKay, David; Rosair, Georgina M; Welch, Alan J

    2012-08-28

    Reduction of the tethered carborane 1,2-μ-(CH(2)SiMe(2)CH(2))-1,2-closo-C(2)B(10)H(10) followed by metallation with {CpCo} or {(p-cymene)Ru} fragments affords both C,C'-dimethyl 4,1,2-MC(2)B(10) and 4,1,6-MC(2)B(10) species. DFT calculations indicate that the barriers to isomerisation of both 4-Cp-4,1,2-closo-CoC(2)B(10)H(12) and 4-(η-C(6)H(6))-4,1,2-closo-RuC(2)B(10)H(12) to their respective 4,1,6-isomers are too high for this to be the origin of the unexpected formation of 4,1,6-MC(2)B(10) products (in marked contrast to the related isomerisation of 1,2-closo-C(2)B(11)H(13) to 1,6-closo-C(2)B(11)H(13)), and, indeed, the 4,1,2-species are recovered unchanged from refluxing toluene. Equally, the DFT-calculated profile for the isomerisation of [7,8-nido-C(2)B(10)H(12)](2-) to [7,9-nido-C(2)B(10)H(12)](2-) suggests that the unexpected formation of 4,1,6-metallacarboranes is unlikely to result from isomerisation of a reduced (nido) carborane following desilylation. Instead, the source of the 4,1,6-MC(2)B(10) compounds is traced to desilylation of 1,2-μ-(CH(2)SiMe(2)CH(2))-1,2-closo-C(2)B(10)H(10) by Li or Na prior to reduction. The supraicosahedral metallacarboranes 1,8-Me(2)-4-Cp-4,1,8-closo-CoC(2)B(10)H(10), 1,12-Me(2)-4-Cp-4,1,12-closo-CoC(2)B(10)H(10) and 1,12-Me(2)-4-(p-cymene)-4,1,12-closo-RuC(2)B(10)H(10) are also reported with all new species characterised both spectroscopically and crystallographically.

  14. Review of magnetic features observed in (A,A')Ni 2B 2C solid solutions

    NASA Astrophysics Data System (ADS)

    Kuznietz, Moshe; Gonçalves, António P.; Almeida, Manuel

    2002-08-01

    The nickel-borocarbides ANi 2B 2C [A=Y, Ln (lanthanide), An(actinide)], crystallizing in the body-centred tetragonal LuNi 2B 2C-type structure, are classified according to the existence or coexistence of superconducting and antiferromagnetic states (AF). The magnetic features observed in polycrystalline (A,A')Ni 2B 2C solid solutions, adopting the same crystal structure, are reviewed and discussed. Published data on the magnetism in (A,Ln)Ni 2B 2C systems (ANi 2B 2C nonmagnetic, A=Y,La,Lu) indicate a gradual rise in the threshold content, x( m), in (Y 1- xLn x)Ni 2B 2C (Ln=Gd,Tb,Dy,Ho,Er) for the establishment of AF states. (A,A')Ni 2B 2C systems with magnetic end compounds show gradual variation in magnetic features when A and A' are both heavy Ln. The behaviour of (A,A')Ni 2B 2C systems of light A (Pr or U) and heavy A' (Dy or Tm) depends on the magnetic structures of the end compounds. In intermediate compositions, incomplete moment compensation in (Pr,Dy)Ni 2B 2C decreases TN, while different moment directions in the end compounds in (U,Dy)Ni 2B 2C lead to a directional frustration of ordered moments. Such a frustration in (U,Tm)Ni 2B 2C is related to different magnetic structures of the end compounds.

  15. SH2B1 in β-Cells Promotes Insulin Expression and Glucose Metabolism in Mice

    PubMed Central

    Chen, Zheng; Morris, David L.; Jiang, Lin; Liu, Yong

    2014-01-01

    Insulin deficiency drives the progression of both type 1 and type 2 diabetes. Pancreatic β-cell insulin expression and secretion are tightly regulated by nutrients and hormones; however, intracellular signaling proteins that mediate nutrient and hormonal regulation of insulin synthesis and secretion are not fully understood. SH2B1 is an SH2 domain-containing adaptor protein. It enhances the activation of the Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription and the phosphatidylinositol 3-kinase pathways in response to a verity of hormones, growth factors, and cytokines. Here we identify SH2B1 as a new regulator of insulin expression. In rat INS-1 832/13 β-cells, SH2B1 knockdown decreased, whereas SH2B1 overexpression increased, both insulin expression and glucose-stimulated insulin secretion. SH2B1-deficent islets also had reduced insulin expression, insulin content, and glucose-stimulated insulin secretion. Heterozygous deletion of SH2B1 decreased pancreatic insulin content and plasma insulin levels in leptin-deficient ob/ob mice, thus exacerbating hyperglycemia and glucose intolerance. In addition, overexpression of JAK2 increased insulin promoter activity, and SH2B1 enhanced the ability of JAK2 to activate the insulin promoter. Overexpression of SH2B1 also increased the expression of Pdx1 and the recruitment of Pdx1 to the insulin promoter in INS-1 832/13 cells, whereas silencing of SH2B1 had the opposite effects. Consistently, Pdx1 expression was lower in SH2B1-deficient islets. These data suggest that the SH2B1 in β-cells promotes insulin synthesis and secretion at least in part by enhancing activation of JAK2 and/or Pdx1 pathways in response to hormonal and nutritional signals. PMID:24645678

  16. SH2B1 in β-cells promotes insulin expression and glucose metabolism in mice.

    PubMed

    Chen, Zheng; Morris, David L; Jiang, Lin; Liu, Yong; Rui, Liangyou

    2014-05-01

    Insulin deficiency drives the progression of both type 1 and type 2 diabetes. Pancreatic β-cell insulin expression and secretion are tightly regulated by nutrients and hormones; however, intracellular signaling proteins that mediate nutrient and hormonal regulation of insulin synthesis and secretion are not fully understood. SH2B1 is an SH2 domain-containing adaptor protein. It enhances the activation of the Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription and the phosphatidylinositol 3-kinase pathways in response to a verity of hormones, growth factors, and cytokines. Here we identify SH2B1 as a new regulator of insulin expression. In rat INS-1 832/13 β-cells, SH2B1 knockdown decreased, whereas SH2B1 overexpression increased, both insulin expression and glucose-stimulated insulin secretion. SH2B1-deficent islets also had reduced insulin expression, insulin content, and glucose-stimulated insulin secretion. Heterozygous deletion of SH2B1 decreased pancreatic insulin content and plasma insulin levels in leptin-deficient ob/ob mice, thus exacerbating hyperglycemia and glucose intolerance. In addition, overexpression of JAK2 increased insulin promoter activity, and SH2B1 enhanced the ability of JAK2 to activate the insulin promoter. Overexpression of SH2B1 also increased the expression of Pdx1 and the recruitment of Pdx1 to the insulin promoter in INS-1 832/13 cells, whereas silencing of SH2B1 had the opposite effects. Consistently, Pdx1 expression was lower in SH2B1-deficient islets. These data suggest that the SH2B1 in β-cells promotes insulin synthesis and secretion at least in part by enhancing activation of JAK2 and/or Pdx1 pathways in response to hormonal and nutritional signals.

  17. Tycho Brahe - Instrumentenbauer und Meister der Beobachtungstechnik

    NASA Astrophysics Data System (ADS)

    Wolfschmidt, Gudrun

    Vor der Erfindung des Fernrohrs war der dänische Astronom Tycho Brahe (1546 - 1601) der bedeutendste beobachtende Astronom. Von seinem Observatorium Uraniborg auf der - damals dänischen - Insel Hven ist heute noch der Grundriß erkennbar, von Stjerneborg sind die Fundamente erhalten, die Kuppeln in den 1950er Jahren ergänzt. In der Astronomie-Ausstellung im Deutschen Museum gibt es ein Modell der Sternwarte Uraniborg und der zugehörigen Instrumente (Maßstab 1:10); das größere Modell wurde dem Technischen Museum in Malmö geschenkt. Die Instrumente, die er in den Observatorien Uraniborg und Stjerneborg benutzte, sind nicht erhalten. Aber es gibt gute Beschreibungen der Instrumente (Halbkreis, Quadranten, Sextanten, Armillarsphären, Triquetrum, Himmelsglobus) in seinem Buch Astronomiae instauratae mechanica (Wandsbek 1598). Eine Nachbildung des großen hölzernen Quadranten kann man im Runden Turm in Kopenhagen sehen. Zwei Sextanten, hergestellt für Tycho um 1600 von Jost Bürgi und Erasmus Habermel, gibt es noch im Nationalmuseum für Technik in Prag. Ähnlichkeiten von Tychos Instrumenten mit Groß-Instrumenten aus dem islamischen Kulturkreis sind auffällig. Tycho Brahes Meßgeräte markieren einen großen Fortschritt in der Entwicklung astronomischer Instrumente und Meßtechniken und bilden die Grundlage für den weiteren Fortschritt der Positionsastronomie und der damit verbundenen Tabellenwerke. Die Nachwirkungen sind bis ins 17. und 18. Jahrhundert nachweisbar.

  18. Cost effectiveness of peginterferon α-2b plus ribavirin versus interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C

    PubMed Central

    Siebert, U; Sroczynski, G; Rossol, S; Wasem, J; Ravens-Sieberer, U; Kurth, B M; Manns, M P; McHutchison, J G; Wong, J B

    2003-01-01

    Background: Peginterferon α-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. Aims: To estimate the cost effectiveness of treatment with peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. Methods: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. Results: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon α-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of €11 800 and €6600 per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. Conclusions: Peginterferon α-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C. PMID:12584228

  19. Mutations of the human interferon alpha-2b (hIFN-α2b) gene in occupationally protracted low dose radiation exposed personnel.

    PubMed

    Shahid, Saman; Mahmood, Nasir; Chaudhry, Muhammad Nawaz; Sheikh, Shaharyar; Ahmad, Nauman

    2015-05-01

    Ionizing radiations impact human tissues by affecting the DNA bases which constitute genes. Human interferon alpha 2b gene synthesizes a protein which is an important anticancerous, immunomodulatory, anti-proliferative and antiviral protein. This study was aimed to identify interferon alpha-2b mutations as a consequence of the use of occupational chronic low dose radiation by hospital radiation exposed workers. A molecular analysis was done in which DNAs were extracted from blood samples from radiology, radiotherapy and nuclear medicine workers. The gene was amplified through polymerase chain reaction and further genetic data from sequencing results analyzed by bioinformatics tools in order to determine as to how mutations in interferon alpha 2b sequences will lead to changes in human interferon alpha-2b protein. A total of 41% gene mutations was detected among all radiation exposed workers in which higher percentage (5.4%) of base insertion mutations and 14% frameshift mutations were found in radiology workers. The chronic use of low dose of radiations by occupational workers has a significant correlation with mutational effects on interferon alpha 2b gene, further evident by depressed interferon alpha levels in serum. This can lead to depressed immunity in radiation exposed workers. Hematological profiling of this group also showed hyperimmune response in the form of lymphocytosis.

  20. Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera

    PubMed Central

    Zagrijtschuk, Oleh; Buxhofer-Ausch, Veronika; Thaler, Josef; Schloegl, Ernst; Gastl, Guenther A.; Wolf, Dominik; Kralovics, Robert; Gisslinger, Bettina; Strecker, Karin; Egle, Alexander; Melchardt, Thomas; Burgstaller, Sonja; Willenbacher, Ella; Schalling, Martin; Them, Nicole C.; Kadlecova, Pavla; Klade, Christoph; Greil, Richard

    2015-01-01

    In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient. PMID:26261238

  1. Fabrication Report for the AFC-2A and AFC-2B Capsule Irradiations in the ATR

    SciTech Connect

    Timothy A. Hyde

    2007-10-01

    This document provides a general narrative description of the AFC-2A and 2B fuel fabrication processes for the AFC 2A and AFC 2B fuel irradiation experiments fabricated at the Idaho National Laboratory’s Materials and Fuels Complex (MFC) for irradiation in the Advanced Test Reactor (ATR).

  2. A Decompositional Approach to Executing Quality Data Model Algorithms on the i2b2 Platform.

    PubMed

    Mo, Huan; Jiang, Guoqian; Pacheco, Jennifer A; Kiefer, Richard; Rasmussen, Luke V; Pathak, Jyotishman; Denny, Joshua C; Thompson, William K

    2016-01-01

    The Quality Data Model (QDM) is an established standard for representing electronic clinical quality measures on electronic health record (EHR) repositories. The Informatics for Integrated Biology and the Bedside (i2b2) is a widely used platform for implementing clinical data repositories. However, translation from QDM to i2b2 is challenging, since QDM allows for complex queries beyond the capability of single i2b2 messages. We have developed an approach to decompose complex QDM algorithms into workflows of single i2b2 messages, and execute them on the KNIME data analytics platform. Each workflow operation module is composed of parameter lists, a template for the i2b2 message, an mechanism to create parameter updates, and a web service call to i2b2. The communication between workflow modules relies on passing keys ofi2b2 result sets. As a demonstration of validity, we describe the implementation and execution of a type 2 diabetes mellitus phenotype algorithm against an i2b2 data repository. PMID:27570665

  3. Immunohistochemical location of serotonin and serotonin 2B receptor in the small intestine of pigs.

    PubMed

    Zhang, Han; Zhang, Tao; Wang, Lei; Teng, Kedao

    2009-01-01

    The distribution of serotonin and serotonin 2B receptor in the small intestines of pigs newborn, 5, 15 and 100 days of age were examined qualitatively and quantitatively by immunohistochemical labeling, microscopic observation and image analysis. The results showed serotonin immunopositive cells distributed diffusely among the epithelial cells of the middle and more basal parts of villi and intestinal glands in all segments of all pigs examined. Serotonin 2B receptor was first localized in the duodenum of 15-day-old pigs, whereas in 100-day-old pigs, serotonin 2B receptor was immunolabeled abundantly in all segments. Serotonin 2B receptor was distributed in the connective tissue of the small intestinal mucosa, lamina propria and in some myenteric neurons. The density of serotonin 2B receptor immunopositive cells in the duodenum of 100-day-old pigs was higher than that of 15-day-old pigs. The density of serotonin 2B receptor immunopositive cells in the duodenum was the highest among the three segments of the 100-day-old pigs. The study indicates that the distribution of serotonin 2B receptor is species different in the pig small intestine and the intensity of serotonin 2B receptor becomes stronger as the small intestine matures.

  4. First identification of Porcine Circovirus Type 2b mutant in pigs from Uruguay.

    PubMed

    Ramos, Natalia; Mirazo, Santiago; Castro, Gustavo; Arbiza, Juan

    2015-07-01

    Porcine Circovirus Type 2 (PCV2) is a worldwide distributed virus and is considered an important emerging pathogen related to several distinct disease syndromes in pigs. PCV2 strains are classified into three genotypes: PCV2a, with five subtypes (2A-2E), PCV2b with three subtypes (1A-1C) and PCV2c, only found in Denmark. Recently, several reports suggested the circulation of newly emerging PCV2b mutants (mPCV2b) isolated from pigs with PCVAD in cases of suspected vaccine failure. In this work, we report for the first time the identification of mPCV2b in pigs from Uruguay, providing an additional evidence of a global circulation. Complete genome characterization and phylogenetic analysis reveal that Uruguayan strains, as well as mPCV2b previously reported are closely related to other sequences already classified as PCV2b-1C. Furthermore, results showed that mPCV2b presented different genetic markers in the capsid protein compared with classical PCV2a/b strains. Further investigation about antigenic shift of the mPCV2b strains including the Uruguayan isolates is needed.

  5. Pathogenesis of PCV2a and PCV2b virus in germ-free pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic analysis of porcine circovirus type 2 (PCV2) reveals 2 subgroups that will be referred to as PCV2a and PCV2b representing the North American and European prototypes respectfully. This paper summarizes 3 studies comparing the pathogenesis of 2a and 2b viruses in germ-free pigs. In this PCV2...

  6. A Decompositional Approach to Executing Quality Data Model Algorithms on the i2b2 Platform.

    PubMed

    Mo, Huan; Jiang, Guoqian; Pacheco, Jennifer A; Kiefer, Richard; Rasmussen, Luke V; Pathak, Jyotishman; Denny, Joshua C; Thompson, William K

    2016-01-01

    The Quality Data Model (QDM) is an established standard for representing electronic clinical quality measures on electronic health record (EHR) repositories. The Informatics for Integrated Biology and the Bedside (i2b2) is a widely used platform for implementing clinical data repositories. However, translation from QDM to i2b2 is challenging, since QDM allows for complex queries beyond the capability of single i2b2 messages. We have developed an approach to decompose complex QDM algorithms into workflows of single i2b2 messages, and execute them on the KNIME data analytics platform. Each workflow operation module is composed of parameter lists, a template for the i2b2 message, an mechanism to create parameter updates, and a web service call to i2b2. The communication between workflow modules relies on passing keys ofi2b2 result sets. As a demonstration of validity, we describe the implementation and execution of a type 2 diabetes mellitus phenotype algorithm against an i2b2 data repository.

  7. Neutralising antibodies in patients with multiple myeloma receiving maintenance therapy with interferon alpha 2b.

    PubMed Central

    Bell, J. B.; Barfoot, R.; Iveson, T.; Powles, R. L.; Millar, B. C.

    1994-01-01

    In a study of 29 patients who were receiving or had received interferon alpha 2b (IFN-alpha 2b) as maintenance therapy for multiple myeloma, antibodies were detected in 58% (17/29) of patients measured by a solid-phase enzyme-linked immunosorbent assay (ELISA). Only 7/17 patients who were positive for antibody in the ELISA had neutralising antibody to IFN-alpha 2b, measured by virus growth inhibition. These patients comprised six who were receiving IFN-alpha 2b at the time of assessment and one who had finished treatment. Among patients who were receiving the cytokine, four had progressive disease, one was in complete remission and one in partial remission. Neutralising activity was also detected to natural human leucocyte IFN-alpha in the same patients. Two patients who were positive for neutralising antibody remain in remission and are continuing to receive IFN-alpha 2b. These two patients have since lost their neutralising titre. No neutralising antibody to IFN-alpha 2b or natural human leucocyte IFN-alpha was detected in serum from six normal donors. The data suggest that neutralising antibody formation in patients with multiple myeloma is not responsible for relapse in patients receiving IFN-alpha 2b. The transient nature of neutralising antibody production in patients who remain in remission suggests that this response to IFN-alpha 2b is not associated with memory B cells. PMID:7917911

  8. A Decompositional Approach to Executing Quality Data Model Algorithms on the i2b2 Platform

    PubMed Central

    Mo, Huan; Jiang, Guoqian; Pacheco, Jennifer A.; Kiefer, Richard; Rasmussen, Luke V.; Pathak, Jyotishman; Denny, Joshua C.; Thompson, William K.

    2016-01-01

    The Quality Data Model (QDM) is an established standard for representing electronic clinical quality measures on electronic health record (EHR) repositories. The Informatics for Integrated Biology and the Bedside (i2b2) is a widely used platform for implementing clinical data repositories. However, translation from QDM to i2b2 is challenging, since QDM allows for complex queries beyond the capability of single i2b2 messages. We have developed an approach to decompose complex QDM algorithms into workflows of single i2b2 messages, and execute them on the KNIME data analytics platform. Each workflow operation module is composed of parameter lists, a template for the i2b2 message, an mechanism to create parameter updates, and a web service call to i2b2. The communication between workflow modules relies on passing keys ofi2b2 result sets. As a demonstration of validity, we describe the implementation and execution of a type 2 diabetes mellitus phenotype algorithm against an i2b2 data repository. PMID:27570665

  9. 50 CFR Table 2b to Part 679 - Species Codes: FMP Prohibited Species and CR Crab

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CR Crab 2b Table 2b to Part 679 Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL... CR Crab Species Description Code CR Crab Groundfish PSC CRAB Box Lopholithodes mandtii 900 ✓ Dungeness Cancer magister 910 ✓ King, blue Paralithodes platypus 922 ✓ ✓ King, golden (brown)...

  10. Noncanonical sortase-mediated assembly of pilus type 2b in group B Streptococcus.

    PubMed

    Lazzarin, Maddalena; Cozzi, Roberta; Malito, Enrico; Martinelli, Manuele; D'Onofrio, Mariapina; Maione, Domenico; Margarit, Immaculada; Rinaudo, C Daniela

    2015-11-01

    Group B Streptococcus (GBS) expresses 3 structurally distinct pilus types (1, 2a, and 2b) identified as important virulence factors and vaccine targets. These pili are heterotrimeric polymers, covalently assembled on the cell wall by sortase (Srt) enzymes. We investigated the pilus-2b biogenesis mechanism by using a multidisciplinary approach integrating genetic, biochemical, and structural studies to dissect the role of the 2 pilus-2b-associated Srts. We show that only 1 sortase (SrtC1-2b) is responsible for pilus protein polymerization, whereas the second one (Srt2-2b) does not act as a pilin polymerase, but similarly to the housekeeping class A Srt (SrtA), it is involved in cell-wall pilus anchoring by targeting the minor ancillary subunit. Based on its function and sequence features, Srt2-2b does not belong to class C Srts (SrtCs), nor is it a canonical member of any other known family of Srts. We also report the crystal structure of SrtC1-2b at 1.9 Å resolution. The overall fold resembles the typical structure of SrtCs except for the N-terminal lid region that appears in an open conformation displaced from the active site. Our findings reveal that GBS pilus type 2b biogenesis differs significantly from the current model of pilus assembly in gram-positive pathogens.

  11. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    ERIC Educational Resources Information Center

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  12. NMDA receptor surface mobility depends on NR2A-2B subunits

    PubMed Central

    Groc, Laurent; Heine, Martin; Cousins, Sarah L.; Stephenson, F. Anne; Lounis, Brahim; Cognet, Laurent; Choquet, Daniel

    2006-01-01

    The NR2 subunit composition of NMDA receptors (NMDARs) varies during development, and this change is important in NMDAR-dependent signaling. In particular, synaptic NMDAR switch from containing mostly NR2B subunit to a mixture of NR2B and NR2A subunits. The pathways by which neurons differentially traffic NR2A- and NR2B-containing NMDARs are poorly understood. Using single-particle and -molecule approaches and specific antibodies directed against NR2A and NR2B extracellular epitopes, we investigated the surface mobility of native NR2A and NR2B subunits at the surface of cultured neurons. The surface mobility of NMDARs depends on the NR2 subunit subtype, with NR2A-containing NMDARs being more stable than NR2B-containing ones, and NR2A subunit overexpression stabilizes surface NR2B-containing NMDARs. The developmental change in the synaptic surface content of NR2A and NR2B subunits was correlated with a developmental change in the time spent by the subunits within synapses. This suggests that the switch in synaptic NMDAR subtypes depends on the regulation of the receptor surface trafficking. PMID:17124177

  13. i2b2t2: Unlocking Visualization for Clinical Research

    PubMed Central

    Harris, Daniel R.; Henderson, Darren W.

    2016-01-01

    We introduce a tool that extracts clinical data sets and provides visualizations from clinical data warehouses that use the Informatics for Integrating Biology and the Bedside (i2b2) query tool. Our tool, i2b2t2 (i2b2 to Tableau), can extract and visualize any i2b2 query into a portable format that researchers can easily explore without needing a highly technical or statistical background. This user-friendly format provides a quick visual summary of the queried population and is easily extendable to develop more intricate and robust visualizations. Extraction and visualization can be provided as a service by clinical data warehouses to expedite the release of data sets for research. i2b2t2 also encourages visualization as a self-service; a motivated researcher can develop custom visualizations for exploration or publication. PMID:27570658

  14. i2b2t2: Unlocking Visualization for Clinical Research.

    PubMed

    Harris, Daniel R; Henderson, Darren W

    2016-01-01

    We introduce a tool that extracts clinical data sets and provides visualizations from clinical data warehouses that use the Informatics for Integrating Biology and the Bedside (i2b2) query tool. Our tool, i2b2t2 (i2b2 to Tableau), can extract and visualize any i2b2 query into a portable format that researchers can easily explore without needing a highly technical or statistical background. This user-friendly format provides a quick visual summary of the queried population and is easily extendable to develop more intricate and robust visualizations. Extraction and visualization can be provided as a service by clinical data warehouses to expedite the release of data sets for research. i2b2t2 also encourages visualization as a self-service; a motivated researcher can develop custom visualizations for exploration or publication. PMID:27570658

  15. Leitbilder und Handlungsstrategien für die Raumentwicklung in Deutschland. Entwicklungs-, Umsetzungs- und Fortschreibungsprozess der Bund-Länder-Strategie für Städte und Regionen

    NASA Astrophysics Data System (ADS)

    Issaoui, Mariam; Sinz, Manfred

    2010-09-01

    Die Ministerkonferenz für Raumordnung stellte im Mai 2010 fest, dass sich die „Leitbilder und Handlungsstrategien für die Raumentwicklung in Deutschland“ (2006) bewährt haben und bei der Gestaltung der räumlichen Entwicklung umgesetzt werden. Um die Leitbilder den sich verändernden wirtschaftlichen, sozialen und naturräumlichen Rahmenbedingungen anzupassen und die Erkenntnisse aus dem bisherigen Diskussions- und Umsetzungsprozess in Politik und Praxis einzubeziehen, sind sie zu ergänzen und weiterzuentwickeln. Im Mittelpunkt der Fortschreibung werden die Themen „Partnerschaften und Strategien für Stadtregionen und ländliche Räume“, „Mobilität und Logistik“ sowie „Klimaschutz und Energieversorgung“ stehen.

  16. Cytochrome P450 2B Diversity and Dietary Novelty in the Herbivorous, Desert Woodrat (Neotoma lepida)

    PubMed Central

    Malenke, Jael R.; Magnanou, Elodie; Thomas, Kirk; Dearing, M. Denise

    2012-01-01

    Detoxification enzymes play a key role in plant-herbivore interactions, contributing to the on-going evolution of ecosystem functional diversity. Mammalian detoxification systems have been well studied by the medical and pharmacological industries to understand human drug metabolism; however, little is known of the mechanisms employed by wild herbivores to metabolize toxic plant secondary compounds. Using a wild rodent herbivore, the desert woodrat (Neotoma lepida), we investigated genomic structural variation, sequence variability, and expression patterns in a multigene subfamily involved in xenobiotic metabolism, cytochrome P450 2B (CYP2B). We hypothesized that differences in CYP2B expression and sequence diversity could explain differential abilities of woodrat populations to consume native plant toxins. Woodrats from two distinct populations were fed diets supplemented with either juniper (Juniperus osteosperma) or creosote bush (Larrea tridentata), plants consumed by woodrats in their respective desert habitats. We used Southern blot and quantitative PCR to determine that the genomic copy number of CYP2B in both populations was equivalent, and similar in number to known rodent copy number. We compared CYP2B expression patterns and sequence diversity using cloned hepatic CYP2B cDNA. The resulting sequences were very diverse, and clustered into four major clades by amino acid similarity. Sequences from the experimental treatments were distributed non-randomly across a CYP2B tree, indicating unique expression patterns from woodrats on different diets and from different habitats. Furthermore, within each major CYP2B clade, sequences shared a unique combination of amino acid residues at 13 sites throughout the protein known to be important for CYP2B enzyme function, implying differences in the function of each major CYP2B variant. This work is the most comprehensive investigation of the genetic diversity of a detoxification enzyme subfamily in a wild mammalian

  17. A2B Adenosine Receptor Agonist Improves Erectile Function in Diabetic Rats.

    PubMed

    Wen, Jiaming; Wang, Bohan; Du, Chuanjun; Xu, Gang; Zhang, Zhewei; Li, Yi; Zhang, Nan

    2015-01-01

    Diabetes is an important risk factor for erectile dysfunction (ED). Recent studies have indicated that A2B adenosine receptor (ADORA2B) signaling is essential for penile erection. Thus, we hypothesize that diabetic ED may be attributed to impaired A2B adenosine signaling. To test this hypothesis, we generated diabetic rats by injecting streptozocin as animal model. After 12 weeks, immunohistochemistry staining was used to localize the expression of ADORA2B. Western Blot and quantitative PCR were employed to determine ADORA2B expression level. Intracavernosal pressure (ICP) measurement was used to evaluate erectile function. Diabetic rats received a single intravenous injection of BAY 60-6583, an ADORA2B agonist, or vehicle solution, at 60 min before the ICP measurement. The results showed that ADORA2B expressed in the nerve bundle, smooth muscle, and endothelium in penile tissue of control mice. Western Blot and quantitative PCR results indicated that the expression levels of ADORA2B protein and mRNA were significantly reduced in penile tissues of diabetic rats. Functional studies showed that the erectile response induced by electrical stimulation was remarkably decreased in diabetic rats, compared with age-matched control rats. However, at 60 min after BAY 60-6583 treatment, the erectile function was improved in diabetic rats, suggesting that enhancement of ADORA2B signaling may improve erectile function in diabetic ED. This preclinical study has revealed a previously unrecognized therapeutic possibility of BAY 60-6583 as an effective and mechanism-based drug to treat diabetic ED. In conclusion, we propose that impaired A2B adenosine signaling is one of the pathological mechanisms of diabetic ED.

  18. Cloning and expression of a rat brain. alpha. sub 2B -adrenergic receptor

    SciTech Connect

    Flordellis, C.S.; Handy, D.E.; Bresnahan, M.R.; Zannis, V.I.; Gavras, H. )

    1991-02-01

    The authors isolated a cDNA clone (RB{alpha}{sub 2B}) and its homologous gene (GR{alpha}{sub 2B}) encoding an {alpha}{sub 2B}-adrenergic receptor subtype by screening a rat brain cDNA and a rat genomic library. Nucleotide sequence analysis showed that both clones code for a protein of 458 amino acids, which is 87% homologous to the human kidney glycosylated adrenergic receptor ({alpha}{sub 2}-C4) and divergent from the rat kidney nonglycosylated {alpha}{sub 2B} subtype (RNG{alpha}{sub 2}). Transient expression of RB{alpha}{sub 2B} in COS-7 cells resulted in high-affinity saturable binding for ({sup 3}H)rauwolscine and a high receptor number in the membranes of transfected COS-7 cells. Pharmacological analysis demonstrated that the expressed receptor bound adrenergic ligands with the following order of potency: rauwolscine {gt} yohimbine {gt} prazosin {gt} oxymetazoline, with a prazosin-to-oxymetazoline K{sub i} ratio of 0.34. This profile is characteristic of the {alpha}{sub 2B}-adrenergic receptor subtype. Blotting analysis of rat brain mRNA gave one major and two minor mRNA species, and hybridization with strand-specific probes showed that both DNA strands of GR{alpha}{sub 2B} may be transcriptionally active. These findings show that rat brain expresses an {alpha}{sub 2B}-adrenergic receptor subtype that is structurally different from the rat kidney nonglycosylated {alpha}{sub 2B} subtype. Thus the rat expresses at least two divergent {alpha}{sub 2B}-adrenergic receptors.

  19. Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.

    PubMed

    Ikram, Fakhera; Ackermann, Sandra; Kahlert, Yvonne; Volland, Ruth; Roels, Frederik; Engesser, Anne; Hertwig, Falk; Kocak, Hayriye; Hero, Barbara; Dreidax, Daniel; Henrich, Kai-Oliver; Berthold, Frank; Nürnberg, Peter; Westermann, Frank; Fischer, Matthias

    2016-02-01

    Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma. PMID:26598443

  20. A2B Adenosine Receptor Agonist Improves Erectile Function in Diabetic Rats.

    PubMed

    Wen, Jiaming; Wang, Bohan; Du, Chuanjun; Xu, Gang; Zhang, Zhewei; Li, Yi; Zhang, Nan

    2015-01-01

    Diabetes is an important risk factor for erectile dysfunction (ED). Recent studies have indicated that A2B adenosine receptor (ADORA2B) signaling is essential for penile erection. Thus, we hypothesize that diabetic ED may be attributed to impaired A2B adenosine signaling. To test this hypothesis, we generated diabetic rats by injecting streptozocin as animal model. After 12 weeks, immunohistochemistry staining was used to localize the expression of ADORA2B. Western Blot and quantitative PCR were employed to determine ADORA2B expression level. Intracavernosal pressure (ICP) measurement was used to evaluate erectile function. Diabetic rats received a single intravenous injection of BAY 60-6583, an ADORA2B agonist, or vehicle solution, at 60 min before the ICP measurement. The results showed that ADORA2B expressed in the nerve bundle, smooth muscle, and endothelium in penile tissue of control mice. Western Blot and quantitative PCR results indicated that the expression levels of ADORA2B protein and mRNA were significantly reduced in penile tissues of diabetic rats. Functional studies showed that the erectile response induced by electrical stimulation was remarkably decreased in diabetic rats, compared with age-matched control rats. However, at 60 min after BAY 60-6583 treatment, the erectile function was improved in diabetic rats, suggesting that enhancement of ADORA2B signaling may improve erectile function in diabetic ED. This preclinical study has revealed a previously unrecognized therapeutic possibility of BAY 60-6583 as an effective and mechanism-based drug to treat diabetic ED. In conclusion, we propose that impaired A2B adenosine signaling is one of the pathological mechanisms of diabetic ED. PMID:26447087

  1. Die neue Kosmologie. Von Dunkelmaterie, GUTs und Superhaufen.

    NASA Astrophysics Data System (ADS)

    Cornell, J.

    This book is a German translation, by M. Röser, of the American original "Bubbles, voids, and bumps in time: the new cosmology", published 1989 (see 49.003.045). Contents: 1. Die Entdeckung des Weltalls: Eine Einleitung (A. P. Lightman). 2. Die Vermessung des Weltalls: Rotverschiebungen und Standardkerzen (R. P. Kirshner). 3. Die Kartierung des Weltalls: Scheiben und Blasen (M. J. Geller). 4. Die Bestimmung der Masse im Weltall: Dunkelmaterie und fehlende Masse (V. C. Rubin). 5. Der Beginn des Weltalls: Urknall und kosmische Inflation (A. H. Guth). 6. Die Ausweitung des Weltalls: Das Weltraumteleskop und Perspektiven für die nächsten 20 Jahre (J. E. Gunn).

  2. Zwischen Web 2.0, virtuellen Welten und Game-based Learning - Einsatzszenarien und Prototypen im Hochschulumfeld

    NASA Astrophysics Data System (ADS)

    Pongratz, Hans

    Web 2.0, virtuelle Welten und Game-based Learning werden als Allheilmittel moderner Wissensvermittlung an Hochschulen genannt. Dieser Artikel beschreibt nach einer Einführung in die Thematik Einsatzszenarien und Prototypen im Hochschulumfeld anhand ausgewählter Web 2.0-Dienste, der virtuellen Welt Second Life, eines an der TUM entwickelten Frameworks für Gamebased Learning Applikationen und eines Lernspiels. Diese werden anhand von konkreten Lehr- und Lernszenarien vorgestellt und anhand der bisherigen Erfahrungen in diesem Bereich kritisch beleuchtet.

  3. SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling.

    PubMed

    Donatello, S; Fiorino, A; Degl'Innocenti, D; Alberti, L; Miranda, C; Gorla, L; Bongarzone, I; Rizzetti, M G; Pierotti, M A; Borrello, M G

    2007-10-01

    The RET gene encodes two main isoforms of a receptor tyrosine kinase (RTK) implicated in various human diseases. Activating germ-line point mutations are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinomas, inactivating germ-line mutations for Hirschsprung's disease, while somatic rearrangements (RET/PTCs) are specific to papillary thyroid carcinomas. SH2B1beta, a member of the SH2B adaptors family, and binding partner for several RTKs, has been recently described to interact with proto-RET. Here, we show that both RET isoforms and its oncogenic derivatives bind to SH2B1beta through the SRC homology 2 (SH2) domain and a kinase activity-dependent mechanism. As a result, RET phosphorylates SH2B1beta, which in turn enhances its autophosphorylation, kinase activity, and downstream signaling. RET tyrosine residues 905 and 981 are important determinants for functional binding of the adaptor, as removal of both autophosphorylation sites displaces its recruitment. Binding of SH2B1beta appears to protect RET from dephosphorylation by protein tyrosine phosphatases, and might represent a likely mechanism contributing to its upregulation. Thus, overexpression of SH2B1beta, by enhancing phosphorylation/activation of RET transducers, potentiates the cellular differentiation and the neoplastic transformation thereby induced, and counteracts the action of RET inhibitors. Overall, our results identify SH2B1beta as a key enhancer of RET physiologic and pathologic activities.

  4. Structural Basis for RNA-Silencing Suppression by Tomato Aspermy Virus Protein 2b

    SciTech Connect

    Chen,H.; Yang, J.; Lin, C.; Yuan, Y.

    2008-01-01

    The 2b proteins encoded by cucumovirus act as post-transcriptional gene silencing suppressors to counter host defence during infection. Here we report the crystal structure of Tomato aspermy virus 2b (TAV2b) protein bound to a 19 bp small interfering RNA (siRNA) duplex. TAV2b adopts an all {alpha}-helix structure and forms a homodimer to measure siRNA duplex in a length-preference mode. TAV2b has a pair of hook-like structures to recognize simultaneously two {alpha}-helical turns of A-form RNA duplex by fitting its {alpha}-helix backbone into two adjacent major grooves of siRNA duplex. The conserved {pi}-stackings between tryptophan and the 5'-terminal base of siRNA duplex from both ends enhance the recognition. TAV2b further oligomerizes to form a dimer of dimers through the conserved leucine-zipper-like motif at its amino-terminal {alpha}-helix. Biochemical experiments suggest that TAV2b might interfere with the post-transcriptional gene silencing pathway by directly binding to siRNA duplex.

  5. Splicing factor TRA2B is required for neural progenitor survival.

    PubMed

    Roberts, Jacqueline M; Ennajdaoui, Hanane; Edmondson, Carina; Wirth, Brunhilde; Sanford, Jeremy R; Chen, Bin

    2014-02-01

    Alternative splicing of pre-mRNAs can rapidly regulate the expression of large groups of proteins. The RNA binding protein TRA2B (SFRS10) plays well-established roles in developmentally regulated alternative splicing during Drosophila sexual differentiation. TRA2B is also essential for mammalian embryogenesis and is implicated in numerous human diseases. Precise regulation of alternative splicing is critical to the development and function of the central nervous system; however, the requirements for specific splicing factors in neurogenesis are poorly understood. This study focuses on the role of TRA2B in mammalian brain development. We show that, during murine cortical neurogenesis, TRA2B is expressed in both neural progenitors and cortical projection neurons. Using cortex-specific Tra2b mutant mice, we show that TRA2B depletion results in apoptosis of the neural progenitor cells as well as disorganization of the cortical plate. Thus, TRA2B is essential for proper development of the cerebral cortex. PMID:23818142

  6. The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease.

    PubMed

    Karmouty-Quintana, Harry; Zhong, Hongyan; Acero, Luis; Weng, Tingting; Melicoff, Ernestina; West, James D; Hemnes, Anna; Grenz, Almut; Eltzschig, Holger K; Blackwell, Timothy S; Xia, Yang; Johnston, Richard A; Zeng, Dewan; Belardinelli, Luiz; Blackburn, Michael R

    2012-06-01

    Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.

  7. CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients[S

    PubMed Central

    Horswell, Stuart D.; Fryer, Lee G. D.; Hutchison, Claire E.; Zindrou, Dlear; Speedy, Helen E.; Town, Margaret-M.; Duncan, Emma J.; Sivapackianathan, Rasheeta; Patel, Hetal N.; Jones, Emma L.; Braithwaite, Adam; Salm, Max P. A.; Neuwirth, Claire K. Y.; Potter, Elizabeth; Anderson, Jonathan R.; Taylor, Kenneth M.; Seed, Mary; Betteridge, D. John; Crook, Martin A.; Wierzbicki, Anthony S.; Scott, James; Naoumova, Rossi P.; Shoulders, Carol C.

    2013-01-01

    The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating five overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular trafficking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2B were increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2B knockdown induced C/EBPα expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR-323b-5p mimic significantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B 3′UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2B mRNA in the MuTHER adipose tissue dataset, family studies suggest the association between increased CDKN2B expression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis. PMID:24103848

  8. Differential role of SH2-B and APS in regulating energy and glucose homeostasis.

    PubMed

    Li, Minghua; Ren, Decheng; Iseki, Masanori; Takaki, Satoshi; Rui, Liangyou

    2006-05-01

    SH2-B and APS, two members of a pleckstrin homology and SH2 domain-containing adaptor family, promote both insulin and leptin signaling in a similar fashion in cultured cells. In addition, APS mediates insulin-stimulated activation of the c-Cbl/CAP/TC10 pathway in cultured adipocytes. Here we characterized genetically modified mice lacking SH2-B, APS, or both to determine the physiological roles of these two proteins in animals. Disruption of the SH2-B gene resulted in obesity, hyperglycemia, hyperinsulinemia, and glucose intolerance. Conversely, deletion of the APS gene did not alter adiposity, energy balance, and glucose metabolism. Energy intake, energy expenditure, fat content, body weight, and plasma insulin, leptin, glucose, and lipid levels were similar between APS(-/-) and WT littermates fed either normal chow or a high-fat diet. Moreover, deletion of APS failed to alter insulin and glucose tolerance. APS(-/-)/SH2-B(-/-) double knockout mice also developed energy imbalance, obesity, hyperleptinemia, hyperinsulinemia, hyperglycemia, and glucose intolerance; however, plasma leptin and insulin levels were significantly lower in APS(-/-)/SH2-B(-/-) than in SH2-B(-/-) mice. These results suggest that SH2-B, but not APS, is a key positive regulator of energy and glucose metabolism in mice.

  9. The C ∼ 2B3u ← X ∼ 2B2g electronic absorption spectrum of butatriene cation in a neon matrix

    NASA Astrophysics Data System (ADS)

    Filipkowski, Karol; Fulara, Jan; Maier, John P.

    2015-04-01

    The C ∼ 2B3u ← X ∼ 2B2g electronic absorption of butatriene cation (BT+) has been observed in a 6 K neon matrix. The origin band lies at 511.9 nm. The electronic transition assignment is based on comparison with the photoelectron spectrum of butatriene and the vibrational frequencies of BT+ calculated with the CASPT2 (5, 6) method. Three vibrational modes of energy 207, 511 and 813 cm-1, with their overtones and combinations, are active in the C ∼ 2B3u state of BT+. It is shown that the emission observed from a glow discharge of 2-butyne at 491 nm and attributed to the origin band of this electronic transition [1] of BT+ is due to another species, because the difference of 850 cm-1 to the absorption spectrum is too large. No fluorescence of BT+ was detected in the matrix and it is expected that the C ∼ 2B3u electronic state relaxes non-radiatively on a fs time scale.

  10. Lentivirus-mediated downregulation of MAT2B inhibits cell proliferation and induces apoptosis in melanoma.

    PubMed

    Lei, Yu; Zhang, Bo; Zhang, Yaohua; Zhao, Yuan; Sun, Jingying; Zhang, Xuejun; Yang, Sen

    2016-09-01

    Malignant melanoma is the most lethal of skin cancers and its pathogenesis is complex and heterogeneous. The efficacy of conventional therapeutic regimens for melanoma remains limited. Thus, it is important to explore novel effective therapeutic targets in the treatment of melanoma. The MAT2B gene encodes for the regulatory subunit of methionine adenosyltransferase (MAT). Recent studies have suggested that MAT2B may have functional roles other than modulating catalytic activity of MAT. In order to identify the roles of MAT2B in the tumorigenesis of malignant melanoma, we compared MAT2B expression profile in melanoma tissues with that in benign nevus samples. We employed lentivirus-mediated RNAi to downregulate the expression of MAT2B in malignant melanoma cell lines (A375 and Mel-RM), and investigated the effects of MAT2B on cell growth, colony-formation ability and apoptosis in vitro, as well as tumor growth of a xenograft model in vivo. The expression levels of BCL2 and XAF1 proteins, which were closely related to tumor cell apoptosis, were analyzed by western blot analysis. Our data showed that MAT2B was elevated in both primary and metastatic melanoma tissues compared with benign nevus samples. Lentivirus-mediated downregulation of MAT2B suppressed cell growth, colony formation and induced apoptosis in A375 and Mel-RM cell lines in vitro, affected protein expression of BCL2 and XAF1, extended the transplanted tumor growth in vivo. These results indicated that MAT2B was critical in the proliferation of melanoma cells and tumorigenicity. It may be considered as a potential anti-melanoma therapeutic target. PMID:27573889

  11. Vaccination of dogs with canine parvovirus type 2b (CPV-2b) induces neutralising antibody responses to CPV-2a and CPV-2c.

    PubMed

    Wilson, Stephen; Illambas, Joanna; Siedek, Elisabeth; Stirling, Catrina; Thomas, Anne; Plevová, Edita; Sture, Gordon; Salt, Jeremy

    2014-09-22

    Since the identification of canine parvovirus type 2, three variants have subsequently been observed differing from the historical CPV-2 and each other by 1-2 amino acids only. As a result there has been considerable research into differential diagnostics, with some researchers indicating there is a need for new vaccines containing different strains of CPV-2. In this study we investigated whether vaccination with a CPV-2b containing vaccine would induce cross-reactive antibody responses to the other CPV-2 variants. Two studies where dogs were vaccinated with a multivalent vaccine, subsequently challenged with CPV-2b and sera samples analysed are presented. Six week old pups with defined serological status were vaccinated twice, three weeks apart and challenged either 5 weeks (MDA override study) or one year after vaccination (duration of immunity study). Sera samples were collected before each vaccination and at periods throughout each study. In each study the antibody profiles were very similar; serological responses against CPV-2a, CPV-2b and CPV-2c were higher than those for CPV-2. Nevertheless, responses against CPV-2 were well above levels considered clinically protective. In each study dogs also showed a rapid increase in antibody titres following vaccination, reached a plateau following second vaccination with a slight decline to challenge after which rapid anamnestic responses were seen. Evaluation of the serological responses suggests vaccination with CPV-2b would cross-protect against CPV-2a and CPV-2c, as well as against CPV-2 which is now extinct in the field. In conclusion we have demonstrated that vaccination of minimum aged dogs with a multivalent vaccine containing the CPV-2b variant strain will induce serological responses which are cross-reactive against all currently circulating field strains, CPV-2a and CPV-2c, and the now extinct field strain CPV-2. PMID:25148778

  12. Vaccination of dogs with canine parvovirus type 2b (CPV-2b) induces neutralising antibody responses to CPV-2a and CPV-2c.

    PubMed

    Wilson, Stephen; Illambas, Joanna; Siedek, Elisabeth; Stirling, Catrina; Thomas, Anne; Plevová, Edita; Sture, Gordon; Salt, Jeremy

    2014-09-22

    Since the identification of canine parvovirus type 2, three variants have subsequently been observed differing from the historical CPV-2 and each other by 1-2 amino acids only. As a result there has been considerable research into differential diagnostics, with some researchers indicating there is a need for new vaccines containing different strains of CPV-2. In this study we investigated whether vaccination with a CPV-2b containing vaccine would induce cross-reactive antibody responses to the other CPV-2 variants. Two studies where dogs were vaccinated with a multivalent vaccine, subsequently challenged with CPV-2b and sera samples analysed are presented. Six week old pups with defined serological status were vaccinated twice, three weeks apart and challenged either 5 weeks (MDA override study) or one year after vaccination (duration of immunity study). Sera samples were collected before each vaccination and at periods throughout each study. In each study the antibody profiles were very similar; serological responses against CPV-2a, CPV-2b and CPV-2c were higher than those for CPV-2. Nevertheless, responses against CPV-2 were well above levels considered clinically protective. In each study dogs also showed a rapid increase in antibody titres following vaccination, reached a plateau following second vaccination with a slight decline to challenge after which rapid anamnestic responses were seen. Evaluation of the serological responses suggests vaccination with CPV-2b would cross-protect against CPV-2a and CPV-2c, as well as against CPV-2 which is now extinct in the field. In conclusion we have demonstrated that vaccination of minimum aged dogs with a multivalent vaccine containing the CPV-2b variant strain will induce serological responses which are cross-reactive against all currently circulating field strains, CPV-2a and CPV-2c, and the now extinct field strain CPV-2.

  13. Wilhelm Julius Foerster und die "Vereinigung von Freunden der Astronomie und kosmischen Physik" (1891 bis 1914).

    NASA Astrophysics Data System (ADS)

    Tiemann, K.-H.

    Am 19. Mai 1891 wurde ins Leben gerufen die "Vereinigung von Freunden der Astronomie und der kosmischen Physik (nachfolg.: V.A.P.) - eine der beiden institutionellen Vorläufer der sich 1953 konstituierenden "Vereinigung der Sternfreunde".

  14. Gravitation und Kosmologie. Eine Einführung in die allgemeine Relativitätstheorie.

    NASA Astrophysics Data System (ADS)

    Sexl, R. U.; Urbantke, H. K.

    Contents: 1. Physikalische Grundlagen. 2. Riemannsche Geometrie. 3. Gravitationstheorie. 4. Experimentelle Tests. 5. Kosmologie. 6. Gravitationswellen. 7. Neue differentialgeometrische Methoden. 8. Sternbau und Gravitationskollaps. 9. Felder im Riemannschen Raum. 10. Gravitation und Feldtheorie. 11. Gravitation und Eichtheorie.

  15. Beyond Cohort Selection: An Analytics-Enabled i2b2.

    PubMed

    Gabetta, Matteo; Malovini, Alberto; Bucalo, Mauro; Zini, Elisa; Tibollo, Valentina; Priori, Silvia G; Vettoretti, Simone; Larizza, Cristiana; Bellazzi, Riccardo; Barbarini, Nicola

    2016-01-01

    The i2b2 software is a widely adopted solution for secondary use of clinical data for clinical research, specifically designed for cohort identification. i2b2 is still lacking functionalities for data analysis. The aim of this work is to empower the i2b2 framework enabling clinical researchers to perform statistical analyses for accelerating the process of hypothesis testing. To this aim we have developed a flexible extension of i2b2 able to exploit different statistical engines. We have implemented some first applications for basic statistics and survival analyses, exploiting this extension and accessible through suitable user interfaces designed with a special consideration for usability. PMID:27577448

  16. Marine microbial biodiversity, bioinformatics and biotechnology (M2B3) data reporting and service standards.

    PubMed

    Ten Hoopen, Petra; Pesant, Stéphane; Kottmann, Renzo; Kopf, Anna; Bicak, Mesude; Claus, Simon; Deneudt, Klaas; Borremans, Catherine; Thijsse, Peter; Dekeyzer, Stefanie; Schaap, Dick Ma; Bowler, Chris; Glöckner, Frank Oliver; Cochrane, Guy

    2015-01-01

    Contextual data collected concurrently with molecular samples are critical to the use of metagenomics in the fields of marine biodiversity, bioinformatics and biotechnology. We present here Marine Microbial Biodiversity, Bioinformatics and Biotechnology (M2B3) standards for "Reporting" and "Serving" data. The M2B3 Reporting Standard (1) describes minimal mandatory and recommended contextual information for a marine microbial sample obtained in the epipelagic zone, (2) includes meaningful information for researchers in the oceanographic, biodiversity and molecular disciplines, and (3) can easily be adopted by any marine laboratory with minimum sampling resources. The M2B3 Service Standard defines a software interface through which these data can be discovered and explored in data repositories. The M2B3 Standards were developed by the European project Micro B3, funded under 7(th) Framework Programme "Ocean of Tomorrow", and were first used with the Ocean Sampling Day initiative. We believe that these standards have value in broader marine science.

  17. Tat-NR2B9c prevents excitotoxic neuronal superoxide production

    PubMed Central

    Chen, Yanting; Brennan-Minnella, Angela M; Sheth, Sunil; El-Benna, Jamel; Swanson, Raymond A

    2015-01-01

    The Tat-NR2B9c peptide has shown clinical efficacy as a neuroprotective agent in acute stroke. Tat-NR2B9c is designed to prevent nitric oxide (NO) production by preventing postsynaptic density protein 95 (PSD-95) binding to N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase; however, PSD-95 is a scaffolding protein that also couples NMDA receptors to other downstream effects. Here, using neuronal cultures, we show that Tat-NR2B9c also prevents NMDA-induced activation of neuronal NADPH oxidase, thereby blocking superoxide production. Given that both superoxide and NO are required for excitotoxic injury, the neuroprotective effect of Tat-NR2B9c may alternatively be attributable to uncoupling neuronal NADPH oxidase from NMDA receptor activation. PMID:25669908

  18. Ground-water flow beneath levee 35A from conservation area 2B, Broward County, Florida

    USGS Publications Warehouse

    Swayze, L.J.

    1988-01-01

    Conservation Area 2B is an area of recharge for the surficial aquifer system in Broward County. Water stored in the conservation area provides the hydraulic potential for downward flow to the high permeability zone of the Biscayne aquifer. A 5.64 ft head differential (average for the period of record) between water levels in Conservation Area 2B and water levels in the adjacent levee 35A borrow canal causes water to leak into the canal at an average rate of about 0.0022 cu ft per sec per lineal foot of canal and accounts for a loss of 0.013 foot per day of surface water from Conservation Area 2B. Amounts of canal leakage and underflow are constantly changing and are dependent upon the head differential between Conservation Area 2B and the levee 35A borrow canal. (Author 's abstract)

  19. Thermoluminescence characteristics of gamma irradiated Li2B4O7:Cu nanophosphor

    NASA Astrophysics Data System (ADS)

    Chopra, Vibha; Singh, Lakhwant; Lochab, S. P.

    2013-07-01

    Nanocrystals of the Li2B4O7:Cu were synthesized by the combustion method using different concentrations of Cu. X-ray diffraction (XRD) spectra and transmission electron microscopy (TEM) image confirm the nanometric size of synthesized material. The thermal stability of phosphor was obtained by thermogravimetric analysis (TGA). TL characteristics of the synthesized Li2B4O7:Cu material doped with Cu of concentrations 1000 ppm and 2500 ppm were studied. It is observed that Li2B4O7:Cu doped with Cu (both 1000 ppm and 2500 ppm) exhibit a linear response in the range 1×100-5×103 Gy of gamma radiations. Finally the trapping parameters associated with the glow peaks were calculated using the glow curve deconvolution (GCD) glow fit method. Fading and reproducibility of phosphors were also studied and it was found that the Li2B4O7:Cu is quite suitable for radiation dosimetry.

  20. The letrozole phase 1 metabolite carbinol as a novel probe drug for UGT2B7.

    PubMed

    Precht, Jana C; Schroth, Werner; Klein, Kathrin; Brauch, Hiltrud; Krynetskiy, Evgeny; Schwab, Matthias; Mürdter, Thomas E

    2013-11-01

    Carbinol [4,4'-(hydroxymethylene)dibenzonitrile] is the main phase 1 metabolite of letrozole, a nonsteroidal aromatase inhibitor used for endocrine therapy in postmenopausal breast cancer. We elucidated the contribution of UDP-glucuronosyltransferase (UGT) isoforms on the glucuronidation of carbinol. Identification of UGT isoforms was performed using a panel of recombinant human UGT enzymes. Kinetic studies were done in recombinant human UGT2B7 and pooled human liver microsomes (HLMs). A liquid chromatography-tandem mass spectrometry method was used for detection of metabolites. To assess the impact of UGT2B7*2, we determined the carbinol glucuronidation activity using HLM as well as UGT2B7 protein expression in 148 human livers. Moreover, we analyzed the plasma concentrations of 60 letrozole-treated breast cancer patients. We identified UGT2B7 as the predominant UGT isoform involved in carbinol glucuronidation. In HLMs and recombinant UGT2B7, we determined K(m) values (9.99 and 9.56 µM) and V(max) values (3430 and 2399 pmol/min per milligram of protein), respectively. In the set of 148 human livers, carbinol glucuronidation activity significantly correlated with UGT2B7 protein as determined by Western blotting (r(s) = 0.5088, P < 0.0001). Neither carbinol glucuronidation activity (*1/*1: n = 25, 2434 ± 1018; *1/*2: n = 80, 2356 ± 1372; *2/*2: n = 43, 2251 ± 1421 pmol/min per milligram of protein) nor UGT2B7 protein expression was altered by the UGT2B7*2 genotype. No impact of UGT2B7*2 on plasma levels of carbinol and carbinol-gluc [bis(4-cyanophenyl)methyl hexopyranosiduronic acid] in 60 letrozole-treated patients was found. Taken together, these findings suggest carbinol as a novel in vitro probe substrate for UGT2B7. In vitro and in vivo data suggest a lack of influence of the UGT2B7*2 polymorphism on carbinol glucuronidation.

  1. Stable high volumetric production of glycosylated human recombinant IFNalpha2b in HEK293 cells

    PubMed Central

    Loignon, Martin; Perret, Sylvie; Kelly, John; Boulais, Denise; Cass, Brian; Bisson, Louis; Afkhamizarreh, Fatemeh; Durocher, Yves

    2008-01-01

    Background Mammalian cells are becoming the prevailing expression system for the production of recombinant proteins because of their capacity for proper protein folding, assembly, and post-translational modifications. These systems currently allow high volumetric production of monoclonal recombinant antibodies in the range of grams per litre. However their use for large-scale expression of cytokines typically results in much lower volumetric productivity. Results We have engineered a HEK293 cell clone for high level production of human recombinant glycosylated IFNα2b and developed a rapid and efficient method for its purification. This clone steadily produces more than 200 mg (up to 333 mg) of human recombinant IFNα2b per liter of serum-free culture, which can be purified by a single-step cation-exchange chromatography following media acidification and clarification. This rapid procedure yields 98% pure IFNα2b with a recovery greater than 70%. Purified IFNα2b migrates on SDS-PAGE as two species, a major 21 kDa band and a minor 19 kDa band. N-terminal sequences of both forms are identical and correspond to the expected mature protein. Purified IFNα2b elutes at neutral pH as a single peak with an apparent molecular weight of 44,000 Da as determined by size-exclusion chromatography. The presence of intramolecular and absence of intermolecular disulfide bridges is evidenced by the fact that non-reduced IFNα2b has a greater electrophoretic mobility than the reduced form. Treatment of purified IFNα2b with neuraminidase followed by O-glycosidase both increases electrophoretic mobility, indicating the presence of sialylated O-linked glycan. A detailed analysis of glycosylation by mass spectroscopy identifies disialylated and monosialylated forms as the major constituents of purified IFNα2b. Electron transfer dissociation (ETD) shows that the glycans are linked to the expected threonine at position 106. Other minor glycosylated forms and non-sialylated species are

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

    PubMed Central

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

    2012-01-01

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

  3. Differential effects of enrichment on learning and memory function in NR2B transgenic mice.

    PubMed

    Tang, Y P; Wang, H; Feng, R; Kyin, M; Tsien, J Z

    2001-11-01

    It has been known that environmental enrichment leads to better learning and memory in mice. However, the molecular mechanisms are not known. In this study, we used the 10th-12th of the NR2B transgenic (Tg) lines, in which the NMDA receptor function is enhanced via the NR2B subunit transgene in neurons of the forebrain, to test the hypothesis of the involvement of NMDA receptor function in enrichment-induced better learning and memory. Consistent with our previous results, both larger long-term potentiation (LTP) in the hippocampus and superior learning and memory were observed in naive NR2B Tg mice even after the 10th-12th generation of breeding. After enrichment, wild-type mice exhibited overall improvement in their performances in contextual and cued conditioning, fear extinctions, and novel object recognition tasks. Interestingly, the same enrichment procedures could not further increase the performance of NR2B Tg mice in contextual conditioning, cued conditioning, or fear extinction, thereby indicating that enhanced NMDA receptor function can occlude these enrichment effects. However, we found that in the novel object recognition task enriched NR2B Tg mice exhibited much longer recognition memory (up to 1 week), compared to that (up to 3 days) in naive NR2B Tg mice. Furthermore, our biochemical experiments showed that enrichment significantly increased protein levels of GluR1, NR2B, and NR2A subunits of glutamate receptors in both wild-type and NR2B Tg mice. Therefore, our results suggest an interactive nature of molecular pathways involved in both environmental and genetic NMDA receptor manipulations for enhancing learning and memory.

  4. Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine.

    PubMed

    Mijatovic, Jelena; Patrikainen, Outi; Yavich, Leonid; Airavaara, Mikko; Ahtee, Liisa; Saarma, Mart; Piepponen, T Petteri

    2008-06-01

    The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of alpha-methyl-para-tyrosine (alphaMT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity. PMID:18248620

  5. [Prooxidant and cytotoxic action of N-acetylcysteine and glutathione combined with vitamin Bl2b].

    PubMed

    Solov'eva, M E; Solov'ev, V V; Faskhutdinova, A A; Kudriavtsev, A A; Akatov, V S

    2007-01-01

    We studied the prooxidant and cytotoxic action of thiols N-acetylcystein (NAC) and glutathione (GSH) combined with vitamin Bl2b. The synergism of action of the thiols and Bl2b resulted in human carcinoma cell damage was found. It was shown that GSH and NAC in physiological doses combined with Bl2b caused the initiation of apoptosis. It was established that prooxidant action of the thiols combined with vitamin Bl2b, i. e. generation and accumulation of hydrogen peroxide in culture medium, led to intracellular oxidative stress and injury of cell redox system. These effects were completely abolished by nonthiol antioxidants catalase and pyruvate. The chelators of iron phenanthroline and deferoxamine did not suppress the H2O2 accumulation in culture medium but significantly inhibited the cell death induced by the thiols combined with Bl2b. Therefore, the thiols GSH and NAC widely used as antioxidants, in combination with vitamin Bl2b show prooxidant characteristics and induce, with the participation of intracellular iron, apoptotic HEp-2 cell death.

  6. Allosteric inhibition of the NS2B-NS3 protease from dengue virus.

    PubMed

    Yildiz, Muslum; Ghosh, Sumana; Bell, Jeffrey A; Sherman, Woody; Hardy, Jeanne A

    2013-12-20

    Dengue virus is the flavivirus that causes dengue fever, dengue hemorrhagic disease, and dengue shock syndrome, which are currently increasing in incidence worldwide. Dengue virus protease (NS2B-NS3pro) is essential for dengue virus infection and is thus a target of therapeutic interest. To date, attention has focused on developing active-site inhibitors of NS2B-NS3pro. The flat and charged nature of the NS2B-NS3pro active site may contribute to difficulties in developing inhibitors and suggests that a strategy of identifying allosteric sites may be useful. We report an approach that allowed us to scan the NS2B-NS3pro surface by cysteine mutagenesis and use cysteine reactive probes to identify regions of the protein that are susceptible to allosteric inhibition. This method identified a new allosteric site utilizing a circumscribed panel of just eight cysteine variants and only five cysteine reactive probes. The allosterically sensitive site is centered at Ala125, between the 120s loop and the 150s loop. The crystal structures of WT and modified NS2B-NS3pro demonstrate that the 120s loop is flexible. Our work suggests that binding at this site prevents a conformational rearrangement of the NS2B region of the protein, which is required for activation. Preventing this movement locks the protein into the open, inactive conformation, suggesting that this site may be useful in the future development of therapeutic allosteric inhibitors. PMID:24164286

  7. Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III.

    PubMed

    Zhang, Qian; Cao, Yun-Feng; Ran, Rui-Xue; Li, Rong-Shan; Wu, Xue; Dong, Pei-Pei; Zhang, Yan-Yan; Hu, Cui-Min; Wang, Wei-Ming

    2016-01-01

    Drug-metabolizing enzymes inhibition-based drug-drug interaction remains to be the key limiting factor for the research and development of efficient herbal components to become clinical drugs. The present study aims to determine the inhibition of uridine 5'-diphospho-glucuronosyltransferases (UGTs) isoforms by two important efficient herbal ingredients isolated from Atractylodes macrocephala Koidz, atractylenolide I and III. In vitro recombinant UGTs-catalysed glucuronidation of 4-methylumbelliferone was used to determine the inhibition capability and kinetics of atractylenolide I and III towards UGT2B7, and in silico docking method was employed to explain the possible mechanism. Atractylenolide I and III exhibited specific inhibition towards UGT2B7, with negligible influence towards other UGT isoforms. Atractylenolide I exerted stronger inhibition potential than atractylenolide III towards UGT2B7, which is attributed to the different hydrogen bonds and hydrophobic interactions. Inhibition kinetic analysis was performed for the inhibition of atractylenolide I towards UGT2B7. Inhibition kinetic determination showed that atractylenolide I competitively inhibited UGT2B7, and inhibition kinetic parameter (Ki) was calculated to be 6.4 μM. In combination of the maximum plasma concentration of atractylenolide I after oral administration of 50 mg/kg atractylenolide I, the area under the plasma concentration-time curve ration AUCi /AUC was calculated to be 1.17, indicating the highly possible drug-drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7-catalysed metabolism. PMID:26536846

  8. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension.

    PubMed

    Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F; Chen, Ning-Yuan; Weng, Tingting; Molina, Jose G; Luo, Fayong; Davies, Jonathan; Le, Ngoc-Bao; Bunge, Isabelle; Volcik, Kelly A; Le, Thanh-Thuy T; Johnston, Richard A; Xia, Yang; Eltzschig, Holger K; Blackburn, Michael R

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B(f/f)-LysM(Cre)) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B(f/f)-LysM(Cre) mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.

  9. Functional importance of a peripheral pocket in mammalian cytochrome P450 2B enzymes.

    PubMed

    Jang, Hyun-Hee; Liu, Jingbao; Lee, Ga-Young; Halpert, James R; Wilderman, P Ross

    2015-10-15

    The functional importance of a peripheral pocket found in previously published X-ray crystal structures of CYP2B4 and CYP2B6 was probed using a biophysical approach. Introduction of tryptophan within the pocket of CYP2B4 at F202 or I241 leads to marked impairment of 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) or 7-benzyloxyresorufin O-dealkylation efficiency; a similar substitution at F195, near the surface access to the pocket, does not affect these activities. The analogous CYP2B6 F202W mutant is inactive in the 7-EFC O-dealkylation assay. The stoichiometry of 7-EFC deethylation suggested that the decreased activity of F202W and I241W in CYP2B4 and lack of activity of F202W in CYP2B6 coincided with a sharp increase in the flux of reducing equivalents through the oxidase shunt to produce excess water. The results indicate that the chemical identity of residues within this peripheral pocket, but not at the mouth of the pocket, is important in substrate turnover and redox coupling, likely through effects on active site topology.

  10. Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

    PubMed Central

    Andricovich, Jaclyn; Kai, Yan; Peng, Weiqun; Foudi, Adlen; Tzatsos, Alexandros

    2016-01-01

    The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context. PMID:26808549

  11. R Engine Cell: integrating R into the i2b2 software infrastructure

    PubMed Central

    Segagni, Daniele; Ferrazzi, Fulvia; Larizza, Cristiana; Tibollo, Valentina; Napolitano, Carlo; Priori, Silvia G

    2011-01-01

    Informatics for Integrating Biology and the Bedside (i2b2) is an initiative funded by the NIH that aims at building an informatics infrastructure to support biomedical research. The University of Pavia has recently integrated i2b2 infrastructure with a registry of inherited arrhythmogenic diseases. Within this project, the authors created a novel i2b2 cell, named R Engine Cell, which allows the communication between i2b2 and the R statistical software. As survival analyses are routinely performed by cardiology researchers, the authors have first concentrated on making Kaplan–Meier analyses available within the i2b2 web interface. To this aim, the authors developed a web-client plug-in to select the patient set on which to perform the analysis and to display the results in a graphical, intuitive way. R Engine Cell has been designed to easily support the integration of other R-based statistical analyses into i2b2. PMID:21262924

  12. Collisional Removal of O2(b1Σ ^+g, v = 1) by Atomic Oxygen

    NASA Astrophysics Data System (ADS)

    Kalogerakis, K. S.; Pejaković, D. A.; Copeland, R. A.; Slanger, T. G.

    2004-12-01

    In the thermosphere, energy transfer between excited O atoms and ground-state molecular oxygen produces O2 in the first two vibrational levels of the b1Σ ^+g state: O(1D) + O2 -> O(3P) + O2(b1Σ ^+g, v = 0, 1). Subsequent radiative decay of O2(b1Σ ^+g, v = 0, 1) to the ground state O2(X3Σ ^-g) results in the Atmospheric Band emissions. Atmospheric observations suggest that above ˜120 km O(3P) plays an important role in removing O2(b1Σ ^+g, v = 1). Therefore, knowledge of the rate coefficient for collisional removal of O2(b1Σ ^+g<, v = 1) by O(3P) is important for detailed understanding of the Atmospheric Band emissions. Measurements are reported of the room-temperature rate coefficient for removal of O2(b1Σ ^+g, v = 1) by O(3P). A commercial F2 laser with pulsed energy output of up to 50 mJ at 157 nm is used to photodissociate a large fraction of molecular oxygen in a O2/N2 mixture. Photodissociation of an O2 molecule produces a ground-state oxygen atom O(3P) and an excited oxygen atom O(1D), and O(1D) rapidly transfers energy to the remaining O2 to produce O2(b1Σ ^+g, v = 0, 1). The O2(b1Σ ^+g, v = 1) population is monitored by observing emission in the O2 (b-X) 1--1 band at 771 nm. To extract the O2(b1Σ ^+g, v = 1) + O(3P) rate coefficient, knowledge of the O(3P) partial pressure or, equivalently, the fraction of dissociated O2, is necessary. Based on the F2 laser fluence, the signal dependence on the fraction of dissociation, and computer modeling, the signals measured in our experiments correspond to about 50% dissociation. Our measurements yield a preliminary value of the rate coefficient for O2(b1Σ ^+g, v = 1) removal by O(3P) of 6 × 10-12 cm3s-1. The results will be compared to the rate coefficients for corresponding processes in the ground and a1Δ g states of O2, and implications of the results for modeling of the upper atmosphere will be discussed. This work is supported by the NSF Aeronomy Program under grant ATM-0209229. The F2 laser was

  13. Herstellung von Chitosan und einige Anwendungen

    NASA Astrophysics Data System (ADS)

    Struszczyk, Marcin Henryk

    2001-05-01

    1. Die Deacetylierung von crabshell - Chitosan führte gleichzeitig zu einem drastischen Abfall der mittleren viscosimetrischen Molmasse ( Mv), insbesondere wenn die Temperatur und die Konzentration an NaOH erhöht werden. Diese Parameter beeinflussten jedoch nicht den Grad der Deacetylierung (DD). Wichtig ist jedoch die Quelle des Ausgangsmaterials: Chitin aus Pandalus borealis ist ein guter Rohstoff für die Herstellung von Chitosan mit niedrigem DD und gleichzeitig hoher mittlerer Mv, während Krill-Chitin (Euphausia superba) ein gutes Ausgangsmaterial zur Herstellung von Chitosan mit hohem DD und niedrigem Mv ist. Chitosan, das aus Insekten (Calliphora erythrocephala), unter milden Bedingungen (Temperatur: 100°C, NaOH-Konzentration: 40 %, Zeit: 1-2h ) hergestellt wurde, hatte die gleichen Eigenschaften hinsichtlich DD und Mv wie das aus Krill hergestellte Chitosan. Der Bedarf an Zeit, Energie und NaOH ist für die Herstellung von Insekten-Chitosan geringer als für crabshell-Chitosan vergleichbare Resultaten für DD und Mv. 2. Chitosan wurde durch den Schimmelpilz Aspergillus fumigatus zu Chitooligomeren fermentiert. Die Ausbeute beträgt 25%. Die Chitooligomere wurden mit Hilfe von HPLC und MALDI-TOF-Massenspektrmetrie identifiziert. Die Fermentationsmischung fördert die Immunität von Pflanzen gegen Bakterien und Virusinfektion. Die Zunahme der Immunität schwankt jedoch je nach System Pflanze-Pathogen. Die Fermentation von Chitosan durch Aspergillus fumigatus könnte eine schnelle und billige Methode zur Herstellung von Chitooligomeren mit guter Reinheit und Ausbeute sein. Eine partiell aufgereinigte Fermentationsmischung dieser Art könnte in der Landwirtschaft als Pathogeninhibitor genutzt werden. Durch kontrollierte Fermentation, die Chitooligomere in definierter Zusammensetzung (d.h. definierter Verteilung des Depolymerisationsgrades) liefert, könnte man zu Mischungen kommen, die für die jeweilige Anwendung eine optimale Bioaktivität besitzen. 3

  14. Functional characterization of a type 2 metallothionein isoform (OsMTI-2b) from rice.

    PubMed

    Pirzadeh, Soheil; Shahpiri, Azar

    2016-07-01

    Metallothioneins (MTs) are a family of Cys-rich, low molecular weight, cytoplasmic metal binding proteins. MTs are present in all eukaryotes as well as some prokaryotes. Plant MTs are divided into four types based on Cys distribution pattern in their amino acid sequences. In the present work, the gene encoding OsMTI-2b, a type 2 MT found in rice, was cloned into pET41a vector. The resulting construct was transformed into Escherichia coli strain Rosetta (DE3). Following the induction with Isopropyl β-d-1-thiogalactopyranoside the OsMTI-2b was expressed as carboxyl-terminal extensions of glutathione-S-transferase (GST-tag), a 6His-tag, and an S-tag. The expressed recombinant fusion protein was named GST-OsMTI-2b. As compared with control, transgenic E. coli cells expressing GST-OsMTI-2b accumulated more Pb(2+), Ni(2+), Cd(2+), Zn(2+) and Cu(2+) from culture medium and showed increased tolerance against these metals. Furthermore the E. coli cells expressing OsMTI-2b accumulated significantly higher Pb(2+) than previously made strains which expressing other rice OsMT isoforms. The recombinant GST-OsMTI-2b was purified using affinity chromatography. According to in vitro assays the protein GST-OsMTI-2b was able to form complexes with Pb(2+), Ni(2+), Cd(2+) and Zn(2+). However, the binding ability for the different metals differed in the order: Pb(2+)>Cd(2+)>Zn(2+)>Ni(2+). PMID:27079330

  15. The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength.

    PubMed

    Barcomb, Kelsey; Hell, Johannes W; Benke, Tim A; Bayer, K Ulrich

    2016-07-29

    Learning, memory, and cognition are thought to require normal long-term potentiation (LTP) of synaptic strength, which in turn requires binding of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B. For LTP induction, many additional required players are known. Here we tested the hypothesis that CaMKII/GluN2B binding also mediates the more elusive maintenance of synaptic strength. Intriguingly, the CaMKII inhibitor tatCN21 reduces synaptic strength only at high concentrations necessary for CaMKII/NMDAR disruption (20 μm) but not at lower concentrations sufficient for kinase inhibition (5 μm). However, increased concentration also causes unrelated effects. Thus, to distinguish between correlation and causality, we used a pharmacogenetic approach. In a mouse with a mutant NMDAR GluN2B subunit that is CaMKII binding-incompetent, any tatCN21 effects that are specific to the CaMKII/GluN2B interaction should be abolished, and any remaining tatCN21 effects have to be nonspecific (i.e. mediated by other targets). The results showed that the persistent reduction of synaptic strength by transient application of 20 μm tatCN21 had a nonspecific presynaptic component (on fiber volley amplitude) that was unrelated to the CaMKII/GluN2B interaction or CaMKII activity. However, the remaining component of the persistent tatCN21 effect was almost completely abolished in the GluN2B mutant mouse. These results highlight the requirement for stringent pharmacogenetic approaches to separate specific on-target effects from nonspecific off-target effects. Importantly, they also demonstrate that the CaMKII/GluN2B interaction is required not only for normal LTP induction but also for the maintenance of synaptic strength. PMID:27246855

  16. Probing biased/partial agonism at the G protein-coupled A(2B) adenosine receptor.

    PubMed

    Gao, Zhan-Guo; Balasubramanian, Ramachandran; Kiselev, Evgeny; Wei, Qiang; Jacobson, Kenneth A

    2014-08-01

    G protein-coupled A(2B) adenosine receptor (AR) regulates numerous important physiological functions, but its activation by diverse A(2B)AR agonists is poorly profiled. We probed potential partial and/or biased agonism in cell lines expressing variable levels of endogenous or recombinant A(2B)AR. In cAMP accumulation assays, both 5'-substituted NECA and C2-substituted MRS3997 are full agonists. However, only 5'-substituted adenosine analogs are full agonists in calcium mobilization, ERK1/2 phosphorylation and β-arrestin translocation. A(2B)AR overexpression in HEK293 cells markedly increased the agonist potency and maximum effect in cAMP accumulation, but less in calcium and ERK1/2. A(2B)AR siRNA silencing was more effective in reducing the maximum cAMP effect of non-nucleoside agonist BAY60-6583 than NECA's. A quantitative 'operational model' characterized C2-substituted MRS3997 as either balanced (cAMP accumulation, ERK1/2) or strongly biased agonist (against calcium, β-arrestin). N⁶-substitution biased against ERK1/2 (weakly) and calcium and β-arrestin (strongly) pathways. BAY60-6583 is ERK1/2-biased, suggesting a mechanism distinct from adenosine derivatives. BAY60-6583, as A(2B)AR antagonist in MIN-6 mouse pancreatic β cells expressing low A(2B)AR levels, induced insulin release. This is the first relatively systematic study of structure-efficacy relationships of this emerging drug target.

  17. LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

    PubMed Central

    Poirault-Chassac, Sonia; Adam, Frédéric; Muczynski, Vincent; Aymé, Gabriel; Casari, Caterina; Bordet, Jean-Claude; Soukaseum, Christelle; Rothschild, Chantal; Proulle, Valérie; Pietrzyk-Nivau, Audrey; Berrou, Eliane; Christophe, Olivier D.; Rosa, Jean-Philippe; Lenting, Peter J.; Bryckaert, Marijke; Baruch, Dominique

    2016-01-01

    von Willebrand disease type 2B (VWD-type 2B) is characterized by gain-of-function mutations of von Willebrand factor (vWF) that enhance its binding to platelet glycoprotein Ibα and alter the protein’s multimeric structure. Patients with VWD-type 2B display variable extents of bleeding associated with macrothrombocytopenia and sometimes with thrombopathy. Here, we addressed the molecular mechanism underlying the severe macrothrombocytopenia both in a knockin murine model for VWD-type 2B by introducing the p.V1316M mutation in the murine Vwf gene and in a patient bearing this mutation. We provide evidence of a profound defect in megakaryocyte (MK) function since: (a) the extent of proplatelet formation was drastically decreased in 2B MKs, with thick proplatelet extensions and large swellings; and (b) 2B MKs presented actin disorganization that was controlled by upregulation of the RhoA/LIM kinase (LIMK)/cofilin pathway. In vitro and in vivo inhibition of the LIMK/cofilin signaling pathway rescued actin turnover and restored normal proplatelet formation, platelet count, and platelet size. These data indicate, to our knowledge for the first time, that the severe macrothrombocytopenia in VWD-type 2B p.V1316M is due to an MK dysfunction that originates from a constitutive activation of the RhoA/LIMK/cofilin pathway and actin disorganization. This suggests a potentially new function of vWF during platelet formation that involves regulation of actin dynamics. PMID:27734030

  18. Conditional loss of GluN2B in cortex and hippocampus impairs attentional set formation

    PubMed Central

    Thompson, Shannon M.; Josey, Megan; Holmes, Andrew; Brigman, Jonathan L.

    2015-01-01

    The ability to attend to appropriate stimuli, to plan actions and then alter those actions when environmental conditions change, is essential for an organism to thrive. There is increasing evidence that these executive control processes are mediated in part by N-methyl-D-aspartate receptors (NMDAR). NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules and are differentially expressed during development. Recent findings have suggested that the GluN2B subunit may play a unique role in both the acquisition of adaptive choice and the behavioral flexibility required to shift between choices. Here we investigated the role of GluN2B containing NMDARs in the ability to learn, reverse and shift between stimulus dimensions. Mutant mice (floxed-GluN2B x CaMKII-Cre) lacking GluN2B in the dorsal CA1 of the hippocampus and throughout the cortex were tested on an attentional set-shifting task. To explore the role that alterations in motor behavior may have on these behaviors, gross and fine motor behaviors were analyzed in mutant and floxed-control mice. Results show that corticohippocampal loss of GluN2B selectively impaired an initial reversal in a stimulus specific manner and impaired the ability of mutant mice to form an attentional set. Further, GluN2B mice showed normal motor behavior in both overall movement and individual limb behaviors. Together, these results further support the role of NMDAR, and GluN2B in particular, in aspects of executive control including behavioral flexibility and attentional processes. PMID:25798630

  19. Increased extrasynaptic GluN2B expression is involved in cognitive impairment after isoflurane anesthesia

    PubMed Central

    LI, LUNXU; LI, ZHENGQIAN; CAO, YIYUN; FAN, DONGSHENG; CHUI, DEHUA; GUO, XIANGYANG

    2016-01-01

    There is increasing concern regarding the postoperative cognitive dysfunction (POCD) in the aging population, and general anesthetics are believed to be involved. Isoflurane exposure induced increased N-methyl-D-aspartic acid receptor (NMDAR) GluN2B subunit expression following anesthesia, which was accompanied by alteration of the cognitive function. However, whether isoflurane affects this expression in different subcellular compartments, and is involved in the development of POCD remains to be elucidated. The aims of the study were to investigate the effects of isoflurane on the expression of the synaptic and extrasynaptic NMDAR subunits, GluN2A and GluN2B, as well as the associated alteration of cognitive function in aged rats. The GluN2B antagonist, Ro25–6981, was given to rats exposed to isoflurane to determine the role of GluN2B in the isoflurane-induced alteration of cognitive function. The results showed that spatial learning and memory tested in the Morris water maze (MWM) was impaired at least 7 days after isoflurane exposure, and was returned to control levels 30 days thereafter. Ro25-6981 treatment can alleviate this impairment. Extrasynaptic GluN2B protein expression, but not synaptic GluN2B or GluN2A, increased significantly after isoflurane exposure compared to non-isoflurane exposure, and returned to control levels approximately 30 days thereafter. The results of the present study indicated that isoflurane induced the prolonged upregulation of extrasynaptic GluN2B expression after anesthesia and is involved in reversible cognitive impairment. PMID:27347033

  20. Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B

    PubMed Central

    Chassefeyre, Romain; Martínez-Hernández, José; Bertaso, Federica; Bouquier, Nathalie; Blot, Béatrice; Laporte, Marine; Fraboulet, Sandrine; Couté, Yohann; Devoy, Anny; Isaacs, Adrian M.; Pernet-Gallay, Karin; Fagni, Laurent

    2015-01-01

    The charged multivesicular body proteins (Chmp1–7) are an evolutionarily conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause frontotemporal dementia, suggesting that this protein may normally control some neuron-specific process. Here, we examined the function, localization, and interactions of neuronal Chmp2b. The protein was highly expressed in mouse brain and could be readily detected in neuronal dendrites and spines. Depletion of endogenous Chmp2b reduced dendritic branching of cultured hippocampal neurons, decreased excitatory synapse density in vitro and in vivo, and abolished activity-induced spine enlargement and synaptic potentiation. To understand the synaptic effects of Chmp2b, we determined its ultrastructural distribution by quantitative immuno-electron microscopy and its biochemical interactions by coimmunoprecipitation and mass spectrometry. In the hippocampus in situ, a subset of neuronal Chmp2b was shown to concentrate beneath the perisynaptic membrane of dendritic spines. In synaptoneurosome lysates, Chmp2b was stably bound to a large complex containing other members of the Chmp family, as well as postsynaptic scaffolds. The supramolecular Chmp assembly detected here corresponds to a stable form of the endosomal sorting complex required for transport-III (ESCRT-III), a ubiquitous cytoplasmic protein complex known to play a central role in remodeling of lipid membranes. We conclude that Chmp2b-containing ESCRT-III complexes are also present at dendritic spines, where they regulate synaptic plasticity. We propose that synaptic ESCRT-III filaments may function as a novel element of the submembrane cytoskeleton of spines. PMID:25698751

  1. Absence of the functional Myosin heavy chain 2b isoform in equine skeletal muscles.

    PubMed

    Chikuni, Koichi; Muroya, Susumu; Nakajima, Ikuyo

    2004-05-01

    Nucleotide sequences which included the full coding region for three types of myosin heavy chain (MyHC) isoforms were determined from equine skeletal muscles. The deduced amino acid sequences were 1937, 1938, and 1935 residues for the MyHC-2a, -2x, and -slow, respectively. No MyHC-2b isoform was amplified from the equine muscle cDNA except for one pseudogene fragment. One nucleotide was inserted in the coding region of the equine pseudogene product, a minute amount of which was expressed in the skeletal muscle. The 596 bp sequence of the equine MyHC pseudogene was categorized into the MyHC-2b genes on the phylogenetic tree of the mammalian MyHC genes. These results suggest that an ancestral MyHC-2b gene had lost its function and changed to a pseudogene during the course of horse history. The MyHC genes in some ungulates were analyzed through the PCR amplifications using the MyHC isoform-specific primers to confirm the presence of the MyHC-2b and -2x genes. The exon coding the 3' untranslated region of the MyHC-2x was successfully amplified from the all ungulates examined; however, that of the MyHC-2b gene was amplified only from horses, pigs and lesser mouse deer. The PCR analyses from rhinoceros, sika deer, moose, giraffes, water buffalo, bovine, Japanese serow and sheep genes implied the absence of the MyHC-2b-specific sequence in their genomes. These results suggest that the MyHC-2b gene independently lost its function in some ungulate species.

  2. Bemerkungen zur Relativitätstheorie und zu den Quanten

    NASA Astrophysics Data System (ADS)

    Bergmann, Peter G.

    Die theoretischen und experimentellen Grundlagen von Gravitations- und Quantenphysik, die Beziehung beider Theorien und die Bedeutung wesentlicher Begriffe, wie Observable, werden diskutiert.Translated AbstractRemarks on Relativity and on Quantum TheoryThe theoretical and experimental foundations of gravitation and quantum physics are discussed as well as the relation of these two theories and the role of basic notions like observables.

  3. Vom Urknall zum Zerfall. Die Welt zwischen Anfang und Ende.

    NASA Astrophysics Data System (ADS)

    Fritzsch, H.

    Contents: Der Tanz mit dem Ozean. Galaktische Landkarte. Das Maß der Dinge. Der würfelnde Gott der Quantenphysik. Geheimnisvolle Felder. Materie und Antimaterie. Quarks - Urstoff unserer Welt. Zerfallende Protonen und die Einheit der Physik. Der Zauberofen. Das überschaubare Universum. Das explodierende Universum. Nachhall der Schöpfung. Der achtfache Weg der kosmischen Entwicklung. Das Ende der Welt. Einheit in der Vielfalt. Das geistige Universum. Gott und das absurde Universum.

  4. Differential expression of hoxa2a and hoxa2b genes during striped bass embryonic development.

    PubMed

    Scemama, Jean-Luc; Vernon, Jamie L; Stellwag, Edmund J

    2006-10-01

    Here, we report the cloning and expression analysis of two previously uncharacterized paralogs group 2 Hox genes, striped bass hoxa2a and hoxa2b, and the developmental regulatory gene egr2. We demonstrate that both Hox genes are expressed in the rhombomeres of the developing hindbrain and the pharyngeal arches albeit with different spatio-temporal distributions relative to one another. While both hoxa2a and hoxa2b share the r1/r2 anterior boundary of expression characteristic of the hoxa2 paralog genes of other species, hoxa2a gene expression extends throughout the hindbrain, whereas hoxa2b gene expression is restricted to the r2-r5 region. Egr2, which is used in this study as an early developmental marker of rhombomeres 3 and 5, is expressed in two distinct bands with a location and spacing typical for these two rhombomeres in other species. Within the pharyngeal arches, hoxa2a is expressed at higher levels in the second pharyngeal arch, while hoxa2b is more strongly expressed in the posterior arches. Further, hoxa2b expression within the arches becomes undetectable at 60hpf, while hoxa2a expression is maintained at least up until the beginning of chondrogenesis. Comparison of the striped bass HoxA cluster paralog group 2 (PG2) genes to their orthologs and trans-orthologs shows that the striped bass hoxa2a gene expression pattern is similar to the overall expression pattern described for the hoxa2 genes in the lobe-finned fish lineage and for the hoxa2b gene from zebrafish. It is notable that the pharyngeal arch expression pattern of the striped bass hoxa2a gene is more divergent from its sister paralog, hoxa2b, than from the zebrafish hoxa2b gene. Overall, our results suggest that differences in the Hox PG2 gene complement of striped bass and zebrafish affects both their rhombomeric and pharyngeal arch expression patterns and may account for the similarities in pharyngeal arch expression between striped bass hoxa2a and zebrafish hoxa2b.

  5. Supporting the Health Quality Measures Format in i2b2.

    PubMed

    Klann, Jeffrey G; Murphy, Shawn N

    2013-01-01

    The Health Quality Measures Format (HQMF) is an HL7 standard for expressing computable queries of clinical data. It is becoming increasingly consequential for both quality measurement and population health research. A variety of national leadership is involved in its development and deployment, including the Meaningful Use incentive program, the Query Health initiative, the Joint Commission, the National Quality Forum (NQF), and the Food and Drug Administration. Here we analyze the structure of HQMF and apply this to computation of HQMF on Informatics for Integrating Biology and the Bedside (i2b2). i2b2 is a widely used, modular, open-source clinical research data repository. We implement a translator to convert between HQMF and i2b2-XML format that covers the subset of HQMF supported in i2b2-XML, which will be expanded in the next release of i2b2. This translator is part of the freely-available reference implementation of the QueryHealth initiative. PMID:24303250

  6. Early changes of type 2B fibers after denervation of rat EDL skeletal muscle.

    PubMed

    Germinario, Elena; Esposito, Alessandra; Megighian, Aram; Midrio, Menotti; Biral, Donatella; Betto, Romeo; Danieli-Betto, Daniela

    2002-05-01

    Skeletal muscle type 2B fibers normally receive a moderate level of motoneuron discharge. As a consequence, we hypothesize that type 2B fiber properties should be less sensitive to the absence of the nerve. Therefore, we have investigated the response of sarcoplasmic reticulum and myofibrillar proteins of type 2B fibers isolated from rat extensor digitorum longus muscle after denervation (2 and 7 days). Single fibers were identified by SDS-PAGE of myosin heavy chain isoforms. Electrophysiological and isometric contractile properties of the whole muscle were also analyzed. The pCa-tension relationship of type 2B single fibers was shifted to the left at 2 days and to right at 7 days after denervation, with significant differences in the Hill coefficients and pCa threshold values in 2- vs. 7-day-denervated fibers. The sarcoplasmic reticulum Ca2+ uptake capacity and rate significantly decreased after 2 days of denervation, whereas both increased at 7 days. Caffeine sensitivity of sarcoplasmic reticulum Ca2+ release was transitory and markedly increased in 2-day-denervated fibers. Our results indicate that type 2B fiber functional properties are highly sensitive to the interruption of nerve supply. Moreover, most of 2-day-denervated changes were reverted at 7 days. PMID:11960956

  7. Effects of nano bamboo charcoal on PAHs-degrading strain Sphingomonas sp. GY2B.

    PubMed

    She, Bojia; Tao, Xueqin; Huang, Ting; Lu, Guining; Zhou, Zhili; Guo, Chuling; Dang, Zhi

    2016-03-01

    Nano bamboo charcoal (NBC) has been commonly used in the production of textiles, plastics, paint, etc. However, little is known regarding their effects towards the microorganisms. The effects of NBC on phenanthrene degrading strain Sphingomonas sp. GY2B were investigated in the present study. Results showed that the addition of NBC could improve the phenanthrene removal by Sphingomonas sp. GY2B, with removal efficiencies increased by 10.29-18.56% in comparison to the control at 24h, and phenanthrene was almost completely removed at 48h. With the presence of low dose of NBC (20 and 50mgL(-1)), strain GY2B displayed a better growth at 6h, suggesting that NBC was beneficial to the growth of GY2B and thus resulting in the quick removal of phenanthrene from water. However, the growth of strain GY2B in high dose of NBC (200mgL(-1)) was inhibited at 6h, and the inhibition could be attenuated and eliminated after 12h. NBC-effected phenanthrene solubility experiment suggested that NBC makes a negligible contribution to the solubilization of phenanthrene in water. Results of electronic microscopy analysis (SEM and TEM) indicated NBC may interact with the cell membrane, causing the enhanced membrane permeability and then NBC adsorbed on the membrane would enter into the cells. The findings of this work would provide important information for the future usage and long-term environmental risk assessment of NBC.

  8. Myosin heavy chain-2b transcripts and isoform are expressed in human laryngeal muscles.

    PubMed

    Smerdu, Vika; Cvetko, Erika

    2013-01-01

    Three fast myosin heavy chain (MyHC) isoforms, i.e. MyHC-2a, -2x and -2b, are expressed in skeletal muscles of smaller mammals. In contrast, only MyHC-2a and -2x have been revealed in humans so far. The expression of MyHC isoforms is known to be wider in the functionally more specialized laryngeal muscles. Though mRNA transcripts of the MyHC-2b gene were found to be expressed in certain human skeletal and laryngeal muscles, the corresponding isoform has not been demonstrated in these muscles. To our knowledge, we are the first to demonstrate not only the expression of MyHC-2b transcripts using an in situ hybridization technique but also the corresponding protein, i.e. the MyHC-2b isoform, in some human laryngeal muscles by immunohistochemistry but not by polyacrylamide gel electrophoresis. Using a set of antibodies specific to MyHC isoforms, we demonstrated that MyHC-2b was always co-expressed with the major MyHC isoforms, not only with the fast ones (MyHC-2a and -2x) but with the slow isoform (MyHC-1) as well.

  9. Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects

    PubMed Central

    Ravnskjaer, Kim; Hogan, Meghan F.; Lackey, Denise; Tora, Laszlo; Dent, Sharon Y.R.; Olefsky, Jerrold; Montminy, Marc

    2013-01-01

    Circulating pancreatic glucagon is increased during fasting and maintains glucose balance by stimulating hepatic gluconeogenesis. Glucagon triggering of the cAMP pathway upregulates the gluconeogenic program through the phosphorylation of cAMP response element–binding protein (CREB) and the dephosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic gene expression by promoting epigenetic changes that facilitate assembly of the transcriptional machinery. However, the nature of these modifications is unclear. Using mouse models and in vitro assays, we show that histone H3 acetylation at Lys 9 (H3K9Ac) was elevated over gluconeogenic genes and contributed to increased hepatic glucose production during fasting and in diabetes. Dephosphorylation of CRTC2 promoted increased H3K9Ac through recruitment of the lysine acetyltransferase 2B (KAT2B) and WD repeat–containing protein 5 (WDR5), a core subunit of histone methyltransferase (HMT) complexes. KAT2B and WDR5 stimulated the gluconeogenic program through a self-reinforcing cycle, whereby increases in H3K9Ac further potentiated CRTC2 occupancy at CREB binding sites. Depletion of KAT2B or WDR5 decreased gluconeogenic gene expression, consequently breaking the cycle. Administration of a small-molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, suggesting that this enzyme may be a useful target for diabetes treatment. PMID:24051374

  10. Thermal, magnetic and electronic properties of non-centrosymmetric YbPt2B

    NASA Astrophysics Data System (ADS)

    Khan, R. T.; Kneidinger, F.; Hilscher, G.; Sidorenko, A.; Sologub, O.; Michor, H.; Bauer, E.; Rogl, P.; Giester, G.

    2015-04-01

    Ternary YbPt2B crystallizes in the non-centrosymmetric hexagonal CePt2B-type structure (space group P6222). Electrical resistivity, specific heat and magnetic measurements reveal a magnetic instability at 5.6 K. Furthermore, a spin-reorientation of presumably a ferromagnetic type occurs around 1.5 K. The behaviour at low temperature is governed by a rather weak Kondo effect, TK ⩽ 1 K, in the presence of strong crystalline electric field splitting, with a doublet ground state. Besides, the complex magnetic behaviour presumably results from a Dzyaloshinskii-Moriya interaction triggered by the absence of inversion symmetry in the crystal structure. Scaling according to the de Gennes factor traces back magnetic ordering in YbPt2B to the Rudermann-Kittel-Kasuya-Yoshida (RKKY) interaction and the smooth evolution of the lattice constants and the unit cell volume of REPt2B (RE = rare earths) refers to the 4f13 electronic configuration of Yb in YbPt2B.

  11. Scintigraphic portrayal of the syndrome of multiple endocrine neoplasia type-2B

    SciTech Connect

    Yobbagy, J.J.; Levatter, R.; Sisson, J.C.; Shulkin, B.L.; Polley, T.

    1988-06-01

    The scintigraphic appearance of the neoplasms in multiple endocrine neoplasia type 2B (MEN-2B) and the interpretations of the image patterns are described. An 18-year-old male patient with the MEN-2B syndrome underwent TI-201 imaging that showed concentrations of TI-201 in the primary medullary thyroid carcinoma (MTC) tumor and in cervical lymph node metastases. After total thyroidectomy and lymph node dissection, the TI-201 image was normal. Catecholamine levels in the blood and urine were only borderline elevated. Yet, greater than normal concentrations of I-131 metaiodobenzylguanidine (I-131 MIBG) were present in both adrenal glands. Computed tomography of the abdomen showed normal adrenal glands. These results were consistent with the diagnosis of adrenal medullary hyperplasia, a precursor of pheochromocytoma. No operation was indicated to remove the adrenal glands. Imaging with TI-201 appears to be useful in identifying sites of MTC in patients with the MEN-2B syndrome. I-131 MIBG imaging, in conjunction with computed tomography of the adrenal glands and appropriate catecholamine measurements, should be performed in patients with the MEN-2B syndrome to determine the status of the adrenal medullae, which then may be classified as normal, hyperplastic, or tumorous with pheochromocytoma.

  12. MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B

    PubMed Central

    Zhu, Yuekun; Feng, Xing; Ding, Zhijie; Zhang, Shifeng; Zhong, Lifeng; Zhuang, Yifan; Su, Chen; Hong, Xinya; Cai, Jianchun

    2016-01-01

    MicroRNAs are critical in various human cancers, including gastric cancer (GC). However, the mechanism underlying the GC development remains elusive. In this study, we demonstrate that miR-448 is increased in GC samples and cell lines. Overexpression of miR-448 facilitated the proliferation of GC cells by stimulating glycolysis. Mechanistically, we identified KDM2B, a reader for methylated CpGs, as the target of miR-448 that represses glycolysis and promotes oxidative phosphorylation. Overexpression of miR-448 reduced both the mRNA and protein levels of KDM2B, whereas KDM2B re-expression abrogated the miR-448-mediated glycolytic activities. Furthermore, we discovered Myc as a key target of KDM2B that controls metabolic switch in GC. Importantly, a cohort of 81 GC tissues revealed that miR-448 level closely associated with a battery of glycolytic genes, in which KDM2B showed the strongest anti-correlation coefficient. In addition, enhanced miR-448 level was significantly associated with poor clinical outcomes of GC patients. Hence, we identified a previously unappreciated mechanism by which miR-448 orchestrate epigenetic, transcriptional and metabolic networks to promote GC progression, suggesting the possibility of therapeutic intervention against cancer metabolic pathways. PMID:26989077

  13. Serotonin 2B receptor: upregulated with age and hearing loss in mouse auditory system.

    PubMed

    Tadros, Sherif F; D'Souza, Mary; Zettel, Martha L; Zhu, XiaoXia; Lynch-Erhardt, Martha; Frisina, Robert D

    2007-07-01

    Serotonin (5-HT) is a monoamine neurotransmitter. Serotonin may modulate afferent fiber discharges in the cochlea, inferior colliculus (IC) and auditory cortex. Specific functions of serotonin are exerted upon its interaction with specific receptors; one of those receptors is the serotonin 2B receptor. The aim of this study was to investigate the differences in gene expression of serotonin 2B receptors with age in cochlea and IC, and the possible correlation between gene expression and functional hearing measurements in CBA/CaJ mice. Immunohistochemical examinations of protein expression of IC in mice of different age groups were also performed. Gene expression results showed that serotonin 2B receptor gene was upregulated with age in both cochlea and IC. A significant correlation between gene expression and functional hearing results was established. Immunohistochemical protein expression studies of IC showed more serotonin 2B receptor cells in old mice relative to young adult mice, particularly in the external nucleus. We conclude that serotonin 2B receptors may play a role in the pathogenesis of age-related hearing loss.

  14. Das menschliche Gehör und Grundlagen der Psychoakustik

    NASA Astrophysics Data System (ADS)

    Genuit, Klaus; Sottek, Roland

    Das menschliche Gehör ist ein äußerst komplexes Empfangs- und Signalverarbeitungssystem. Es ist als Schallanalysator in Leistungsfähigkeit und Vielseitigkeit von technisch-analytischen Verfahren nach wie vor unerreicht. Die Signalverarbeitung läuft auf Grundlage komplexer Prozesse ab, die in ihrer Gesamtheit bislang nicht vollständig erfasst sind. Verschiedene Modelle zur gehörgerechten Zeit- und Frequenzanalyse ahmen jene komplexen Prozesse und Verarbeitungsmechanismen nach, die im menschlichen Gehör vollzogen werden.

  15. Ökologische Grundlagen und limitierende Faktoren der Renaturierung

    NASA Astrophysics Data System (ADS)

    Rosenthal, Gert; Eichberg, Carsten

    In den dicht besiedelten und agrarisch besonders intensiv genutzten Regionen Mittel- und Westeuropas ist seit Ende des Zweiten Weltkrieges ein fortschreitender Verlust an naturnahen ökosystemen mit hoher biologischer Vielfalt zu verzeichnen. Spätestens seit den 1970er-Jahren ist daher die Neuschaffung und Wiederherstellung gefährdeter Lebensräume und Biozönosen zunehmend in den Mittelpunkt von Naturschutzmaßnahmen gerückt (Bakker 1989, Muller et al. 1998, Bakker und Berendse 1999). Aufgrund fehlender wissenschaftlicher Grundlagen und praktischer Erfahrungen wurden Renaturierungsmaßnahmen anfangs fast durchweg nach dem trial and error-Prinzip durchgeführt. Im Vordergrund standen dabei zunächst die Wiederherstellung adäquater abiotischer Standortbedingungen sowie die Reorganisation traditioneller Nutzungsmanagements. Bei Ersterem ging es neben der Wiedervernässung entwässerter Feuchtgebiete (Pfadenhauer und Grootjans 1999) vor allem darum, Eutrophierungseffekte zu beseitigen und die Produktivität des Standortes auf das Niveau der Zielgemeinschaft zurückzuführen (Gough und Marrs 1990, Oomes et al. 1996, Snow et al. 1997, Tallowin et al. 1998).

  16. Apps to display patient data, making SMART available in the i2b2 platform

    PubMed Central

    Wattanasin, Nich; Porter, Alyssa; Ubaha, Stella; Mendis, Michael; Phillips, Lori; Mandel, Joshua; Ramoni, Rachel; Mandl, Kenneth; Kohane, Isaac; Murphy, Shawn N.

    2012-01-01

    The Substitutable Medical Apps, Reusable Technologies (SMART) project provides a framework of core services to facilitate the use of substitutable health-related web applications. The platform offers a common interface used to “SMART-ready” health IT systems allowing any SMART application to be able to interact with those systems. At Partners Healthcare, we have SMART-enabled the Informatics for Integrating Biology and the Bedside (i2b2) open source analytical platform, enabling the use of SMART applications directly within the i2b2 web client. In i2b2, viewing the patient in an EMR-like view enables a natural-feeling medical review process for each patient. PMID:23304371

  17. Drosophila stem cells share a common requirement for the histone H2B ubiquitin protease scrawny.

    PubMed

    Buszczak, Michael; Paterno, Shelley; Spradling, Allan C

    2009-01-01

    Stem cells within diverse tissues share the need for a chromatin configuration that promotes self-renewal, yet few chromatin proteins are known to regulate multiple types of stem cells. We describe a Drosophila gene, scrawny (scny), encoding a ubiquitin-specific protease, which is required in germline, epithelial, and intestinal stem cells. Like its yeast relative UBP10, Scrawny deubiquitylates histone H2B and functions in gene silencing. Consistent with previous studies of this conserved pathway of chromatin regulation, scny mutant cells have elevated levels of ubiquitinylated H2B and trimethylated H3K4. Our findings suggest that inhibiting H2B ubiquitylation through scny represents a common mechanism within stem cells that is used to repress the premature expression of key differentiation genes, including Notch target genes.

  18. Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators.

    PubMed

    Vu, Chi B; Bemis, Jean E; Disch, Jeremy S; Ng, Pui Yee; Nunes, Joseph J; Milne, Jill C; Carney, David P; Lynch, Amy V; Smith, Jesse J; Lavu, Siva; Lambert, Philip D; Gagne, David J; Jirousek, Michael R; Schenk, Simon; Olefsky, Jerrold M; Perni, Robert B

    2009-03-12

    A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.

  19. Laboratory Study of O2(b1Σ g+, υ = 1) Collisional Removal at Thermospheric Temperatures

    NASA Astrophysics Data System (ADS)

    Wouters, E. R.; Pejaković, D. A.; Phillips, K. E.; Kalogerakis, K. S.

    2003-12-01

    In the Earth's thermosphere, energy transfer from O(1D) to O2 generates oxygen molecules in the υ = 0 and 1 levels of the O2(b1Σg+) state. The emissions in the O2(b1Σ g+ - X3Σ g-) system (Atmospheric Band) present a major component of the Earth's airglow. Interpretation of the measured intensities of O2 Atmospheric Band emissions can yield altitude profiles of oxygen atom density and local temperature in the lower thermosphere. To achieve this goal accurate laboratory measurements of the collisional removal rate coefficients of O2(b, υ = 1) and their temperature dependence are essential. Atmospheric observations suggest that the relevant colliders for the removal of O2(b, υ = 1) in the lower thermosphere are O2 and O(3P). We report measurements of the rate coefficients for the collisional removal of O2(b, υ = 1) by O2, N2, and CO2, at temperatures in the range 300--1000 K. A state-specific two-laser technique is used, in which the visible output of the first laser directly excites O2 to O2(b, υ = 1), and the ultraviolet output of the second laser probes the O2(b, υ = 1) population by resonantly enhanced multiphoton ionization via the υ= 4 level of the d1Π g Rydberg state. The temporal evolution of the O2(b, υ = 1) population is monitored by varying the time delay between the two laser pulses. The rate coefficient of the collisional removal of O2(b, υ = 1) by O2 increases monotonically with temperature from about 1.5 x 10-11 cm3 s-1 to about 6*E-11 cm3 s-1 in the range 300--1000 K. Experiments with colliders N2 and CO2 determine the upper limits for the removal rate coefficients of O2(b, υ = 1) by N2 and CO2 to be 2 orders of magnitude smaller. This work extends previous studies of O2(b, υ = 1) at room and low temperatures.1,2 We are currently planning experiments to investigate the collisional removal of O2(b, υ = 1) by O atoms. This study was supported by the NSF's Grant ATM-0209229. The participation of K. Phillips in this project was funded by

  20. Crystal structure and physical properties of Mo{sub 2}B: First-principle calculations

    SciTech Connect

    Zhou, Dan; Cui, Qiliang E-mail: liquan777@jlu.edu.cn; Li, Quan E-mail: liquan777@jlu.edu.cn; Wang, Jingshu

    2014-03-21

    Several decades ago, Mo{sub 2}B was assumed to have an Al{sub 2}Cu-type structure with I4/mcm space group. Using ab initio phonon calculations, we identify the earlier proposed Al{sub 2}Cu-type structure is dynamically unstable at ambient pressure. An energetically more favorable phase with the tetragonal I4/m structure was then predicted by employing frozen-phonon technique. The currently predicted I4/m phase is mechanically and dynamically stable and energetically more favorable than that of the earlier proposed Al{sub 2}Cu-type structure. The electronic structures calculations indicate that Mo{sub 2}B is a metal with several bands crossing the Fermi level. Our analysis indicates that the three-dimensional network of the covalent Mo-B bond is responsible for the ultra-incompressible property of Mo{sub 2}B.

  1. Oral application of freeze-dried yeast particles expressing the PCV2b Cap protein on their surface induce protection to subsequent PCV2b challenge in vivo.

    PubMed

    Patterson, Robert; Eley, Thomas; Browne, Christopher; Martineau, Henny M; Werling, Dirk

    2015-11-17

    Porcine circovirus type 2 (PCV2) is now endemic in every major pig producing country, causing PCV-associated disease (PCVAD), linked with large scale economic losses. Current vaccination strategies are based on the capsid protein of the virus and are reasonably successful in preventing PCVAD but fail to induce sterile immunity. Additionally, vaccinating whole herds is expensive and time consuming. In the present study a "proof of concept" vaccine trial was employed to test the effectiveness of powdered freeze-dried recombinant Saccharomyces cerevisiae yeast stably expressing the capsid protein of PCV2b on its surface as an orally applied vaccine. PCV2-free pigs were given 3 doses of vaccine or left un-vaccinated before challenge with a defined PCV2b strain. Rectal temperatures were measured and serum and faeces samples were collected weekly. At the end of the study, pigs were euthanized, tissue samples taken and tested for PCV2b load by qPCR and immunohistochemistry. The peak of viraemia in sera and faeces of unvaccinated pigs was higher than that of vaccinated pigs. Additionally more sIgA was found in faeces of vaccinated pigs than unvaccinated. Vaccination was associated with lower serum concentrations of TNFα and IL-1β but higher concentrations of IFNα and IFNγ in comparison to the unvaccinated animals. At the end of the trial, a higher viral load was found in several lymphatic tissues and the ileum of unvaccinated pigs in comparison to vaccinated pigs. The difference between groups was especially apparent in the ileum. The results presented here demonstrate a possible use for recombinant S. cerevisiae expressing viral proteins as an oral vaccine against PCV2. A powdered freeze-dried recombinant S. cerevisiae used as an oral vaccine could be mixed with feed and may offer a cheap and less labour intensive alternative to inoculation with the additional advantage that no cooling chain would be required for vaccine transport and storage. PMID:26476879

  2. Oral application of freeze-dried yeast particles expressing the PCV2b Cap protein on their surface induce protection to subsequent PCV2b challenge in vivo.

    PubMed

    Patterson, Robert; Eley, Thomas; Browne, Christopher; Martineau, Henny M; Werling, Dirk

    2015-11-17

    Porcine circovirus type 2 (PCV2) is now endemic in every major pig producing country, causing PCV-associated disease (PCVAD), linked with large scale economic losses. Current vaccination strategies are based on the capsid protein of the virus and are reasonably successful in preventing PCVAD but fail to induce sterile immunity. Additionally, vaccinating whole herds is expensive and time consuming. In the present study a "proof of concept" vaccine trial was employed to test the effectiveness of powdered freeze-dried recombinant Saccharomyces cerevisiae yeast stably expressing the capsid protein of PCV2b on its surface as an orally applied vaccine. PCV2-free pigs were given 3 doses of vaccine or left un-vaccinated before challenge with a defined PCV2b strain. Rectal temperatures were measured and serum and faeces samples were collected weekly. At the end of the study, pigs were euthanized, tissue samples taken and tested for PCV2b load by qPCR and immunohistochemistry. The peak of viraemia in sera and faeces of unvaccinated pigs was higher than that of vaccinated pigs. Additionally more sIgA was found in faeces of vaccinated pigs than unvaccinated. Vaccination was associated with lower serum concentrations of TNFα and IL-1β but higher concentrations of IFNα and IFNγ in comparison to the unvaccinated animals. At the end of the trial, a higher viral load was found in several lymphatic tissues and the ileum of unvaccinated pigs in comparison to vaccinated pigs. The difference between groups was especially apparent in the ileum. The results presented here demonstrate a possible use for recombinant S. cerevisiae expressing viral proteins as an oral vaccine against PCV2. A powdered freeze-dried recombinant S. cerevisiae used as an oral vaccine could be mixed with feed and may offer a cheap and less labour intensive alternative to inoculation with the additional advantage that no cooling chain would be required for vaccine transport and storage.

  3. Oral application of freeze-dried yeast particles expressing the PCV2b Cap protein on their surface induce protection to subsequent PCV2b challenge in vivo

    PubMed Central

    Patterson, Robert; Eley, Thomas; Browne, Christopher; Martineau, Henny M.; Werling, Dirk

    2015-01-01

    Porcine circovirus type 2 (PCV2) is now endemic in every major pig producing country, causing PCV-associated disease (PCVAD), linked with large scale economic losses. Current vaccination strategies are based on the capsid protein of the virus and are reasonably successful in preventing PCVAD but fail to induce sterile immunity. Additionally, vaccinating whole herds is expensive and time consuming. In the present study a “proof of concept” vaccine trial was employed to test the effectiveness of powdered freeze-dried recombinant Saccharomyces cerevisiae yeast stably expressing the capsid protein of PCV2b on its surface as an orally applied vaccine. PCV2-free pigs were given 3 doses of vaccine or left un-vaccinated before challenge with a defined PCV2b strain. Rectal temperatures were measured and serum and faeces samples were collected weekly. At the end of the study, pigs were euthanized, tissue samples taken and tested for PCV2b load by qPCR and immunohistochemistry. The peak of viraemia in sera and faeces of unvaccinated pigs was higher than that of vaccinated pigs. Additionally more sIgA was found in faeces of vaccinated pigs than unvaccinated. Vaccination was associated with lower serum concentrations of TNFα and IL-1β but higher concentrations of IFNα and IFNγ in comparison to the unvaccinated animals. At the end of the trial, a higher viral load was found in several lymphatic tissues and the ileum of unvaccinated pigs in comparison to vaccinated pigs. The difference between groups was especially apparent in the ileum. The results presented here demonstrate a possible use for recombinant S. cerevisiae expressing viral proteins as an oral vaccine against PCV2. A powdered freeze-dried recombinant S. cerevisiae used as an oral vaccine could be mixed with feed and may offer a cheap and less labour intensive alternative to inoculation with the additional advantage that no cooling chain would be required for vaccine transport and storage. PMID:26476879

  4. Molecular and functional characterization of the first tick CAP2b (periviscerokinin) receptor from Rhipicephalus (Boophilus) microplus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cDNA of the receptor for CAP2b/periviscerokinin (PVK) neuropeptides, designated Rhimi-CAP2b-R, was cloned from synganglia of tick Rhipicephalus (Boophilus) microplus. This receptor is the ortholog of the insect CAP2b/PVK receptor, as concluded from analyses of the predicted protein sequence, ph...

  5. 26 CFR 301.6103(p)(2)(B)-1 - Disclosure of returns and return information by other agencies.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... other agencies. 301.6103(p)(2)(B)-1 Section 301.6103(p)(2)(B)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(2)(B)-1 Disclosure of returns and return information... regulations thereunder, including, if applicable, safeguards imposed by section 6103(p)(4). (d) Records...

  6. 26 CFR 301.6103(p)(2)(B)-1 - Disclosure of returns and return information by other agencies.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... other agencies. 301.6103(p)(2)(B)-1 Section 301.6103(p)(2)(B)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(2)(B)-1 Disclosure of returns and return information... regulations thereunder, including, if applicable, safeguards imposed by section 6103(p)(4). (d) Records...

  7. 26 CFR 301.6103(p)(2)(B)-1 - Disclosure of returns and return information by other agencies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... other agencies. 301.6103(p)(2)(B)-1 Section 301.6103(p)(2)(B)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(2)(B)-1 Disclosure of returns and return information... regulations thereunder, including, if applicable, safeguards imposed by section 6103(p)(4). (d) Records...

  8. 26 CFR 301.6103(p)(2)(B)-1 - Disclosure of returns and return information by other agencies.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... other agencies. 301.6103(p)(2)(B)-1 Section 301.6103(p)(2)(B)-1 Internal Revenue INTERNAL REVENUE... Information and Returns Returns and Records § 301.6103(p)(2)(B)-1 Disclosure of returns and return information... regulations thereunder, including, if applicable, safeguards imposed by section 6103(p)(4). (d) Records...

  9. Identification of the Pro orientation of CAP2b peptides for antidiuretic activity in the stink bug Acrosternum hilare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The CAP2b neuropeptide family plays an important role in the regulation of the processes of diuresis and/or antidiuresis in a variety of insects. While Manse-CAP2b (pELYAFPRVamide) and native CAP2bs elicit diuretic activity in a number of species of flies, native CAP2b sequences have been shown to ...

  10. 77 FR 28764 - Temporary Non-agricultural Employment of H-2B Aliens in the United States

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-16

    ... published a Final Rule amending the H-2B regulations at 20 CFR part 655, Subpart A. 77 FR 10038, February 21... Agriculture or Registered Nursing in the United States (H-2B Workers), and Other Technical Changes, 73 FR... H-2B Aliens in the United States AGENCY: Employment and Training Administration, Labor. ]...

  11. Structural Basis for Host Membrane Remodeling Induced by Protein 2B of Hepatitis A Virus

    PubMed Central

    Vives-Adrián, Laia; Garriga, Damià; Buxaderas, Mònica; Fraga, Joana; Pereira, Pedro José Barbosa

    2015-01-01

    ABSTRACT The complexity of viral RNA synthesis and the numerous participating factors require a mechanism to topologically coordinate and concentrate these multiple viral and cellular components, ensuring a concerted function. Similarly to all other positive-strand RNA viruses, picornaviruses induce rearrangements of host intracellular membranes to create structures that act as functional scaffolds for genome replication. The membrane-targeting proteins 2B and 2C, their precursor 2BC, and protein 3A appear to be primarily involved in membrane remodeling. Little is known about the structure of these proteins and the mechanisms by which they induce massive membrane remodeling. Here we report the crystal structure of the soluble region of hepatitis A virus (HAV) protein 2B, consisting of two domains: a C-terminal helical bundle preceded by an N-terminally curved five-stranded antiparallel β-sheet that displays striking structural similarity to the β-barrel domain of enteroviral 2A proteins. Moreover, the helicoidal arrangement of the protein molecules in the crystal provides a model for 2B-induced host membrane remodeling during HAV infection. IMPORTANCE No structural information is currently available for the 2B protein of any picornavirus despite it being involved in a critical process in viral factory formation: the rearrangement of host intracellular membranes. Here we present the structure of the soluble domain of the 2B protein of hepatitis A virus (HAV). Its arrangement, both in crystals and in solution under physiological conditions, can help to understand its function and sheds some light on the membrane rearrangement process, a putative target of future antiviral drugs. Moreover, this first structure of a picornaviral 2B protein also unveils a closer evolutionary relationship between the hepatovirus and enterovirus genera within the Picornaviridae family. PMID:25589659

  12. Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population.

    PubMed

    Yang, Yongfeng; Li, Wenqiang; Zhang, Hongxing; Yang, Ge; Wang, Xiujuan; Ding, Minli; Jiang, Tianzi; Lv, Luxian

    2015-01-01

    Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamatergic system is the major excitatory neurotransmitter system in the central nervous system, and is mediated by N-methyl-D-aspartate (NMDA) receptors. Disturbances in this system have been hypothesized to play a major role in SZ pathogenesis. Several studies have revealed that the NMDA receptor subunit 2B (GRIN2B) potentially associates with SZ and its psychiatric symptoms. In this study, we performed a case-control study to identify polymorphisms of the GRIN2B gene that may confer susceptibility to SZ in the Han Chinese population. Thirty-four single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was observed in allele and genotype between SZ and controls at rs2098469 (χ2 = 8.425 and 4.994; p = 0.025 and 0.014, respectively). Significant associations were found in the allele at rs12319804 (χ2 = 4.436; p = 0.035), as well as in the genotype at rs12820037 and rs7298664 between SZ and controls (χ2 = 11.162 and 38.204; p = 0.003 and 4.27×10(-8), respectively). After applying the Bonferroni correction, rs7298664 still had significant genotype associations with SZ (p = 1.71×10(-7)). In addition, rs2098469 genotype and allele frequencies, and 12820037 allele frequencies were nominally associated with SZ. Three haplotypes, CGA (rs10845849-rs12319804-rs10845851), CC (rs12582848-rs7952915), and AAGAC (rs2041986-rs11055665-rs7314376-rs7297101-rs2098469), had significant differences between SZ and controls (χ2 = 4.324, 4.582, and 4.492; p = 0.037, 0.032, and 0.034, respectively). In addition, three SNPs, rs2098469, rs12820037, and rs7298664, were significantly associated with cognition factors PANSS subscores in SZ (F = 16.799, 7.112, and 13.357; p = 0.000, 0.017, and 0.000, respectively). In conclusion, our study provides novel evidence for an association between GRIN2B

  13. Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population

    PubMed Central

    Zhang, Hongxing; Yang, Ge; Wang, Xiujuan; Ding, Minli; Jiang, Tianzi; Lv, Luxian

    2015-01-01

    Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamatergic system is the major excitatory neurotransmitter system in the central nervous system, and is mediated by N-methyl-D-aspartate (NMDA) receptors. Disturbances in this system have been hypothesized to play a major role in SZ pathogenesis. Several studies have revealed that the NMDA receptor subunit 2B (GRIN2B) potentially associates with SZ and its psychiatric symptoms. In this study, we performed a case–control study to identify polymorphisms of the GRIN2B gene that may confer susceptibility to SZ in the Han Chinese population. Thirty-four single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was observed in allele and genotype between SZ and controls at rs2098469 (χ2 = 8.425 and 4.994; p = 0.025 and 0.014, respectively). Significant associations were found in the allele at rs12319804 (χ2 = 4.436; p = 0.035), as well as in the genotype at rs12820037 and rs7298664 between SZ and controls (χ2 = 11.162 and 38.204; p = 0.003 and 4.27×10-8, respectively). After applying the Bonferroni correction, rs7298664 still had significant genotype associations with SZ (p = 1.71×10-7). In addition, rs2098469 genotype and allele frequencies, and 12820037 allele frequencies were nominally associated with SZ. Three haplotypes, CGA (rs10845849—rs12319804—rs10845851), CC (rs12582848—rs7952915), and AAGAC (rs2041986—rs11055665—rs7314376—rs7297101—rs2098469), had significant differences between SZ and controls (χ2 = 4.324, 4.582, and 4.492; p = 0.037, 0.032, and 0.034, respectively). In addition, three SNPs, rs2098469, rs12820037, and rs7298664, were significantly associated with cognition factors PANSS subscores in SZ (F = 16.799, 7.112, and 13.357; p = 0.000, 0.017, and 0.000, respectively). In conclusion, our study provides novel evidence for an association between

  14. Supraleitung und Interkontinentalraketen „On-line computing“ zwischen Militär, Industrie und Wissenschaft

    NASA Astrophysics Data System (ADS)

    Knolle, Johannes; Joas, Christian

    Der zweite Weltkrieg und der Kalte Krieg veränderten nicht nur das Verhältnis zwischen Militär, Industrie und Wissenschaft, sondern auch die wissenschaftliche Praxis von Physikern und anderen Wissenschaftlern. In den 1950er Jahren stellte die Entwicklung von Interkontinentalraketen die Auftragnehmer des Militärs in der Industrie vor komplexe Fragestellungen, zu deren Lösung sie auf die Expertise von Wissenschaftlern angewiesen waren. Industrieunternehmen gründeten eigene Forschungseinheiten zur Lösung technischer und wissenschaftlicher Probleme.

  15. New halogenated tris-(phenylalkyl)amines as h5-HT2B receptor ligands.

    PubMed

    Kapadia, Nirav; Ahmed, Shahrear; Harding, Wayne W

    2016-07-15

    A series of compounds in which various halogen substituents were incorporated into a phenyl ring of a tris-(phenylalkyl)amine scaffold, was synthesized and evaluated for affinity to h5-HT2 receptors. In general, all compounds were found to have good affinity for the 5-HT2B receptor and were selective over 5-HT2A and 5-HT2C receptors. Compound 9i was the most selective compound in this study and is the highest affinity 5-HT2B receptor ligand bearing a tris-(phenylalkyl)amine scaffold to date. PMID:27261181

  16. The role of transcriptional coactivator ADA2b in Arabidopsis abiotic stress responses

    PubMed Central

    Kaldis, Athanasios; Nikoloudi, Adriana; Tsementzi, Despoina

    2011-01-01

    Plant growth and crop production can be greatly affected by common environmental stresses such as drought, high salinity and low temperatures. Gene expression is affected by several abiotic stresses. Stress-inducible genes are regulated by transcription factors and epigenetic mechanisms such as histone modifications. In this mini-review, we have explored the role of transcriptional adaptor ADA2b in Arabidopsis responses to abiotic stress. ADA2b is required for the expression of genes involved in abiotic stress either by controlling H3 and H4 acetylation in the case of salt stress or affecting nucleosome occupancy in low temperatures response. PMID:21897124

  17. Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist

    PubMed Central

    2010-01-01

    The structure−activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels. PMID:24900298

  18. Design and analysis report for the RL10-2B breadboard low thrust engine

    NASA Technical Reports Server (NTRS)

    Brown, J. R.; Foust, R. R.; Galler, D. E.; Kanic, P. G.; Kmiec, T. D.; Limerick, C. D.; Peckham, R. J.; Swartwout, T.

    1984-01-01

    The breadboard low thrust RL10-2B engine is described. A summary of the analysis and design effort to define the multimode thrust concept applicable to the requirements for the upper stage vehicles is provided. Baseline requirements were established for operation of the RL10-2B engine under the following conditions: (1) tank head idle at low propellant tank pressures without vehicle propellant conditioning or settling thrust; (2) pumped idle at a ten percent thrust level for low G deployment and/or vehicle tank pressurization; and (3) full thrust (15,000 lb.). Several variations of the engine configuration were investigated and results of the analyses are included.

  19. Microwave-assisted synthesis and electrochemical evaluation of VO2 (B) nanostructures

    SciTech Connect

    Ashton, Thomas E.; Borras, David Hevia; Iadecola, Antonella; Wiaderek, Kamila Magdalena; Chapman, Karena W.; Corr, Serena A.

    2015-12-01

    Abstract Understanding how intercalation materials change during electrochemical operation is paramount to optimising their behaviour and function and in situ characterisation methods allow us to observe these changes without sample destruction. Here, we first report the improved intercalation properties of bronze phase vanadium dioxide VO2 (B) prepared by a microwave assisted route which exhibits a larger electrochemical capacity (232 mAh g-1) compared to VO2 (B) prepared by a solvothermal route (197 mAh g-1). These electrochemical differences have also been followed using in situ X-ray absorption spectroscopy allowing us to follow oxidation state changes as they occur during battery operation.

  20. Transport Anisotropy in ErNi2B2C Along c-AXIS

    NASA Astrophysics Data System (ADS)

    Lee, W. C.

    The resistivities along c-axis ρc(H, T) of ErNi2 B2C have been measured with H⊥ and H‖ c-axis for 2 < T < 300 K and the superconducting upper critical field Hc2(T) curves of ErNi2B2C were constructed for each magnetic fields. Our Hc2(T) curves have been compared and discussed with those from ρab(H, T) measurements which explain the anisotropy and its temperature dependence of Hc2(T) are thought to arise from magnetic pair breaking and the anisotropic field dependence of Néel temperature TN originated from Er+3 sublattice.

  1. The role of transcriptional coactivator ADA2b in Arabidopsis abiotic stress responses.

    PubMed

    Vlachonasios, Konstantinos E; Kaldis, Athanasios; Nikoloudi, Adriana; Tsementzi, Despoina

    2011-10-01

    Plant growth and crop production can be greatly affected by common environmental stresses such as drought, high salinity and low temperatures. Gene expression is affected by several abiotic stresses. Stress-inducible genes are regulated by transcription factors and epigenetic mechanisms such as histone modifications. In this Mini-Review, we have explored the role of transcriptional adaptor ADA2b in Arabidopsis responses to abiotic stress. ADA2b is required for the expression of genes involved in abiotic stress either by controlling H3 and H4 acetylation in the case of salt stress or affecting nucleosome occupancy in low temperatures response.

  2. Darwin, Engels und die Rolle der Arbeit in der biologischen und kulturellen Evolution des Menschen

    NASA Astrophysics Data System (ADS)

    Reichholf, Josef H.

    Im Jahre 1876, 5 Jahre nach Erscheinen von Darwins Buch über die Evolution des Menschen und die sexuelle Selektion (Darwin 1871), veröffentlichte Friedrich Engels den berühmt gewordenen Essay "Anteil der Arbeit an der Menschwerdung des Affen“ (Engels 1876). Die Kernfrage darin lautet in Kurzform: Warum hat der Mensch eigentlich ein Bedürfnis nach Arbeit? Engels Antwort wird nachfolgend näher betrachtet und vom gegenwärtigen Kenntnisstand aus beurteilt. Wie sich zeigen wird, beantworten seine Überlegungen die Frage nicht wirklich. Sie ist weiterhin offen. Es können lediglich einige zusätzliche Anhaltspunkte zur Diskussion gestellt werden. Angesichts des drängenden Problems millionenfacher Arbeitslosigkeit und der Forderungen nach einem "Grundrecht auf Arbeit“ kommt den Überlegungen zum möglichen Ursprung des Bedürfnisses nach Arbeit mehr als nur akademisches Interesse zu.

  3. Haptische Modellierung und Deformation einer Kugelzelle

    NASA Astrophysics Data System (ADS)

    Schippritt, Darius; Wiemann, Martin; Lipinski, Hans-Gerd

    Haptische Simulationsmodelle dienen in der Medizin in erster Linie dem Training operativer Eingriffe. Sie basieren zumeist auf physikalischen Gewebemodellen, welche eine sehr genaue Simulation der biomechanischen Eigenschaften des betreffenden Gewebes erlauben, aber gleichzeitig sehr rechenintensiv und damit zeitaufwändig in der Ausführung sind. Die menschliche Wahrnehmung kann allerdings auch eine ungenaue haptische Modellierung psychooptisch ausgleichen. Daher kann es sinnvoll sein, haptische Simulationen auch mit nicht vollständig physikalisch definierten Deformationsmodellen durchzuführen. Am Beispiel der haptischer Simulation einer in-vitro Fertilisation wird gezeigt, dass durch die Anwendung eines geometrischen Deformationsmodells eine künstliche Befruchtung unter realistischen experimentellen Bedingungen in Echtzeit haptisch simuliert und damit trainiert werden kann.

  4. Biochips und ihr Einsatz in der Lebensmittelanalytik

    NASA Astrophysics Data System (ADS)

    Huber, Ingrid; Zeltz, Patric

    Mit der Verbreitung des Begriffes "Biochip“ in den biotechnologischen Medien wurde Ende der 1990er-Jahre zunächst der Eindruck erweckt, dass die Computerelektronik in die molekularbiologischen Anwendungen eingestiegen ist [18]. In nur wenigen Jahren hat sich die Biochiptechnologie zu einem Verfahren entwickelt, das aus der molekularbiologischen Grundlagenforschung nicht mehr wegzudenken ist und über eine Vielzahl von Einsatzbereichen verfügt. Die Biochiptechnologie ermöglicht die Miniaturisierung von DNA-, RNA- bzw. Proteinanalytik in hochparallelen Formaten. Dieser hohe Parallelisierungsgrad ist einer der wesentlichen Vorteile dieser Technik gegenüber klassischen molekularbiologischen Methoden. Sie wird heutzutage vor allem in der Genomforschung eingesetzt, für Genexpressionsstudien, zum Screening von single nucleotide polymorphisms (SNPs), in der pharmakogenetischen Forschung sowie in der Erforschung von Erbkrankheiten und in der Krebsforschung [1, 7, 19]. Neben vielen weiteren Bereichen finden Biochips auch spezielle Anwendungen in der Lebensmittelanalytik.

  5. CYP2B6*6 and CYP2B6*18 Predict Long-Term Efavirenz Exposure Measured in Hair Samples in HIV-Positive South African Women.

    PubMed

    Röhrich, Carola R; Drögemöller, Britt I; Ikediobi, Ogechi; van der Merwe, Lize; Grobbelaar, Nelis; Wright, Galen E B; McGregor, Nathaniel; Warnich, Louise

    2016-06-01

    Long-term exposure to efavirenz (EFV) measured in hair samples may predict response to antiretroviral treatment (ART). Polymorphisms in CYP2B6 are known to alter EFV levels. The aim of this study was to assess the relationship between CYP2B6 genotype, EFV levels measured in hair, and virological outcomes on ART in a real-world setting. We measured EFV levels in hair from HIV-positive South African females who had been receiving EFV-based treatment for at least 3 months from the South African Black (SAB) (n = 81) and Cape Mixed Ancestry (CMA) (n = 53) populations. Common genetic variation in CYP2B6 was determined in 15 individuals from each population using bidirectional Sanger sequencing. Prioritized variants (n = 16) were subsequently genotyped in the entire patient cohort (n = 134). The predictive value of EFV levels in hair and selected variants in CYP2B6 on virological treatment outcomes was assessed. Previously described alleles (CYP2B6*2, CYP2B6*5, CYP2B6*6, CYP2B6*17, and CYP2B6*18), as well as two novel alleles (CYP2B6*31 and CYP2B6*32), were detected in this study. Compared to noncarriers, individuals homozygous for CYP2B6*6 had ∼109% increased EFV levels in hair (p = .016) and CYP2B6*18 heterozygotes demonstrated 82% higher EFV hair levels (p = .0006). This study confirmed that alleles affecting CYP2B6 metabolism and subsequent EFV exposure are present at significant frequencies in both the SAB and CMA populations. Furthermore, this study demonstrated that the use of hair samples for testing EFV concentrations may be a useful tool in determining long-term drug exposure in resource-limited countries.

  6. Li4Ge2B as a new derivative of the Mo2B5 and Li5Sn2 structure types.

    PubMed

    Pavlyuk, Volodymyr; Ciesielski, Wojciech; Rozdzynska-Kielbik, Beata; Dmytriv, Grygoriy; Ehrenberg, Helmut

    2016-07-01

    Binary and multicomponent intermetallic compounds based on lithium and p-elements of Groups III-V of the Periodic Table are useful as modern electrode materials in lithium-ion batteries. However, the interactions between the components in the Li-Ge-B ternary system have not been reported. The structure of tetralithium digermanium boride, Li4Ge2B, exhibits a new structure type, in the noncentrosymmetric space group R3m, in which all the Li, Ge and B atoms occupy sites with 3m symmetry. The title structure is closely related to the Mo2B5 and Li5Sn2 structure types, which crystallize in the centrosymmetric space group R-3m. All the atoms in the title structure are coordinated by rhombic dodecahedra (coordination number = 14), similar to the atoms in related structures. According to electronic structure calculations using the tight-binding-linear muffin-tin orbital-atomic spheres approximation (TB-LMTO-ASA) method, strong covalent Ge-Ge and Ge-B interactions were established. PMID:27377278

  7. Li4Ge2B as a new derivative of the Mo2B5 and Li5Sn2 structure types.

    PubMed

    Pavlyuk, Volodymyr; Ciesielski, Wojciech; Rozdzynska-Kielbik, Beata; Dmytriv, Grygoriy; Ehrenberg, Helmut

    2016-07-01

    Binary and multicomponent intermetallic compounds based on lithium and p-elements of Groups III-V of the Periodic Table are useful as modern electrode materials in lithium-ion batteries. However, the interactions between the components in the Li-Ge-B ternary system have not been reported. The structure of tetralithium digermanium boride, Li4Ge2B, exhibits a new structure type, in the noncentrosymmetric space group R3m, in which all the Li, Ge and B atoms occupy sites with 3m symmetry. The title structure is closely related to the Mo2B5 and Li5Sn2 structure types, which crystallize in the centrosymmetric space group R-3m. All the atoms in the title structure are coordinated by rhombic dodecahedra (coordination number = 14), similar to the atoms in related structures. According to electronic structure calculations using the tight-binding-linear muffin-tin orbital-atomic spheres approximation (TB-LMTO-ASA) method, strong covalent Ge-Ge and Ge-B interactions were established.

  8. Pharmacogenetics of CYP2B6, CYP2A6 and UGT2B7 in HIV treatment in African populations: focus on efavirenz and nevirapine.

    PubMed

    Čolić, Antoinette; Alessandrini, Marco; Pepper, Michael S

    2015-05-01

    The CYP450 and UGT enzymes are involved in phase I and phase II metabolism of the majority of clinically prescribed drugs, including the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine, used in the treatment of HIV/AIDS. Variations in the activity of these enzymes due to gene polymorphisms can affect an individual's drug response or may lead to adverse drug reactions. There is an inter-ethnic distribution in the frequency of these polymorphisms, with African populations exhibiting higher genetic diversity compared to other populations. African specific alleles with clinical relevance have also emerged. Given the high prevalence of HIV/AIDS in sub-Saharan Africa, understanding the frequency of pharmacogenetically relevant alleles in populations of African origin, and their impact on efavirenz and nevirapine metabolism, is becoming increasingly critical. This review aims to investigate ethnic variation of CYP2B6, CYP2A6 and UGT2B7, and to understand the pharmacogenetic relevance when comparing frequencies in African populations to other populations worldwide. PMID:25391641

  9. 76 FR 70382 - Airworthiness Directives; General Electric Company (GE) CF6-80C2B Series Turbofan Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-14

    ...-07, Amendment 39-15085 (72 FR 31174, June 6, 2007), and adding the following new AD: General Electric... Federal Aviation Administration 14 CFR Part 39 RIN 2120-AA64 Airworthiness Directives; General Electric... General Electric Company (GE) CF6-80C2B1F, CF6-80C2B1F1, CF6-80C2B1F2, CF6-80C2B2F, CF6-80C2B3F,...

  10. Elektronische Citizen Cards in Deutschland und Europa

    NASA Astrophysics Data System (ADS)

    Kowalski, Bernd

    Meine sehr geehrten Damen und Herren, der Bedarf an elektronischen Identitäten entsteht durch die wachsende Mobilität der Gesellschaft bei einem gleichzeitig steigenden Bedarf an Onlinepräsenz. Diese elektronischen Identitäten machen natürlich auch vor den staatlichen Ausweisen nicht halt, wie zum Beispiel dem Reisepass, aber auch dem Personalausweis und weiteren Ausweisdokumenten. Wobei es bei den staatlich herausgegebenen oder kontrollierten Ausweisen immer um zwei verschiedene Dinge geht: Einmal um die hoheitliche Funktion, wie zum Beispiel beim Reisepass. Hier geht es zum Beispiel darum, in einem Europa mit gefallenen Grenzen und bei freiem Reiseverkehr für alle Personen, die in diesem Raum wohnen, insbesondere auch im Schengener Raum, die Möglichkeit zu schaffen, auch künftig noch Personenkontrollen durchzuführen. Auch der Reiseverkehr über die europäischen Grenzen hinaus ist insofern ein Problem, da die Identitätenprüfung an den Grenzkontrollen immer schwieriger wird. Deswegen braucht man an dieser Stelle Möglichkeiten, um eine Personenüberprüfung durchzuführen, um feststellen zu können, dass diese Person auch zum Dokument gehört.

  11. Therapeutisches Management kutaner und genitaler Warzen.

    PubMed

    Ockenfels, Hans Michael

    2016-09-01

    Mindestens 10 % der Bevölkerung erkranken während ihres Lebens an einer Infektion mit humanen Papillomaviren (HPV), welche sich klinisch anhand der Ausbildung kutaner oder genitaler Warzen manifestiert. Obwohl Warzen ubiquitär sind, existieren keine definierten Behandlungen. Warzen zeigen, insbesondere in den ersten sechs Monaten, eine erhöhte Selbstheilungsrate. Dieser Umstand erschwert die Interpretation von Studien, da häufig Patienten mit Neuinfektionen zusammen mit Patienten mit Altinfektionen behandelt werden. Lokalisationen, Größe und Dicke der Warzen sind ebenfalls in den meisten Fällen nicht berücksichtigt. Ziel dieses Übersichtsartikels ist eine Analyse des vorliegenden Studienmaterials, unter der für den klinischen Alltag so wichtigen Berücksichtigung von Subtypen und Lokalisationen. Insbesondere die Abgrenzung zwischen frischen und chronisch-therapieresistenten Verrucae vulgares spiegelt sich in einem Therapiealgorithmus wider. Bei genitalen Warzen wird der Therapiealgorithmus deutlicher durch das Ausmaß der infizierten Fläche als durch das Alter der Warzen bestimmt. Bei immunkompetenten Personen muss es mit den hier aufgezeigten therapeutischen Methoden immer das Ziel sein, eine komplette Abheilung zu erzielen. PMID:27607029

  12. Homomultimerization of the Coxsackievirus 2B Protein in Living Cells Visualized by Fluorescence Resonance Energy Transfer Microscopy

    PubMed Central

    van Kuppeveld, Frank J. M.; Melchers, Willem J. G.; Willems, Peter H. G. M.; Gadella, Jr., Theodorus W. J.

    2002-01-01

    The 2B protein of enteroviruses is the viral membrane-active protein that is responsible for the modifications in host cell membrane permeability that take place in enterovirus-infected cells. The 2B protein shows structural similarities to the group of lytic polypeptides, polypeptides that permeate membranes either by forming multimeric membrane-integral pores or, alternatively, by lying parallel to the lipid bilayer and disturbing the curvature and symmetry of the membrane. Our aim is to gain more insight into the molecular architecture of the 2B protein in vivo. In this study, the possible existence of multimers of the coxsackie B3 virus 2B protein in single living cells was explored by fluorescence resonance energy transfer (FRET) microscopy. FRET between fusion proteins 2B-ECFP and 2B-EYFP (enhanced cyan and yellow fluorescent variants of green fluorescent protein) was monitored by using spectral imaging microscopy (SPIM) and fluorescence lifetime imaging microscopy (FLIM). Both techniques revealed the occurrence of intermolecular FRET between 2B-ECFP and 2B-EYFP, providing evidence for the formation of protein 2B homomultimers. Putative models for the mode of action of the membrane-active 2B protein and the formation of membrane-integral pores by 2B multimers are discussed. PMID:12186926

  13. Lovastatin exerts protective effects on endothelial cells via upregulation of PTK2B

    PubMed Central

    Chu, Weiwei; Guan, Lili; Huang, Dihua; Ren, Yuezhong; Zhou, Yan

    2016-01-01

    Statins are HMG-CoA reductase inhibitors that are used to decrease the blood levels of low-density lipoprotein (LDL). In addition, they have been shown to exert pleiotropic protective effects in the absence of LDL-lowering activity. The present study investigated the effects of lovastatin on global gene expression in human umbilical vein endothelial cells (HUVECs), in order to further explore its ability to protect against oxidized (ox)-LDL-induced cytotoxicity. HUVECs were treated with lovastatin for 2–24 h, and gene expression patterns were analyzed using cDNA microarrays. The results suggested that numerous genes were regulated by lovastatin, including certain genes associated with cell survival, such as PTK2B, BCL2 and MAP3K3. In particular, PTK2B, which has been shown to exert anti-apoptotic effects against ox-LDL-induced cell injury, was upregulated by lovastatin. Knockdown of PTK2B was able to attenuate ox-LDL-induced cell injury, and this was associated with decreased levels of phosphorylated-AKT and eNOS, and inhibition of mitochondrial-dependent apoptosis. In conclusion, the results of the present study suggested that lovastatin protects against ox-LDL-induced cell injury, potentially via the upregulation of PTK2B, which regulates the anti-apoptosis signaling pathway. PMID:27602089

  14. IN VITRO GLUCURONIDATION OF APREPITANT: A MODERATE INHIBITOR OF UGT2B7

    PubMed Central

    House, Larry; Ramirez, Jacqueline; Seminerio, Michael; Mirkov, Snezana; Ratain, Mark J.

    2016-01-01

    Aprepitant, an oral antiemetic, commonly used in the prevention of chemotherapy-induced nausea and vomiting, is primarily metabolized by CYP3A4. Aprepitant glucuronidation has yet to be evaluated in humans. The contribution of human UDP-glucuronosyltransferase (UGT) isoforms to the metabolism of aprepitant was investigated by performing kinetic studies, inhibition studies, and correlation analyses. In addition, aprepitant was evaluated as an inhibitor of UGTs.Glucuronidation of aprepitant was catalyzed by UGT1A4 (82%), UGT1A3 (12%), and UGT1A8 (6%) and Kms were 161.6 ± 15.6 µM, 69.4 ± 1.9 µM, and 197.1 ± 28.2 µM, respectively. Aprepitant glucuronidation was significantly correlated with both UGT1A4 substrates anastrazole and imipramine (rs = 0.77, P < 0.0001 for both substrates; n = 44), and with the UGT1A3 substrate thyroxine (rs = 0.58, P < 0.0001; n = 44).We found aprepitant to be a moderate inhibitor of UGT2B7 with a Ki of ~10 µM for 4-MU, morphine, and zidovudine. Our results suggest aprepitant can alter clearance of drugs primarily eliminated by UGT2B7. Given the likelihood for first-pass metabolism by intestinal UGT2B7, this is of particular concern for oral aprepitant co-administered with oral substrates of UGT2B7, such as zidovudine and morphine. PMID:26053558

  15. Elementary Career Education Guide, Volume 2B: Career Awareness--Intermediate.

    ERIC Educational Resources Information Center

    Watertown Independent School District 1, SD.

    Volume 2B of the six-volume articulated elementary education career guide deals with the career awareness level of career education and aims at developing student career identity. The lessons in the volume are divided and color-coded by intermediate grade levels 1-3 corresponding respectively with grades 4-6 and are categorized by subject area and…

  16. A Cross-Industry Review of B2B Critical Success Factors.

    ERIC Educational Resources Information Center

    Eid, Riyad; Trueman, Myfanwy; Ahmed, Abdel Moneim

    2002-01-01

    Presents a comprehensive review of B2B (business-to- business) international Internet marketing and identifies 21 critical success factors in five categories: marketing strategy, including management support, strategic goals, and collaboration; Web site factors, including Web site design; global factors, including multilanguage sites and cultural…

  17. Long life hearth in blast furnace -- Kokura No. 2 B.F. of Sumitomo Metals

    SciTech Connect

    Yamamoto, Takaiku; Sunahara, Kouhei; Inada, Takanobu; Takatani, Kouji; Miyahara, Mitsuo; Sato, Yasusi; Hatano, Yasuhiko; Takata, Kouzo

    1997-12-31

    The factors elongating hearth life of Sumitomo Kokura No. 2 B.F. were investigated by use of an estimation system of the furnace hearth condition, which consisted of four mathematical simulation models. Lowered heat load operation together with integrated design of both refractories and cooling enabled the furnace life to be extended for over 16 years without severe damage in the hearth.

  18. 29 CFR 503.17 - Document retention requirements of H-2B employers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... community-based organizations, if applicable, as specified in 20 CFR 655.45(a), (b) and (c); and (v... REGULATIONS ENFORCEMENT OF OBLIGATIONS FOR TEMPORARY NONIMMIGRANT NON-AGRICULTURAL WORKERS ADMITTED UNDER... for Temporary Employment Certification requesting H-2B workers are required to retain the...

  19. 29 CFR 503.17 - Document retention requirements of H-2B employers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... community-based organizations, if applicable, as specified in 20 CFR 655.45(a), (b) and (c); and (v... REGULATIONS ENFORCEMENT OF OBLIGATIONS FOR TEMPORARY NONIMMIGRANT NON-AGRICULTURAL WORKERS ADMITTED UNDER... for Temporary Employment Certification requesting H-2B workers are required to retain the...

  20. Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.

    PubMed

    Meegalla, Sanath K; Huang, Hui; Illig, Carl R; Parks, Daniel J; Chen, Jinsheng; Lee, Yu-Kai; Wilson, Kenneth J; Patel, Sharmila K; Cheung, Wing S; Lu, Tianbao; Kirchner, Thomas; Askari, Hossein B; Geisler, John; Patch, Raymond J; Gibbs, Alan C; Rady, Brian; Connelly, Margery; Player, Mark R

    2016-09-01

    Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo. PMID:27491708

  1. Structure-activity relationships for in vitro diuretic activity of CAP2b in the housefly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A series of truncated and Ala-replacement analogs of the peptide Manse-CAP2b (pELYAFPRV-NH2) were assayed for diuretic activity on Malpighian tubules of the housefly Musca domestica. The C-terminal hexapeptide proved to be the active core, the minimum sequence required to retain significant diureti...

  2. Anomalous behavior of PrNi{sub 2}B{sub 2}C borocarbide

    SciTech Connect

    Narozhnyi, V.N.; Freudenberger, J.; Fuchs, G.; Nenkov, K.A.; Eckert, D.; Czopnik, A.; Mueller, K.H.

    1999-12-01

    Electrical resistivity {rho}(T), specific heat C{sub p}(T), magnetic susceptibility {chi}(T), and magnetization M(H) have been measured for polycrystalline PrNi{sub 2}B{sub 2}C. Maxima in C{sub p}(T) and {vert{underscore}bar}d{chi}(T)/dT{vert{underscore}bar} dependencies were found at T{sub N} {approx} 4.3 K connected with AFM ordering observed earlier by neutron diffraction. The Sommerfeld coefficient is at least 250 mJ/mol K{sup 2}. The values of T{sub N} for PrNi{sub 2}B{sub 2}C and {vert{underscore}bar}d{Tc}/dx{vert{underscore}bar} for Y{sub 1{minus}x}Pr{sub x}Ni{sub 2}B{sub 2}C were found to be much larger than estimated by the de Gennes scaling from the Gd-based borocarbides. These facts as well as anomalous decrease of {rho}(T) found below 20K are connected with moderate heavy fermion behavior of antiferromagnetic PrNi{sub 2}B{sub 2}C.

  3. The photometric follow-up observations for transiting exoplanet XO-2b

    NASA Astrophysics Data System (ADS)

    Gu, Sheng-hong; Collier Cameron, Andrew; Wang, Xiao-bin; Fang, Xiang-song; Cao, Dong-tao; Zhang, Li-yun

    2011-11-01

    Four new transit light curves of XO-2b obtained in 2008 and 2009, are analyzed by using MCMC algorithm, and the system parameters are derived. The result demonstrates that the orbital period of the system obtained from new observations is almost the same as Burke et al.'s one (2007), which does not confirm the result of Fernandez et al. (2009).

  4. 76 FR 3451 - Wage Methodology for the Temporary Non-agricultural Employment H-2B Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-19

    ... revised its regulation governing the permanent program. 69 FR 77326, Dec. 27, 2004. These revisions... govern the H-2B temporary worker program. 73 FR 78020, Dec. 19, 2008 (the 2008 Final Rule). The 2008... NPRM in accordance with the court's order, allowing a 30-day comment period. 75 FR 61578, Oct. 5,...

  5. Anti-H-Y responses of H-2b mutant mice.

    PubMed

    Simpson, E; Gordon, R D; Chandler, P R; Bailey, D

    1978-10-01

    Two strains of H-2b mutant mice, H-2ba and H-2bf, in which the mutational event took place at H-2K, make anti-H-Y cytotoxic T cell responses which are H-2-restricted, Db-associated and indistinguishable in target cell specificity from those of H-2b mice. Thus, alteration of the H-2K molecule affects neither the Ir gene controlling the response, nor the associative antigen. On the other hand, one H-2Db mutant strain, H-2bo, although it makes a good anti-H-Y cytotoxic response, shows target cell specificity restricted to its own Dbo antigen(s), and neither H-2b, H-2ba or H-2bf anti-H-Y cytotoxic cells kill H-2bo male target cells. Thus, the alteration of the H-2Db molecule does not affect the Ir gene of H-2b mice, but it does alter the H-2Db-associative antigen.

  6. Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B

    PubMed Central

    Takahashi, Toshiaki; Aoki, Masashi; Suzuki, Naoki; Tateyama, Maki; Yaginuma, Chikako; Sato, Hitomi; Hayasaka, Miho; Sugawara, Hitomi; Ito, Mariko; Abe-Kondo, Emi; Shimakura, Naoko; Ibi, Tohru; Kuru, Satoshi; Wakayama, Tadashi; Sobue, Gen; Fujii, Naoki; Saito, Toshio; Matsumura, Tsuyoshi; Funakawa, Itaru; Mukai, Eiichiro; Kawanami, Toru; Morita, Mitsuya; Yamazaki, Mineo; Hasegawa, Takashi; Shimizu, Jun; Tsuji, Shoji; Kuzuhara, Shigeki; Tanaka, Hiroyasu; Yoshioka, Masaru; Konno, Hidehiko; Onodera, Hiroshi; Itoyama, Yasuto

    2013-01-01

    Objective and methods Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. Results and conclusions Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations. PMID:23243261

  7. 20 CFR 655.22 - Obligations of H-2B employers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Obligations of H-2B employers. 655.22 Section 655.22 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR TEMPORARY EMPLOYMENT OF FOREIGN WORKERS IN THE UNITED STATES Labor Certification Process and Enforcement of Attestations for Temporary Employment in...

  8. 40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Alkanes (2 to 460-580 Alkanes (8 to 22% Aromatics) 1.49 * Average Boiling Point = (Initial Boiling Point + Dry Point) / 2 (b) Aromatic Hydrocarbon Solvents ... Hydrocarbon Solvent Mixtures Bin Averageboiling point * (degrees F) Criteria Reactivityfactor 1 80-205...

  9. 40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-580 Alkanes (2 to 460-580 Alkanes (8 to 22% Aromatics) 1.49 * Average Boiling Point = (Initial Boiling Point + Dry Point)/2(b) Aromatic Hydrocarbon Solvents ... Hydrocarbon Solvent Mixtures Bin Averageboiling point* (degrees F) Criteria Reactivityfactor (g O3/g VOC) 1...

  10. 40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...-580 Alkanes (2 to 460-580 Alkanes (8 to 22% Aromatics) 1.49 * Average Boiling Point = (Initial Boiling Point + Dry Point)/2(b) Aromatic Hydrocarbon Solvents ... Hydrocarbon Solvent Mixtures Bin Averageboiling point* (degrees F) Criteria Reactivityfactor (g O3/g VOC) 1...

  11. 40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-580 Alkanes (2 to 460-580 Alkanes (8 to 22% Aromatics) 1.49 * Average Boiling Point = (Initial Boiling Point + Dry Point)/2(b) Aromatic Hydrocarbon Solvents ... Hydrocarbon Solvent Mixtures Bin Averageboiling point* (degrees F) Criteria Reactivityfactor (g O3/g VOC) 1...

  12. 40 CFR Table 2b to Subpart E of... - Reactivity Factors for Aliphatic Hydrocarbon Solvent Mixtures

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Alkanes (2 to 460-580 Alkanes (8 to 22% Aromatics) 1.49 * Average Boiling Point = (Initial Boiling Point + Dry Point) / 2 (b) Aromatic Hydrocarbon Solvents ... Hydrocarbon Solvent Mixtures Bin Averageboiling point * (degrees F) Criteria Reactivityfactor 1 80-205...

  13. The Atmospheric Circulation of Eccentric Hot Jupiter HAT-P-2b

    NASA Astrophysics Data System (ADS)

    Lewis, Nikole; Knutson, H.; Showman, A. P.; Fortney, J. J.; Agol, E.; Burrows, A.; Charbonneau, D.; Cowan, N. B.; Deming, D.; Desert, J.; Langton, J.; Laughlin, G.; Mighell, K.

    2011-09-01

    The Spitzer warm mission has already greatly expanded the field of exoplanet characterization with over 3000 hours of time dedicated to exoplanet observations. Observations of eclipsing systems with Spitzer are at the heart of these advances, as they allow us to move beyond simple mass and period estimates to determine planetary radius, dayside emission, and emission variations as a function of orbital phase. The eclipsing system HAT-P-2 is of special interest because the massive Jovian sized planet in this system is on a highly eccentric orbit (e=0.5171). Because HAT-P-2b's orbit is eccentric, the planet is subject to time variable heating and probable non-synchronous rotation. Circulation patterns that we expect to develop in HAT-P-2b's atmosphere will likely vary with both planetary local time and orbital phase. Here we present an analysis of two full-orbit light curves for the HAT-P-2 system obtained at 3.6 and 4.5 microns during the first two years of the Spitzer warm mission and discuss the observational constraints imposed on the atmospheric circulation of HAT-P-2b. Additionally, three-dimensional atmospheric models that incorporate realistic radiative transfer will be presented to further elucidate possible global scale circulations patterns present in the atmosphere of HAT-P-2b. Support for this work was provided by NASA.

  14. 76 FR 21036 - Application of the Prevailing Wage Methodology in the H-2B Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-14

    .... \\1\\ Wage Methodology for the Temporary Non-agricultural Employment H-2B Program, 76 FR 3452, Jan. 19... Program, 75 FR 61578, Oct. 5, 2010. The NPRM proposed to revise the methodology by which prevailing wages... work performed on or after January 1, 2012.'' 76 FR 3452, 3462, Jan. 19, 2011. The Department...

  15. Endemic versus epidemic viral spreads display distinct patterns of HTLV-2b replication

    SciTech Connect

    Gabet, Anne-Sophie; Moules, Vincent; Sibon, David; Nass, Catharie C.; Mortreux, Franck; Mauclere, Philippe; Gessain, Antoine; Murphy, Edward L.; Wattel, Eric . E-mail: wattel@lyon.fnclcc.fr

    2006-02-05

    As the replication pattern of leukemogenic PTLVs possesses a strong pathogenic impact, we investigated HTLV-2 replication in vivo in asymptomatic carriers belonging into 2 distinct populations infected by the same HTLV-2b subtype. They include epidemically infected American blood donors, in whom HTLV-2b has been present for only 30 years, and endemically infected Bakola Pygmies from Cameroon, characterized by a long viral endemicity (at least few generations). In blood donors, both the circulating proviral loads and the degree of infected cell proliferation were largely lower than those characterizing asymptomatic carriers infected with leukemogenic PTLVs (HTLV-1, STLV-1). This might contribute to explain the lack of known link between HTLV-2b infection and the development of malignancies in this population. In contrast, endemically infected individuals displayed high proviral loads resulting from the extensive proliferation of infected cells. The route and/or the duration of infection, viral genetic drift, host immune response, genetic background, co-infections or a combination thereof might have contributed to these differences between endemically and epidemically infected subjects. As the clonality pattern observed in endemically infected individuals is very reminiscent of that of leukemogenic PTLVs at the pre-leukemic stage, our results highlight the possible oncogenic effect of HTLV-2b infection in such population.

  16. Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression.

    PubMed

    Dogra, Shalini; Kumar, Ajeet; Umrao, Deepmala; Sahasrabuddhe, Amogh A; Yadav, Prem N

    2016-01-01

    Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice. PMID:27634008

  17. Marine microbial biodiversity, bioinformatics and biotechnology (M2B3) data reporting and service standards

    PubMed Central

    2015-01-01

    Contextual data collected concurrently with molecular samples are critical to the use of metagenomics in the fields of marine biodiversity, bioinformatics and biotechnology. We present here Marine Microbial Biodiversity, Bioinformatics and Biotechnology (M2B3) standards for “Reporting” and “Serving” data. The M2B3 Reporting Standard (1) describes minimal mandatory and recommended contextual information for a marine microbial sample obtained in the epipelagic zone, (2) includes meaningful information for researchers in the oceanographic, biodiversity and molecular disciplines, and (3) can easily be adopted by any marine laboratory with minimum sampling resources. The M2B3 Service Standard defines a software interface through which these data can be discovered and explored in data repositories. The M2B3 Standards were developed by the European project Micro B3, funded under 7th Framework Programme “Ocean of Tomorrow”, and were first used with the Ocean Sampling Day initiative. We believe that these standards have value in broader marine science. PMID:26203332

  18. 75 FR 61577 - Wage Methodology for the Temporary Non-Agricultural Employment H-2B Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-05

    ... appointment to review the comments and/or obtain the rule in an alternate format, contact the Office of Policy... Department proposed and finalized regulations that currently govern the H-2B temporary worker program. 73 FR 29942, May 22, 2008; 73 FR 78020, Dec. 19, 2008 (the 2008 Final Rule). The 2008 Final Rule...

  19. Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3.

    PubMed

    Ezhkova, Elena; Tansey, William P

    2004-02-13

    In Saccharomyces cerevisiae, methylation of histone H3 at active genes is an epigenetic mark that distinguishes active from silent chromatin and functions as a short-term "memory" of recent transcription. Methylation of H3 at lysine residues K4 and K79 depends on ubiquitylation of histone H2B, but the mechanisms linking H2B ubiquitylation to H3 methylation are unknown. Here, we demonstrate that proteasomal ATPases Rpt4 and Rpt6 function to connect these two histone modifications. We show that recruitment of proteasome subunits to chromatin depends on H2B ubiquitylation and that mutations in Rpt4 and Rpt6 disrupt H3 methylation at K4 and K79 but leave H2B ubiquitylation intact. Consistent with their role in H3 methylation, we also find that mutations in Rpt4 and 6-but not components of the 20S proteasome-disrupt telomeric gene silencing. These data reveal that proteasome subunits function in epigenetic gene regulation by linking chromatin modifications that establish the histone code. PMID:14967150

  20. Using the Internet for B2B Activities: A Review and Future Directions for Research.

    ERIC Educational Resources Information Center

    Gattiker, Urs E.; Perlusz, Stefano; Bohmann, Kristoffer

    2000-01-01

    Illustrates some of the challenges that electronic commerce practitioners and researchers face, focusing on business to business (B2B) transactions. Highlights include a conceptual framework of Web user behavior; purchasing context; socio-demographic characteristics; cultural factors; economic factors; attitudes toward information technology;…

  1. Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population

    PubMed Central

    Takasaki, Yuto; Koide, Takayoshi; Wang, Chenyao; Kimura, Hiroki; Xing, Jingrui; Kushima, Itaru; Ishizuka, Kanako; Mori, Daisuke; Sekiguchi, Mariko; Ikeda, Masashi; Aizawa, Miki; Tsurumaru, Naoko; Iwayama, Yoshimi; Yoshimi, Akira; Arioka, Yuko; Yoshida, Mami; Noma, Hiromi; Oya-Ito, Tomoko; Nakamura, Yukako; Kunimoto, Shohko; Aleksic, Branko; Uno, Yota; Okada, Takashi; Ujike, Hiroshi; Egawa, Jun; Kuwabara, Hitoshi; Someya, Toshiyuki; Yoshikawa, Takeo; Iwata, Nakao; Ozaki, Norio

    2016-01-01

    N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed. PMID:27616045

  2. Evaluation of the 2b-RAD method for genomic selection in scallop breeding.

    PubMed

    Dou, Jinzhuang; Li, Xue; Fu, Qiang; Jiao, Wenqian; Li, Yangping; Li, Tianqi; Wang, Yangfan; Hu, Xiaoli; Wang, Shi; Bao, Zhenmin

    2016-01-01

    The recently developed 2b-restriction site-associated DNA (2b-RAD) sequencing method provides a cost-effective and flexible genotyping platform for aquaculture species lacking sufficient genomic resources. Here, we evaluated the performance of this method in the genomic selection (GS) of Yesso scallop (Patinopecten yessoensis) through simulation and real data analyses using six statistical models. Our simulation analysis revealed that the prediction accuracies obtained using the 2b-RAD markers were slightly lower than those obtained using all polymorphic loci in the genome. Furthermore, a small subset of markers obtained from a reduced tag representation (RTR) library presented comparable performance to that obtained using all markers, making RTR be an attractive approach for GS purpose. Six GS models exhibited variable performance in prediction accuracy depending on the scenarios (e.g., heritability, sample size, population structure), but Bayes-alphabet and BLUP-based models generally outperformed other models. Finally, we performed the evaluation using an empirical dataset composed of 349 Yesso scallops that were derived from five families. The prediction accuracy for this empirical dataset could reach 0.4 based on optimal GS models. In summary, the genotyping flexibility and cost-effectiveness make 2b-RAD be an ideal genotyping platform for genomic selection in aquaculture breeding programs. PMID:26754638

  3. Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population.

    PubMed

    Takasaki, Yuto; Koide, Takayoshi; Wang, Chenyao; Kimura, Hiroki; Xing, Jingrui; Kushima, Itaru; Ishizuka, Kanako; Mori, Daisuke; Sekiguchi, Mariko; Ikeda, Masashi; Aizawa, Miki; Tsurumaru, Naoko; Iwayama, Yoshimi; Yoshimi, Akira; Arioka, Yuko; Yoshida, Mami; Noma, Hiromi; Oya-Ito, Tomoko; Nakamura, Yukako; Kunimoto, Shohko; Aleksic, Branko; Uno, Yota; Okada, Takashi; Ujike, Hiroshi; Egawa, Jun; Kuwabara, Hitoshi; Someya, Toshiyuki; Yoshikawa, Takeo; Iwata, Nakao; Ozaki, Norio

    2016-01-01

    N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed. PMID:27616045

  4. Evaluation of the 2b-RAD method for genomic selection in scallop breeding

    PubMed Central

    Dou, Jinzhuang; Li, Xue; Fu, Qiang; Jiao, Wenqian; Li, Yangping; Li, Tianqi; Wang, Yangfan; Hu, Xiaoli; Wang, Shi; Bao, Zhenmin

    2016-01-01

    The recently developed 2b-restriction site-associated DNA (2b-RAD) sequencing method provides a cost-effective and flexible genotyping platform for aquaculture species lacking sufficient genomic resources. Here, we evaluated the performance of this method in the genomic selection (GS) of Yesso scallop (Patinopecten yessoensis) through simulation and real data analyses using six statistical models. Our simulation analysis revealed that the prediction accuracies obtained using the 2b-RAD markers were slightly lower than those obtained using all polymorphic loci in the genome. Furthermore, a small subset of markers obtained from a reduced tag representation (RTR) library presented comparable performance to that obtained using all markers, making RTR be an attractive approach for GS purpose. Six GS models exhibited variable performance in prediction accuracy depending on the scenarios (e.g., heritability, sample size, population structure), but Bayes-alphabet and BLUP-based models generally outperformed other models. Finally, we performed the evaluation using an empirical dataset composed of 349 Yesso scallops that were derived from five families. The prediction accuracy for this empirical dataset could reach 0.4 based on optimal GS models. In summary, the genotyping flexibility and cost-effectiveness make 2b-RAD be an ideal genotyping platform for genomic selection in aquaculture breeding programs. PMID:26754638

  5. Quantitative insights towards the design of potent deazaxanthine antagonists of adenosine 2B receptors.

    PubMed

    Paz, Odailson Santos; Brito, Camila Carane Bitencourt; Castilho, Marcelo Santos

    2014-08-01

    Adenosine receptors have been considered as potential targets for drug development, but one of the main obstacles to this goal is to selectively inhibit one receptor subtype over the others. This subject is particularly crucial for adenosine A2b receptor antagonists (AdoRA2B). The structure–activity relationships of xanthine derivatives which are AdoRA2B have been comprehensively investigated, but the steric and electronic requirements of deazaxanthine AdoRA2B have not been described from a quantitative standpoint of view. Herein we report our efforts to shorten this knowledge gap through 2D-QSAR (HQSAR) and 3D-QSAR (CoMFA) approaches. The good statistical quality (HQSAR--r(2) = 0.85, q(2)(LOO) = 0.77; CoMFA – r(2) = 0.86, q(2) = 0.70) and predictive ability (r(2) = (pred1) = 0.78, r(2)(pred2) = 0.78 and r(2) = (pred1) = 0.70, r(2) = (pred2) = 0.70,respectively) of the models, along with the information provided by contribution and contour maps hints their usefulness to the design of more potent 9-deazaxanthine derivatives.

  6. 20 CFR 655.56 - Document retention requirements of H-2B employers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... and records proving compliance with 29 CFR part 503 and this subpart, including but not limited to... Temporary Employment Certification, as specified in § 655.20(y); (11) The H-2B Registration, job order and a... modifications, amendments or extensions will be signed by the employer as directed by the CO and retained;...

  7. 20 CFR 655.56 - Document retention requirements of H-2B employers.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... and records proving compliance with 29 CFR part 503 and this subpart, including but not limited to... Temporary Employment Certification, as specified in § 655.20(y); (11) The H-2B Registration, job order and a... modifications, amendments or extensions will be signed by the employer as directed by the CO and retained;...

  8. CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines

    PubMed Central

    Belly, Agnès; Bodon, Gilles; Blot, Béatrice; Bouron, Alexandre; Sadoul, Rémy; Goldberg, Yves

    2010-01-01

    Summary The highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause fronto-temporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2Bintron5 and CHMP2BΔ10 in cultured hippocampal neurones modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2BΔ10 induced a drop in frequency and amplitude of spontaneous excitatory post-synaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development. PMID:20699355

  9. Structure and assembly of group B streptococcus pilus 2b backbone protein.

    PubMed

    Cozzi, Roberta; Malito, Enrico; Lazzarin, Maddalena; Nuccitelli, Annalisa; Castagnetti, Andrea; Bottomley, Matthew J; Margarit, Immaculada; Maione, Domenico; Rinaudo, C Daniela

    2015-01-01

    Group B Streptococcus (GBS) is a major cause of invasive disease in infants. Like other Gram-positive bacteria, GBS uses a sortase C-catalyzed transpeptidation mechanism to generate cell surface pili from backbone and ancillary pilin precursor substrates. The three pilus types identified in GBS contain structural subunits that are highly immunogenic and are promising candidates for the development of a broadly-protective vaccine. Here we report the X-ray crystal structure of the backbone protein of pilus 2b (BP-2b) at 1.06Å resolution. The structure reveals a classical IgG-like fold typical of the pilin subunits of other Gram-positive bacteria. The crystallized portion of the protein (residues 185-468) encompasses domains D2 and D3 that together confer high stability to the protein due to the presence of an internal isopeptide bond within each domain. The D2+D3 region, lacking the N-terminal D1 domain, was as potent as the entire protein in conferring protection against GBS challenge in a well-established mouse model. By site-directed mutagenesis and complementation studies in GBS knock-out strains we identified the residues and motives essential for assembly of the BP-2b monomers into high-molecular weight complexes, thus providing new insights into pilus 2b polymerization.

  10. Structure and Assembly of Group B Streptococcus Pilus 2b Backbone Protein

    PubMed Central

    Cozzi, Roberta; Malito, Enrico; Lazzarin, Maddalena; Nuccitelli, Annalisa; Castagnetti, Andrea; Bottomley, Matthew J.; Margarit, Immaculada; Maione, Domenico; Rinaudo, C. Daniela

    2015-01-01

    Group B Streptococcus (GBS) is a major cause of invasive disease in infants. Like other Gram-positive bacteria, GBS uses a sortase C-catalyzed transpeptidation mechanism to generate cell surface pili from backbone and ancillary pilin precursor substrates. The three pilus types identified in GBS contain structural subunits that are highly immunogenic and are promising candidates for the development of a broadly-protective vaccine. Here we report the X-ray crystal structure of the backbone protein of pilus 2b (BP-2b) at 1.06Å resolution. The structure reveals a classical IgG-like fold typical of the pilin subunits of other Gram-positive bacteria. The crystallized portion of the protein (residues 185-468) encompasses domains D2 and D3 that together confer high stability to the protein due to the presence of an internal isopeptide bond within each domain. The D2+D3 region, lacking the N-terminal D1 domain, was as potent as the entire protein in conferring protection against GBS challenge in a well-established mouse model. By site-directed mutagenesis and complementation studies in GBS knock-out strains we identified the residues and motives essential for assembly of the BP-2b monomers into high-molecular weight complexes, thus providing new insights into pilus 2b polymerization. PMID:25942637

  11. Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression

    PubMed Central

    Dogra, Shalini; Kumar, Ajeet; Umrao, Deepmala; Sahasrabuddhe, Amogh A.; Yadav, Prem N.

    2016-01-01

    Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice. PMID:27634008

  12. VIEW OF ROOM 2B, LOOKING TOWARDS SIDE 3 OF THE ...

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

    VIEW OF ROOM 2B, LOOKING TOWARDS SIDE 3 OF THE MLP. NOTE: SOUND SUPPRESSION PIPE IN THE FOREGROUND - Cape Canaveral Air Force Station, Launch Complex 39, Mobile Launcher Platforms, Launcher Road, East of Kennedy Parkway North, Cape Canaveral, Brevard County, FL

  13. Mutations of TFAP2B in congenital heart disease patients in Mysore, South India

    PubMed Central

    Lingaiah, Kusuma; Sosalagere, Dinesh M.; Mysore, Savitha R.; Krishnamurthy, B.; Narayanappa, Doddaiah; Nallur, Ramachandra B.

    2011-01-01

    Background & objectives: Cardiac malformations in the young constitute a major portion of clinically significant birth defects. Congenital heart disease (CHD) is a common congenital cardiac birth defect, affecting nearly 1 per cent of all live births. Patent ductus arteriosus (PDA) is clinically significant foetal circulation anomaly, second most common form of CHD which constitutes approximately 10 per cent of total CHDs. The study aimed to screen for TFAP2B mutations in CHD patients of Mysore. Methods: With informed consent, 100 clinically diagnosed CHD patients and 50 healthy controls in Mysore, south India, were recruited for the analysis of screening of mutations. MassARRAY analysis of 5 prominent mutations of TFAP2B was performed. Results: The analysis did not show any of the five mutations of TFAP2B screened by massARRAY in patients and controls, indicating that these mutations were not involved in the manifestation of CHD in the patients at Mysore, south India. Interpretation & Conclusions: The findings suggest the lack of involvement of known mutations of TFAP2B with syndromic or nonsyndromic CHDs in Mysore patients. PMID:22199100

  14. Lovastatin exerts protective effects on endothelial cells via upregulation of PTK2B

    PubMed Central

    Chu, Weiwei; Guan, Lili; Huang, Dihua; Ren, Yuezhong; Zhou, Yan

    2016-01-01

    Statins are HMG-CoA reductase inhibitors that are used to decrease the blood levels of low-density lipoprotein (LDL). In addition, they have been shown to exert pleiotropic protective effects in the absence of LDL-lowering activity. The present study investigated the effects of lovastatin on global gene expression in human umbilical vein endothelial cells (HUVECs), in order to further explore its ability to protect against oxidized (ox)-LDL-induced cytotoxicity. HUVECs were treated with lovastatin for 2–24 h, and gene expression patterns were analyzed using cDNA microarrays. The results suggested that numerous genes were regulated by lovastatin, including certain genes associated with cell survival, such as PTK2B, BCL2 and MAP3K3. In particular, PTK2B, which has been shown to exert anti-apoptotic effects against ox-LDL-induced cell injury, was upregulated by lovastatin. Knockdown of PTK2B was able to attenuate ox-LDL-induced cell injury, and this was associated with decreased levels of phosphorylated-AKT and eNOS, and inhibition of mitochondrial-dependent apoptosis. In conclusion, the results of the present study suggested that lovastatin protects against ox-LDL-induced cell injury, potentially via the upregulation of PTK2B, which regulates the anti-apoptosis signaling pathway.

  15. Efavirenz intoxication due to a new CYP2B6 constellation.

    PubMed

    Anagnostopoulos, Alexia; Rotger, Margalida; Aouri, Manel; Kuster, Stefan P; Telenti, Amalio; Décosterd, Laurent A; Günthard, Huldrych F

    2013-01-01

    Here, we describe severe neuropsychiatric symptoms in an HIV-positive Asian man with extremely high efavirenz plasma levels while receiving standard treatment with efavirenz/tenofovir/emtricitabine fixed-dose regimen. Genetic examination revealed compound homozygosity for loss-of-function alleles of CYP2B6, including coding for a rare truncated protein. Neuropsychiatric symptoms resolved completely after efavirenz discontinuation.

  16. Enantiomeric Propanolamines as selective N-Methyl-d-aspartate 2B Receptor Antagonists†

    PubMed Central

    Tahirovic, Yesim A.; Geballe, Matthew; Gruszecka-Kowalik, Ewa; Myers, Scott J.; Lyuboslavsky, Polina; Le, Phuong; French, Adam; Irier, Hasan; Choi, Woo-baeg; Easterling, Keith; Yuan, Hongjie; Wilson, Lawrence J.; Kotloski, Robert; McNamara, James O.; Dingledine, Raymond; Liotta, Dennis C.; Traynelis, Stephen F.; Snyder, James P.

    2011-01-01

    Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11–64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30–100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties. PMID:18800760

  17. Magnetic structures in RNi{sub 2}B{sub 2}C (R = Ho, Er) superconductors

    SciTech Connect

    Stassis, C.; Goldman, A.I.; Dervenagas, P.; Zarestky, J.; Canfield, P.C.; Cho, B.K.; Johnston, D.C.; Sternlieb, B.; Sternlieb, B.

    1994-12-31

    Single crystal neutron diffraction techniques have been employed to study the evolution of magnetic structures in RNi{sub 2}B{sub 2}C compounds in an attempt to understand the relationship between magnetic ordering and superconductivity in several members of this series. For HoNi{sub 2}B{sub 2}C, below the superconducting transition (T{sub c} = 8 K), an incommensurate magnetic structure characterized by two wave vectors (0.585 a* and 0.915 c*) is found in a narrow temperature range between 4.7 K and 6 K. This is the same temperature range where bulk measurements find a deep minimum in the upper critical field, H{sub c2}. Below 4.7 K, HoNi{sub 2}B{sub 2}C is a simple collinear antiferromagnet. ErNi{sub 2}B{sub 2}C ({Tc} = 11 K) orders in an incommensurate modulated antiferromagnetic state characterized by an ordering wave vector 0.553 a* below 7 K, which coexists with superconductivity.

  18. Improved Serodiagnosis of Cystic Echinococcosis Using the New Recombinant 2B2t Antigen

    PubMed Central

    Hernández-González, Ana; Santivañez, Saúl; García, Héctor H.; Rodríguez, Silvia; Muñoz, Santiago; Ramos, Guillermo; Orduña, Antonio; Siles-Lucas, Mar

    2012-01-01

    A standardized test for the serodiagnosis of human cystic echinococcosis (CE) is still needed, because of the low specificity and sensitivity of the currently available commercial tools and the lack of proper evaluation of the existing recombinant antigens. In a previous work, we defined the new ELISA-B2t diagnostic tool for the detection of specific IgGs in CE patients, which showed high sensitivity and specificity, and was useful in monitoring the clinical evolution of surgically treated CE patients. Nevertheless, this recombinant antigen gave rise to false-negative results in a percentage of CE patients. Therefore, in an attempt to improve its sensitivity, we constructed B2t-derived recombinant antigens with two, four and eight tandem repeat of B2t units, and tested them by ELISA on serum samples of CE patients and patients with related parasites. The best diagnostic values were obtained with the two tandem repeat 2B2t antigen. The influence of several clinical variables on the performance of the tests was also evaluated. Finally, the diagnostic performance of the 2B2t-ELISA was compared with that of an indirect haemagglutination commercial test. The 2B2t recombinant antigen performed better than the HF and B2t antigens, and the IHA commercial kit. Therefore, this new 2B2t-ELISA is a promising candidate test for the serodiagnosis of CE in clinical settings. PMID:22802975

  19. Copy number variations in the amylase gene (AMY2B) in Japanese native dog breeds.

    PubMed

    Tonoike, A; Hori, Y; Inoue-Murayama, M; Konno, A; Fujita, K; Miyado, M; Fukami, M; Nagasawa, M; Mogi, K; Kikusui, T

    2015-10-01

    A recent study suggested that increased copy numbers of the AMY2B gene might be a crucial genetic change that occurred during the domestication of dogs. To investigate AMY2B expansion in ancient breeds, which are highly divergent from modern breeds of presumed European origins, we analysed copy numbers in native Japanese dog breeds. Copy numbers in the Akita and Shiba, two ancient breeds in Japan, were higher than those in wolves. However, compared to a group of various modern breeds, Akitas had fewer copy numbers, whereas Shibas exhibited the same level of expansion as modern breeds. Interestingly, average AMY2B copy numbers in the Jomon-Shiba, a unique line of the Shiba that has been bred to maintain their appearance resembling ancestors of native Japanese dogs and that originated in the same region as the Akita, were lower than those in the Shiba. These differences may have arisen from the earlier introduction of rice farming to the region in which the Shiba originated compared to the region in which the Akita and the Jomon-Shiba originated. Thus, our data provide insights into the relationship between the introduction of agriculture and AMY2B expansion in dogs.

  20. Combustion of Na 2B 4O 7 + Mg + C to synthesis B 4C powders

    NASA Astrophysics Data System (ADS)

    Guojian, Jiang; Jiayue, Xu; Hanrui, Zhuang; Wenlan, Li

    2009-09-01

    Boron carbide powder was fabricated by combustion synthesis (CS) method directly from mixed powders of borax (Na 2B 4O 7), magnesium (Mg) and carbon. The adiabatic temperature of the combustion reaction of Na 2B 4O 7 + 6 Mg + C was calculated. The control of the reactions was achieved by selecting reactant composition, relative density of powder compact and gas pressure in CS reactor. The effects of these different influential factors on the composition and morphologies of combustion products were investigated. The results show that, it is advantageous for more Mg/Na 2B 4O 7 than stoichiometric ratio in Na 2B 4O 7 + Mg + C system and high atmosphere pressure in the CS reactor to increase the conversion degree of reactants to end product. The final product with the minimal impurities' content could be fabricated at appropriate relative density of powder compact. At last, boron carbide without impurities could be obtained after the acid enrichment and distilled water washing.

  1. Copy number variations in the amylase gene (AMY2B) in Japanese native dog breeds.

    PubMed

    Tonoike, A; Hori, Y; Inoue-Murayama, M; Konno, A; Fujita, K; Miyado, M; Fukami, M; Nagasawa, M; Mogi, K; Kikusui, T

    2015-10-01

    A recent study suggested that increased copy numbers of the AMY2B gene might be a crucial genetic change that occurred during the domestication of dogs. To investigate AMY2B expansion in ancient breeds, which are highly divergent from modern breeds of presumed European origins, we analysed copy numbers in native Japanese dog breeds. Copy numbers in the Akita and Shiba, two ancient breeds in Japan, were higher than those in wolves. However, compared to a group of various modern breeds, Akitas had fewer copy numbers, whereas Shibas exhibited the same level of expansion as modern breeds. Interestingly, average AMY2B copy numbers in the Jomon-Shiba, a unique line of the Shiba that has been bred to maintain their appearance resembling ancestors of native Japanese dogs and that originated in the same region as the Akita, were lower than those in the Shiba. These differences may have arisen from the earlier introduction of rice farming to the region in which the Shiba originated compared to the region in which the Akita and the Jomon-Shiba originated. Thus, our data provide insights into the relationship between the introduction of agriculture and AMY2B expansion in dogs. PMID:26358734

  2. MEF2B mutations lead to deregulated expression of the BCL6 oncogene in Diffuse Large B cell Lymphoma

    PubMed Central

    Ying, Carol Y.; Dominguez-Sola, David; Fabi, Melissa; Lorenz, Ivo C.; Hussein, Shafinaz; Bansal, Mukesh; Califano, Andrea; Pasqualucci, Laura; Basso, Katia; Dalla-Favera, Riccardo

    2014-01-01

    The MEF2B gene encodes a transcriptional activator and is found mutated in ∼11% of diffuse large B cell lymphomas (DLBCLs) and ∼12% of follicular lymphomas. Here, we show that MEF2B directly activates the transcription of the proto-oncogene BCL6 in normal germinal-center B cells and is required for DLBCL proliferation. MEF2B mutations enhance MEF2B transcriptional activity either by disrupting its interaction with the co-repressor CABIN1, or by rendering it insensitive to phosphorylation- and sumoylation-mediated inhibitory signaling events. Consequently, Bcl-6 transcriptional activity is deregulated in DLBCL harboring MEF2B mutations. Thus, somatic mutations of MEF2B may contribute to lymphomagenesis by deregulating the expression of the BCL6 oncogene, and MEF2B may represent an alternative target to block Bcl-6 activity in DLBCLs. PMID:23974956

  3. First detection of canine parvovirus type 2b from diarrheic dogs in Himachal Pradesh

    PubMed Central

    Sharma, Shalini; Dhar, Prasenjit; Thakur, Aneesh; Sharma, Vivek; Sharma, Mandeep

    2016-01-01

    Aim: The present study was conducted to detect the presence of canine parvovirus (CPV) among diarrheic dogs in Himachal Pradesh and to identify the most prevalent antigenic variant of CPV based on molecular typing and sequence analysis of VP2 gene. Materials and Methods: A total of 102 fecal samples were collected from clinical cases of diarrhea or hemorrhagic gastroenteritis from CPV vaccinated or non-vaccinated dogs. Samples were tested using CPV-specific polymerase chain reaction (PCR) targeting VP2 gene, multiplex PCR for detection of CPV-2a and CPV-2b antigenic variants, and a PCR for the detection of CPV-2c. CPV-2b isolate was cultured on Madin-Darby canine kidney (MDCK) cell lines and sequenced using VP2 structural protein gene. Multiple alignment and phylogenetic analysis was done using ClustalW and MEGA6 and inferred using the Neighbor-Joining method. Results: No sample was found positive for the original CPV strain usually present in the vaccine. However, about 50% (52 out of 102) of the samples were found to be positive with CPV-2ab PCR assay that detects newer variants of CPV circulating in the field. In addition, multiplex PCR assay that identifies both CPV-2ab and CPV-2b revealed that CPV-2b was the major antigenic variant present in the affected dogs. A PCR positive isolate of CPV-2b was adapted to grow in MDCK cells and produced characteristic cytopathic effect after 5th passage. Multiple sequence alignment of VP2 structural gene of CPV-2b isolate (Accession number HG004610) used in the study was found to be similar to other sequenced isolates in NCBI sequence database and showed 98-99% homology. Conclusion: This study reports the first detection of CPV-2b in dogs with hemorrhagic gastroenteritis in Himachal Pradesh and absence of other antigenic types of CPV. Further, CPV-specific PCR assay can be used for rapid confirmation of circulating virus strains under field conditions. PMID:27733797

  4. Induction and inhibition of mouse cytochrome P-450 2B enzymes by musk xylene.

    PubMed

    Lehman-McKeeman, L D; Johnson, D R; Caudill, D

    1997-01-01

    Musk xylene (MX) (1,3,5-trinitro-2-t-butylxylene) is a nitromusk perfume ingredient that although uniformly negative in a battery of genotoxicity tests, produces a high incidence of liver tumors in mice. The purpose of this work was to characterize the profile and dose-response relationship of microsomal enzyme induction following exposure to MX. MX was dosed by gavage to male B6C3F1 mice for 7 days at 0, 1, 5, 10, 20, 50, 100, and 200 mg/kg after which microsomes were prepared. At 200 mg/kg, MX increased liver weight by about 65% and increased microsomal cytochrome P-450 content 2-fold over control. MX increased microsomal activity for O-dealkylation of 7-ethoxy and 7-methoxyresorufin 4- and 2-fold, respectively, and increased the N-demethylation of erythromycin approximately 2-fold. These results were generally consistent with increased CYP1A1, 1A2, and 3A protein levels determined by Western blotting. In contrast, whereas no increase in O-dealkylation of 7-pentoxyresorufin (PROD) was observed, MX treatment increased CYP2B protein levels about 25-fold over control at 200 mg/kg. Furthermore, a single dosage of MX (200 mg/kg) increased Cyp2b-10 mRNA to a maximal level and with a time course similar to phenobarbital (PB). To study inhibition of CYP2B enzymes in vivo, mice were treated with PB (0.05% in drinking water for 5 days), then given a single dosage of corn oil or MX (200 mg/kg) at 2 or 18 hr before necropsy. PB treatment increased PROD activity 25-fold, and at 2 hr after MX treatment (associated with peak plasma levels of MX), there was no change in the PB-induced PROD activity. However, at 18 hr, MX treatment decreased PROD activity by 90%. Despite the in vivo inhibition, in vitro studies indicated that MX did not cause mechanism-based inactivation of CYP2B enzymes. The potential for nitroreduction of MX (catalyzed by anaerobic intestinal bacteria) to contribute to the inhibition of CYP2B enzyme activity was evaluated in a separate group of PB-induced mice

  5. Equine cytochrome P450 2B6 — Genomic identification, expression and functional characterization with ketamine

    SciTech Connect

    Peters, L.M.; Demmel, S.; Pusch, G.; Buters, J.T.M.; Zielinski, J.; Leeb, T.; Mevissen, M.; Schmitz, A.

    2013-01-01

    Ketamine is an anesthetic and analgesic regularly used in veterinary patients. As ketamine is almost always administered in combination with other drugs, interactions between ketamine and other drugs bear the risk of either adverse effects or diminished efficacy. Since cytochrome P450 enzymes (CYPs) play a pivotal role in the phase I metabolism of the majority of all marketed drugs, drug–drug interactions often occur at the active site of these enzymes. CYPs have been thoroughly examined in humans and laboratory animals, but little is known about equine CYPs. The characterization of equine CYPs is essential for a better understanding of drug metabolism in horses. We report annotation, cloning and heterologous expression of the equine CYP2B6 in V79 Chinese hamster fibroblasts. After computational annotation of all CYP2B genes, the coding sequence (CDS) of equine CYP2B6 was amplified by RT-PCR from horse liver total RNA and revealed an amino acid sequence identity of 77% and a similarity of 93.7% to its human ortholog. A non-synonymous variant c.226G>A in exon 2 of the equine CYP2B6 was detected in 97 horses. The mutant A-allele showed an allele frequency of 82%. Two further variants in exon 3 were detected in one and two horses of this group, respectively. Transfected V79 cells were incubated with racemic ketamine and norketamine as probe substrates to determine metabolic activity. The recombinant equine CYP2B6 N-demethylated ketamine to norketamine and produced metabolites of norketamine, such as hydroxylated norketamines and 5,6-dehydronorketamine. V{sub max} for S-/and R-norketamine formation was 0.49 and 0.45 nmol/h/mg cellular protein and K{sub m} was 3.41 and 2.66 μM, respectively. The N-demethylation of S-/R-ketamine was inhibited concentration-dependently with clopidogrel showing an IC{sub 50} of 5.63 and 6.26 μM, respectively. The functional importance of the recorded genetic variants remains to be explored. Equine CYP2B6 was determined to be a CYP

  6. Herstellung von Chitosan und einige Anwendungen

    NASA Astrophysics Data System (ADS)

    Struszczyk, Marcin Henryk

    2001-05-01

    1. Die Deacetylierung von crabshell - Chitosan führte gleichzeitig zu einem drastischen Abfall der mittleren viscosimetrischen Molmasse ( Mv), insbesondere wenn die Temperatur und die Konzentration an NaOH erhöht werden. Diese Parameter beeinflussten jedoch nicht den Grad der Deacetylierung (DD). Wichtig ist jedoch die Quelle des Ausgangsmaterials: Chitin aus Pandalus borealis ist ein guter Rohstoff für die Herstellung von Chitosan mit niedrigem DD und gleichzeitig hoher mittlerer Mv, während Krill-Chitin (Euphausia superba) ein gutes Ausgangsmaterial zur Herstellung von Chitosan mit hohem DD und niedrigem Mv ist. Chitosan, das aus Insekten (Calliphora erythrocephala), unter milden Bedingungen (Temperatur: 100°C, NaOH-Konzentration: 40 %, Zeit: 1-2h ) hergestellt wurde, hatte die gleichen Eigenschaften hinsichtlich DD und Mv wie das aus Krill hergestellte Chitosan. Der Bedarf an Zeit, Energie und NaOH ist für die Herstellung von Insekten-Chitosan geringer als für crabshell-Chitosan vergleichbare Resultaten für DD und Mv. 2. Chitosan wurde durch den Schimmelpilz Aspergillus fumigatus zu Chitooligomeren fermentiert. Die Ausbeute beträgt 25%. Die Chitooligomere wurden mit Hilfe von HPLC und MALDI-TOF-Massenspektrmetrie identifiziert. Die Fermentationsmischung fördert die Immunität von Pflanzen gegen Bakterien und Virusinfektion. Die Zunahme der Immunität schwankt jedoch je nach System Pflanze-Pathogen. Die Fermentation von Chitosan durch Aspergillus fumigatus könnte eine schnelle und billige Methode zur Herstellung von Chitooligomeren mit guter Reinheit und Ausbeute sein. Eine partiell aufgereinigte Fermentationsmischung dieser Art könnte in der Landwirtschaft als Pathogeninhibitor genutzt werden. Durch kontrollierte Fermentation, die Chitooligomere in definierter Zusammensetzung (d.h. definierter Verteilung des Depolymerisationsgrades) liefert, könnte man zu Mischungen kommen, die für die jeweilige Anwendung eine optimale Bioaktivität besitzen. 3

  7. Dorfentwicklung und Dorferneuerung . Die neuen Bundesländer

    NASA Astrophysics Data System (ADS)

    Bender, Oliver; Richter, Horst P.

    1997-03-01

    Das 1975 in Kraft getretene Bundesraumordnungsprogramm forderte, in allen Landesteilen angemessene und gleichwertige Lebensbedingungen herzustellen. Mit der Novellierung des Flurbereinigungsgesetzes 1976 bzw. dem Zukunftsinvestitionsprogramm 1977 bis 1980 startete die Dorfentwicklung/Dorferneuerung nicht zuletzt als Initiative zur Konjunkturbelebung im ländlichen Raum. Seit 1984 ist sie Bestandteil der von Bund und Ländern getragenen Gemeinschaftsaufgabe "Verbesserung der Agrarstruktur und des Küstenschutzes" (GAK) und liegt im Zuständigkeitsbereich der Landwirtschaftsministerien. Die Dorferneuerungsprogramme der Länder werden aus Mitteln der GAK, der EU und des Landes finanziert. Neben Ortssanierungen nach dem Städtebauförderungsgesetz bzw. Baugesetzbuch stellen sie das wichtigste Instrument zur Förderung von ländlichen Orten und Gemeinden dar. Nach der Vereinigung wurde das Dorferneuerungsrecht auf die neuen Bundesländer übertragen, indem man sich zunächst an den Regelungen der jeweiligen Partnerländer im Westen orientierte. Doch hatten sich die Dörfer in Ost- und Westdeutschland nach dem Zweiten Weltkrieg völlig unterschiedlich entwickelt, so dass sich im Osten ein erweiterter Handlungsbedarf zeigte. Für Fachleute aus Politik, Verwaltung, Wissenschaft und freien Planungsberufen, nicht zuletzt für angewandt arbeitende Geographen, stellten sich neue Herausforderungen.

  8. Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6.

    PubMed

    Sridar, Chitra; Kent, Ute M; Notley, Lisa M; Gillam, Elizabeth M J; Hollenberg, Paul F

    2002-06-01

    Tamoxifen is primarily used in the treatment of breast cancer. It has been approved as a chemopreventive agent for individuals at high risk for this disease. Tamoxifen is metabolized to a number of different products by cytochrome P450 enzymes. The effect of tamoxifen on the enzymatic activity of bacterially expressed human cytochrome CYP2B6 in a reconstituted system has been investigated. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified CYP2B6 was inactivated by tamoxifen in a time- and concentration-dependent manner. Enzymatic activity was lost only in samples that were incubated with both tamoxifen and NADPH. The inactivation was characterized by a K(I) of 0.9 microM, a k(inact) of 0.02 min(-1), and a t(1/2) of 34 min. The loss in the 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity did not result in a similar percentage loss in the reduced carbon monoxide spectrum, suggesting that the heme moiety was not the major site of modification. The activity of CYP2B6 was not recovered after removal of free tamoxifen using spin column gel filtration. The loss in activity seemed to be due to a modification of the CYP2B6 and not reductase because adding fresh reductase back to the inactivated samples did not restore enzymatic activity. A reconstituted system containing purified CYP2B6, NADPH-reductase, and NADPH-generating system was found to catalyze tamoxifen metabolism to 4-OH-tamoxifen, 4'-OH-tamoxifen, and N-desmethyl-tamoxifen as analyzed by high-performance liquid chromatography analysis. Preliminary studies showed that tamoxifen had no effect on the activities of CYP1B1 and CYP3A4, whereas CYP2D6 and CYP2C9 exhibited a 25% loss in enzymatic activity. PMID:12023523

  9. Atmospheric circulation of eccentric hot Jupiter HAT-P-2B

    SciTech Connect

    Lewis, Nikole K.; Showman, Adam P.; Fortney, Jonathan J.; Knutson, Heather A.; Marley, Mark S.

    2014-11-10

    The hot Jupiter HAT-P-2b has become a prime target for Spitzer Space Telescope observations aimed at understanding the atmospheric response of exoplanets on highly eccentric orbits. Here we present a suite of three-dimensional atmospheric circulation models for HAT-P-2b that investigate the effects of assumed atmospheric composition and rotation rate on global scale winds and thermal patterns. We compare and contrast atmospheric models for HAT-P-2b, which assume one and five times solar metallicity, both with and without TiO/VO as atmospheric constituents. Additionally we compare models that assume a rotation period of half, one, and two times the nominal pseudo-synchronous rotation period. We find that changes in assumed atmospheric metallicity and rotation rate do not significantly affect model predictions of the planetary flux as a function of orbital phase. However, models in which TiO/VO are present in the atmosphere develop a transient temperature inversion between the transit and secondary eclipse events that results in significant variations in the timing and magnitude of the peak of the planetary flux compared with models in which TiO/VO are omitted from the opacity tables. We find that no one single atmospheric model can reproduce the recently observed full orbit phase curves at 3.6, 4.5 and 8.0 μm, which is likely due to a chemical process not captured by our current atmospheric models for HAT-P-2b. Further modeling and observational efforts focused on understanding the chemistry of HAT-P-2b's atmosphere are needed and could provide key insights into the interplay between radiative, dynamical, and chemical processes in a wide range of exoplanet atmospheres.

  10. Atmospheric Circulation of Eccentric Hot Jupiter HAT-P-2b

    NASA Astrophysics Data System (ADS)

    Lewis, Nikole K.; Showman, Adam P.; Fortney, Jonathan J.; Knutson, Heather A.; Marley, Mark S.

    2014-11-01

    The hot Jupiter HAT-P-2b has become a prime target for Spitzer Space Telescope observations aimed at understanding the atmospheric response of exoplanets on highly eccentric orbits. Here we present a suite of three-dimensional atmospheric circulation models for HAT-P-2b that investigate the effects of assumed atmospheric composition and rotation rate on global scale winds and thermal patterns. We compare and contrast atmospheric models for HAT-P-2b, which assume one and five times solar metallicity, both with and without TiO/VO as atmospheric constituents. Additionally we compare models that assume a rotation period of half, one, and two times the nominal pseudo-synchronous rotation period. We find that changes in assumed atmospheric metallicity and rotation rate do not significantly affect model predictions of the planetary flux as a function of orbital phase. However, models in which TiO/VO are present in the atmosphere develop a transient temperature inversion between the transit and secondary eclipse events that results in significant variations in the timing and magnitude of the peak of the planetary flux compared with models in which TiO/VO are omitted from the opacity tables. We find that no one single atmospheric model can reproduce the recently observed full orbit phase curves at 3.6, 4.5 and 8.0 μm, which is likely due to a chemical process not captured by our current atmospheric models for HAT-P-2b. Further modeling and observational efforts focused on understanding the chemistry of HAT-P-2b's atmosphere are needed and could provide key insights into the interplay between radiative, dynamical, and chemical processes in a wide range of exoplanet atmospheres.

  11. Quadrupolar interaction of ^57Fe in compounds RENi_2B_2C: Experimental and Theoretical Studies

    NASA Astrophysics Data System (ADS)

    Zeng, Zhi; Guenzburger, Diana; Sanchez, D. R. S.; Bud'Ko, S. L.; Fontes, Magda B.; Baggia-Saitovitch, E. M.; Ellis, D. E.

    1996-03-01

    ^57Fe Mössbauer spectra were taken with the RE(Ni_0.99^57Fe_0.01)_2B_2C (RE=Tb, Dy, Ho, Er) samples in a variable temperature helium crysostat to study the interplay between superconductivity and magnetism in the RENi_2B_2C (RE=Dy, Ho, Er, Tm) compounds. The rare earth dependent quadrupole splitting (QS) from ^57Fe Mössbauer spectra decreases with the lanthanide contraction^footnotetext^The lanthanide contraction causes an increase in the ratio c/a along the RE series. from QS=0.27mm/s for TbNi_2B_2C to QS=0.14mm/s for ErNi_2B_2C. Self-consistent frist-principles electronic structure calculation[1] were performed for clusters with 71 atoms (Fe-12RE-14Ni-32B-12C), which were embedded in the charge denisity of several shells of neighbours in the crystal, representing the doped compounds RE(Ni_0.93Fe_0.07)_2B_2C (RE=Gd, Tb, Dy, Ho, and Er). The quadrupole splitting was obtained with the nuclear quadrupole moment Q=0.16b of ^57Fe[2]. The calculated results are in good agreement with experiment. The theoretical results give negative signs for all the QS values; which have not been determined by experiment, except for the compounds with Tb and Ho, for which they are negative. REFERENCES D.E. Ellis, Int. J. Quant. Chem. Suppl. 2, 35(1968); D.E. Ellis and G.S. Painter, Phys. Rev. B, 2, 2887(1970). Ohilipp Dufek, Peter Blaha and K. Schwarz, Phys. Rev. Lett. 75, 3545(1995).

  12. Estrogen receptor 2b deficiency impairs the antiviral response of zebrafish.

    PubMed

    López-Muñoz, Azucena; Liarte, Sergio; Gómez-González, Nuria E; Cabas, Isabel; Meseguer, José; García-Ayala, Alfonsa; Mulero, Victoriano

    2015-11-01

    Although several studies have demonstrated the ability of some endocrine disruptive chemicals (EDCs) to alter the physiology of zebrafish, the immune-reproductive interaction has received little attention in this species. In this study, we used a homozygous line carrying an insertion of 8 amino acids in the ligand-binding domain of the estrogen receptor 2b gene (esr2b) to further understand the role of estrogen signaling on innate immunity. Adult mutant fish showed distorted sexual ratios related with alterations in testicular morphology and supraphysiological testosterone and 17β-estradiol (E2) levels. Immunity-wise, although esr2b mutant fish showed unaltered antibacterial responses, they were unable to mount an effective antiviral response upon viral challenge. RT-qPCR analysis demonstrated that mutant fish were able to induce the genes encoding major antiviral molecules, including Ifnphi1, Ifnphi2, Infphi3, Mxb and Mxc, and the negative feedback regulator of cytokine signaling Socs1. Notably, although esr2b mutant larvae showed a similar resistance to SVCV infection to their wild type siblings, waterborne E2 increased their viral susceptibility. Similarly, the exposure of adult wild type zebrafish to E2 also resulted in increased susceptibility to SVCV infection. Finally, the administration of recombinant Ifnphi1 hardly reversed the higher viral susceptibility of esr2b mutant zebrafish, suggesting that elevated socs1 levels impair Ifn signaling. All together, these results uncover an important role for E2 and Esr signaling in the fine-tuning of sexual hormone balance and the antiviral response of vertebrates.

  13. Nematode and Arthropod Genomes Provide New Insights into the Evolution of Class 2 B1 GPCRs

    PubMed Central

    Cardoso, João C. R.; Félix, Rute C.; Power, Deborah M.

    2014-01-01

    Nematodes and arthropods are the most speciose animal groups and possess Class 2 B1 G-protein coupled receptors (GPCRs). Existing models of invertebrate Class 2 B1 GPCR evolution are mainly centered on Caenorhabditis elegans and Drosophila melanogaster and a few other nematode and arthropod representatives. The present study reevaluates the evolution of metazoan Class 2 B1 GPCRs and orthologues by exploring the receptors in several nematode and arthropod genomes and comparing them to the human receptors. Three novel receptor phylogenetic clusters were identified and designated cluster A, cluster B and PDF-R-related cluster. Clusters A and B were identified in several nematode and arthropod genomes but were absent from D. melanogaster and Culicidae genomes, whereas the majority of the members of the PDF-R-related cluster were from nematodes. Cluster A receptors were nematode and arthropod-specific but shared a conserved gene environment with human receptor loci. Cluster B members were orthologous to human GCGR, PTHR and Secretin members with which they probably shared a common origin. PDF-R and PDF-R related clusters were present in representatives of both nematodes and arthropods. The results of comparative analysis of GPCR evolution and diversity in protostomes confirm previous notions that C. elegans and D. melanogaster genomes are not good representatives of nematode and arthropod phyla. We hypothesize that at least four ancestral Class 2 B1 genes emerged early in the metazoan radiation, which after the protostome-deuterostome split underwent distinct selective pressures that resulted in duplication and deletion events that originated the current Class 2 B1 GPCRs in nematode and arthropod genomes. PMID:24651821

  14. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension

    PubMed Central

    Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F.; Chen, Ning-Yuan; Weng, Tingting; Molina, Jose G.; Luo, Fayong; Davies, Jonathan; Le, Ngoc-Bao; Bunge, Isabelle; Volcik, Kelly A.; Le, Thanh-Thuy T.; Johnston, Richard A.; Xia, Yang; Eltzschig, Holger K.; Blackburn, Michael R.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2Bf/f-LysMCre) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2Bf/f-LysMCre mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.—Karmouty-Quintana, H., Philip, K., Acero, L. F., Chen, N.-Y., Weng, T., Molina, J. G., Luo, F., Davies, J., Le, N.-B., Bunge, I., Volcik, K. A., Le, T.-T. T., Johnston, R. A., Xia, Y., Eltzschig, H. K., Blackburn, M. R. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension. PMID:25318478

  15. Using msa-2b as a molecular marker for genotyping Mexican isolates of Babesia bovis.

    PubMed

    Genis, Alma D; Perez, Jocelin; Mosqueda, Juan J; Alvarez, Antonio; Camacho, Minerva; Muñoz, Maria de Lourdes; Rojas, Carmen; Figueroa, Julio V

    2009-12-01

    Variable merozoite surface antigens of Babesia bovis are exposed glycoproteins having a role in erythrocyte invasion. Members of this gene family include msa-1 and msa-2 (msa-2c, msa-2a(1), msa-2a(2) and msa-2b). To determine the sequence variation among B. bovis Mexican isolates using msa-2b as a genetic marker, PCR amplicons corresponding to msa-2b were cloned and plasmids carrying the corresponding inserts were purified and sequenced. Comparative analysis of nucleotide and deduced amino acid sequences revealed distinct degrees of variability and identity among the coding gene sequences obtained from 16 geographically different Mexican B. bovis isolates and a reference strain. Clustal-W multiple alignments of the MSA-2b deduced amino acid sequences performed with the 17 B. bovis Mexican isolates, revealed the identification of three genotypes with a distinct set each of amino acid residues present at the variable region: Genotype I represented by the MO7 strain (in vitro culture-derived from the Mexico isolate) as well as RAD, Chiapas-1, Tabasco and Veracruz-3 isolates; Genotype II, represented by the Jalisco, Mexico and Veracruz-2 isolates; and Genotype III comprising the sequences from most of the isolates studied, Tamaulipas-1, Chiapas-2, Guerrero-1, Nayarit, Quintana Roo, Nuevo Leon, Tamaulipas-2, Yucatan and Guerrero-2. Moreover, these three genotypes could be discriminated against each other by using a PCR-RFLP approach. The results suggest that occurrence of indels within the variable region of msa-2b sequences can be useful markers for identifying a particular genotype present in field populations of B. bovis isolated from infected cattle in Mexico.

  16. A(2B) receptors mediate antimitogenesis in vascular smooth muscle cells.

    PubMed

    Dubey, R K; Gillespie, D G; Shue, H; Jackson, E K

    2000-01-01

    Adenosine inhibits growth of vascular smooth muscle cells. The goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat aortic vascular smooth muscle cells, platelet-derived growth factor-BB (PDGF-BB) (25 ng/mL) stimulated DNA synthesis ([(3)H]thymidine incorporation), cellular proliferation (cell number), collagen synthesis ([(3)H]proline incorporation), total protein synthesis ([(3)H]leucine incorporation), and mitogen-activated protein (MAP) kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, but not N(6)-cyclopentyladenosine or CGS21680, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A(2B) receptor-mediated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl-8-p-sulfophenylxanthine, but not 8-cyclopentyl-1, 3-dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, an antagonist profile consistent with an A(2) receptor-mediated effect. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor stimulated basal and PDGF-induced DNA synthesis, cell proliferation, and MAP kinase activity. Moreover, the growth-inhibitory effects of 2-chloroadenosine, 5'-N-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. Our findings strongly support the hypothesis that adenosine causes inhibition of vascular smooth muscle cell growth by activating A(2B) receptors coupled to inhibition of MAP kinase activity. Pharmacological or molecular biological activation of A(2B) receptors may prevent vascular remodeling associated with hypertension, atherosclerosis, and restenosis

  17. The International Space Station 2B Photovoltaic Thermal Control System (PVTCS) Leak: An Operational History

    NASA Technical Reports Server (NTRS)

    Vareha, Anthony N.

    2014-01-01

    As early as 2004, the Photovoltaic Thermal Control System (PVTCS) for the International Space Station's 2B electrical power channel began slowly leaking ammonia overboard. Initially, the operations strategy was "feed the leak," a strategy successfully put into action via Extra Vehicular Activity (EVA) during the STS-134 Space Shuttle mission. This recharge was to have allowed for continued power channel operation into 2014 or 2015, at which point another EVA would have been required. In mid-2012, the leak rate increased from 1.5lbm/year to approximately 5lbm/year. As a result, an EVA was planned and executed within a 5 week timeframe to drastically alter the architecture of the PVTCS via connection to an adjacent dormant thermal control system. This EVA, US EVA 20, was successfully executed on November 1, 2012 and left the 2B PVTCS in a configuration where the system was now being adequately cooled via a different radiator than what the system was designed to utilize. Data monitoring over the next several months showed that the isolated radiator had not been leaking, and the system itself continued to leak steadily until May 9th, 2013. It was on this day that the ISS crew noticed the visible presence of ammonia crystals escaping from the 2B channel's truss segment, signifying a rapid acceleration of the leak from 5lbm/year to 5lbm/day. Within 48 hours of the crew noticing the leak, US EVA 21 was in progress to replace the coolant pump - the only remaining replaceable leak source. This was successful, and telemetry monitoring has shown that indeed the coolant pump was the leak source and was thus isolated from the running 2B PVTCS. This paper will explore the management of the 2B PVTCS leak from the operations perspective.

  18. Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy

    PubMed Central

    Radke, Michael H.; Peng, Jun; Wu, Yiming; McNabb, Mark; Nelson, O. Lynne; Granzier, Henk; Gotthardt, Michael

    2007-01-01

    Titin is a giant protein that is in charge of the assembly and passive mechanical properties of the sarcomere. Cardiac titin contains a unique N2B region, which has been proposed to modulate elasticity of the titin filament and to be important for hypertrophy signaling and the ischemic stress response through its binding proteins FHL2 and αB-crystallin, respectively. To study the role of the titin N2B region in systole and diastole of the heart, we generated a knockout (KO) mouse deleting only the N2B exon 49 and leaving the remainder of the titin gene intact. The resulting mice survived to adulthood and were fertile. Although KO hearts were small, they produced normal ejection volumes because of an increased ejection fraction. FHL2 protein levels were significantly reduced in the KO mice, a finding consistent with the reduced size of KO hearts. Ultrastructural analysis revealed an increased extension of the remaining spring elements of titin (tandem Ig segments and the PEVK region), which, together with the reduced sarcomere length and increased passive tension derived from skinned cardiomyocyte experiments, translates to diastolic dysfunction as documented by echocardiography. We conclude from our work that the titin N2B region is dispensable for cardiac development and systolic properties but is important to integrate trophic and elastic functions of the heart. The N2B-KO mouse is the first titin-based model of diastolic dysfunction and, considering the high prevalence of diastolic heart failure, it could provide future mechanistic insights into the disease process. PMID:17360664

  19. Der neue Kosmos. Einführung in die Astronomie und Astrophysik

    NASA Astrophysics Data System (ADS)

    Unsöld, Albrecht; Baschek, Bodo

    Der neue Kosmos bietet in überschaubarem Umfang eine zusammenhängende Einführung in das Gesamtgebiet der Astronomie und Astrophysik. Aus den Bereichen: Klassische Astronomie und Planetensystem, Instrumente und Beobachtungsverfahren, Sonne und Sterne, Milchstraße und Galaxien, Kosmologie, Entstehung des Planetensystems, Entwicklung der Erde und des Lebens werden die Beobachtungsmethoden und die Ergebnisse astronomischer Forschung sowie deren theoretische Grundlagen und wechselseitigen Zusammenhänge vermittelt. Die aktualisierte 7. Auflage berücksichtigt den raschen Fortschritt astronomischer Forschung der letzten drei Jahre von unserem Planetensystem und den Entdeckungen zahlreicher Planeten bei anderen Sternen, über die fernsten Galaxien und Quasare bis zur Entwicklung der modernen Kosmologie.

  20. Renaturierung von subalpinen und alpinen Ökosystemen

    NASA Astrophysics Data System (ADS)

    Krautzer, B.; Klug, Brigitte

    Die große Vielfalt an alpinen und subalpinen Ökosystemen auf waldfreien Standorten stellt besonders hohe Anforderungen an Planung und Durchführung von Renaturierungsmaßnahmen. Zunehmende Meereshöhe, starke Hangneigungen und extreme klimatische Verhältnisse im Gebirge bedingen zudem seit jeher natürliche Erosionsprozesse. Die zahllosen menschlichen Aktivitäten der letzten Jahrzehnte, gepaart mit unzureichenden Begrünungsmaßnahmen, erhöhen dieses Risiko noch um ein Vielfaches: Geländekorrekturen im Zuge von Skipistenbauten, Almrevitalisierungen, Forst- und Almwegebauten, Maßnahmen zur Verbesserung der touristischen Infrastruktur oder Wildbach- und Lawinenverbauungen. Nur durch Verwendung von hochwertigem, dem Standort angepasstem Pflanzen-oder Saatgutmaterial in Kombination mit der passenden Begrünungstechnik kann dieser Bedrohung dauerhaft entgegengewirkt werden. Dabei sind folgende limitierende Faktoren besonders zu beachten.

  1. CMV2b-AGO Interaction Is Required for the Suppression of RDR-Dependent Antiviral Silencing in Arabidopsis

    PubMed Central

    Fang, Yuan-Yuan; Zhao, Jian-Hua; Liu, Shang-Wu; Wang, Sheng; Duan, Cheng-Guo; Guo, Hui-Shan

    2016-01-01

    Using a transient plant system, it was previously found that the suppression of Cucumber mosaic virus (CMV) 2b protein relies on its double-strand (ds) RNA binding capacity, but it is independent of its interaction with ARGONAUTE (AGO) proteins. Thus, the biological meaning of the 2b-AGO interaction in the context of virus infection remains elusive. In this study, we created infectious clones of CMV mutants that expressed the 2b functional domains of dsRNA or AGO binding and tested the effect of these CMV mutants on viral pathogenicity. We found that the mutant CMV2b(1–76) expressing the 2b dsRNA-binding domain exhibited the same virulence as wild-type CMV in infection with either wild-type Arabidopsis or rdr1/6 plants with RDR1- and RDR6-deficient mutations. However, remarkably reduced viral RNA levels and increased virus (v)siRNAs were detected in CMV2b(1–76)-infected Arabidopsis in comparison to CMV infection, which demonstrated that the 2b(1–76) deleted AGO-binding domain failed to suppress the RDR1/RDR6-dependent degradation of viral RNAs. The mutant CMV2b(8–111) expressing mutant 2b, in which the N-terminal 7 amino acid (aa) was deleted, exhibited slightly reduced virulence, but not viral RNA levels, in both wild-type and rdr1/6 plants, which indicated that 2b retained the AGO-binding activity acquired the counter-RDRs degradation of viral RNAs. The deletion of the N-terminal 7 aa of 2b affected virulence due to the reduced affinity for long dsRNA. The mutant CMV2b(18–111) expressing mutant 2b lacked the N-terminal 17 aa but retained its AGO-binding activity greatly reduced virulence and viral RNA level. Together with the instability of both 2b(18–111)-EGFP and RFP-AGO4 proteins when co-expressed in Nicotiana benthamiana leaves, our data demonstrates that the effect of 2b-AGO interaction on counter-RDRs antiviral defense required the presence of 2b dsRNA-binding activity. Taken together, our findings demonstrate that the dsRNA-binding activity of

  2. CMV2b-AGO Interaction Is Required for the Suppression of RDR-Dependent Antiviral Silencing in Arabidopsis.

    PubMed

    Fang, Yuan-Yuan; Zhao, Jian-Hua; Liu, Shang-Wu; Wang, Sheng; Duan, Cheng-Guo; Guo, Hui-Shan

    2016-01-01

    Using a transient plant system, it was previously found that the suppression of Cucumber mosaic virus (CMV) 2b protein relies on its double-strand (ds) RNA binding capacity, but it is independent of its interaction with ARGONAUTE (AGO) proteins. Thus, the biological meaning of the 2b-AGO interaction in the context of virus infection remains elusive. In this study, we created infectious clones of CMV mutants that expressed the 2b functional domains of dsRNA or AGO binding and tested the effect of these CMV mutants on viral pathogenicity. We found that the mutant CMV2b(1-76) expressing the 2b dsRNA-binding domain exhibited the same virulence as wild-type CMV in infection with either wild-type Arabidopsis or rdr1/6 plants with RDR1- and RDR6-deficient mutations. However, remarkably reduced viral RNA levels and increased virus (v)siRNAs were detected in CMV2b(1-76)-infected Arabidopsis in comparison to CMV infection, which demonstrated that the 2b(1-76) deleted AGO-binding domain failed to suppress the RDR1/RDR6-dependent degradation of viral RNAs. The mutant CMV2b(8-111) expressing mutant 2b, in which the N-terminal 7 amino acid (aa) was deleted, exhibited slightly reduced virulence, but not viral RNA levels, in both wild-type and rdr1/6 plants, which indicated that 2b retained the AGO-binding activity acquired the counter-RDRs degradation of viral RNAs. The deletion of the N-terminal 7 aa of 2b affected virulence due to the reduced affinity for long dsRNA. The mutant CMV2b(18-111) expressing mutant 2b lacked the N-terminal 17 aa but retained its AGO-binding activity greatly reduced virulence and viral RNA level. Together with the instability of both 2b(18-111)-EGFP and RFP-AGO4 proteins when co-expressed in Nicotiana benthamiana leaves, our data demonstrates that the effect of 2b-AGO interaction on counter-RDRs antiviral defense required the presence of 2b dsRNA-binding activity. Taken together, our findings demonstrate that the dsRNA-binding activity of the 2b was

  3. CMV2b-AGO Interaction Is Required for the Suppression of RDR-Dependent Antiviral Silencing in Arabidopsis

    PubMed Central

    Fang, Yuan-Yuan; Zhao, Jian-Hua; Liu, Shang-Wu; Wang, Sheng; Duan, Cheng-Guo; Guo, Hui-Shan

    2016-01-01

    Using a transient plant system, it was previously found that the suppression of Cucumber mosaic virus (CMV) 2b protein relies on its double-strand (ds) RNA binding capacity, but it is independent of its interaction with ARGONAUTE (AGO) proteins. Thus, the biological meaning of the 2b-AGO interaction in the context of virus infection remains elusive. In this study, we created infectious clones of CMV mutants that expressed the 2b functional domains of dsRNA or AGO binding and tested the effect of these CMV mutants on viral pathogenicity. We found that the mutant CMV2b(1–76) expressing the 2b dsRNA-binding domain exhibited the same virulence as wild-type CMV in infection with either wild-type Arabidopsis or rdr1/6 plants with RDR1- and RDR6-deficient mutations. However, remarkably reduced viral RNA levels and increased virus (v)siRNAs were detected in CMV2b(1–76)-infected Arabidopsis in comparison to CMV infection, which demonstrated that the 2b(1–76) deleted AGO-binding domain failed to suppress the RDR1/RDR6-dependent degradation of viral RNAs. The mutant CMV2b(8–111) expressing mutant 2b, in which the N-terminal 7 amino acid (aa) was deleted, exhibited slightly reduced virulence, but not viral RNA levels, in both wild-type and rdr1/6 plants, which indicated that 2b retained the AGO-binding activity acquired the counter-RDRs degradation of viral RNAs. The deletion of the N-terminal 7 aa of 2b affected virulence due to the reduced affinity for long dsRNA. The mutant CMV2b(18–111) expressing mutant 2b lacked the N-terminal 17 aa but retained its AGO-binding activity greatly reduced virulence and viral RNA level. Together with the instability of both 2b(18–111)-EGFP and RFP-AGO4 proteins when co-expressed in Nicotiana benthamiana leaves, our data demonstrates that the effect of 2b-AGO interaction on counter-RDRs antiviral defense required the presence of 2b dsRNA-binding activity. Taken together, our findings demonstrate that the dsRNA-binding activity of

  4. Capsid proteins from PCV2a genotype confer greater protection against a PCV2b strain than those from PCV2b genotype in pigs: evidence for PCV2b strains becoming more predominant than PCV2a strains from 2000 to 2010s.

    PubMed

    Huang, Liping; Wang, Yiping; Wei, Yanwu; Chen, Dongjie; Liu, Dan; Du, Wenjuan; Xia, Deli; Wu, Hongli; Feng, Li; Liu, Changming

    2016-07-01

    Two major porcine circovirus type 2 (PCV2) genotypes, PCV2a and PCV2b, are recognized. PCV2a was predominant in the global pig population until 2000 while PCV2b became predominant from 2003 onward. The aim of this study was to analyze the immune protection conferred by two PCV2a and two PCV2b capsid proteins (Caps) in pigs challenged with a mutant PCV2b/YJ (mPCV2b/YJ) strain. Pigs vaccinated with PCV2a/LG-Cap and PCV2a/CL-Cap elicited significantly higher levels of PCV2-specific antibodies and neutralizing antibodies compared with PCV2b/JF-Cap and mPCV2b/YJ-Cap. Following a mPCV2b/YJ challenge, no viremia was detected in the PCV2a/LG-Cap and PCV2a/CL-Cap groups, while viremias were found in 20 and 40 % of the pigs in the PCV2b/JF-Cap and mPCV2b/YJ-Cap groups, respectively. Viral loads in the inguinal lymph nodes of pigs from the PCV2b/JF-Cap and mPCV2b/YJ-Cap groups were significantly higher than those in the PCV2a/LG-Cap and PCV2a/CL-Cap groups, but significantly lower than those of the challenge control group. Furthermore, PCV2 antigens were not detected in the inguinal lymph nodes of pigs from commercial vaccine groups, as well as the PCV2a/LG-Cap and PCV2a/CL-Cap groups, but were found in the challenge control (100 %, 5/5), PCV2b/JF-Cap (20 %, 1/5), and mPCV2b/YJ-Cap (20 %, 1/5) groups. These findings suggest that mPCV2b/YJ-Cap and PCV2b/JF-Cap were less immunogenic than PCV2a/LG-Cap and PCV2a/CL-Cap. We speculate that a genotypic shift from PCV2a to PCV2b might be the result of the majority of PCV2a strains being more immunogenic than the majority of PCV2b strains. These results provide a possible explanation for why PCV2b strains are more likely to cause epidemics than PCV2a strains. It tells us that PCV2 pathogenesis may be associated with its immunogenicity to some extent. PMID:27020283

  5. Strahlen-und kinetische Waffen: Neue Waffentechniken und Rüstungskontrolle

    NASA Astrophysics Data System (ADS)

    Neuneck, Götz

    Laserstrahlen, Mikrowellen oder elektromagnetische Beschleuniger lassen sich nicht nur für zivile, sondern für militärische Zwecke einsetzen. Die Aufgabe einer vorbeugenden Rüstungskontrolle wäre es, diese wie andere künftige Waffentechnologien auf ihren destabilisierenden Charakter hin zu untersuchen und ihre Stationierung zu beschränken oder zu verhindern.

  6. Zebrafish stem/progenitor factor msi2b exhibits two phases of activity mediated by different splice variants.

    PubMed

    Hochgreb-Hägele, Tatiana; Koo, Daniel E S; Das, Neha M; Bronner, Marianne E

    2014-02-01

    The Musashi (Msi) family of RNA-binding proteins is important in stem and differentiating cells in many species. Here, we present a zebrafish gene/protein trap line gt(msi2b-citrine)(ct) (57) (a) that expresses a Citrine fusion protein with endogenous Msi2b. Our results reveal two phases of Msi2b expression: ubiquitous expression in progenitor cells in the early embryo and later, tissue-specific expression in differentiating cells in the olfactory organ, pineal gland, and subpopulations of neurons in the central nervous system (CNS). Interestingly, this division between early and late phases is paralleled by differential expression of msi2b alternative splicing products. Whereas the full-length and long variant v3 Msi2b predominate at early stages, the later expression of variants in differentiating tissues appears to be tissue specific. Using the gt(msi2b-citrine)(ct) (57) (a), we characterized tissue-specific expression of Msi2b with cellular resolution in subsets of differentiating cells in the olfactory organ, pineal gland, CNS, and ventral neural tube. By performing transcription activator-like effectors nuclease-mediated biallelic genome editing or morpholino knockdown of Msi2b in zebrafish, our results show that early inactivation of Msi2b results in severe embryonic defects including hypertrophy of the ventricles and shortening of the body, consistent with an important role in cell proliferation and survival. Moreover, specific inactivation of Msi2b full-length indicates that this species is essential for the early role of Msi2b. This line provides a valuable tool both for live imaging of the endogenous Msi2b at subcellular resolution and manipulation of Msi2b-expressing cells.

  7. Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

    PubMed Central

    Rossi, Diane L.; Cardillo, Thomas M.; Stein, Rhona; Chang, Chien-Hsing

    2011-01-01

    The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting mAb (mAb-IFNα) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFNα comprising tetrameric IFNα2b site-specifically linked to hL243 (humanized anti–HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFNα or a mixture comprising the parental mAb and IFNα. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFNα and hL243. C2-2b-2b induced more potent and longer-lasting IFNα signaling compared with nontargeted IFNα. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFNα, peginterferonalfa-2a, or a combination of hL243 and IFNα, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. PMID:21680794

  8. Changes in the Adult GluN2B Associated Proteome following Adolescent Intermittent Ethanol Exposure.

    PubMed

    Swartzwelder, H Scott; Risher, Mary-Louise; Miller, Kelsey M; Colbran, Roger J; Winder, Danny G; Wills, Tiffany A

    2016-01-01

    Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE) produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70) from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further, the robust change in

  9. Reaction and reorientation of electronically excited H[sub 2](B)

    SciTech Connect

    Pibel, C.D.

    1992-09-01

    The room temperature rate (TR) constants for fluorescence quenching fluorescence of H[sub 2], HD, and D[sub 2] B [sup 1][Sigma][sub u][sup +] by [sup 4]He were measured as a function of the initially excited rotational and vibrational level of the hydrogen molecule, and the RT rate constants for molecular angular momentum reorientation of H[sub 2], HD and D[sub 2] (B [sup 1][Sigma][sub u][sup +]. v[prime]=0, J[prime]=1, M[sub J]=0) in collisions with He, Ne, Ar and H[sub 2](X [sup 1][Sigma][sub g][sup +]) were also measured. Vibrational state dependence of the quenching cross sections fits a vibrationally adiabatic model of the quenching process. From the vibrational state dependence of the quenching cross section, the barrier height for the quenching reaction is found to be 250[plus minus]40 cm[sup [minus]1], and the difference in the H-H stretching frequencies between H[sub 2](B) and the H[sub 2]-He complex at the barrier to reaction is 140[plus minus]80 cm[sup [minus]1]. The effective cross sections for angular momentum reorientation in collisions of H[sub 2], HD, D[sub 2] with He and Ne were found to be about 30 [Angstrom][sup 2] and were nearly the same for each isotope and with He and Ne as collision partners. Cross sections forreorientation of HD and D[sub 2] in collisions with Ar were 10.6[plus minus]2.0 and 13.9[plus minus]3.0 [Angstrom][sup 2], respectively. Reorientation of D[sub 2](B) in collisions with room temperature H[sub 2](X) occurs with a 7.6[plus minus]3.4 [Angstrom][sup 2] cross section. Calculated cross sections using semiclassical and quantum close coupled methods give cross sections for reorientation of H[sub 2](B) and D[sub 2](B) in collisions with He that agree quantitatively with experiment. Discrepancy between the calculated and experimental cross sections for HD(B)-HE are likely due to rotational relaxation in HD a Turbo PASCAL version of the data-taking program is included.

  10. Reaction and reorientation of electronically excited H{sub 2}(B)

    SciTech Connect

    Pibel, C.D.

    1992-09-01

    The room temperature rate (TR) constants for fluorescence quenching fluorescence of H{sub 2}, HD, and D{sub 2} B {sup 1}{Sigma}{sub u}{sup +} by {sup 4}He were measured as a function of the initially excited rotational and vibrational level of the hydrogen molecule, and the RT rate constants for molecular angular momentum reorientation of H{sub 2}, HD and D{sub 2} (B {sup 1}{Sigma}{sub u}{sup +}. v{prime}=0, J{prime}=1, M{sub J}=0) in collisions with He, Ne, Ar and H{sub 2}(X {sup 1}{Sigma}{sub g}{sup +}) were also measured. Vibrational state dependence of the quenching cross sections fits a vibrationally adiabatic model of the quenching process. From the vibrational state dependence of the quenching cross section, the barrier height for the quenching reaction is found to be 250{plus_minus}40 cm{sup {minus}1}, and the difference in the H-H stretching frequencies between H{sub 2}(B) and the H{sub 2}-He complex at the barrier to reaction is 140{plus_minus}80 cm{sup {minus}1}. The effective cross sections for angular momentum reorientation in collisions of H{sub 2}, HD, D{sub 2} with He and Ne were found to be about 30 {Angstrom}{sup 2} and were nearly the same for each isotope and with He and Ne as collision partners. Cross sections forreorientation of HD and D{sub 2} in collisions with Ar were 10.6{plus_minus}2.0 and 13.9{plus_minus}3.0 {Angstrom}{sup 2}, respectively. Reorientation of D{sub 2}(B) in collisions with room temperature H{sub 2}(X) occurs with a 7.6{plus_minus}3.4 {Angstrom}{sup 2} cross section. Calculated cross sections using semiclassical and quantum close coupled methods give cross sections for reorientation of H{sub 2}(B) and D{sub 2}(B) in collisions with He that agree quantitatively with experiment. Discrepancy between the calculated and experimental cross sections for HD(B)-HE are likely due to rotational relaxation in HD a Turbo PASCAL version of the data-taking program is included.

  11. Changes in the Adult GluN2B Associated Proteome following Adolescent Intermittent Ethanol Exposure

    PubMed Central

    Swartzwelder, H. Scott; Risher, Mary-Louise; Miller, Kelsey M.; Colbran, Roger J.; Winder, Danny G.; Wills, Tiffany A.

    2016-01-01

    Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE) produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70) from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further, the robust change in

  12. Photoelectron Spectroscopy Study of [Ta2B6]-: a Hexagonal Bipyramdial Cluster

    NASA Astrophysics Data System (ADS)

    Jian, Tian; Li, Weili; Romanescu, Constantin; Wang, Lai-Sheng

    2014-06-01

    It has been a long-sought goal in cluster science to discover stable atomic clusters as building blocks for cluster-assembled nanomaterials, as exemplified by the fullerenes and their subsequent bulk syntheses.[1,2] Clusters have also been considered as models to understand bulk properties, providing a bridge between molecular and solid-state chemistry.[3] Herein we report a joint photoelectron spectroscopy and theoretical study on the [Ta2B6]- and [Ta2B6] clusters.[4] The photoelectron spectrum of [Ta2B6]- displays a simple spectral pattern and a large HOMO-LUMO gap, suggesting its high symmetry. Theoretical calculations show that both the neutral and anion are D6h pyramidal. The chemical bonding analyses for [Ta2B6] revealed the nature of the B6 and Ta interactions and uncovered strong covalent bonding between B6 and Ta. The D6h-[TaB6Ta] gaseous cluster is reminiscent of the structural pattern in the ReB6X6Re core in the [(Cp*Re)2B6H4Cl2] and the TiB6Ti motif in the newly synthesized Ti7Rh4Ir2B8 solid-state compound.[5,6] The current work provides an intrinsic link between a gaseous cluster and motifs for solid materials. Continued investigations of the transition-metal boron clusters may lead to the discovery of new structural motifs involving pure boron clusters for the design of novel boride materials. Reference [1] H.W. Kroto, J. R. Heath, S. C. OBrien, R. F. Curl, R. E. Smalley, Nature 1985, 318, 162 - 163. [2] W. Krtschmer, L. D. Lamb, K. Fostiropoulos, D. R. Huffman, Nature 1990, 347, 354 - 358. [3] T. P. Fehlner, J.-F. Halet, J.-Y. Saillard, Molecular Clusters: A Bridge to Solid-State Chemitry, Cambridge University Press, UK, 2007. [4] W. L. Li, L. Xie, T. Jian, C. Romanescu, X. Huang, L.-S. Wang, Angew. Chem. Int. Ed. 2014, 126, 1312 - 1316. [5] B. Le Guennic, H. Jiao, S. Kahlal, J.-Y. Saillard, J.-F. Halet, S. Ghosh, M. Shang, A. M. Beatty, A. L. Rheingold, T. P. Fehlner, J. Am. Chem. Soc. 2004, 126, 3203 - 3217. [6] B. P. T. Fokwa, M. Hermus, Angew

  13. A chimeric Plasmodium falciparum Pfnbp2b/Pfnbp2a gene originated during asexual growth.

    PubMed

    Cortés, Alfred

    2005-02-01

    The Plasmodium falciparum line 3D7-A has an unusual invasion phenotype, such that it can invade enzyme-treated and mutant red blood cells that are resistant to invasion by other parasite lines. 3D7-A has a chimeric Pfnbp2b gene that contains part of the repeat region of the paralogous gene Pfnbp2a. This chimeric gene originated by spontaneous gene conversion during normal maintenance in culture, indicating that ectopic recombination and gene conversion during asexual growth are potentially important mechanisms participating in the evolution of paralogous genes in Plasmodium. However, the presence of the chimeric Pfnbp2b gene in 3D7-A was not associated with its peculiar invasion phenotype.

  14. Superconductivity of magnetic Sm-substituted LaCo{sub 2}B{sub 2}

    SciTech Connect

    Wang, Y.; Ren, W. J. Duan, T. F.; Li, D.; Li, J.; Zhang, Z. D.

    2015-05-07

    In this work, superconductivity with a maximum superconducting transition onset temperature T{sub C} of 3.6 K is reported in La{sub 1-x}Sm{sub x}Co{sub 2}B{sub 2} in the concentration range 0.12 ≤ x ≤ 0.20. Substitution of magnetic Sm ions with 4f electrons for La is beneficial for superconductivity in the system. The low upper critical field of La{sub 0.8}Sm{sub 0.2}Co{sub 2}B{sub 2} suggests that the dominant magnetic-field suppressing superconducting mechanism is the orbit pair-breaking effect. A special specific-heat anomaly is observed around T{sub C}.

  15. Modeling the High Speed Research Cycle 2B Longitudinal Aerodynamic Database Using Multivariate Orthogonal Functions

    NASA Technical Reports Server (NTRS)

    Morelli, E. A.; Proffitt, M. S.

    1999-01-01

    The data for longitudinal non-dimensional, aerodynamic coefficients in the High Speed Research Cycle 2B aerodynamic database were modeled using polynomial expressions identified with an orthogonal function modeling technique. The discrepancy between the tabular aerodynamic data and the polynomial models was tested and shown to be less than 15 percent for drag, lift, and pitching moment coefficients over the entire flight envelope. Most of this discrepancy was traced to smoothing local measurement noise and to the omission of mass case 5 data in the modeling process. A simulation check case showed that the polynomial models provided a compact and accurate representation of the nonlinear aerodynamic dependencies contained in the HSR Cycle 2B tabular aerodynamic database.

  16. Convoluted nozzle design for the RL10 derivative 2B engine

    NASA Technical Reports Server (NTRS)

    1985-01-01

    The convoluted nozzle is a conventional refractory metal nozzle extension that is formed with a portion of the nozzle convoluted to show the extendible nozzle within the length of the rocket engine. The convoluted nozzle (CN) was deployed by a system of four gas driven actuators. For spacecraft applications the optimum CN may be self-deployed by internal pressure retained, during deployment, by a jettisonable exit closure. The convoluted nozzle is included in a study of extendible nozzles for the RL10 Engine Derivative 2B for use in an early orbit transfer vehicle (OTV). Four extendible nozzle configurations for the RL10-2B engine were evaluated. Three configurations of the two position nozzle were studied including a hydrogen dump cooled metal nozzle and radiation cooled nozzles of refractory metal and carbon/carbon composite construction respectively.

  17. Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes.

    PubMed

    El Maatougui, Abdelaziz; Azuaje, Jhonny; González-Gómez, Manuel; Miguez, Gabriel; Crespo, Abel; Carbajales, Carlos; Escalante, Luz; García-Mera, Xerardo; Gutiérrez-de-Terán, Hugo; Sotelo, Eddy

    2016-03-10

    Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.

  18. Electronic structure study of TiB{sub 2} and Ti{sub 2}B

    SciTech Connect

    Vashistha, M. Vyas, V.; Kabra, K.; Sharma, G.

    2015-06-24

    In this paper, the electronic properties of TiB{sub 2} and Ti{sub 2}B are computed within the framework of Density Functional Theory (DFT) based on Linear Combination of Atomic Orbitals (LCAO) method. In the present calculations, the generalized gradient approximation (GGA) proposed by Perdew-Burke-Erenzerhof (PBE) and Becke’s scheme are considered to treat the correlation and exchange effects respectively. TiB{sub 2} crystallizes in the hexagonal AlB{sub 2} type structure which is designated as C32 with the space group P6/mmm. While the crystal structure of Ti{sub 2}B described in this paper is isomorphous to the body centered tetragonal (Al{sub 2}Cu - type) structure with space group I4/mcm.

  19. A systematic analysis of the Braitenberg vehicle 2b for point-like stimulus sources.

    PubMed

    Rañó, Iñaki

    2012-09-01

    Braitenberg vehicles have been used experimentally for decades in robotics with limited empirical understanding. This paper presents the first mathematical model of the vehicle 2b, displaying so-called aggression behaviour, and analyses the possible trajectories for point-like smooth stimulus sources. This sensory-motor steering control mechanism is used to implement biologically grounded target approach, target-seeking or obstacle-avoidance behaviour. However, the analysis of the resulting model reveals that complex and unexpected trajectories can result even for point-like stimuli. We also prove how the implementation of the controller and the vehicle morphology interact to affect the behaviour of the vehicle. This work provides a better understanding of Braitenberg vehicle 2b, explains experimental results and paves the way for a formally grounded application on robotics as well as for a new way of understanding target seeking in biology.

  20. Ground-based Multi-object Spectroscopy of XO-2b using a Systematic Wavelength Calibration

    NASA Astrophysics Data System (ADS)

    Pearson, Kyle; Griffith, Caitlin Ann; Zellem, Robert Thomas

    2016-10-01

    Here we present multiple observations of the primary transit of the bright hot-Jupiter XO-2b with visible wavelength spectroscopy. Repeated observations of XO-2b record simulatenous measurements of both the exoplanet host star and one or more comparison stars. Ideally, the comparison star measures errors, such as airmass variations and telescope jitter. The hypothesis is that these errors can then be divided out from the target star to achieve higher SNR and improve estimation of the small transit signal. However, we find that the astrophysical signals are subject to time-varying translations along the spectroscopic dispersion axis that change according to wavelength. Improper alignment prior to dividing the astrophysical signals can result in spurious spectral features or inadequate removal of shared systematics. We showcase ways to check for inadequate alignment and offer corrections to such problems.

  1. Genetic characterization of a noncytopathic bovine viral diarrhea virus 2b isolated from cattle in China.

    PubMed

    Wang, Wei; Shi, Xinchuan; Chen, Chaoyang; Wu, Hua

    2014-10-01

    In January 2013, several clinical signs of cattle with diarrhea, cough, nasal discharge, and fever were reported in Jilin province, China. One virus named SD1301 was isolated and identified. Complete genome of the virus is 12258nt in length and contains a 5'UTR, one open reading frame encoding a polyprotein of 3,897 amino acids and a 3'UTR. Phylogenetic analysis of 5'UTR, N(pro), E1 and E2 gene demonstrated the virus belonged to BVDV 2b, and genetically related to the BVDV strain Hokudai-Lab/09 from Japan in 2010. This bovine viral diarrhea virus displays a unique genetic signature with 27-nucleotide deletion in the 5'UTR, which is similar to the bovine viral diarrhea virus C413 (AF002227). This was the first confirmed isolation of ncp BVDV2b circulating in bovine herd of China.

  2. Modeling viral and drug kinetics: hepatitis C virus treatment with pegylated interferon alfa-2b.

    PubMed

    Powers, Kimberly A; Dixit, Narendra M; Ribeiro, Ruy M; Golia, Preeti; Talal, Andrew H; Perelson, Alan S

    2003-01-01

    Administration of peginterferon alfa-2b plus ribavirin results in an early hepatitis C virus (HCV) RNA decay followed by an increase as the drug concentration declines between doses. Upon administration of the next dose 1 week later, the same pattern is observed. We have incorporated pharmacokinetic/pharmacodynamic analysis into a model of viral dynamics to describe the effect that changes in drug concentration and effectiveness can have on viral levels. To illustrate the relationship between pharmacokinetics and viral dynamics, we fit the model to data from four HCV/human immunodeficiency virus co-infected patients, and obtained good agreement with the measured serum HCV RNA levels. We were able to account for the observed increases in HCV RNA, and estimate virion and drug half-lives that are in agreement with previous reports. Models incorporating pharmacokinetics are needed to correctly interpret viral load changes and estimate drug effectiveness in treatment protocols using peginterferon alfa-2b. PMID:12934163

  3. Thermal neutron response of the Li 2B 4O 7:Cu TL dosimeter

    NASA Astrophysics Data System (ADS)

    Gauld, I. C.; Harvey, J. W.; Kennett, T. J.; Prestwich, W. V.

    1986-10-01

    A measurement of the thermal neutron response of the Li 2B 4O 7:Cu TLD has been conducted. The results obtained using the Panasonic UD-806 dosimeter and UD-854A holder yield a free-in-air response of 3.3±0.1 R 60Co equivalent per mSv of thermal neutrons. A thermal neutron response of over 7 R 60Co equivalent per mSv was observed when the dosimeter was irradiated on water phantoms. The high sensitivity may result in a substantial overestimate of the gamma dose equivalent if the TLD is used in a mixed neutron and gamma environment of unknown ratio. Measurements of the Li 2B 4O 7:Cu glow curve, TL saturation curve and the thermal neutron response dependence of the dosimeter filtration thickness are also presented.

  4. Populating the i2b2 database with heterogeneous EMR data: a semantic network approach.

    PubMed

    Mate, Sebastian; Bürkle, Thomas; Köpcke, Felix; Breil, Bernhard; Wullich, Bernd; Dugas, Martin; Prokosch, Hans-Ulrich; Ganslandt, Thomas

    2011-01-01

    In an ongoing effort to share heterogeneous electronic medical record (EMR) data in an i2b2 instance between the University Hospitals Münster and Erlangen for joint cancer research projects, an ontology based system for the mapping of EMR data to a set of common data elements has been developed. The system translates the mappings into local SQL scripts, which are then used to extract, transform and load the facts data from each EMR into the i2b2 database. By using Semantic Web standards, it is the authors' goal to reuse the laboriously compiled "mapping knowledge" in future projects, such as a comprehensive cancer ontology or even a hospital-wide clinical ontology.

  5. Abraham Lincoln's marfanoid mother: the earliest known case of multiple endocrine neoplasia type 2B?

    PubMed

    Sotos, John G

    2012-07-01

    The nature and cause of President Abraham Lincoln's unusual physical features have long been debated, with the greatest attention directed at two monogenic disorders of the transforming growth factor β system: Marfan syndrome and multiple endocrine neoplasia type 2B. The present report examines newly discovered phenotypic information about Lincoln's biological mother, Nancy Hanks Lincoln, and concludes that (a) Lincoln's mother was skeletally marfanoid, (b) the President and his mother were highly concordant for the presence of numerous facial features found in various transforming growth factor β disorders, and (c) Lincoln's mother, like her son, had hypotonic skeletal muscles, resulting in myopathic facies and 'pseudodepression'. These conclusions establish that mother and son had the same monogenic autosomal dominant marfanoid disorder. A description of Nancy Hanks Lincoln as coarse-featured, and a little-known statement that a wasting disease contributed to her death at age 34, lends support to the multiple endocrine neoplasia type 2B hypothesis.

  6. UGT2B10 genotype influences nicotine glucuronidation, oxidation and consumption

    PubMed Central

    Berg, Jeannette Zinggeler; von Weymarn, Linda; Thompson, Elizabeth A.; Wickham, Katherine M.; Weisensel, Natalie A.; Hatsukami, Dorothy K.; Murphy, Sharon E.

    2010-01-01

    Background Tobacco exposure is routinely assessed by quantifying nicotine metabolites in plasma or urine. On average, 80% of nicotine undergoes C-oxidation to cotinine. However, interindividual variation in nicotine glucuronidation is substantial and glucuronidation accounts for from 0 to 40% of total nicotine metabolism. We report here the effect of a polymorphism in a UDP-glucuronsyl transferase, UGT2B10, on nicotine metabolism and consumption. Methods Nicotine, cotinine, their N-glucuronide conjugates, and total trans-3'-hydroxycotinine were quantified in the urine (n=327) and plasma (n =115) of smokers. Urinary nicotine N-oxide was quantified in 105 smokers. Nicotine equivalents, the sum of nicotine and all major metabolites, were calculated for each smoker. The relationship of the UGT2B10 Asp67Tyr allele to nicotine equivalents, N-glucuronidation, and C-oxidation was determined. Results Individuals heterozygous for the Asp67Tyr allele excreted less nicotine or cotinine as their glucuronide conjugates than wild-type, resulting in a 60% lower ratio of cotinine glucuronide:cotinine, a 50% lower ratio of nicotine glucuronide:nicotine and increased cotinine and trans-3'-hydroxycotinine. Nicotine equivalents, a robust biomarker of nicotine intake, were lower among Asp67Tyr heterozygotes compared to individuals without this allele; 58.2 nmol/ml (95% CI, 48.9 – 68.2) versus 69.2 nmol/ml (95% CI, 64.3 – 74.5). Conclusions Individuals heterozygous for UGT2B10 Asp67Tyr consume less nicotine than do wild type smokers. This striking observation suggests that variations in nicotine N-glucuronidation, as reported for nicotine C-oxidation, may influence smoking behavior. Impact UGT2B10 genotype influences nicotine metabolism and should be taken into account when characterizing the role of nicotine metabolism on smoking. PMID:20501767

  7. Everolimus Stabilizes Podocyte Microtubules via Enhancing TUBB2B and DCDC2 Expression

    PubMed Central

    Jeruschke, Stefanie; Jeruschke, Kay; DiStasio, Andrew; Karaterzi, Sinem; Büscher, Anja K.; Nalbant, Perihan; Klein-Hitpass, Ludger; Hoyer, Peter F.; Weiss, Jürgen; Stottmann, Rolf W.; Weber, Stefanie

    2015-01-01

    Background Glomerular podocytes are highly differentiated cells that are key components of the kidney filtration units. The podocyte cytoskeleton builds the basis for the dynamic podocyte cytoarchitecture and plays a central role for proper podocyte function. Recent studies implicate that immunosuppressive agents including the mTOR-inhibitor everolimus have a protective role directly on the stability of the podocyte actin cytoskeleton. In contrast, a potential stabilization of microtubules by everolimus has not been studied so far. Methods To elucidate mechanisms underlying mTOR-inhibitor mediated cytoskeletal rearrangements, we carried out microarray gene expression studies to identify target genes and corresponding pathways in response to everolimus. We analyzed the effect of everolimus in a puromycin aminonucleoside experimental in vitro model of podocyte injury. Results Upon treatment with puromycin aminonucleoside, microarray analysis revealed gene clusters involved in cytoskeletal reorganization, cell adhesion, migration and extracellular matrix composition to be affected. Everolimus was capable of protecting podocytes from injury, both on transcriptional and protein level. Rescued genes included tubulin beta 2B class IIb (TUBB2B) and doublecortin domain containing 2 (DCDC2), both involved in microtubule structure formation in neuronal cells but not identified in podocytes so far. Validating gene expression data, Western-blot analysis in cultured podocytes demonstrated an increase of TUBB2B and DCDC2 protein after everolimus treatment, and immunohistochemistry in healthy control kidneys confirmed a podocyte-specific expression. Interestingly, Tubb2bbrdp/brdp mice revealed a delay in glomerular podocyte development as showed by podocyte-specific markers Wilm’s tumour 1, Podocin, Nephrin and Synaptopodin. Conclusions Taken together, our study suggests that off-target, non-immune mediated effects of the mTOR-inhibitor everolimus on the podocyte cytoskeleton

  8. Medical i2b2 NLP smoking challenge: the A-Life system architecture and methodology.

    PubMed

    Heinze, Daniel T; Morsch, Mark L; Potter, Brian C; Sheffer, Ronald E

    2008-01-01

    We describe the architecture of LifeCode (A-Life Medical, Inc.), a natural language processing system for free-text clinical information extraction, our methodology in applying LifeCode to the i2b2 smoking challenge, and statistical measures for performance evaluation. Due to the limited test size and the coefficient of variation in the test standard, it is difficult to draw conclusions regarding the relative efficacy of approaches that were applied to this challenge.

  9. The α2B adrenergic receptor is mutant in cortical myoclonus and epilepsy

    PubMed Central

    De Fusco, Maurizio; Vago, Riccardo; Striano, Pasquale; Di Bonaventura, Carlo; Zara, Federico; Mei, Davide; Kim, Min Seuk; Muallem, Shmuel; Chen, Yunjia; Wang, Qin; Guerrini, Renzo; Casari, Giorgio

    2013-01-01

    Objective Autosomal dominant cortical myoclonus and epilepsy (ADCME) is characterized by distal, fairly rhythmic myoclonus and epilepsy with variable severity. We have previously mapped the disease locus on chromosome 2p11.1-q12.2 by genome-wide linkage analysis. Additional pedigrees affected by similar forms of epilepsy have been associated to chromosome 8q, 5p and 3q, but none of the causing genes has been identified. We aim at identifying the mutant gene responsible for this epileptic form. Methods Genes included in the ADCME critical region were prioritized and directly sequenced. Co-immunoprecipitation, immunofluorescence and electrophysiology approaches on transfected human cells have been utilized for testing the functional significance of the identified mutation. Results Here we show that mutation in the α2-adrenergic receptor subtype B (α2B-AR) associates to ADCME by identifying a novel in-frame insertion/deletion in two Italian families. The mutation alters several conserved residues of the third intracellular (3i) loop, neither hampering the α2B-AR plasma membrane localization nor the arrestin-mediated internalization capacity, but altering the binding with the scaffolding protein spinophilin upon neurotransmitter activation. Spinophilin, in turn, regulates interaction of GPCRs with Regulators of G proteins Signaling proteins. Accordingly, the mutant α2B-AR increases the epinephrine-stimulated calcium signaling. Interpretation The identified mutation is responsible for ADCME, as the loss of α2B-AR/spinophilin interaction causes a gain of function effect. This work implicates for the first time the α-adrenergic system in human epilepsy and opens new ways for understanding the molecular pathway of epileptogenesis, widening the spectrum of possible therapeutic targets. PMID:24114805

  10. Influence of Surface Preparation for Different Groups of A2B6 Mixed Crystals

    NASA Astrophysics Data System (ADS)

    Zakrzewski, J.; Maliński, M.; Strzałkowski, K.; Firszt, F.; Łęgowski, S.; Męczyńska, H.

    2010-01-01

    Piezoelectric photothermal spectroscopy has been used for measurements of the optical and thermal parameters of semiconductors. The investigated crystals were grown by the high-pressure Bridgman method under argon overpressure. The obtained photoacoustic (PA) spectra show the complexity of the effects observed for the different groups of selected A2B6 crystals. These effects comprise ideal samples and samples with damaged surfaces. The spectra show the influence of the surface treatment on the PA amplitude and phase spectra.

  11. A Phox2b BAC Transgenic Rat Line Useful for Understanding Respiratory Rhythm Generator Neural Circuitry

    PubMed Central

    Ikeda, Keiko; Takahashi, Masanori; Sato, Shigeru; Igarashi, Hiroyuki; Ishizuka, Toru; Yawo, Hiromu; Arata, Satoru; Southard-Smith, E. Michelle; Kawakami, Kiyoshi; Onimaru, Hiroshi

    2015-01-01

    The key role of the respiratory neural center is respiratory rhythm generation to maintain homeostasis through the control of arterial blood pCO2/pH and pO2 levels. The neuronal network responsible for respiratory rhythm generation in neonatal rat resides in the ventral side of the medulla and is composed of two groups; the parafacial respiratory group (pFRG) and the pre-Bötzinger complex group (preBötC). The pFRG partially overlaps in the retrotrapezoid nucleus (RTN), which was originally identified in adult cats and rats. Part of the pre-inspiratory (Pre-I) neurons in the RTN/pFRG serves as central chemoreceptor neurons and the CO2 sensitive Pre-I neurons express homeobox gene Phox2b. Phox2b encodes a transcription factor and is essential for the development of the sensory-motor visceral circuits. Mutations in human PHOX2B cause congenital hypoventilation syndrome, which is characterized by blunted ventilatory response to hypercapnia. Here we describe the generation of a novel transgenic (Tg) rat harboring fluorescently labeled Pre-I neurons in the RTN/pFRG. In addition, the Tg rat showed fluorescent signals in autonomic enteric neurons and carotid bodies. Because the Tg rat expresses inducible Cre recombinase in PHOX2B-positive cells during development, it is a potentially powerful tool for dissecting the entire picture of the respiratory neural network during development and for identifying the CO2/O2 sensor molecules in the adult central and peripheral nervous systems. PMID:26147470

  12. Zebrafish Zic2a and Zic2b regulate neural crest and craniofacial development.

    PubMed

    Teslaa, Jessica J; Keller, Abigail N; Nyholm, Molly K; Grinblat, Yevgenya

    2013-08-01

    Holoprosencephaly (HPE), the most common malformation of the human forebrain, is associated with defects of the craniofacial skeleton. ZIC2, a zinc-finger transcription factor, is strongly linked to HPE and to a characteristic set of dysmorphic facial features in humans. We have previously identified important functions for zebrafish Zic2 in the developing forebrain. Here, we demonstrate that ZIC2 orthologs zic2a and zic2b also regulate the forming zebrafish craniofacial skeleton, including the jaw and neurocranial cartilages, and use the zebrafish to study Zic2-regulated processes that may contribute to the complex etiology of HPE. Using temporally controlled Zic2a overexpression, we show that the developing craniofacial cartilages are sensitive to Zic2 elevation prior to 24hpf. This window of sensitivity overlaps the critical expansion and migration of the neural crest (NC) cells, which migrate from the developing neural tube to populate vertebrate craniofacial structures. We demonstrate that zic2b influences the induction of NC at the neural plate border, while both zic2a and zic2b regulate NC migratory onset and strongly contribute to chromatophore development. Both Zic2 depletion and early ectopic Zic2 expression cause moderate, incompletely penetrant mispatterning of the NC-derived jaw precursors at 24hpf, yet by 2dpf these changes in Zic2 expression result in profoundly mispatterned chondrogenic condensations. We attribute this discrepancy to an additional role for Zic2a and Zic2b in patterning the forebrain primordium, an important signaling source during craniofacial development. This hypothesis is supported by evidence that transplanted Zic2-deficient cells can contribute to craniofacial cartilages in a wild-type background. Collectively, these data suggest that zebrafish Zic2 plays a dual role during craniofacial development, contributing to two disparate aspects of craniofacial morphogenesis: (1) neural crest induction and migration, and (2) early

  13. Astrocytes increase the activity of synaptic GluN2B NMDA receptors

    PubMed Central

    Hahn, Junghyun; Wang, Xianhong; Margeta, Marta

    2015-01-01

    Astrocytes regulate excitatory synapse formation and surface expression of glutamate AMPA receptors (AMPARs) during development. Less is known about glial modulation of glutamate NMDA receptors (NMDARs), which mediate synaptic plasticity and regulate neuronal survival in a subunit- and subcellular localization-dependent manner. Using primary hippocampal cultures with mature synapses, we found that the density of NMDA-evoked whole-cell currents was approximately twice as large in neurons cultured in the presence of glia compared to neurons cultured alone. The glial effect was mediated by (an) astrocyte-secreted soluble factor(s), was Mg2+ and voltage independent, and could not be explained by a significant change in the synaptic density. Instead, we found that the peak amplitudes of total and NMDAR miniature excitatory postsynaptic currents (mEPSCs), but not AMPAR mEPSCs, were significantly larger in mixed than neuronal cultures, resulting in a decreased synaptic AMPAR/NMDAR ratio. Astrocytic modulation was restricted to synaptic NMDARs that contain the GluN2B subunit, did not involve an increase in the cell surface expression of NMDAR subunits, and was mediated by protein kinase C (PKC). Taken together, our findings indicate that astrocyte-secreted soluble factor(s) can fine-tune synaptic NMDAR activity through the PKC-mediated regulation of GluN2B NMDAR channels already localized at postsynaptic sites, presumably on a rapid time scale. Given that physiologic activation of synaptic NMDARs is neuroprotective and that an increase in the synaptic GluN2B current is associated with improved learning and memory, the astrocyte-induced potentiation of synaptic GluN2B receptor activity is likely to enhance cognitive function while simultaneously strengthening neuroprotective signaling pathways. PMID:25941471

  14. Mesoporous TiO2-B Microspheres with Superior Rate Performance for Lithium Ion Batteries

    SciTech Connect

    Liu, Hansan; Bi, Zhonghe; Sun, Xiao-Guang; Unocic, Raymond R; Paranthaman, Mariappan Parans; Dai, Sheng; Brown, Gilbert M

    2011-01-01

    Mesoporous TiO2-B microsperes with a favorable material architecture are designed and synthesized for high power lithium ion batteries. This material, combining the advantages of fast lithium transport with a pseudocapacitive mechanism, adequate electrode-electrolyte contact and compact particle packing in electrode layer, shows superior high-rate charge-discharge capability and long-time cyclability for lithium ion batteries.

  15. Ambient Findability: Developing a Flowsheet Ontology for i2B2

    PubMed Central

    Warren, Judith J.; Manos, E. LaVerne; Connolly, Daniel W.; Waitman, Lemuel R.

    2012-01-01

    The process of moving from the locally defined flowsheet ontology containing redundancy and jargon to one understandable by researchers is described. Over 250 million nursing flowsheet observations were imported into a data repository that uses the i2b2 framework. Focus groups were used to derive a new ontology model--18 templates were identified. One hundred measures, 50% of all patient observations over 36 months, were encoded in SNOMED CT©. 78% of the concepts were mapped. PMID:24199136

  16. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential.

    PubMed

    Mony, Laetitia; Kew, James N C; Gunthorpe, Martin J; Paoletti, Pierre

    2009-08-01

    N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson's and Alzheimer's disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H+, Mg2+, Zn2+, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives ('prodils') are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity.

  17. Interactive Cohort Identification of Sleep Disorder Patients Using Natural Language Processing and i2b2

    PubMed Central

    Chen, W.; Kowatch, R.; Lin, S.; Splaingard, M.

    2015-01-01

    Summary Nationwide Children’s Hospital established an i2b2 (Informatics for Integrating Biology & the Bedside) application for sleep disorder cohort identification. Discrete data were gleaned from semistructured sleep study reports. The system showed to work more efficiently than the traditional manual chart review method, and it also enabled searching capabilities that were previously not possible. Objective We report on the development and implementation of the sleep disorder i2b2 cohort identification system using natural language processing of semi-structured documents. Methods We developed a natural language processing approach to automatically parse concepts and their values from semi-structured sleep study documents. Two parsers were developed: a regular expression parser for extracting numeric concepts and a NLP based tree parser for extracting textual concepts. Concepts were further organized into i2b2 ontologies based on document structures and in-domain knowledge. Results 26,550 concepts were extracted with 99% being textual concepts. 1.01 million facts were extracted from sleep study documents such as demographic information, sleep study lab results, medications, procedures, diagnoses, among others. The average accuracy of terminology parsing was over 83% when comparing against those by experts. The system is capable of capturing both standard and non-standard terminologies. The time for cohort identification has been reduced significantly from a few weeks to a few seconds. Conclusion Natural language processing was shown to be powerful for quickly converting large amount of semi-structured or unstructured clinical data into discrete concepts, which in combination of intuitive domain specific ontologies, allows fast and effective interactive cohort identification through the i2b2 platform for research and clinical use. PMID:26171080

  18. A Phox2b BAC Transgenic Rat Line Useful for Understanding Respiratory Rhythm Generator Neural Circuitry.

    PubMed

    Ikeda, Keiko; Takahashi, Masanori; Sato, Shigeru; Igarashi, Hiroyuki; Ishizuka, Toru; Yawo, Hiromu; Arata, Satoru; Southard-Smith, E Michelle; Kawakami, Kiyoshi; Onimaru, Hiroshi

    2015-01-01

    The key role of the respiratory neural center is respiratory rhythm generation to maintain homeostasis through the control of arterial blood pCO2/pH and pO2 levels. The neuronal network responsible for respiratory rhythm generation in neonatal rat resides in the ventral side of the medulla and is composed of two groups; the parafacial respiratory group (pFRG) and the pre-Bötzinger complex group (preBötC). The pFRG partially overlaps in the retrotrapezoid nucleus (RTN), which was originally identified in adult cats and rats. Part of the pre-inspiratory (Pre-I) neurons in the RTN/pFRG serves as central chemoreceptor neurons and the CO2 sensitive Pre-I neurons express homeobox gene Phox2b. Phox2b encodes a transcription factor and is essential for the development of the sensory-motor visceral circuits. Mutations in human PHOX2B cause congenital hypoventilation syndrome, which is characterized by blunted ventilatory response to hypercapnia. Here we describe the generation of a novel transgenic (Tg) rat harboring fluorescently labeled Pre-I neurons in the RTN/pFRG. In addition, the Tg rat showed fluorescent signals in autonomic enteric neurons and carotid bodies. Because the Tg rat expresses inducible Cre recombinase in PHOX2B-positive cells during development, it is a potentially powerful tool for dissecting the entire picture of the respiratory neural network during development and for identifying the CO2/O2 sensor molecules in the adult central and peripheral nervous systems.

  19. Astrocytic 5-HT(2B) receptor as in vitro and in vivo target of SSRIs.

    PubMed

    Peng, Liang; Huang, Jingyang

    2012-12-01

    Most studies in this journal describe recent patents. The present study only has one such reference. Instead, we hope that its contents will trigger investigation of antidepressant drugs along the suggested lines and lead to ensuing patent applications - first and foremost by more focus on astrocytes. Clinical research has already pointed towards the importance of these cells, which account for one quarter of brain cortical volume and at least as much of its oxidative metabolism. Astrocytes express a multitude of receptors, including 5-HT(2B) receptors. In cultured astrocytes acute treatment with any of the five SSRIs, fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram, stimulates equipotently and with sufficient affinity to be therapeutically relevant, the 5-HT(2B) receptor. Following EGF receptor transactivation and a resultant autocrine HB-EGF stimulation, these drugs activate two interdependent signal pathways i) the Ras-Raf-Mek-ERK phosphorylation pathway and ii) the PI3K-AKT-GSK-3β pathway, eventually altering gene expression. Chronic treatment with fluoxetine upregulates gene expression of cPLA₂, ADAR2, GluK2 and 5-HT(2B) receptors, and RNA editing of the later two in cultured astrocytes and in astrocytes obtained by fluorescence-activated cell sorting of cells from fluoxetinetreated mice. Chronic treatment also down-regulates the Gq-protein-coupled receptor-induced increase of intracellular Ca²⁺ by inhibiting TRPC function, compromising astrocytic Ca²⁺ re-filling. This affects glycogenolysis and several steps in the signal pathways. Since astrocytes in the mature brain and in our cultures do not express SERT, both acute and chronic effects in cultured astrocytes must be directly mediated by 5-HT(2B) receptor activation. PMID:22963281

  20. Technical description of space ultra reliable modular computer (SUMC), model 2 B

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The design features of the SUMC-2B computer, also called the IBM-HTC are described. It is general purpose digital computer implemented with flexible hardware elements and microprograming to enable low cost customizing to a wide range of applications. It executes the S/360 standard instruction set to maintain problem state compability. Memory technology, extended instruction sets, and I/O channel variations are among the available options.

  1. Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines.

    PubMed

    Mony, Laetitia; Zhu, Shujia; Carvalho, Stéphanie; Paoletti, Pierre

    2011-06-17

    NMDA receptors (NMDARs) form glutamate-gated ion channels that have central roles in neuronal communication and plasticity throughout the brain. Dysfunctions of NMDARs are involved in several central nervous system disorders, including stroke, chronic pain and schizophrenia. One hallmark of NMDARs is that their activity can be allosterically regulated by a variety of extracellular small ligands. While much has been learned recently regarding allosteric inhibition of NMDARs, the structural determinants underlying positive allosteric modulation of these receptors remain poorly defined. Here, we show that polyamines, naturally occurring polycations that selectively enhance NMDARs containing the GluN2B subunit, bind at a dimer interface between GluN1 and GluN2B subunit N-terminal domains (NTDs). Polyamines act by shielding negative charges present on GluN1 and GluN2B NTD lower lobes, allowing their close apposition, an effect that in turn prevents NTD clamshell closure. Our work reveals the mechanistic basis for positive allosteric modulation of NMDARs. It provides the first example of an intersubunit binding site in this class of receptors, a discovery that holds promise for future drug interventions.

  2. Imported Genotype 2B Rubella Virus Caused the 2012 Outbreak in Anqing City, China.

    PubMed

    Zhu, Zhen; Pan, Guixia; Zhou, Shujie; Dai, Jingjing; Chen, Xia; Tang, Jihai; Chen, Shuping; Zheng, Yilun; Song, Jie; Xu, Wenbo

    2015-01-01

    A rubella outbreak occurred in Anqing city of Anhui province, China, from February to July of 2012, and a total of 241 clinically diagnosed or lab-confirmed patients were reported. The highest number of rubella cases during this outbreak was recorded in teenagers between 10 and 19 years of age who had not previously received the rubella vaccine. Genotyping results indicated that the genotype 2B rubella virus (RV) was responsible for the outbreak. However, a phylogenetic analysis showed that the genotype 2B RVs isolated in Anqing City were not related to 2B RVs found in other cities of Anhui province and in other provinces of China, thus providing evidence for importation. After importation, the transmission of Anqing RVs was interrupted owing to an effective immunization campaign against rubella, suggesting the timeliness and effectiveness of contingency vaccination. Strengthening rubella surveillance, including the integration of epidemiologic information and laboratory data, is a vital strategy for rubella control and elimination. In addition, except for routine immunization, targeted supplementary immunization activities aimed at susceptible groups according to sero-epidemiological surveillance data also play a key role in stopping the continuous transmission of rubella viruses and in preventing further congenital rubella syndrome cases.

  3. Structural and biochemical analyses of monoubiquitinated human histones H2B and H4

    PubMed Central

    Machida, Shinichi; Sekine, Satoshi; Nishiyama, Yuuki; Horikoshi, Naoki; Kurumizaka, Hitoshi

    2016-01-01

    Monoubiquitination is a major histone post-translational modification. In humans, the histone H2B K120 and histone H4 K31 residues are monoubiquitinated and may form transcriptionally active chromatin. In this study, we reconstituted nucleosomes containing H2B monoubiquitinated at position 120 (H2Bub120) and/or H4 monoubiquitinated at position 31 (H4ub31). We found that the H2Bub120 and H4ub31 monoubiquitinations differently affect nucleosome stability: the H2Bub120 monoubiquitination enhances the H2A–H2B association with the nucleosome, while the H4ub31 monoubiquitination decreases the H3–H4 stability in the nucleosome, when compared with the unmodified nucleosome. The H2Bub120 and H4ub31 monoubiquitinations both antagonize the Mg2+-dependent compaction of a poly-nucleosome, suggesting that these monoubiquitinations maintain more relaxed conformations of chromatin. In the crystal structure, the H2Bub120 and H4ub31 monoubiquitinations do not change the structure of the nucleosome core particle and the ubiquitin molecules were flexibly disordered in the H2Bub120/H4ub31 nucleosome structure. These results revealed the differences and similarities of the H2Bub120 and H4ub31 monoubiquitinations at the mono- and poly-nucleosome levels and provide novel information to clarify the roles of monoubiquitination in chromatin. PMID:27335322

  4. A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent

    PubMed Central

    Oh, Eun Ju; Park, Jong Il; Lee, Ji Eun; Myung, Cheol Hwan; Kim, Su Yeon; Chang, Sung Eun; Hwang, Jae Sung

    2016-01-01

    BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B (5-HTR2B) agonist on melanogenesis and elucidate the mechanism involved. BW723C86 reduced melanin synthesis and intracellular tyrosinase activity in melan-A cells and normal human melanocytes. The expression of melanogenesis-related proteins (tyrosinase, TRP-1 and TRP-2) and microphthalmia-associated transcription factor (MITF) in melan-A cells decreased after BW723C86 treatment. The promoter activity of MITF was also reduced by BW723C86 treatment. The reduced level of MITF was associated with inhibition of protein kinase A (PKA) and cAMP response element-binding protein (CREB) activation by BW723C86 treatment. These results suggest that the serotonin agonist BW723C86 could be a potential therapeutic agent for skin hyperpigmentation disorders. PMID:27077852

  5. The binding of calmodulin to myelin basic protein and histone H2B.

    PubMed Central

    Grand, R J; Perry, S V

    1980-01-01

    1. A calmodulin-binding protein of apparent mol.wt. 19 000 has been purified from chicken gizzard. Similar proteins have been isolated from bovine uterus, rabbit skeletal muscle and rabbit liver. 2. These proteins migrated as an equimolar complex with bovine brain calmodulin on electroporesis on polyacrylamide gels in the presence of Ca2+ and 6M-urea. The complex was dissociated in the presence of EGTA. 2. The chicken gizzard calmodulin-binding protein has been shown to be identical with chicken erythrocyte histone H2B on the basis of partial amino acid sequence determination. 4. The calmodulin-binding proteins of apparent mol.wt. 22 000 isolated previously from bovine brain [Grand & Perry (1979) Biochem. J. 183, 285-295] has been shown, on the basis of partial amino-acid-sequence determination, to be identical with myelin basic protein. 5. The activation of bovine brain phosphodiesterase by calmodulin is inhibited by excess bovine uterus calmodulin-binding protein (histone H2B). 6. The phosphorylation of myelin basic protein by phosphorylase kinase is partially inhibited, whereas the phosphorylation of uterus calmodulin-binding protein (histone H2B) is unaffected by calmodulin or troponin C. 7. The subcellular distribution of myelin basic protein and calmodulin suggests that the two proteins do not exist as a complex in vivo. Images Fig. 3. Fig. 4. PMID:6161607

  6. Metabolism studies of ifenprodil, a potent GluN2B receptor antagonist.

    PubMed

    Falck, Evamaria; Begrow, Frank; Verspohl, Eugen; Wünsch, Bernhard

    2014-01-01

    The NMDA receptor antagonist ifenprodil is an important lead structure for developing new GluN2B selective NMDA receptor antagonists. Ifenprodil itself has a high affinity to the GluN2B subunit but a poor selectivity for the NMDA receptor. This aspect and the fast biotransformation are the major drawbacks of ifenprodil. In order to optimize the development of new and more selective GluN2B (NMDA) receptor antagonists, the identification of the main metabolic pathways of ifenprodil is necessary. Herein the in vitro and in vivo phase I and phase II metabolites of ifenprodil were generated and analyzed via LC-MS(n) experiments. In vitro experiments were carried out with rat liver microsomes and various co-factors to generate phase I and phase II metabolites. The application of ifenprodil to a rat and the analysis of its urine led to the identification of diverse formed in vivo metabolites. The phenol represents the metabolically most labile structural element since glucuronide 7 and 8 appeared as main metabolites.

  7. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models.

    PubMed

    Sabha, Nesrin; Volpatti, Jonathan R; Gonorazky, Hernan; Reifler, Aaron; Davidson, Ann E; Li, Xingli; Eltayeb, Nadine M; Dall'Armi, Claudia; Di Paolo, Gilbert; Brooks, Susan V; Buj-Bello, Ana; Feldman, Eva L; Dowling, James J

    2016-09-01

    Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets. PMID:27548528

  8. APOSTLE: LONGTERM TRANSIT MONITORING AND STABILITY ANALYSIS OF XO-2b

    SciTech Connect

    Kundurthy, P.; Barnes, R.; Becker, A. C.; Agol, E.; Williams, B. F.; Rose, A.; Gorelick, N.

    2013-06-10

    The Apache Point Survey of Transit Lightcurves of Exoplanets (APOSTLE) observed 10 transits of XO-2b over a period of 3 yr. We present measurements that confirm previous estimates of system parameters like the normalized semi-major axis (a/R{sub *}), stellar density ({rho}{sub *}), impact parameter (b), and orbital inclination (i{sub orb}). Our errors on system parameters like a/R{sub *} and {rho}{sub *} have improved by {approx}40% compared to previous best ground-based measurements. Our study of the transit times show no evidence for transit timing variations (TTVs) and we are able to rule out co-planar companions with masses {>=}0.20 M{sub Circled-Plus} in low order mean motion resonance with XO-2b. We also explored the stability of the XO-2 system given various orbital configurations of a hypothetical planet near the 2:1 mean motion resonance. We find that a wide range of orbits (including Earth-mass perturbers) are both dynamically stable and produce observable TTVs. We find that up to 51% of our stable simulations show TTVs that are smaller than the typical transit timing errors ({approx}20 s) measured for XO-2b, and hence remain undetectable.

  9. What Caused the Lead burn-out in Spectrometer Magnet 2B

    SciTech Connect

    Green, Michael A

    2010-11-29

    The spectrometer solenoids are supposed to be the first magnets installed in the MICE Cooling Channel. The results of the test of Spectrometer Magnet 2B are reported in a previous MICE Note. Magnet 2B was tested with all five coils connected in series. The magnet failed because a lead to coil M2 failed before it could be trained to its full design current of 275 A. First, this report describes the condition of the magnet when the lead failure occurred. The lead that failed was between the cold mass feed-through and the heavy lead that connected to coil M2 and the quench protection diodes. It is believed that the lead failed because the minimum propagation zone (MPZ) length was too short. The quench was probably triggered by lead motion in the field external to the magnet center coil. The effect of heat transfer on quench propagation and MPZ length is discussed. The MPZ length is compared for a number of cases that apply to the spectrometer solenoid 2B as built and as it has been repaired. The required heat transfer coefficient for cryogenic stability and the quench propagation velocity along the leads are compared for various parts of the Magnet leads inside the cold mass cryostat. The effect of the insulation on leads on heat transfer is and stability is discussed.

  10. Pre-Launch Absolute Calibration of CCD/CBERS-2B Sensor

    PubMed Central

    Ponzoni, Flávio Jorge; Albuquerque, Bráulio Fonseca Carneiro

    2008-01-01

    Pre-launch absolute calibration coefficients for the CCD/CBERS-2B sensor have been calculated from radiometric measurements performed in a satellite integration and test hall in the Chinese Academy of Space Technology (CAST) headquarters, located in Beijing, China. An illuminated integrating sphere was positioned in the test hall facilities to allow the CCD/CBERS-2B imagery of the entire sphere aperture. Calibration images were recorded and a relative calibration procedure adopted exclusively in Brazil was applied to equalize the detectors responses. Averages of digital numbers (DN) from these images were determined and correlated to their respective radiance levels in order to calculate the absolute calibration coefficients. It has been the first time these pre-launch absolute calibration coefficients have been calculated considering the Brazilian image processing criteria. Now it will be possible to compare them to those that will be calculated from vicarious calibration campaigns. This comparison will permit the CCD/CBERS-2B monitoring and the frequently data updating to the user community.

  11. Analysis of HAT-P-2b Warm Spitzer Full Orbit Light Curve

    NASA Astrophysics Data System (ADS)

    Lewis, Nikole; Knuston, H.; Showman, A. P.; Fortney, J. J.; Agol, E.; Burrows, A.; Charbonneau, D.; Cowan, N. B.; Deming, D.; Desert, J.; Langton, J.; Laughlin, G.; Mighell, K. J.

    2011-05-01

    The Spitzer warm mission has already greatly expanded the field of exoplanet characterization with over 3000 hours of time dedicated to exoplanet observations. Observations of eclipsing systems with Spitzer are at the heart of these advances, as they allow us to move beyond simple mass and period estimates to determine planetary radius, dayside emission, and emission variations as a function of orbital phase. The eclipsing system HAT-P-2 is of special interest because the massive Jovian sized planet in this system is on a highly eccentric orbit (e=0.5171). Because HAT-P-2b's orbit is eccentric, the planet is subject to time variable heating and probable non-synchronous rotation. Circulation patterns that we expect to develop in HAT-P-2b's atmosphere will likely vary with both planetary local time and orbital phase. Here we present an analysis of a full orbit light curve from the HAT-P-2 system obtained during the most recent cycle of the Spitzer warm mission and discuss the constraints it imposes on the atmospheric circulation of HAT-P-2b. Support for this work was provided by NASA.

  12. TRANSMISSION SPECTROSCOPY OF EXOPLANET XO-2b OBSERVED WITH HUBBLE SPACE TELESCOPE NICMOS

    SciTech Connect

    Crouzet, N.; McCullough, P. R.; Long, D.; Burke, C.

    2012-12-10

    Spectroscopy during planetary transits is a powerful tool to probe exoplanet atmospheres. We present the near-infrared transit spectroscopy of XO-2b obtained with Hubble Space Telescope NICMOS. Uniquely for NICMOS transit spectroscopy, a companion star of similar properties to XO-2 is present in the field of view. We derive improved star and planet parameters through a photometric white-light analysis. We show a clear correlation of the spectrum noise with instrumental parameters, in particular the angle of the spectral trace on the detector. An MCMC method using a decorrelation from instrumental parameters is used to extract the planetary spectrum. Spectra derived independently from each of the three visits have an rms of 430, 510, and 1000 ppm, respectively. The same analysis is performed on the companion star after numerical injection of a transit with a depth constant at all wavelengths. The extracted spectra exhibit residuals of similar amplitude as for XO-2, which represent the level of remaining NICMOS systematics. This shows that extracting planetary spectra is at the limit of NICMOS's capability. We derive a spectrum for the planet XO-2b using the companion star as a reference. The derived spectrum can be represented by a theoretical model including atmospheric water vapor or by a flat spectrum model. We derive a 3{sigma} upper limit of 1570 ppm on the presence of water vapor absorption in the atmosphere of XO-2b. In the Appendix, we perform a similar analysis for the gas giant planet XO-1b.

  13. Structure and regulation of histone H2B mRNAs from Leishmania enriettii.

    PubMed Central

    Genske, J E; Cairns, B R; Stack, S P; Landfear, S M

    1991-01-01

    We have studied the structure and expression of histone H2B mRNA and genes in the parasitic protozoan Leishmania enrietti. A genomic clone containing three tandemly repeated genes has been sequenced and shown to encode three identical histone proteins and two types of closely related mRNA sequence. We have also sequenced three independent cDNA clones and demonstrated that the Leishmania H2B mRNAs are polyadenylated, similar to the basal histone mRNAs of higher eucaryotes and the histone mRNAs of yeast. In addition, the Leishmania mRNAs contain inverted repeats near the poly(A) tail which could form stem-loops similar in secondary structure, but not in sequence, to the 3' stem-loops of nonpolyadenylated replication-dependent histones of higher eucaryotes. Unlike the replication-dependent histones, the Leishmania histone H2B mRNAs do not decrease in abundance following treatment with inhibitors of DNA synthesis. The histone mRNAs are differentially expressed during the parasite life cycle and accumulate to a higher level in the extracellular promastigotes (the form which in nature lives within the gut of the insect vector) than in the intracellular amastigotes (the form that lives within the mammalian host macrophages). Images PMID:1986223

  14. A study of single nucleotide polymorphisms of GRIN2B in schizophrenia from Chinese Han population.

    PubMed

    Guo, Zhenming; Niu, Weibo; Bi, Yan; Zhang, Rui; Ren, Decheng; Hu, Jiaxin; Huang, Xiaoye; Wu, Xi; Cao, Yanfei; Yang, Fengping; Wang, Lu; Li, Weidong; Li, Xingwang; Xu, Yifeng; He, Lin; Yu, Tao; He, Guang

    2016-09-01

    Schizophrenia is a severe and complex mental disorder with high heritability. There is evidence that mutations in the gene of Nmethyl-d-aspartate-type glutamate receptors (NMDAR) are associated with schizophrenia. GRIN2B encodes a subunit of NMDARs, and has been identified as a candidate gene for many psychiatric disorders, especially schizophrenia. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in GRIN2B were associated with schizophrenia. Four SNPs (rs890, rs1806191, rs219872, rs172677) were genotyped in 752 schizophrenic patients and 846 healthy controls of the Chinese Han population. Our results indicate differences in allele and genotype frequencies of rs890 between case and control. These results were assessed by adapting different genetic models (codominant, dominant, recessive, overdominant, log-additive models). After controlling for confounding factors including sex and age, rs890 remained associated with schizophrenia. In addition, rs890 and rs1806191 were found to form a haplotype associated with schizophrenia. In summary, our results indicate that the GRIN2B SNP rs890 might be associated with schizophrenia in the Chinese Han population. PMID:27453061

  15. CRL4Wdr70 regulates H2B monoubiquitination and facilitates Exo1-dependent resection

    PubMed Central

    Zeng, Ming; Ren, Laifeng; Mizuno, Ken'Ichi; Nestoras, Konstantinos; Wang, Haibin; Tang, Zizhi; Guo, Liandi; Kong, Daochun; Hu, Qiwen; He, Qun; Du, Lilin; Carr, Antony M.; Liu, Cong

    2016-01-01

    Double-strand breaks repaired by homologous recombination (HR) are first resected to form single-stranded DNA, which binds replication protein A (RPA). RPA attracts mediators that load the Rad51 filament to promote strand invasion, the defining feature of HR. How the resection machinery navigates nucleosome-packaged DNA is poorly understood. Here we report that in Schizosaccharomyces pombe a conserved DDB1-CUL4-associated factor (DCAF), Wdr70, is recruited to DSBs as part of the Cullin4-DDB1 ubiquitin ligase (CRL4Wdr70) and stimulates distal H2B lysine 119 mono-ubiquitination (uH2B). Wdr70 deletion, or uH2B loss, results in increased loading of the checkpoint adaptor and resection inhibitor Crb253BP1, decreased Exo1 association and delayed resection. Wdr70 is dispensable for resection upon Crb253BP1 loss, or when the Set9 methyltransferase that creates docking sites for Crb2 is deleted. Finally, we establish that this histone regulatory cascade similarly controls DSB resection in human cells. PMID:27098497

  16. Continuous infusion of 5-fluorouracil with alpha 2b interferon for advanced colorectal carcinoma.

    PubMed Central

    Ferguson, J. E.; Hulse, P.; Lorigan, P.; Jayson, G.; Scarffe, J. H.

    1995-01-01

    Thirty patients with symptomatic colorectal carcinoma were commenced on treatment with 5-fluorouracil (2.5 g week-1) administered by continuous intravenous infusion and alpha 2b interferon (3 x 10(6) U s.c. three times a week). Six out of 30 patients (20%) achieved a partial response. Three patients (10%) had stable disease and 21 patients (70%) progressed on treatment. Twenty patients (67%) completed ten or more weeks of treatment. In nine patients, treatment was withdrawn after 2-9 weeks because of disease progression or death. One patient's treatment was interrupted by emergency surgery. The median survival for all patients was 210 days (7 months). The principal side-effects were oral mucositis (12/30 patients), nausea (8/30 patients) and transient diarrhoea (4/30 patients), and initial constitutional symptoms due to alpha 2b interferon. The combination of low-dose continuous infusional 5-fluorouracil and low-dose alpha 2b interferon is well tolerated but has no obvious advantage over alternative infusional regimens using 5-fluorouracil as a single agent. PMID:7599051

  17. Interstitial pneumonitis associated with pegylated interferon alpha-2b therapy for chronic hepatitis C: case report.

    PubMed

    Carrillo-Esper, Raúl; González-Avila, Daniela; Uribe-Ríos, Marittza; Méndez-Sánchez, Nahum

    2008-01-01

    Since 2004, pegylated interferon (P-IFN) in combination with ribavirin has become the optimal choice of therapy for chronic hepatitis C virus (HCV) infection. IFN a-2b suppresses HCV replication and restores elevated serum aminotransferase levels, leading to improvements in the histological changes in the livers of patients with chronic hepatitis C. Unfortunately, P-IFN has several adverse effects, including pneumonitis. This complication has been reported in the treatment of malignant diseases and CHC. We report a patient with interstitial pneumonitis thought to be caused by an IFN-based treatment in an unusual scenario of a patient with HCV-related Child-Pugh stage A cirrhosis, who experienced dyspnea, fever, and cough after 12 months of treatment with P-IFN a-2b. Her lung injury and pulmonary symptoms did not disappear despite discontinuation of IFN and the administration of corticosteroid. We concluded that the patient developed a fatal interstitial pneumonitis associated with P-INF a-2b therapy. PMID:18376374

  18. Interferon alpha 2b as maintenance therapy improves outcome in follicular lymphoma.

    PubMed

    Avilés, Agustin; Neri, Natividad; Huerta-Guzmán, Judith; Pérez, Felipe; Sotelo, León

    2004-11-01

    The role of interferon alpha as maintenance therapy in follicular lymphoma (FL) remains unsolved. We started a controlled clinical trial to assess if interferon alpha 2b could improve outcome, measured with event free survival (EFS) and overall survival (OS) in patients with FL in complete remission after chemotherapy based anthracyclines and adjuvant radiotherapy to sites of initial bulky disease. Three hundred and eighty four patients in complete response after 6 cycles of CEOP-Bleo (cyclophosphamide, epirubicin, vincristine, prednisone and bleomycin, at standard doses), and adjuvant radiotherapy when necessary, were randomized to received Interferon alpha 2b, three times a week for 1 year or no treatment (control group). Median follow up was 9.8 years (range 7.0-15 years); actuarial curves showed that EFS was 64% (95% confidence interval (CI) 56-71%) in patients treated with interferon that was statistically significant to patients in the control group: 35% (95% CI: 28-43%) (p<.01). OS was also statistically significant: 81% in patients treated with interferon (95% CI: 74-93%) and 57% (95% CI: 50-63%) in the control group (p<.001). Toxicity was mild, all patients received the planned dose of interferon on time. The use of aggressive chemotherapy and maintenance therapy with interferon alpha 2b in follicular lymphoma improved outcome; more than 60% of patients remain alive free of disease at longer follow-up. PMID:15512813

  19. Infrared linear dichroism investigations of deoxyribonucleic complexes with histones H2B and H3.

    PubMed

    Liquier, J; Taboury, J; Taillandier, E; Brahms, J

    1977-07-12

    Complexes between DNA and histones H2B and H3 were studies by means of infrared linear dichroism in a wide range of histone to DNA ratios and of different relative humidities. The measurement of the dichroic ratios allows one to determine the secondary structure of DNA in the complexes. It is shown that the progressive addition of histone H2B or H3 to DNA inhibits the structural B leads to A transition and DNA remains in a B-type form at low relative humidity. A new simple method is proposed to evaluate the amount of A or B forms of DNA when both structures are present. It is found that the B leads to A transition is fully inhibited when only one molecule of H2B or H3 histone is bound per about three or four turns of DNA helix, respectively. It is proposed that about four to three turns of DNA helix represent the "critical length of DNA" (minimum "cooperative unit") for the B leads to A transition.

  20. Targeting the A2B adenosine receptor during gastrointestinal ischemia and inflammation

    PubMed Central

    Eltzschig, Holger K; Rivera-Nieves, Jesus; Colgan, Sean P

    2014-01-01

    Extracellular adenosine functions as an endogenous distress signal via activation of four distinct adenosine receptors (A1, A2A, A2B and A3). Conditions of limited oxygen availability or acute inflammation lead to elevated levels of extracellular adenosine and enhanced signaling events. This relates to a combination of four mechanisms: i) increased production of adenosine via extracellular phosphohydrolysis of precursor molecules (particularly ATP and ADP); ii) increased expression and signaling via hypoxia-induced adenosine receptors, particularly the A2B adenosine receptor; iii) attenuated uptake from the extracellular towards the intracellular compartment; and iv) attenuated intracellular metabolism. Due to their large surface area, mucosal organs are particularly prone to hypoxia and ischemia associated inflammation. Therefore, it is not surprising that adenosine production and signaling plays a central role in attenuating tissue inflammation and injury during intestinal ischemia or inflammation. In fact, recent studies combining pharmacological and genetic approaches demonstrated that adenosine signaling via the A2B adenosine receptor dampens mucosal inflammation and tissue injury during intestinal ischemia or experimental colitis. This review outlines basic principles of extracellular adenosine production, signaling, uptake and metabolism. In addition, we discuss the role of this pathway in dampening hypoxia-elicited inflammation, specifically in the setting of intestinal ischemia and inflammation. PMID:19769545

  1. CDKN2B expression and subcutaneous adipose tissue expandability: Possible influence of the 9p21 atherosclerosis locus

    SciTech Connect

    Svensson, Per-Arne; Wahlstrand, Björn; Olsson, Maja; Froguel, Philippe; Falchi, Mario; Bergman, Richard N.; McTernan, Philip G.; Hedner, Thomas; Carlsson, Lena M.S.; Jacobson, Peter

    2014-04-18

    Highlights: • The tumor suppressor gene CDKN2B is highly expressed in human adipose tissue. • Risk alleles at the 9p21 locus modify CDKN2B expression in a BMI-dependent fashion. • There is an inverse relationship between expression of CDKN2B and adipogenic genes. • CDKN2B expression influences to postprandial triacylglycerol clearance. • CDKN2B expression in adipose tissue is linked to markers of hepatic steatosis. - Abstract: Risk alleles within a gene desert at the 9p21 locus constitute the most prevalent genetic determinant of cardiovascular disease. Previous research has demonstrated that 9p21 risk variants influence gene expression in vascular tissues, yet the biological mechanisms by which this would mediate atherosclerosis merits further investigation. To investigate possible influences of this locus on other tissues, we explored expression patterns of 9p21-regulated genes in a panel of multiple human tissues and found that the tumor suppressor CDKN2B was highly expressed in subcutaneous adipose tissue (SAT). CDKN2B expression was regulated by obesity status, and this effect was stronger in carriers of 9p21 risk alleles. Covariation between expression of CDKN2B and genes implemented in adipogenesis was consistent with an inhibitory effect of CDKN2B on SAT proliferation. Moreover, studies of postprandial triacylglycerol clearance indicated that CDKN2B is involved in down-regulation of SAT fatty acid trafficking. CDKN2B expression in SAT correlated with indicators of ectopic fat accumulation, including markers of hepatic steatosis. Among genes regulated by 9p21 risk variants, CDKN2B appears to play a significant role in the regulation of SAT expandability, which is a strong determinant of lipotoxicity and therefore might contribute to the development of atherosclerosis.

  2. Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer

    SciTech Connect

    Li, Wenjuan; Zhao, Li; Zang, Wen; Liu, Zhifang; Chen, Long; Liu, Tiantian; Jia, Jihui

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer JMJD2B is required for cell proliferation and in vivo tumorigenesis. Black-Right-Pointing-Pointer JMJD2B depletion induces apoptosis and/or cell cycle arrest. Black-Right-Pointing-Pointer JMJD2B depletion activates DNA damage response and enhances p53 stabilization. Black-Right-Pointing-Pointer JMJD2B is overexpressed in human primary gastric cancer. -- Abstract: Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Jumonji domain containing 2B (JMJD2B) is a newly identified histone demethylase that regulates chromatin structure or gene expression by removing methyl residues from trimethylated lysine 9 on histone H3. Recent observations have shown oncogenic activity of JMJD2B. We explored the functional role of JMJD2B in cancer cell proliferation, survival and tumorigenesis, and determined its expression profile in gastric cancer. Knocking down JMJD2B expression by small interfering RNA (siRNA) in gastric and other cancer cells inhibited cell proliferation and/or induced apoptosis and elevated the expression of p53 and p21{sup CIP1} proteins. The enhanced p53 expression resulted from activation of the DNA damage response pathway. JMJD2B knockdown markedly suppressed xenograft tumor growth in vivo in mice. Moreover, JMJD2B expression was increased in primary gastric-cancer tissues of humans. Thus, JMJD2B is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of gastric cancer.

  3. Entwicklungsperspektiven von Social Software und dem Web 2.0

    NASA Astrophysics Data System (ADS)

    Raabe, Alexander

    Der Artikel beschäftigt sich zunächst mit dem derzeitigen und zukünftigen Einsatz von Social Software in Unternehmen. Nach dem großen Erfolg von Social Software im Web beginnen viele Unternehmen eigene Social Software-Initiativen zu entwickeln. Der Artikel zeigt die derzeit wahrgenommenen Einsatzmöglichkeiten von Social Software im Unternehmen auf, erörtert Erfolgsfaktoren für die Einführung und präsentiert mögliche Wege für die Zukunft. Nach der Diskussion des Spezialfalles Social Software in Unternehmen werden anschließend die globalen Trends und Zukunftsperspektiven des Web 2.0 in ihren technischen, wirtschaftlichen und sozialen Dimensionen dargestellt. Wie aus den besprochenen Haupttrends hervorgeht, wird die Masse an digital im Web verfügbaren Informationen stetig weiterwachsen. So stellt sich die Frage, wie es in Zukunft möglich sein wird, die Qualität der Informationssuche und der Wissensgenerierung zu verbessern. Mit dem Einsatz von semantischen Technologien im Web wird hier eine revolutionäre Möglichkeit geboten, Informationen zu filtern und intelligente, gewissermaßen verstehende" Anwendungen zu entwerfen. Auf dem Weg zu einem intelligenten Web werden sich das Semantic Web und Social Software annähern: Anwendungen wie Semantic Wikis, Semantic Weblogs, lightweight Semantic Web-Sprachen wie Microformats oder auch kommerzielle Angebote wie Freebase von Metaweb werden die ersten Vorzeichen einer dritten Generation des Webs sein.

  4. Darwinische Kulturtheorie - Evolutionistische und "evolutionistische`` Theorien sozialen Wandels

    NASA Astrophysics Data System (ADS)

    Antweiler, Christoph

    Evolutionistische Argumentationen außerhalb der Biologie sind weit verbreitet. Wenn sie vertreten werden, heißt das mitnichten, dass sie notwendigerweise von darwinischen Argumenten geprägt sind. Wenn man Evolution und Kultur aus explizit darwinischer Perspektive zusammen bringt, bedeutet das noch lange nicht unbedingt Soziobiologie. Und es bedeutet sicherlich nicht Sozialdarwinismus. Dieser Beitrag soll einen Überblick der so genannten evolutionären Ansätze bzw. evolutionistischen Ansätze zu menschlichen Gesellschaften bzw. Kulturen geben. Es soll gezeigt werden, was in den Ansätzen analytisch zu trennen ist und was synthetisch zusammen gehört. Mein Beitrag ist nicht wissenschaftsgeschichtlich angelegt, sondern systematisch ausgerichtet und hat zwei Schwerpunkte (Antweiler 2008; Antweiler 2009b). Zum einen geht es um kausale Zusammenhänge von organischer Evolution und gesellschaftlichem Wandel. Auf der anderen Seite werden Analogien zwischen biotischer und kultureller Evolution erläutert, die als spezifische Ähnlichkeiten dieser beiden als grundsätzlich verschieden gesehenen Prozesse aufgefasst werden. Dadurch wird die Frage aufgeworfen, ob die Evolution von Organismen einerseits und die Transformation von Gesellschaften bzw. Kulturen andererseits, spezielle Fälle eines allgemeinen Modells von Evolution darstellen.

  5. Das CARNOTsche Paradigma und seine erkenntnistheoretischen Implikationen

    NASA Astrophysics Data System (ADS)

    Schöpf, Hans-Georg

    Der vorliegende historisch-kritische Essay führt die Eigentümlichkeiten der klassischen phänomenologischen Thermodynamik auf das von CARNOT geschaffene Paradigma zurück und greift einige damit zusammenhängende Fragen auf.Translated AbstractCARNOT's Paradigm and its Epistemological ImplicationsThe present historic-critical essay traces the pecularities of classical phenomenological thermodynamics back to the paradigm, created by CARNOT, and takes up some questions to which this paradigm gives rise.

  6. Effects of Hypothyroidism on Expression of CRMP2B and ARPC5 during Development of the Rat Frontal Cortex

    PubMed Central

    Liu, Chun-rong; Miao, Jun; Zhang, Yong-liang; Liu, Ya-min; Yu, Bao-guo

    2013-01-01

    Congenital hypothyroidism (CH) can lead to irreversible central nervous system (CNS) damage. However, the pathogenesis of the developmental brain disorders caused by CH has not been completely elucidated. ARPC5 and CRMP2 are closely associated with neurite outgrowth in brain development. Thus, the aim of the present study was to determine whether CRMP2B and ARPC5 expression is altered in the developing cerebral cortex of rats with CH. Control rats and rats with hypothyroidism were sacrificed at birth and at 15 days postpartum. We performed qRT-PCR to detect differences in the crmp2B and arpc5 mRNA expression in the right half of the frontal cortex of these rats. Western blotting was then used to detect differences in CRMP2B and ARPC5 protein expression. Furthermore, immunohistochemical analysis was performed on the left half of the frontal cortex to detect abnormal localization of CRMP2B and ARPC5. Results showed increased expression of the nuclear short isoform of CRMP2B and decreased expression of full-length CRMP2B and ARPC5 in cortical neurons of rats with hypothyroidism. These findings demonstrate that reduced levels of thyroid hormones can inhibit the expression of full-length CRMP2B and ARPC5 and promote nuclear transformation of the short isoform of CRMP2B. CRMP2B and ARPC5 may participate in CNS injury mediated by hypothyroidism by inducing neurite outgrowth inhibition and cytoskeletal protein disorganization. PMID:23459330

  7. High-throughput screening assays for CYP2B6 metabolism and inhibition using fluorogenic vivid substrates.

    PubMed

    Marks, Bryan D; Goossens, Tony A; Braun, Heidi A; Ozers, Mary S; Smith, Ronald W; Lebakken, Connie; Trubetskoy, Olga V

    2003-01-01

    CYP2B6 is a highly polymorphic P450 isozyme involved in the metabolism of endo- and xenobiotics with known implications for the activation of many procarcinogens resulting in carcinogenesis. However, lack of validated high-throughput screening (HTS) CYP2B6 assays has limited the current understanding and full characterization of this isozyme's involvement in human drug metabolism. Here, we have developed and characterized a fluorescence-based HTS assay employing recombinant human CYP2B6 and 2 novel fluorogenic substrates (the Vivid CYP2B6 Blue and Cyan Substrates). Assay validation included testing the inhibitory potency of a panel of drugs and compounds known to be metabolized by this isozyme, including CYP2B6 substrates, inhibitors, and known inducers. Compound rankings based on inhibitory potency in the Vivid CYP2B6 Blue and Cyan Assays matched compound rankings based on relative affinity measurements from previously published data (K(i), K(d), or K(m) values) for the CYP2B6 isozyme. In conclusion, these assays are proven to be robust and sensitive, with broad dynamic ranges and kinetic parameters allowing screening in HTS mode of a large panel of compounds for CYP2B6 metabolism and inhibition, and are a valuable new tool for CYP2B6 studies.

  8. [Leben im Eismeer - Tauchuntersuchungen zur Biologie arktischer Meerespflanzen und Meerestiere

    PubMed

    Lippert; Karsten; Wiencke

    2000-01-01

    Die Maske wird nochmals auf Dichtigkeit überprüft, der Knoten der Sicherungsleine mit zwei halben Schlägen fixiert, dann rutscht die Taucherin von der Eiskante in das kalte Wasser. Eine halbe Stunde vergeht, bevor ihr Kopf wieder aus dem Eisloch auftaucht und sie ein großes Sammelnetz nach oben reicht, gefüllt mit verschiedenen Arten von Makroalgen. Obwohl noch große Flächen des Kongsfjordes im arktischen Spitzbergen zugefroren sind und das Festland von einer dicken Schneedecke bedeckt ist, hat unter Wasser in den Algenwäldern bereits der Sommer und damit die Saison der Meeresbiologen begonnen.

  9. Jumonji domain-containing protein 2B silencing induces DNA damage response via STAT3 pathway in colorectal cancer

    PubMed Central

    Chen, L; Fu, L; Kong, X; Xu, J; Wang, Z; Ma, X; Akiyama, Y; Chen, Y; Fang, J

    2014-01-01

    Background: Jumonji domain-containing protein 2B (JMJD2B), directly targeted by hypoxia-inducible factor 1α, maintains the histone methylation balance important for the transcriptional activation of many oncogenes. Jumonji domain-containing protein 2B has been implicated in colorectal cancer (CRC) progression; however, the mechanism remains unclear. Methods: Immunofluorescence and western blotting detected phosphorylated histone H2AX, characteristic of double-strand breaks, and comet assay was used to investigate DNA damage, in CRC cells after JMJD2B small interfering RNA (siRNA) transfection. We assessed the resulting in vitro responses, that is, cell cycle progression, apoptosis, and senescence coupled with JMJD2B silencing-induced DNA damage, studying the regulatory role of signal transducers and activators of transcription 3 (STAT3). The JMJD2B silencing anti-cancer effect was determined using an in vivo CRC xenograft model. Results: Jumonji domain-containing protein 2B knockdown induced DNA damage via ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related pathway activation, resulting in cell cycle arrest, apoptosis, and senescence in both normoxia and hypoxia. Signal transducers and activators of transcription 3 suppression by JMJD2B silencing enhanced DNA damage. Intratumoural injection of JMJD2B siRNA suppressed tumour growth in vivo and activated the DNA damage response (DDR). Conclusions: Jumonji domain-containing protein 2B has an essential role in cancer cell survival and tumour growth via DDR mediation, which STAT3 partially regulates, suggesting that JMJD2B is a potential anti-cancer target. PMID:24473398

  10. DFT study of coverage-depended adsorption of NH3 on TiO2-B (100) surface.

    PubMed

    Guo, Xiao-Jing; Liu, Weijia; Fang, Wei; Cai, Lu; Zhu, Yudan; Lu, Linghong; Lu, Xiaohua

    2012-12-28

    A previous study showed that TiO(2)-B (100) surface is very unique. It is characterised by high activity and a loose structure. In this study, we studied the adsorption of ammonia on TiO(2)-B (100) surface at coverages ranging from 1/6 ML to 1 ML using ab initio density functional calculations. We also investigated the adsorption of an isolated ammonia molecule on TiO(2)-B (001) surface to compare the different activities of TiO(2)-B (100) and (001) surfaces towards NH(3). The results showed that the TiO(2)-B (100) surface is more reactive towards NH(3) molecule than TiO(2)-B (001) surface, and the Lewis acid site on TiO(2)-B (100) surface is more acidic. The decrease rate of the average molecular adsorption energy of NH(3) with coverage on TiO(2)-B (100) surface is substantially lower than that on a rutile (011) surface above 1/2 ML coverage due to the open structure of TiO(2)-B (100) surface. The average molecular adsorption energy shows a linear dependence on the coverage of y = 111.0 - 36.3x on TiO(2)-B (100) surface. The possibility of NH(3) molecule onto the Ti(5c) site is nearly equal to forming a dimer with adsorbed NH(3) on TiO(2)-B (100) surface at 5/6 ML coverage. PMID:22955312

  11. Influence of P ion on Sr2B5O9Cl:Eu for TL dosimetry

    NASA Astrophysics Data System (ADS)

    Oza, Abha H.; Dhoble, N. S.; Dhoble, S. J.

    2015-02-01

    This paper investigates luminescence properties of Sr2B5O9Cl:Eu phosphor prepared by modified solid state diffusion. The influence of Phosphorous ion as codopant is also explained in detail. The structural confirmation of the sample was done using the XRD technique. SEM revealed the microcrystalline nature of the prepared phosphor. The characteristic Eu2+ emission at 437 nm and 423 nm was observed for Sr2B5O9Cl:Eu and Sr2B5O9Cl:P,Eu, respectively under 338 nm excitation. Samples in powder form were irradiated with different doses under γ-ray irradiation with 60Co source and the TL glow curves for both Sr2B5O9Cl:Eu and Sr2B5O9Cl:P,Eu samples were studied. In case of Sr2B5O9Cl:Eu phosphor, single glow curve nature centered on 260 °C with a shoulder peak around 144 °C was observed. However; Sr2B5O9Cl:P,Eu have shown slight different and broad glow curve nature. The TL sensitivity in both the cases was compared with CaSO4:Dy phosphor. Sr2B5O9Cl:Eu sample have shown 1.17 times less sensitivity than CaSO4:Dy and for Sr2B5O9Cl:P,Eu it was found to be equal to CaSO4:Dy and Sr2B5O9Cl:P,Eu is 1.21 times more sensitive than Sr2B5O9Cl:Eu. Other TL properties like dose response, fading and reusability were studied for both the samples. The trapping parameters for both the samples were calculated using computerized glow curve deconvolution and reported in this paper.

  12. Transcriptional Regulation of CYP2B6 Expression by Hepatocyte Nuclear Factor 3β in Human Liver Cells

    PubMed Central

    Li, Linhao; Li, Daochuan; Heyward, Scott; Wang, Hongbing

    2016-01-01

    CYP2B6 plays an increasingly important role in xenobiotic metabolism and detoxification. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) have been established as predominant regulators for the inductive expression of CYP2B6 gene in human liver. However, there are dramatic interindividual variabilities in CYP2B6 expression that cannot be fully explained by the CAR/PXR-based modulation alone. Here, we show that expression level of CYP2B6 was correlated with that of hepatocyte nuclear factor 3β (HNF3β) in human primary hepatocytes prepared from 35 liver donors. Utilizing recombinant virus-mediated overexpression or knockdown of HNF3β in HepG2 cells, as well as constructs containing serial deletion and site-directed mutation of HNF3β binding motifs in CYP2B6 luciferase reporter assays, we demonstrated that the presence or lack of HNF3β expression markedly correlated with CYP2B6 gene expression and its promoter activity. Novel enhancer modules of HNF3β located upstream of the CYP2B6 gene transcription start site were identified and functionally validated as key elements governing HNF3β-mediated CYP2B6 expression. Chromatin immunoprecipitation assays in human primary hepatocytes and surface plasmon resonance binding affinity experiments confirmed the essential role of these enhancers in the recruitment of HNF3β to the promoter of CYP2B6 gene. Overall, these findings indicate that HNF3β represents a new liver enriched transcription factor that is involved in the transcription of CYP2B6 gene and contributes to the large interindividual variations of CYP2B6 expression in human population. PMID:26930610

  13. SETDB1 HISTONE METHYLTRANSFERASE REGULATES MOOD-RELATED BEHAVIORS AND EXPRESSION OF THE NMDA RECEPTOR SUBUNIT NR2B

    PubMed Central

    Jiang, Yan; Jakovcevski, Mira; Bharadwaj, Rahul; Connor, Caroline; Schroeder, Frederick A.; Lin, Cong L.; Straubhaar, Juerg; Martin, Gilles; Akbarian, Schahram

    2010-01-01

    Histone methyltransferases specific for the histone H3-lysine 9 (H3K9) residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to less than 1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture (“3C”) and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30Kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wildtype mice, systemic treatment with the NR2B antagonist, Ro-256981, and hippocampal siRNA-mediated NR2B/Grin2b knockdown, resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations. PMID:20505083

  14. Diagnose und Therapie einer Depression im höheren Lebensalter – Einflüsse von Patienten- und Arztmerkmalen

    PubMed Central

    von dem Knesebeck, Olaf; Bönte, Markus; Siegrist, Johannes; Marceau, Lisa; Link, Carol; McKinlay, John

    2013-01-01

    Zusammenfassung Studienergebnissee aus dem englischsprachigen Raum zeigen, dass diagnostische und therapeutische Entscheidungen von Hausärzten bei der Versorgung von depressiven Patienten systematischen Einflüssen unterliegen, und dass sowohl Merkmale des Arztes als auch des Patienten unabhängig vom Krankheitsbild Einfluss auf diese Entscheidungen haben. In der vorliegenden Arbeit werden Ergebnisse einer deutschen Studie präsentiert, in der die Einflüsse von Patienten- und Arztmerkmalen auf diagnostische und therapeutische ärztliche Entscheidungen bei einer Depression untersucht wurden. Unter Anwendung eines faktoriellen Experimentaldesigns spielten professionelle Schauspieler in Videofilmen die Rolle von Patienten, die Symptome für eine depressive Erkrankung äußern. In den Videofilmen, die alle auf einem identischen Skript basieren, wurden systematisch die Patientenmerkmale Alter (55 vs. 75 Jahre), Geschlecht und sozialer Status (Hausmeister vs. Lehrer) variiert. Die randomisierte Ärztestichprobe wurde nach dem Arztgeschlecht und professioneller Erfahrung (< 5 vs. > 15 Jahre) geschichtet. Der Videofilm wurde insgesamt 128 niedergelassenen Ärzten für Allgemeinmedizin und hausärztlich tätigen Internisten in ihrer Praxis vorgespielt. Danach wurden die Ärzte zu unterschiedlichen Aspekten von Diagnose und Therapie befragt. Es wurde erhoben, ob der Arzt dem Patienten über das gezeigte Gespräch hinausgehende Fragen stellen würde, welche Diagnosen er für wahrscheinlich hält, wie sicher er sich mit seiner Diagnose ist, welche diagnostischen Tests er anordnen würde, ob er den Patienten überweisen würde oder ob er Medikamente verordnen oder ihm Empfehlungen zur Änderung seines Lebensstils geben würde. Die Ergebnisse weisen darauf hin, dass sowohl die Diagnose als auch die Therapie einer Depression durch niedergelassene Hausärzte in Deutschland nur geringfügig durch die untersuchten Merkmale der Patienten und der behandelnden Ärzte beeinflusst wird

  15. Histone H2B-IFI16 Recognition of Nuclear Herpesviral Genome Induces Cytoplasmic Interferon-β Responses

    PubMed Central

    Iqbal, Jawed; Ansari, Mairaj Ahmed; Kumar, Binod; Dutta, Dipanjan; Roy, Arunava; Chikoti, Leela; Pisano, Gina; Dutta, Sujoy; Veettil, Mohanan Valiya; Chandran, Bala

    2016-01-01

    IFI16 (gamma-interferon-inducible protein 16), a predominantly nuclear protein involved in transcriptional regulation, also functions as an innate immune response DNA sensor and induces the IL-1β and antiviral type-1 interferon-β (IFN-β) cytokines. We have shown that IFI16, in association with BRCA1, functions as a sequence independent nuclear sensor of episomal dsDNA genomes of KSHV, EBV and HSV-1. Recognition of these herpesvirus genomes resulted in IFI16 acetylation, BRCA1-IFI16-ASC-procaspase-1 inflammasome formation, cytoplasmic translocation, and IL-1β generation. Acetylated IFI16 also interacted with cytoplasmic STING and induced IFN-β. However, the identity of IFI16 associated nuclear proteins involved in STING activation and the mechanism is not known. Mass spectrometry of proteins precipitated by anti-IFI16 antibodies from uninfected endothelial cell nuclear lysate revealed that histone H2B interacts with IFI16. Single and double proximity ligation microscopy, immunoprecipitation, EdU-genome labeled virus infection, and chromatin immunoprecipitation studies demonstrated that H2B is associated with IFI16 and BRCA1 in the nucleus in physiological conditions. De novo KSHV and HSV-1 infection as well as latent KSHV and EBV infection induces the cytoplasmic distribution of H2B-IFI16, H2B-BRCA1 and IFI16-ASC complexes. Vaccinia virus (dsDNA) cytoplasmic replication didn’t induce the redistribution of nuclear H2B-IFI16 or H2B into the cytoplasm. H2B is critical in KSHV and HSV-1 genome recognition by IFI16 during de novo infection. Viral genome sensing by IFI16-H2B-BRCA1 leads to BRCA1 dependent recruitment of p300, and acetylation of H2B and IFI16. BRCA1 knockdown or inhibition of p300 abrogated the acetylation of H2B-IFI16 or H2B. Ran-GTP protein mediated the translocation of acetylated H2B and IFI16 to the cytoplasm along with BRCA1 that is independent of IFI16-ASC inflammasome. ASC knockdown didn’t affect the acetylation of H2B, its cytoplasmic

  16. Serotonin skews human macrophage polarization through HTR2B and HTR7.

    PubMed

    de las Casas-Engel, Mateo; Domínguez-Soto, Angeles; Sierra-Filardi, Elena; Bragado, Rafael; Nieto, Concha; Puig-Kroger, Amaya; Samaniego, Rafael; Loza, Mabel; Corcuera, María Teresa; Gómez-Aguado, Fernando; Bustos, Matilde; Sánchez-Mateos, Paloma; Corbí, Angel L

    2013-03-01

    Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT(1-7)) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization-associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7), whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies. PMID:23355731

  17. The Preparation and Characterization of INTEC Phase 2b Composition Variation Study Glasses

    SciTech Connect

    B. A. Staples; B. A. Scholes; L. L. Torres; C. A. Musick; B. R. Boyle; D. K. Peeler; J. D. Vienna

    2000-02-01

    The second phase of the composition variation study (CVS) for the development of glass compositions to immobilize Idaho Nuclear Technology and Engineering Center (INTEC) high level wastes (HLW) is complete. This phase of the CVS addressed waste composition of high activity waste fractions (HAW) from the initial separations flowsheet. Updated estimates if INTEC calcined HLW compositions and of high activity waste fractions proposed to be separated from dissolved calcine were used as the waste component for this CVS phase. These wastes are of particular interest because high aluminum, calcium, zirconium, fluorine, potassium, and low iron and sodium content places them outside the vitrification experience in the Department of Energy complex. Because of the presence of calcium and fluorine, two major zirconia calcine components not addressed in Phase I, a series of scooping tests, designated Phase 2a, were performed. The results of these tests provided information on the effects of calcium and fluoride solubility and their impacts on product properties and composition boundary information for Phase 2b. Details and results of Phase 2a are reported separately. Through application of statistical techniques and the results of Phase 2a, a test matrix was defined for Phase 2b of the CVS. From this matrix, formulations were systematically selected for preparation and characterization with respect to visual and optical homogeneity, viscosity as a function of melt temperature, liquidus temperature (TL), and leaching properties based on response to the product consistency test. The results of preparing and characterizing the Phase 2b glasses are presented in this document. Based on the results, several formulations investigated have suitable properties for further development. A full analysis of the composition-product characteristic relationship of glasses being developed for immobilizing INTEC wastes will be performed at the completion of composition-property relationship

  18. Spectral analysis of Cu(2+): B(2)O(3)--ZnO--PbO glasses.

    PubMed

    Lakshminarayana, G; Buddhudu, S

    2005-11-01

    A new series of heavy metal oxide (PbO) based zinc borate glasses in the chemical composition of (95-x)B(2)O(3)-5ZnO-xPbO (x=10, 15, 20, 25, 30, 35, 40, 45 and 50 mol%) have been prepared to verify their UV filtering performance. Both direct and indirect optical band gaps (E(opt)) have been evaluated for these glasses. For a reference glass of 45B(2)O(3)-5ZnO-50PbO, refractive indices at different wavelengths are measured and found the results satisfactorily correlated with the theoretical data upon the computation of Cauchy's constants of A=1.766029949, B=159531.024 nm(2) and C=-1.078 x 10(10) nm(4). Measurements concerning X-ray diffraction (XRD), FT-IR, differential scanning colorimeter (DSC) profiles have been carried out for this glass. The FT-IR profile has revealed that the glass has both BO(3) and BO(4) units. From DSC thermogram, glass transition temperature (T(g)), crystallization temperature (T(c)) and melting temperature (T(m)) have been located and from them, other related parameters of the glass have also been calculated. Visible absorption spectra of 45B(2)O(3)-5ZnO-(50-x)PbO-xCuO (x=0. 1, 0.2, 0.5 and 1.0 mol%) have revealed two absorption bands at around 400 nm ((2)B(1g)-->(2)E(g)) and 780 nm ((2)B(1g)-->(2)B(2g)) of Cu(2+) ions, respectively. Emission bands at 422 and 512 nm are found for the 1 mol % CuO doped glass with excitations at 306 and 332 nm.

  19. Macroscale production and analysis of crystalline interferon alpha-2B in microgravity on STS-52

    NASA Astrophysics Data System (ADS)

    Reichert, Paul; Nagabhushan, Tattanahalli L.; Long, Marianna M.; Bugg, Charles E.; DeLucas, Lawrence J.

    1996-03-01

    The development and production of a zinc-interferon alpha-2b crystalline suspension on STS-52 has accelerated our ability to prepare novel high quality pharmaceutical preparations. Crystalline suspensions of protein therapeutics have applications in drug delivery, formulation, and manufacturing. These applications require crystalline suspensions of relatively small particles (<100 microns) of uniform size and shape. Previously, a crystalline form of interferon alpha-2b was identified from microscale crystallization methods with utility in pharmaceutical applications from microscale crystallization methods. Conditions for macroscale crystallization were established by adapting a microscale vapor diffusion method to a macroscale temperature induction method. A series of earth based pilot experiments established conditions to reproducibly crystallize zinc interferon alpha-2b in high yield and under ``cleanroom'' conditions. These conditions were maintained in microgravity. Greater than 95% of the available protein crystallized in both the ground and flight experiments. The samples were analyzed using a battery of physical, biochemical, and biological characterization methods. The results demonstrated that sample processing, polysulfone bottle confinement, and the conditions used for crystallization did not have a negative effect on protein integrity. Redissolved crystals from the flight and ground experiments showed full biological activity in a cytopathic effect inhibition assay as compared to an interferon control standard. Morphometric analysis comparing the overall length and width of the derived crystals showed a 2.4 fold increase in the length and width of the space grown crystals as compared to earth grown crystals. Subcutaneous injections of space grown crystalline preparation was compared to a non-crystalline interferon preparation in a primate pharmacokinetic study. The crystalline interferon preparation had a measured serum half-life of 12 hours as compared

  20. Tbx2b is required for ultraviolet photoreceptor cell specification during zebrafish retinal development

    PubMed Central

    Alvarez-Delfin, Karen; Morris, Ann C.; Snelson, Corey D.; Gamse, Joshua T.; Gupta, Tripti; Marlow, Florence L.; Mullins, Mary C.; Burgess, Harold A.; Granato, Michael; Fadool, James M.

    2009-01-01

    The vertebrate rod and cone photoreceptors are highly specialized sensory neurons that transduce light into the chemical and electrical signals of the nervous system. Although the physiological properties of cones and rods are well known, only a handful of genes have been identified that regulate the specification of photoreceptor subtypes. Taking advantage of the mosaic organization of photoreceptors in zebrafish, we report the isolation of a mutation resulting in a unique change in photoreceptor cell fate. Mutation of the lots-of-rods (lor) locus results in a near one-for-one transformation of UV-cone precursors into rods. The transformed cells exhibit morphological characteristics and a gene-expression pattern typical of rods, but differentiate in a temporal and spatial pattern consistent with UV-cone development. In mutant larvae and adults, the highly ordered photoreceptor mosaic is maintained and degeneration is not observed, suggesting that lor functions after the specification of the other photoreceptor subtypes. In genetic chimeras, lor functions cell-autonomously in the specification of photoreceptor cell fate. Linkage analysis and genetic-complementation testing indicate that lor is an allele of tbx2b/fby (from beyond). fby was identified by a pineal complex phenotype, and carries a nonsense mutation in the T-box domain of the tbx2b transcription factor. Homozygous fby mutant larvae and lor/fby transheterozygotes also display the lots-of-rods phenotype. Based upon these data, we propose a previously undescribed function for tbx2b in photoreceptor cell precursors, to promote the UV cone fate by repressing the rod differentiation pathway. PMID:19179291

  1. E-hubs: the new B2B (business-to-business) marketplaces.

    PubMed

    Kaplan, S; Sawhney, M

    2000-01-01

    Electronic hubs--Internet-based intermediaries that host electronic marketplaces and mediate transactions among businesses--are generating a lot of interest. Companies like Ariba, Chemdex, and Commerce One have already attained breathtaking stock market capitalizations. Venture capitalists are pouring money into more business-to-business start-ups. Even industrial stalwarts like GM and Ford are making plans to set up their own Web markets. As new entrants with new business models pour into the business-to-business space, it's increasingly difficult to make sense of the landscape. This article provides a blueprint of the e-hub arena. The authors start by looking at the two dimensions of purchasing: what businesses buy--manufacturing inputs or operating inputs--and how they buy--through systematic sourcing or spot sourcing. They classify B2B e-hubs into four categories: MRO hubs, yield managers, exchanges, and catalog hubs, and they discuss each type in detail. Drilling deeper into this B2B matrix, the authors look at how e-hubs create value--through aggregation and matching--and explain when each mechanism works best. They also examine the biases of e-hubs. Although many e-hubs are neutral--they're operated by independent third parties--some favor the buyers or sellers. The authors explain the differences and discuss the pros and cons of each position. The B2B marketplace is changing rapidly. This framework helps buyers, sellers, and market makers navigate the landscape by explaining what the different hubs do and how they add the most value. PMID:11183982

  2. HATS-2b: A transiting extrasolar planet orbiting a K-type star showing starspot activity

    NASA Astrophysics Data System (ADS)

    Mohler-Fischer, M.; Mancini, L.; Hartman, J. D.; Bakos, G. Á.; Penev, K.; Bayliss, D.; Jordán, A.; Csubry, Z.; Zhou, G.; Rabus, M.; Nikolov, N.; Brahm, R.; Espinoza, N.; Buchhave, L. A.; Béky, B.; Suc, V.; Csák, B.; Henning, T.; Wright, D. J.; Tinney, C. G.; Addison, B. C.; Schmidt, B.; Noyes, R. W.; Papp, I.; Lázár, J.; Sári, P.; Conroy, P.

    2013-10-01

    We report the discovery of HATS-2b, the second transiting extrasolar planet detected by the HATSouth survey. HATS-2b is moving on a circular orbit around a V = 13.6 mag, K-type dwarf star (GSC 6665-00236), at a separation of 0.0230 ± 0.0003 AU and with a period of 1.3541 days. The planetary parameters have been robustly determined using a simultaneous fit of the HATSouth, MPG/ESO 2.2 m/GROND, Faulkes Telescope South/Spectral transit photometry, and MPG/ESO 2.2 m/FEROS, Euler 1.2 m/CORALIE, AAT 3.9 m/CYCLOPS radial-velocity measurements. HATS-2b has a mass of 1.37 ± 0.16 MJ, a radius of 1.14 ± 0.03 RJ, and an equilibrium temperature of 1567 ± 30 K. The host star has a mass of 0.88 ± 0.04 M⊙ and a radius of 0.89 ± 0.02 R⊙, and it shows starspot activity. We characterized the stellar activity by analyzing two photometric follow-up transit light curves taken with the GROND instrument, both obtained simultaneously in four optical bands (covering the wavelength range of 3860-9520 Å). The two light curves contain anomalies compatible with starspots on the photosphere of the host star along the same transit chord. Tables of the individual photometric measurements are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/558/A55

  3. Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach.

    PubMed

    Mony, Laetitia; Triballeau, Nicolas; Paoletti, Pierre; Acher, Francine C; Bertrand, Hugues-Olivier

    2010-09-15

    We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.

  4. 50 CFR Table 2b to Part 660... - 2014, and Beyond, Allocations by Species or Species Group

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 13 2014-10-01 2014-10-01 false 2014, and Beyond, Allocations by Species or Species Group 2b Table 2b to Part 660, Subpart C Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES...

  5. 3 CFR - Presidential Determination for the Kingdom of Cambodia Under Section 2(b)(2) of the Export-Import...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Cambodia Under Section 2(b)(2) of the Export-Import Bank Act of 1945, as amended Presidential Documents... Determination for the Kingdom of Cambodia Under Section 2(b)(2) of the Export-Import Bank Act of 1945, as... Kingdom of Cambodia has ceased to be a Marxist-Leninist country within the definition of such term...

  6. 76 FR 65199 - International Conference on Harmonisation; E2B(R3) Electronic Transmission of Individual Case...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-20

    ...) Electronic Transmission of Individual Case Safety Reports; Draft Guidance on Implementation; Data Elements... Safety Reports (ICSRs): Implementation Guide--Data Elements and Message Specification'' (the draft E2B(R3... BFC appendix describes the relationship between data elements from the 2001 ICH E2B guidance and...

  7. 76 FR 73508 - Wage Methodology for the Temporary Non-Agricultural Employment H-2B Program; Delay of Effective Date

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-29

    ... Employment H-2B Program; Final Rule, 76 FR 3452, Jan. 19, 2011, (the Wage Rule) to January 1, 2012 in... 655, published at 76 FR 45667, August 1, 2011, as further amended at 76 FR 59896, September 28, 2011... Employment H-2B Program; Final Rule (the Wage Rule) on January 19, 2011, 76 FR 3452. The Wage Rule...

  8. Atomic force microscopy revelation of molecular complexes in the multiprotein cytochrome P450 2B4-containing system.

    PubMed

    Kuznetsov, Vadim Yu; Ivanov, Yuri D; Archakov, Alexander I

    2004-08-01

    The application of atomic force microscopy (AFM) to the identification and visualization of individual molecules and their complexes in a reconstituted monooxygenase P450 2B4 system without the phospholipid was demonstrated. The method employed in this study distinguishes the monomeric proteins from their binary complexes and, also, the binary from the ternary complexes. The AFM images of the full-length P450 2B4 system's constituent components - cytochrome P450 2B4 (2B4), NADPH-cytochrome P450 reductase and cytochrome b5 (b5), were obtained on highly-oriented pyrolitic graphite. The typical heights of the d-2B4, d-flavoprotein (Fp) and d-b5 molecules were measured and found to be 2.2 +/- 0.2, 2.3 +/- 0.2 and 1.8 +/- 0.1 nm, respectively. The measured heights of the binary d-Fp/d-2B4 and d-2B4/d-b5 complexes were estimated to be 3.4 +/- 0.2 and 2.8 +/- 0.2 nm, respectively. No formation of d-Fp/d-b5 complexes was registered. The ternary d-Fp/d-2B4/d-b5 complexes were visualized and their heights were found to be roughly equal to 4.3 +/- 0.3 nm and 6.2 +/- 0.3 nm. PMID:15274134

  9. In vitro processing of dengue virus type 2 nonstructural proteins NS2A, NS2B, and NS3.

    PubMed Central

    Preugschat, F; Yao, C W; Strauss, J H

    1990-01-01

    We have tested the hypothesis that the flavivirus nonstructural protein NS3 is a viral proteinase that generates the termini of several nonstructural proteins by using an efficient in vitro expression system and monospecific antisera directed against the nonstructural proteins NS2B and NS3. A series of cDNA constructs was transcribed by using T7 RNA polymerase, and the RNA was translated in reticulocyte lysates. The resulting protein patterns indicated that proteolytic processing occurred in vitro to generate NS2B and NS3. The amino termini of NS2B and NS3 produced in vitro were found to be the same as the termini of NS2B and NS3 isolated from infected cells. Deletion analysis of cDNA constructs localized the protease domain within NS3 to the first 184 amino acids but did not eliminate the possibility that sequences within NS2B were also required for proper cleavage. Kinetic analysis of processing events in vitro and experiments to examine the sensitivity of processing to dilution suggested that an intramolecular cleavage between NS2A and NS2B preceded an intramolecular cleavage between NS2B and NS3. The data from these expression experiments confirm that NS3 is the viral proteinase responsible for cleavage events generating the amino termini of NS2B and NS3 and presumably for cleavages generating the termini of NS4A and NS5 as well. Images PMID:2143543

  10. RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells.

    PubMed

    Kim, Jaehoon; Guermah, Mohamed; McGinty, Robert K; Lee, Jung-Shin; Tang, Zhanyun; Milne, Thomas A; Shilatifard, Ali; Muir, Tom W; Roeder, Robert G

    2009-05-01

    H2B ubiquitylation has been implicated in active transcription but is not well understood in mammalian cells. Beyond earlier identification of hBRE1 as the E3 ligase for H2B ubiquitylation in human cells, we now show (1) that hRAD6 serves as the cognate E2-conjugating enzyme; (2) that hRAD6, through direct interaction with hPAF-bound hBRE1, is recruited to transcribed genes and ubiquitylates chromatinized H2B at lysine 120; (3) that hPAF-mediated transcription is required for efficient H2B ubiquitylation as a result of hPAF-dependent recruitment of hBRE1-hRAD6 to the Pol II transcription machinery; (4) that H2B ubiquitylation per se does not affect the level of hPAF-, SII-, and p300-dependent transcription and likely functions downstream; and (5) that H2B ubiquitylation directly stimulates hSET1-dependent H3K4 di- and trimethylation. These studies establish the natural H2B ubiquitylation factors in human cells and also detail the mechanistic basis for H2B ubiquitylation and function during transcription. PMID:19410543

  11. 77 FR 24225 - Information Collection Approval; Temporary Non-Agricultural Employment of H-2B Aliens in the...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-23

    ... Employment of H-2B Aliens in the United States; Final Rule. See 77 FR 10038, Feb. 21, 2012. DATES: On April 8....gov/fdsys/browse/collection.action?collectionCode=FR Web site. Copies of this notice may be obtained..., 2012. See 77 FR 10038. The purpose of the Final Rule was to amend the H-2B regulations at 20 CFR...

  12. 26 CFR 301.6103(p)(2)(B)-1 - Disclosure of returns and return information by other agencies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Disclosure of returns and return information by other agencies. 301.6103(p)(2)(B)-1 Section 301.6103(p)(2)(B)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) PROCEDURE AND ADMINISTRATION PROCEDURE AND ADMINISTRATION Information and Returns Returns and Records...

  13. Deletion of JMJD2B in neurons leads to defective spine maturation, hyperactive behavior and memory deficits in mouse

    PubMed Central

    Fujiwara, K; Fujita, Y; Kasai, A; Onaka, Y; Hashimoto, H; Okada, H; Yamashita, T

    2016-01-01

    JMJD2B is a histone demethylase enzyme that regulates gene expression through demethylation of H3K9me3. Although mutations of JMJD2B have been suggested to be responsible for neurodevelopmental disorders, the function of JMJD2B in the central nervous system (CNS) remains to be elucidated. Here we show that JMJD2B has a critical role in the development of the CNS. We observed JMJD2B expression, which was especially strong in the hippocampus, throughout the CNS from embryonic periods through adulthood. We generated neuron-specific JMJD2B-deficient mice using the cre-loxP system. We found an increase in total spine number, but a decrease in mature spines, in the CA1 region of the hippocampus. JMJD2B-deficient mice exhibited hyperactive behavior, sustained hyperactivity in a novel environment, deficits in working memory and spontaneous epileptic-like seizures. Together these observations indicate that JMJD2B mutant mice display symptoms reminiscent of neurodevelopmental disorders. Our findings provide evidence for the involvement of histone demethylation in the formation of functional neural networks during development. PMID:27023172

  14. PON2 and ATP2B2 gene polymorphisms with noise-induced hearing loss

    PubMed Central

    Li, Xiuting; Cao, Jinglian; Wang, Jun; Song, Haiyan; Ji, Guixiang; Dong, Qiu; Wei, Chunlong; Cao, Ying; Wang, Boshen

    2016-01-01

    Background Noise-induced hearing loss (NIHL) is a complex disease induced by a combination of genetic and environmental factors. Paraoxonase2 (PON2) gene involved in the regulation of reactive oxygen species, and affecting the vulnerability of cochlea to NIHL, and ATPase, calcium-transporting, plasma membrane 2 (ATP2B2) gene which encodes plasma membrane calcium-transporting ATPase isoform 2 (PMCA2) are the candidate genes relating to the attack of NIHL. In this study, we investigated whether ATP2B2 and PON2 polymorphisms were associated with NIHL in Chinese of Han nationality population. Methods We performed a case-control study between six single nucleotide polymorphisms (SNPs) (rs1719571, rs3209637 and rs4327369 within ATP2B2, rs12026, rs7785846 and rs12704796 within PON2) and NIHL in 454 subjects. All the SNPs were genotypes, using the TaqMan MGB probe assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs) with logistic regression analysis to test the level of association for SNPs. Results In our study, 221 subjects with hearing loss and 233 subjects without hearing loss were recruited. The frequencies of the CG and CG + GG genotype of rs12026 (PON2) conferred risk factors for NIHL with adjusted OR values of 2.62 (95% CI, 1.69–4.06) and 2.48 (95% CI, 1.63–3.78), respectively. This kind of significance was also found at locus rs7785846, where genotypes CT and CT + TT were the risk types, with adjusted ORs of 2.52 (95% CI, 1.62–3.93) and 2.35 (95% CI, 1.54–3.58), respectively. We performed stratified analysis per noise exposure level, when it came to rs7785846 and rs12026 in the >92 dB(A) noise exposure group, the subjects who carried heterozygote were of significantly (P<0.01) higher susceptibility to NIHL than homozygote carriers. By contrast, no significantly higher risk was found for any rs12704796 genotypes or any genotypes in ATP2B2 (P>0.05), which may suggest that these SNPs did not have significant effects on noise

  15. Angular-dependent I-V characteristics in borocarbide superconductor YNi(2)B(2)C.

    PubMed

    Chu, R M; Chen, Q Y; Chu, W K

    2006-04-26

    We present angular-dependent current-voltage (I-V) measurements in borocarbide YNi(2)B(2)C single crystals near the vortex-glass irreversible line. External magnetic fields are applied along the angle θ with respect to the c-axis. The nonlinear I-V curves reveal scaling behaviour near the transition. Using the scaling analysis, the relevant critical exponents and vortex transition temperatures are determined for all orientations. The data agrees well with the vortex-glass (VG) model. No evidence was found that supports the existence of a Bose-glass (BG) type of transition.

  16. Vortex imaging of magnetic superconductor HoNi 2B 2C by scanning SQUID microscopy

    NASA Astrophysics Data System (ADS)

    Hata, Y.; Suzuki, J.; Kakeya, I.; Kadowaki, K.; Nakayama, S.; Nagata, A.; Odawara, A.; Chinone, K.

    2002-10-01

    We have observed vortex trapped images in the ab-plane of a HoNi 2B 2C single crystal in a magnetic field of 1.2 μT at 4 K using a scanning SQUID microscope. The vortex observed has a fine structure consisting of two regions with opposite signs of the magnetic field which is quantized with multiple flux quanta as a whole. The spatial size of the magnetic field distribution extends over 10 μm. Such giant vortices are also observed at TN< T< TC and disappear above TC where TN is the magnetic transition temperature and TC is the superconducting transition temperature.

  17. Synthesis and fluorosolvatochromism of 3-arylnaphtho[1,2-b]quinolizinium derivatives

    PubMed Central

    Pithan, Phil M; Decker, David; Sardo, Manlio Sutero; Viola, Giampietro

    2016-01-01

    Summary Cationic biaryl derivatives were synthesized by Suzuki–Miyaura coupling of 3-bromonaphtho[1,2-b]quinolizinium bromide with arylboronic acids. The resulting cationic biaryl derivatives exhibit pronounced fluorosolvatochromic properties. First photophysical studies in different solvents showed that the emission energy of the biaryl derivatives decreases with increasing solvent polarity. This red-shifted emission in polar solvents is explained by a charge shift (CS) in the excited state and subsequent solvent relaxation. Furthermore, the polarity of protic polar and aprotic polar solvents affects the emission energy to different extent, which indicates a major influence of hydrogen bonding on the stabilization of the ground and excited states. PMID:27340476

  18. Synthesis and fluorosolvatochromism of 3-arylnaphtho[1,2-b]quinolizinium derivatives.

    PubMed

    Pithan, Phil M; Decker, David; Sardo, Manlio Sutero; Viola, Giampietro; Ihmels, Heiko

    2016-01-01

    Cationic biaryl derivatives were synthesized by Suzuki-Miyaura coupling of 3-bromonaphtho[1,2-b]quinolizinium bromide with arylboronic acids. The resulting cationic biaryl derivatives exhibit pronounced fluorosolvatochromic properties. First photophysical studies in different solvents showed that the emission energy of the biaryl derivatives decreases with increasing solvent polarity. This red-shifted emission in polar solvents is explained by a charge shift (CS) in the excited state and subsequent solvent relaxation. Furthermore, the polarity of protic polar and aprotic polar solvents affects the emission energy to different extent, which indicates a major influence of hydrogen bonding on the stabilization of the ground and excited states. PMID:27340476

  19. Impact of UGT2B17 gene deletion on the steroid profile of an athlete.

    PubMed

    Martín-Escudero, Pilar; Muñoz-Guerra, Jesús; Del Prado, Nayade; Galindo Canales, Mercedes; Fuentes Ferrer, Manuel; Vargas, Soledad; Soldevilla, Ana B; Serrano-Garde, Ester; Miguel-Tobal, Francisco; Maestro de Las Casas, Marisa; Fernandez-Pérez, Cristina

    2015-12-01

    The measurement of the testosterone to epitestosterone ratio (T/E ratio) in urine is often used as a marker for testosterone administration in the doping control field. This study examines the frequencies of the different expression forms of the UGT2B17 gene, and assesses their effects on this marker in volunteer subjects. The sample for this descriptive study was composed of male and female athletes aged between 16 and 55 years old who practiced different sports disciplines. All participants underwent a sports-medical physical examination, and subsequently provided 10 urine samples consecutively over a period of 48 h. The dependent variable examined was T/E and the main independent variable was the UGT2B17 gene polymorphism. During 1 year, 1410 urine samples were obtained from 141 athletes. The frequencies of the three genotypes were as follows: wt homozygotes (ins/ins) 48.2% (n = 68), mutant homozygotes (del/del) 12.1% (n = 17), and heterozygotes (ins/del) 39.7% (n = 56). Genotype distributions varied significantly (P < 0.001) according to ethnicity, 80% of Asian subjects being homozygous for the gene deletion (del/del) compared to 6.9% of Caucasian subjects. A multivariate analysis adjusted for genotype, age, sex, and sports discipline revealed that athletes with the del/del polymorphism showed a significantly lower mean T/E than heterozygotes (ins/del). In contrast, homozygous athletes for the gene insertion (ins/ins) showed higher mean T/E ratios than heterozygotes (ins/del). UGT2B17 gene deletion has a strong influence on the T/E ratio in urine, which is the most efficient indicator of testosterone prohormone misuse. Others factors studied seem not to have such an impact. The genotyping of UGT2B17 is an important source of information for understanding steroid profiling in the doping control field; therefore it is suggested that it be included in the Athletes Biological Passport.

  20. The Women of "Kabale und Liebe": A Teaching Approach

    ERIC Educational Resources Information Center

    Stephan, Naomi I.

    1976-01-01

    The three female characters in Schiller's "Kabale und Liebe" are analyzed. The article questions the value of using this play in a college curriculum because of the oppressive and unenlightened roles of the female characters. (TL)

  1. Ab initio study on structural, electronic properties, and hardness of re-doped W2B5

    NASA Astrophysics Data System (ADS)

    Feng, ShiQuan; Li, XiaoDong; Su, Lei; Li, HaiNing; Yang, Hongyan; Cheng, Xinlu

    2016-11-01

    Using first principle calculations method, we calculated the structural stability, electronic properties and hardness for three Re-doped hexagonal W2B5 compounds. The electronic properties were carried out to discuss the effect of doped Re on the conductivity, chemical bonding components and orbital hybridization of W2B5. What is more, the hardness of these three doped crystals was calculated by a semiempirical method considering the role of metallic components. A Re-doped W2B5 compound with a greater hardness value than that of pure W2B5 was obtained. And the effect of doping on the hardness of hexagonal W2B5was discussed.

  2. Konstruieren von Pkw-Karosserien: Grundlagen, Elemente und Baugruppen, Vorschriftenübersicht, Beispiele mit CATIA V4 und V5

    NASA Astrophysics Data System (ADS)

    Grabner, Jörg; Nothhaft, Richard

    Die Faszination, die vom Auto ausgeht, ist und bleibt ungebrochen. Entsprechend interessant ist es, sich vor dem Hintergrund konventioneller Konstruktionstechniken über die virtuelle Produktentwicklung von Pkw-Karosserien an modernen CAD-Arbeitsplätzen informieren zu können. Die Autoren führen in die Grundlagen ein und zeigen anhand von Beispielen und zahlreichen Abbildungen, wie mit dem System CATIA der Rohbau sowie die Ausstattung innen und au=C3=9Fen konstruiert werden. Darüber hinaus wird das so genannte "Package" an Beispielen beschrieben, also das Management und die Harmonisierung der Anforderungen an die Bauräume (z.

  3. Einstellung und Wissen von Lehramtsstudierenden zur Evolution - ein Vergleich zwischen Deutschland und der Türkei

    NASA Astrophysics Data System (ADS)

    Graf, Dittmar; Soran, Haluk

    Es wird eine Untersuchung vorgestellt, in der Wissen und Überzeugungen von Lehramtsstudierenden aller Fächer zum Thema Evolution an zwei Universitäten in Deutschland und der Türkei erhoben worden sind. Die Befragung wurde in Dortmund und in Ankara durchgeführt. Es stellte sich heraus, dass ausgeprägte Defizite im Verständnis der Evolutionsmechanismen herrschen. Viele Studierende, insbesondere aus der Türkei, sind nicht von der Faktizität der Evolution überzeugt. Dies gilt sowohl für Studierende mit Fach Biologie als auch für Studierende mit anderen Fächern. Näher untersucht worden sind die Faktoren, die die Überzeugungen zur Evolution beeinflussen können, was ja in Anbetracht der hohen Ablehnungsrate der Evolution von besonderem Interesse ist. Das Vertrauen in die Wissenschaft spielt hierbei eine besondere Rolle: Wer der Wissenschaft vertraut, ist auch eher von der Evolution überzeugt, als diejenigen, die skeptisch gegenüber der Wissenschaft sind.

  4. Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

    PubMed Central

    Pitychoutis, Pothitos M; Belmer, Arnauld; Moutkine, Imane; Adrien, Joëlle; Maroteaux, Luc

    2015-01-01

    Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT2B mutant (Htr2B−/−) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr2B−/− mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr2B−/− mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B receptors in the neurobiology of psychotic disorders. PMID:25936642

  5. Physik gestern und heute Von der Metallstange zum Hochenergielaser

    NASA Astrophysics Data System (ADS)

    Heering, Peter

    2002-05-01

    Im Mai 1752 wurde in Marly bei Paris auf Anregung des amerikanischen Forschers und Politikers Benjamin Franklin erstmals die elektrische Natur des Blitzes nachgewiesen. Damals beschrieb Franklin auch eine technische Vorrichtung, die als Schutz von Gebäuden vor Blitzschlägen dienen sollte: den Blitzableiter. Diese aus heutiger Sicht scheinbar triviale Vorrichtung wurde aber keineswegs unmittelbar akzeptiert. Und bis heute ist die Forschung zum Schutz von Einrichtungen vor Blitzschlägen nicht abgeschlossen.

  6. Vortex lattice structures in YNi{sub 2}B{sub 2}C

    SciTech Connect

    Yethiraj, M.; Paul, D.M.; Tomy, C.V.; Forgan, E.M.

    1997-12-01

    The authors observe a flux lattice with square symmetry in the superconductor YNi{sub 2}B{sub 2}C when the applied field is parallel to the c-axis of the crystal. A square lattice observed previously in the isostructural magnetic analog ErNi{sub 2}B{sub 2}C was attributed to the interaction between magnetic order in that system and the flux lattice. Since the Y-based compound does not order magnetically, it is clear that the structure of the flux lattice is unrelated to magnetic order. In fact, they show that the flux lines have a square cross-section when the applied field is parallel to the c-axis of the crystal, since the measured penetration depth along the 100 crystal direction is larger than the penetration depth along the 110 by approximately 60%. This is the likely reason for the square symmetry of the lattice. Although they find considerable disorder in the arrangement of the flux lines at 2.5T, no melting of the vortex lattice was observed.

  7. Optimal Inlet Shape Design of N2B Hybrid Wing Body Configuration

    NASA Technical Reports Server (NTRS)

    Kim, Hyoungjin; Liou, Meng-Sing

    2012-01-01

    The N2B hybrid wing body aircraft was conceptually designed to meet environmental and performance goals for the N+2 generation transport set by the Subsonic Fixed Wing project of NASA Fundamental Aeronautics Program. In the present study, flow simulations are conducted around the N2B configuration by a Reynolds-averaged Navier-Stokes flow solver using unstructured meshes. Boundary conditions at engine fan face and nozzle exhaust planes are provided by the NPSS thermodynamic engine cycle model. The flow simulations reveal challenging design issues arising from boundary layer ingestion offset inlet and airframe-propulsion integration. Adjoint-based optimal designs are then conducted for the inlet shape to minimize the airframe drag force and flow distortion at fan faces. Design surfaces are parameterized by NURBS, and the cowl lip geometry is modified by a spring analogy approach. By the drag minimization design, flow separation on the cowl surfaces are almost removed, and shock wave strength got remarkably reduced. For the distortion minimization design, a circumferential distortion indicator DPCP(sub avg) is adopted as the design objective and diffuser bottom and side wall surfaces are perturbed for the design. The distortion minimization results in a 12.5 % reduction in the objective function.

  8. Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma

    PubMed Central

    Ye, Hui; Tong, Jiansong; Wu, Jianzhang; Xu, Xia; Wu, Shenjie; Tan, Botao; Shi, Mengjing; Wang, Jianguang; Zhao, Weibo; Jiang, Heng; Jin, Sha

    2014-01-01

    Magnetoliposomes are phospholipid vesicles encapsulating magnetic nanoparticles that can be used to encapsulate therapeutic drugs for delivery into specific organs. Herein, we developed magnetoliposomes containing recombinant human IFNα2b, designated as MIL, and evaluated this combination’s biological safety and therapeutic effect on both cellular and animal hepatocellular carcinoma models. Our data showed that MIL neither hemolyzed erythrocytes nor affected platelet-aggregation rates in blood. Nitroblue tetrazolium-reducing testing showed that MIL did not change the absolute numbers or phagocytic activities of leukocytes. Acute-toxicity testing also showed that MIL had no devastating effect on mice behaviors. All the results indicated that the nanoparticles could be a safe biomaterial. Pharmacokinetic analysis and tissue-distribution studies showed that MIL maintained stable and sustained drug concentrations in target organs under a magnetic field, helped to increase bioavailability, and reduced administration time. MIL also dramatically inhibited the growth of hepatoma cells. Targeting of MIL in the livers of nude mice bearing human hepatocellular carcinoma showed that MIL significantly reduced the tumor size to 38% of that of the control group. Further studies proved that growth inhibition of cells or tumors was due to apoptosis-signaling pathway activation by human IFNα2b. PMID:25288882

  9. High heat transfer oxidizer heat exchanger design and analysis. [RL10-2B engine

    NASA Technical Reports Server (NTRS)

    Kmiec, Thomas D.; Kanic, Paul G.; Peckham, Richard J.

    1987-01-01

    The RL10-2B engine, a derivative of the RL10, is capable of multimode thrust operation. This engine operates at two low thrust levels: tank head idle (THI), which is approximately 1 to 2% of full thrust, and pumped idle (PI), which is 10% of full thrust. Operation at THI provides vehicle propellant settling thrust and efficient engine thermal conditioning; PI operation provides vehicle tank pre-pressurization and maneuver thrust for low-g deployment. Stable combustion of the RL10-2B engine during the low thrust operating modes can be accomplished by using a heat exchanger to supply gaseous oxygen to the propellant injector. The oxidizer heat exchanger (OHE) vaporizes the liquid oxygen using hydrogen as the energy source. The design, concept verification testing and analysis for such a heat exchanger is discussed. The design presented uses a high efficiency compact core to vaporize the oxygen, and in the self-contained unit, attenuates any pressure and flow oscillations which result from unstable boiling in the core. This approach is referred to as the high heat transfer design. An alternative approach which prevents unstable boiling of the oxygen by limiting the heat transfer is referred to as the low heat transfer design and is reported in Pratt & Whitney report FR-19135-2.

  10. ANALYSIS OF KEPLER'S SHORT-CADENCE PHOTOMETRY FOR TrES-2b

    SciTech Connect

    Kipping, David; Bakos, Gaspar

    2011-05-20

    We present an analysis of 18 short-cadence (SC) transit light curves of TrES-2b using quarter 0 (Q0) and quarter 1 (Q1) from the Kepler Mission. The photometry is of unprecedented precision, 237 ppm minute{sup -1}, allowing for the most accurate determination of the transit parameters yet obtained for this system. Global fits of the transit photometry, radial velocities, and known transit times are used to obtain a self-consistent set of refined parameters for this system, including updated stellar and planetary parameters. Special attention is paid to fitting for limb darkening and eccentricity. We place an upper limit on the occultation depth to be <72.9 ppm to 3{sigma} confidence, indicating TrES-2b has the lowest determined geometric albedo for an exoplanet, of A{sub g} < 0.146. We also produce a transit timing analysis using Kepler's SC data and demonstrate exceptional timing precision at the level of a few seconds for each transit event. With 18 fully sampled transits at such high precision, we are able to produce stringent constraints on the presence of perturbing planets, Trojans, and extrasolar moons. We introduce the novel use of control data to identify phasing effects. We also exclude the previously proposed hypotheses of short-period transit time variation and additional transits but find that the hypothesis of long-term inclination change is neither supported nor refuted by our analysis.

  11. Crystal Structure and Luminescent Properties of Sr2B2O5:Eu2+ Blue Phosphors

    NASA Astrophysics Data System (ADS)

    Liu, Quan-Sheng; Zheng, Zhao-Yang; Cheng, Li-Qun; Zhang, Xi-Yan; Song, Yue; Liu, Jing-Wen; Cui, Tian

    2013-06-01

    The Sr2B2O5:Eu2+ phosphor was synthesized by high-temperature solid state reaction. The crystal structure of Sr2B2O5:Eu2+ phosphor is monoclinic system with space group of P21/a(14). Due to Eu2+ ion doping, the lattice parameters and unit cell volume decreased. The luminescence spectrum is a broad luminescence band peaking at 468 nm and 478 nm, which corresponds to the transition of 5d-low energy state in Eu2 and Eu1 to the ground state. The excitation spectrum is at UV region less than 264 nm corresponding to the band gap transition of borate host. The low energy level of 5d-band locates 20921 cm-1, the band width is 1 eV. The electronegativity of O2- anions around Eu1 and Eu2 is 3.147 eV and 3.326 eV respectively, which determines the split of 5d energy level.

  12. The impact of adenosine and A(2B) receptors on glucose homoeostasis.

    PubMed

    Rüsing, D; Müller, C E; Verspohl, E J

    2006-12-01

    Adenosine and adenosine receptor antagonists are involved in glucose homoeostasis. The participating receptors are not known, mainly due to a lack of specific agonists and antagonists, but are reasonable targets for anti-diabetic therapy. The stable, albeit nonselective, adenosine analogue NECA (5'-N-ethylcarboxamidoadenosine) (10 microM) reduced glucose-stimulated insulin release from INS-1 cells. This was mimicked by A(1)-(CHA), A(2A)-(CGS-21680) and A(3)-receptor agonists (Cl-IB-MECA). Two newly synthesized A(2B)-receptor antagonists, PSB-53 and PSB-1115, counteracted the inhibitory effect of NECA. These in-vitro effects were mirrored by in-vivo data with respect to CHA, CGS and Cl-IB-MECA. Distinct concentrations of either PSB-53 or PSB-1115 reversed the decrease in plasma insulin induced by NECA. This was not mimicked by a corresponding change in blood glucose. The effect of PSB-1115 was also obvious in diabetic GotoKakizaki rats: plasma insulin was increased whereas blood glucose was unchanged. During most experiments the effects on blood glucose were not impressive probably because of the physiologically necessary homoeostasis. The adenosine levels were not different in normal Wistar rats and in diabetic GotoKakzaki rats. Altogether the A(2B)-receptor antagonists showed an anti-diabetic potential mainly by increasing plasma insulin levels under conditions when the adenosine tonus was elevated in-vivo and increased insulin release in-vitro.

  13. The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease

    PubMed Central

    Karmouty-Quintana, Harry; Zhong, Hongyan; Acero, Luis; Weng, Tingting; Melicoff, Ernestina; West, James D.; Hemnes, Anna; Grenz, Almut; Eltzschig, Holger K.; Blackwell, Timothy S.; Xia, Yang; Johnston, Richard A.; Zeng, Dewan; Belardinelli, Luiz; Blackburn, Michael R.

    2012-01-01

    Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A2BR) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A2BR or treatment with the A2BR antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A2BR attenuated vascular remodeling and hypertension in our model. Furthermore, direct A2BR activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A2BR antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.—Karmouty-Quintana, H., Zhong, H., Acero, L., Weng, T., Melicoff, E., West, J. D., Hemnes, A., Grenz, A., Eltzschig, H. K., Blackwell, T. S., Xia, Y., Johnston, R. A., Zeng, D., Belardinelli, L., Blackburn, M. R. The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease. PMID:22415303

  14. Histone chaperone Chz1p regulates H2B ubiquitination and subtelomeric anti-silencing

    PubMed Central

    Wan, Yakun; Chiang, Jung-Hsien; Lin, Chan-Hsien; Arens, Christina E.; Saleem, Ramsey A.; Smith, Jennifer J.; Aitchison, John D.

    2010-01-01

    Chz1p is a histone chaperone that interacts physically and functionally with the histone variant Htz1p, which has been implicated in establishing and maintaining boundaries between transcriptionally inactive heterochromatin and active euchromatin. To investigate the role of Chz1p in chromatin organization, we performed genome-wide expression arrays and chromatin immunoprecipitations of SIR complex components and modified histones in a CHZ1 deletion strain. Deletion of CHZ1 led to reduced ubiquitination of subtelomere-associated H2B, reduced subtelomeric H3K79 di-methylation, and increased binding of Sir3p, and Sir4p at telomere-distal euchromatin regions, correlating with decreased gene expression in subtelomeric regions. This anti-silencing defect appears to be mediated by enhanced association of de-ubiquitinase Ubp10p with subtelomeric DNA, as detected by chromatin immunoprecipitation analysis. In support of this, we show that deletion of UBP10 can antagonize the subtelomeric silencing phenotype of Δchz1. Taken together, the results demonstrate a novel role for Chz1p in epigenetic regulation, through H2B de-ubiquitination by Ubp10p. PMID:20008511

  15. Summary report on the fuel performance modeling of the AFC-2A, 2B irradiation experiments

    SciTech Connect

    Pavel G. Medvedev

    2013-09-01

    The primary objective of this work at the Idaho National Laboratory (INL) is to determine the fuel and cladding temperature history during irradiation of the AFC-2A, 2B transmutation metallic fuel alloy irradiation experiments containing transuranic and rare earth elements. Addition of the rare earth elements intends to simulate potential fission product carry-over from pyro-metallurgical reprocessing. Post irradiation examination of the AFC-2A, 2B rodlets revealed breaches in the rodlets and fuel melting which was attributed to the release of the fission gas into the helium gap between the rodlet cladding and the capsule which houses six individually encapsulated rodlets. This release is not anticipated during nominal operation of the AFC irradiation vehicle that features a double encapsulated design in which sodium bonded metallic fuel is separated from the ATR coolant by the cladding and the capsule walls. The modeling effort is focused on assessing effects of this unanticipated event on the fuel and cladding temperature with an objective to compare calculated results with the temperature limits of the fuel and the cladding.

  16. Association of eukaryotic translation initiation factor eIF2B with fully solubilized CXCR4.

    PubMed

    Palmesino, Elena; Apuzzo, Tiziana; Thelen, Sylvia; Mueller, Bernd; Langen, Hanno; Thelen, Marcus

    2016-06-01

    Chemokine receptors are key regulators of leukocyte trafficking but also have an important role in development, tumor growth, and metastasis. Among the chemokine receptors, CXCR4 is the only one that leads to perinatal death when genetically ablated in mice, indicating a more-widespread function in development. To identify pathways that are activated downstream of CXCR4, a solubilization protocol was elaborated, which allows for the isolation of the endogenous receptor from human cells in its near-native conformation. Solubilized CXCR4 is recognized by the conformation-sensitive monoclonal antibody 12G5 and retains the ability to bind CXCL12 in solution, which was abolished in the presence of receptor antagonists. Mass spectrometry of CXCR4 immunoprecipitates revealed a specific interaction with the pentameric eukaryotic translation initiation factor 2B. The observation that the addition of CXCL12 leads to the dissociation of eukaryotic translation initiation factor 2B from CXCR4 suggests that stimulation of the receptor may trigger the local protein synthesis required for efficient cell movement. PMID:26609049

  17. Role of Extrachromosomal Histone H2B on Recognition of DNA Viruses and Cell Damage

    PubMed Central

    Kobiyama, Kouji; Kawashima, Akira; Jounai, Nao; Takeshita, Fumihiko; Ishii, Ken J.; Ito, Tetsuhide; Suzuki, Koichi

    2013-01-01

    Histones are essential components of chromatin structure, and histone modification plays an important role in various cellular functions including transcription, gene silencing, and immunity. Histones also play distinct roles in extrachromosomal settings. Extrachromosomal histone H2B acts as a cytosolic sensor to detect double-stranded DNA (dsDNA) fragments derived from infectious agents or damaged cells to activate innate and acquired immune responses in various cell types. It also physically interacts with interferon (IFN)-β promoter stimulator 1 (IPS-1), an essential adaptor molecule that activates innate immunity, through COOH-terminal importin 9-related adaptor organizing histone H2B and IPS-1 (CIAO), resulting in a distinct signaling complex that induces dsDNA-induced type I IFN production. Such a molecular platform acts as a cellular sensor to recognize aberrant dsDNA in cases of viral infection and cell damage. This mechanism may also play roles in autoimmunity, transplantation rejection, gene-mediated vaccines, and other therapeutic applications. PMID:23734163

  18. Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist

    PubMed Central

    Taniguchi, Kana; Shinjo, Katsuhiro; Mizutani, Mayumi; Shimada, Kaoru; Ishikawa, Toshihisa; Menniti, Frank S; Nagahisa, Atsushi

    1997-01-01

    The analgesic activity of CP-101,606, an NR2B subunit-selective N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in carrageenan-induced hyperalgesia, capsaicin- and 4β-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive tests in the rat. CP-101,606 30 mg kg−1, s.c., at 0.5 and 2.5 h after carrageenan challenge suppressed mechanical hyperalgesia without any apparant alternations in motor coordination or behaviour in the rat. CP-101,606 also inhibited capsaicin- and PMA-induced nociceptive responses (licking behaviour) with ED50 values of 7.5 and 5.7 mg kg−1, s.c., respectively. These results suggest that inhibition of the NR2B subunit of the NMDA receptor is effective in vivo at modulating nociception and hyperalgesia responses without causing the behavioural side effects often observed with currently available NMDA receptor antagonists. PMID:9384494

  19. Demonstrating the stability of albinterferon alfa-2b in the presence of silicone oil.

    PubMed

    Auge, Kristin B; Blake-Haskins, Angela W; Devine, Sean; Rizvi, Sophia; Li, Yi-Ming; Hesselberg, Mark; Orvisky, Eduard; Affleck, Richard P; Spitznagel, Thomas M; Perkins, Melissa D

    2011-12-01

    Silicone oil is often used to decrease glide forces in prefilled syringes and cartridges, common primary container closures for biopharmaceutical products. Silicone oil has been linked to inducing protein aggregation (Diabet Med 1989;6:278; Diabet Care 1987;10:786-790), leading to patient safety and immunogenicity concerns. Because of the silicone oil application process (Biotech Adv 2007;25:318-324), silicone oil levels tend to vary between individual container closures. Various silicone oil levels were applied to a container closure prior to filling and lyophilization of an albumin and interferon alfa-2b fusion protein (albinterferon alfa-2b). Data demonstrated that high silicone oil levels in combination with intended and stress storage conditions had no impact on protein purity, higher order structure, stability trajectory, or biological activity. Subvisible particulate analysis (1-10 µm range) from active and placebo samples from siliconized glass barrels showed similar particle counts. Increases in solution turbidity readings for both active and placebo samples correlated well with increases in silicone oil levels, suggesting that the particles in solution are related to the presence of silicone oil and not large protein aggregates. Results from this study demonstrate that silicone oil is not always detrimental to proteins; nevertheless, assessing the impact of silicone oil on a product case-by-case basis is still recommended. PMID:21780119

  20. Anisotropy of the Vortex Magnetic Field Distribution in LuNi2B2

    NASA Astrophysics Data System (ADS)

    Eskildsen, M. R.; Debeer-Schmitt, L.; Rovira, K.; Jenkins, N.; Dewhurst, C. D.; Bud'Ko, S. L.; Canfield, P. C.

    2008-03-01

    It is well known that the vortex lattice (VL) symmetry and orientation in type-II superconductors is very sensitive to any anisotropy within the screening current plane. A classic example is the sequence of transitions from hexagonal to rhombic to square symmetry, which was first observed in the borocarbide superconductors and explained by a Fermi surface anisotropy coupled with the non-local electrodynamics responsible for vortex-vortex interactions. Recently, however, this is mounting experimental evidence for a strong gap anisotropy and possible point nodes in the basal plane of these materials. Here we report on small-angle neutron scattering studies of the VL in a carefully annealed, high quality LuNi2B2C single crystal, which permitted us to measure the VL form factor for a large number of reflections. These measurements allow a reconstruction of the real space profile of the magnetic field around the vortices, reflecting the basal plane anisotropy of the screening currents in LuNi2B2C. The results will be compared to predictions for both Fermi surface and gap anisotropies, and will serve as a valuable reference for more complicated compounds as e.g. Sr2RuO4, heavy fermions and high-Tc's.

  1. 2010 i2b2/VA challenge on concepts, assertions, and relations in clinical text

    PubMed Central

    South, Brett R; Shen, Shuying; DuVall, Scott L

    2011-01-01

    The 2010 i2b2/VA Workshop on Natural Language Processing Challenges for Clinical Records presented three tasks: a concept extraction task focused on the extraction of medical concepts from patient reports; an assertion classification task focused on assigning assertion types for medical problem concepts; and a relation classification task focused on assigning relation types that hold between medical problems, tests, and treatments. i2b2 and the VA provided an annotated reference standard corpus for the three tasks. Using this reference standard, 22 systems were developed for concept extraction, 21 for assertion classification, and 16 for relation classification. These systems showed that machine learning approaches could be augmented with rule-based systems to determine concepts, assertions, and relations. Depending on the task, the rule-based systems can either provide input for machine learning or post-process the output of machine learning. Ensembles of classifiers, information from unlabeled data, and external knowledge sources can help when the training data are inadequate. PMID:21685143

  2. Macroscale production of crystalline interferon alfa-2b in microgravity on STS-52

    NASA Astrophysics Data System (ADS)

    Nagabhushan, Tattanahalli L.; Reichert, Paul; Long, Marianna M.; DeLucas, Lawrence J.; Bugg, Charles E.

    1995-01-01

    Macroscale crystallization of zinc interferon alfa-2b was achieved on STS-52 in October 1992 in the Protein Crystallization Facility. Conditions for crystallization were established by adapting a microscale vapor diffusion method to a macroscale temperature induction method. A series of earth based pilot experiments established conditions to reproducibly crystallize zinc interferon alfa-2b in high yield and under cleanroom conditions. As a control for the STS-52 mission, a ground experiment was run simultaneously and in the same configuration as the flight experiment. Greater than 95% of the available protein crystallized in both the ground and flight experiments. Using a battery of physical, biochemical and biological characterization assays, demonstrated that sample processing, polysulfone bottle confinement and the conditions used for crystallization did not have a negative effect on protein integrity. Redissolved crystals from the flight and ground experiments showed full biological activity in a cytopathic effect inhibition assay as compared to an interferon control standard. Morphometric analysis comparing the overall length and width of the derived crystals showed a 2.4 fold increase in the length and width of the space grown crystals as compared to earth grown crystals. Space grown crystals have remained a stable free flowing suspension for over 2 years. Based on these results, further experiments are envisioned to investigate macroscale crystallization of biologically active macromolecules in microgravity.

  3. Sulfate as a pivotal factor in regulation of Serratia sp. strain S2B pigment biosynthesis.

    PubMed

    Rastegari, Banafsheh; Karbalaei-Heidari, Hamid Reza

    2016-10-01

    In the present work, we investigated the prodiginine family as secondary metabolite members. Bacterial strain S2B, with the ability to produce red pigment, was isolated from the Sarcheshmeh copper mine in Iran. 16S rDNA gene sequencing revealed that the strain was placed in the Serratia genus. Pigment production was optimized using low-cost culture medium and the effects of various physicochemical factors were studied via statistical approaches. Purification of the produced pigment by silica gel column chromatography showed a strong red pigment fraction and a weaker orange band. Mass spectrometry, FT-IR spectroscopy and (1)H NMR analysis revealed that the red pigment was prodigiosin and the orange band was a prodigiosin-like analog, with molecular weights of 323 and 317 Da, respectively. Genotoxicity and cytotoxicity studies confirmed their membership in the prodiginine family. Analysis of the production pattern of the pigments in the presence of different concentrations of ammonium salts revealed the role of sulfate as an important factor in regulation of the pigment biosynthesis pathway. Overall, the data showed that regulation of the pigment biosynthesis pathway in Serratia sp. strain S2B was affected by inorganic micronutrients, particularly the sulfate ions.

  4. Sticktechnologie für medizinische Textilien und Tissue Engineering

    NASA Astrophysics Data System (ADS)

    Karamuk, Erdal; Mayer, Jörg; Wintermantel, Erich

    Textile Strukturen werden in grossem Ausmass als medizinische Implantate eingesetzt, um Weich- und Hartgewebe zu unterstützen oder zu ersetzen. Im Tissue Engineering gewinnen sie an Bedeutung als scaffolds, um biologische Gewebe in vitro zu züchten für anschliessende Implantation oder extrakorporale Anwendungen. Textilien sind gewöhnlich anisotrope zweidimensionale Strukturen mit hoher Steifigkeit in der Ebene und geringer Biegesteifigkeit. Durch eine Vielzahl textiler Prozesse und durch entsprechende Wahl des Fasermaterials ist es möglich, Oberfläche, Porosität und mechanische Anisotropie in hohem Masse zu variieren. Wegen ihrer einzigartigen strukturellen und mechanischen Eigenschaften können faserbasierte Materialien in weitem Masse biologischem Gewebe nachgeahmt werden [1]. Gesticke erweitern das Feld von technischen und besonders medizinischen Textilien, denn sie vereinen sehr hohe strukturelle Variabilität mit der Möglichkeit, mechanische Eigenschaften in einem grossen Bereich einzustellen, um so die mechanischen Anforderungen des Empfängergewebes zu erfüllen (Abb. 42.1).

  5. Zahlen und Rechenvorgänge auf unterschiedlichen Abstraktionsniveaus

    NASA Astrophysics Data System (ADS)

    Rödler, Klaus

    "Das Verständnis geht langsam vor sich!" Diesen wichtigen Satz hörte ich bei einem Vortrag von Martin Lowsky. Auf die hier behandelte Fragestellung übertragen heißt das: Was eine Zahl ist und wie ich sie im Rechenvorgang einsetzen und interpretieren kann, das erschließt sich erst allmählich. Die Zahl des Rechenanfängers ist nicht dieselbe wie die des kompetenten Rechners und es ist nicht die Zahl des Lehrers oder der Lehrerin. Die Zahlen sind nur auf der Oberfläche der Worte und Zeichen gleich. Im Innern, im Verständnis, sind sie völlig verschieden! Ich glaube, dass die Missachtung dieser Divergenz dazu führt, dass manche Kinder in für den Lehrer und Lehrerin nicht nachvollziehbaren Routinen stecken bleiben, einfachste Informationen nicht wirklich integrieren. Die auf beiden Seiten wachsende Verunsicherung durch die nicht erkannte und daher nicht kommunizierbare Diskrepanz im inneren Zahlkonzept stört den allmählichen Aufbau strukturierter Zahlvorstellungen.

  6. S1-Leitlinie zur UV-Phototherapie und Photochemotherapie.

    PubMed

    Herzinger, Thomas; Berneburg, Mark; Ghoreschi, Kamran; Gollnick, Harald; Hölzle, Erhard; Hönigsmann, Herbert; Lehmann, Percy; Peters, Thorsten; Röcken, Martin; Scharffetter-Kochanek, Karin; Schwarz, Thomas; Simon, Jan; Tanew, Adrian; Weichenthal, Michael

    2016-08-01

    Die heilsame Wirkung des Sonnenlichts war teilweise schon im Altertum bekannt und fand in der zweiten Hälfte des 19. Jahrhunderts wieder zunehmend Beachtung. Den Beginn der modernen Phototherapien markiert die Entwicklung einer Apparatur zur ultravioletten Bestrahlung der Hauttuberkulose durch Finnsen zu Beginn des zwanzigsten Jahrhunderts. Zur Therapie von Hauterkrankungen finden beinahe ausschließlich die spektralen Bereiche unterhalb des sichtbaren Lichtes (ultraviolett) Anwendung. Seit den 1970er Jahren stehen zunehmend leistungsfähige künstliche Strahlenquellen bereit für die Therapie mit UVB, UVA und die Kombination von UVA mit Photosensibilisatoren (Photochemotherapie). Hohe strukturelle und prozedurale Qualitätsstandards sind unabdingbare Voraussetzung für die Durchführung einer gleichermaßen wirkungsvollen wie auch sicheren Phototherapie. Die Leitlinie formuliert den aktuellen Konsens führender Experten auf dem Gebiet der Phototherapie in Bezug auf die Indikationen für die jeweiligen Therapieverfahren, deren Gegenanzeigen und Nebenwirkungen und insbesondere für die Wahl der korrekten Dosis zu Beginn und im Verlauf einer Therapie sowie das Management von Nebenwirkungen. PMID:27509439

  7. Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet β cell.

    PubMed

    Johnson, Justin S; Kono, Tatsuyoshi; Tong, Xin; Yamamoto, Wataru R; Zarain-Herzberg, Angel; Merrins, Matthew J; Satin, Leslie S; Gilon, Patrick; Evans-Molina, Carmella

    2014-11-21

    Although the pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in β cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco-endoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) pump maintains a steep Ca(2+) gradient between the cytosol and ER lumen. In models of diabetes, our data demonstrated loss of β cell Pdx-1 that occurs in parallel with altered SERCA2b expression, whereas in silico analysis of the SERCA2b promoter revealed multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b levels and activity with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. The results revealed reduced SERCA2b expression and decreased ER Ca(2+), which was measured using fluorescence lifetime imaging microscopy. Cotransfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity 3- to 4-fold relative to an empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1(+/-) mice were fed a high-fat diet. Isolated islets demonstrated an increased spliced-to-total Xbp1 ratio, whereas SERCA2b overexpression reduced the Xbp1 ratio to that of wild-type controls. Together, these results identify SERCA2b as a novel transcriptional target of Pdx-1 and define a role for altered ER Ca(2+) regulation in Pdx-1-deficient states.

  8. Orbital Phase Variations of the Eccentric Giant Planet HAT-P-2b

    NASA Astrophysics Data System (ADS)

    Lewis, Nikole K.; Knutson, Heather A.; Showman, Adam P.; Cowan, Nicolas B.; Laughlin, Gregory; Burrows, Adam; Deming, Drake; Crepp, Justin R.; Mighell, Kenneth J.; Agol, Eric; Bakos, Gáspár Á.; Charbonneau, David; Désert, Jean-Michel; Fischer, Debra A.; Fortney, Jonathan J.; Hartman, Joel D.; Hinkley, Sasha; Howard, Andrew W.; Johnson, John Asher; Kao, Melodie; Langton, Jonathan; Marcy, Geoffrey W.

    2013-04-01

    We present the first secondary eclipse and phase curve observations for the highly eccentric hot Jupiter HAT-P-2b in the 3.6, 4.5, 5.8, and 8.0 μm bands of the Spitzer Space Telescope. The 3.6 and 4.5 μm data sets span an entire orbital period of HAT-P-2b (P = 5.6334729 d), making them the longest continuous phase curve observations obtained to date and the first full-orbit observations of a planet with an eccentricity exceeding 0.2. We present an improved non-parametric method for removing the intrapixel sensitivity variations in Spitzer data at 3.6 and 4.5 μm that robustly maps position-dependent flux variations. We find that the peak in planetary flux occurs at 4.39 ± 0.28, 5.84 ± 0.39, and 4.68 ± 0.37 hr after periapse passage with corresponding maxima in the planet/star flux ratio of 0.1138% ± 0.0089%, 0.1162% ± 0.0080%, and 0.1888% ± 0.0072% in the 3.6, 4.5, and 8.0 μm bands, respectively. Our measured secondary eclipse depths of 0.0996% ± 0.0072%, 0.1031% ± 0.0061%, 0.071%^{+0.029%}_{-0.013%}, and 0.1392% ± 0.0095% in the 3.6, 4.5, 5.8, and 8.0 μm bands, respectively, indicate that the planet cools significantly from its peak temperature before we measure the dayside flux during secondary eclipse. We compare our measured secondary eclipse depths to the predictions from a one-dimensional radiative transfer model, which suggests the possible presence of a transient day side inversion in HAT-P-2b's atmosphere near periapse. We also derive improved estimates for the system parameters, including its mass, radius, and orbital ephemeris. Our simultaneous fit to the transit, secondary eclipse, and radial velocity data allows us to determine the eccentricity (e = 0.50910 ± 0.00048) and argument of periapse (ω = 188.°09 ± 0.°39) of HAT-P-2b's orbit with a greater precision than has been achieved for any other eccentric extrasolar planet. We also find evidence for a long-term linear trend in the radial velocity data. This trend suggests the presence

  9. ORBITAL PHASE VARIATIONS OF THE ECCENTRIC GIANT PLANET HAT-P-2b

    SciTech Connect

    Lewis, Nikole K.; Showman, Adam P.; Knutson, Heather A.; Desert, Jean-Michel; Kao, Melodie; Cowan, Nicolas B.; Laughlin, Gregory; Fortney, Jonathan J.; Burrows, Adam; Bakos, Gaspar A.; Hartman, Joel D.; Deming, Drake; Crepp, Justin R.; Mighell, Kenneth J.; Agol, Eric; Charbonneau, David; Fischer, Debra A.; Hinkley, Sasha; Johnson, John Asher; Howard, Andrew W.; and others

    2013-04-01

    We present the first secondary eclipse and phase curve observations for the highly eccentric hot Jupiter HAT-P-2b in the 3.6, 4.5, 5.8, and 8.0 {mu}m bands of the Spitzer Space Telescope. The 3.6 and 4.5 {mu}m data sets span an entire orbital period of HAT-P-2b (P = 5.6334729 d), making them the longest continuous phase curve observations obtained to date and the first full-orbit observations of a planet with an eccentricity exceeding 0.2. We present an improved non-parametric method for removing the intrapixel sensitivity variations in Spitzer data at 3.6 and 4.5 {mu}m that robustly maps position-dependent flux variations. We find that the peak in planetary flux occurs at 4.39 {+-} 0.28, 5.84 {+-} 0.39, and 4.68 {+-} 0.37 hr after periapse passage with corresponding maxima in the planet/star flux ratio of 0.1138% {+-} 0.0089%, 0.1162% {+-} 0.0080%, and 0.1888% {+-} 0.0072% in the 3.6, 4.5, and 8.0 {mu}m bands, respectively. Our measured secondary eclipse depths of 0.0996% {+-} 0.0072%, 0.1031% {+-} 0.0061%, 0.071%{sub -0.013%}{sup +0.029,} and 0.1392% {+-} 0.0095% in the 3.6, 4.5, 5.8, and 8.0 {mu}m bands, respectively, indicate that the planet cools significantly from its peak temperature before we measure the dayside flux during secondary eclipse. We compare our measured secondary eclipse depths to the predictions from a one-dimensional radiative transfer model, which suggests the possible presence of a transient day side inversion in HAT-P-2b's atmosphere near periapse. We also derive improved estimates for the system parameters, including its mass, radius, and orbital ephemeris. Our simultaneous fit to the transit, secondary eclipse, and radial velocity data allows us to determine the eccentricity (e = 0.50910 {+-} 0.00048) and argument of periapse ({omega} = 188. Degree-Sign 09 {+-} 0. Degree-Sign 39) of HAT-P-2b's orbit with a greater precision than has been achieved for any other eccentric extrasolar planet. We also find evidence for a long-term linear

  10. VDI-Richtlinien - mit Technischen Regeln Wirtschaftlichkeit erhöhen und Standards setzen

    NASA Astrophysics Data System (ADS)

    Mandelartz, Johannes

    Der Verein Deutscher Ingenieure e.V. (VDI) ist ein gemeinnütziger, wirtschaftlich und politisch unabhängiger, technisch-wissenschaftlicher Verein von Ingenieuren und Naturwissenschaftlern. Mit über 137 000 persönlich zugeordneten Mitgliedern ist er eine der größten Ingenieur-Vereinigungen Europas und gilt in Deutschland als führender Sprecher der Technik und der Ingenieure. 1856 gegründet, hat er viele für die Technik wesentliche Entwicklungen in Gang gesetzt, so im Bereich der technischen Überwachung, der technischen Regelsetzung und Normung, der Arbeitsstudien, im gewerblichen Rechtsschutz und im Patentwesen. Seit seiner Gründung sieht es der VDI als seine Aufgabe, "das Zusammenwirken aller geistiger Kräfte der Technik im Bewusstsein ethischer Verantwortung zu fördern“ und die Lebensmöglichkeiten aller Menschen durch Entwicklung und sinnvoller Anwendung technischer Mittel zu verbessern.

  11. Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon

    PubMed Central

    Tikkanen, R; Tiihonen, J; Rautiainen, M R; Paunio, T; Bevilacqua, L; Panarsky, R; Goldman, D; Virkkunen, M

    2015-01-01

    A relatively common stop codon (Q20*) was identified in the serotonin 2B receptor gene (HTR2B) in a Finnish founder population in 2010 and it was associated with impulsivity. Here we examine the phenotype of HTR2B Q20* carriers in a setting comprising 14 heterozygous HTR2B Q20* carriers and 156 healthy controls without the HTR2B Q20*. The tridimensional personality questionnaire, Brown–Goodwin lifetime aggression scale, the Michigan alcoholism screening test and lifetime drinking history were used to measure personality traits, impulsive and aggressive behavior, both while sober and under the influence of alcohol, and alcohol consumption. Regression analyses showed that among the HTR2B Q20* carriers, temperamental traits resembled a passive-dependent personality profile, and the presence of the HTR2B Q20* predicted impulsive and aggressive behaviors particularly under the influence of alcohol. Results present examples of how one gene may contribute to personality structure and behaviors in a founder population and how personality may translate into behavior. PMID:26575222

  12. NR2B-containing NMDA receptors promote neural progenitor cell proliferation through CaMKIV/CREB pathway

    SciTech Connect

    Li, Mei; Zhang, Dong-Qing; Wang, Xiang-Zhen; Xu, Tie-Jun

    2011-08-12

    Highlights: {yields} The NR2B component of the NMDARs is important for the NSPC proliferation. {yields} pCaMKIV and pCREB exist in NSPCs. {yields} The CaMKIV/CREB pathway mediates NSPC proliferation. -- Abstract: Accumulating evidence indicates the involvement of N-methyl-D-aspartate receptors (NMDARs) in regulating neural stem/progenitor cell (NSPC) proliferation. Functional properties of NMDARs can be markedly influenced by incorporating the regulatory subunit NR2B. Here, we aim to analyze the effect of NR2B-containing NMDARs on the proliferation of hippocampal NSPCs and to explore the mechanism responsible for this effect. NSPCs were shown to express NMDAR subunits NR1 and NR2B. The NR2B selective antagonist, Ro 25-6981, prevented the NMDA-induced increase in cell proliferation. Moreover, we demonstrated that the phosphorylation levels of calcium/calmodulin-dependent protein kinase IV (CaMKIV) and cAMP response element binding protein (CREB) were increased by NMDA treatment, whereas Ro 25-6981 decreased them. The role that NR2B-containing NMDARs plays in NSPC proliferation was abolished when CREB phosphorylation was attenuated by CaMKIV silencing. These results suggest that NR2B-containing NMDARs have a positive role in regulating NSPC proliferation, which may be mediated through CaMKIV phosphorylation and subsequent induction of CREB activation.

  13. Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes

    PubMed Central

    Arendt, Maja; Fall, Tove; Lindblad-Toh, Kerstin; Axelsson, Erik

    2014-01-01

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus. PMID:24975239

  14. Vesicular reuptake inhibition by a synaptotagmin I C2B domain antibody at the squid giant synapse.

    PubMed

    Llinás, Rodolfo R; Sugimori, Mutsuyuki; Moran, Kimberly A; Moreira, Jorge E; Fukuda, Mitsunori

    2004-12-21

    Synaptotagmin (Syt) I, a ubiquitous synaptic vesicle protein, comprises a transmembrane region and two C2 domains. The C2 domains, which have been shown to be essential for both synaptic vesicle exocytosis and endocytosis, are also seen as the Ca(2+) sensors in synaptic vesicular release. In a previous study, we reported that a polyclonal antibody raised against the squid (Loligo pealei) Syt I C2B domain, while inhibiting vesicular endocytosis, was synaptic release neutral at the squid giant synapse. Recent reports concerning the C2B requirements for synaptic release prompted us to readdress the role of C2B in squid giant synapse function. Presynaptic injection of another anti-Syt I-C2B antibody (using recombinant whole C2B domain expressed in mammalian cell culture as an antigen) into the presynaptic terminal reproduced our previous results, i.e., reduction of vesicular endocytosis without affecting synaptic release. This set of results addresses the issue of the geometrical arrangement of the Ca(2+) sensor, allowing the C2B domain antibody to restrict Ca(2+)-dependent C2B self-oligomerization without modifying the Ca(2+)-dependent release process.

  15. Vesicular reuptake inhibition by a synaptotagmin I C2B domain antibody at the squid giant synapse

    PubMed Central

    Llinás, Rodolfo R.; Sugimori, Mutsuyuki; Moran, Kimberly A.; Moreira, Jorge E.; Fukuda, Mitsunori

    2004-01-01

    Synaptotagmin (Syt) I, a ubiquitous synaptic vesicle protein, comprises a transmembrane region and two C2 domains. The C2 domains, which have been shown to be essential for both synaptic vesicle exocytosis and endocytosis, are also seen as the Ca2+ sensors in synaptic vesicular release. In a previous study, we reported that a polyclonal antibody raised against the squid (Loligo pealei) Syt I C2B domain, while inhibiting vesicular endocytosis, was synaptic release neutral at the squid giant synapse. Recent reports concerning the C2B requirements for synaptic release prompted us to readdress the role of C2B in squid giant synapse function. Presynaptic injection of another anti-Syt I-C2B antibody (using recombinant whole C2B domain expressed in mammalian cell culture as an antigen) into the presynaptic terminal reproduced our previous results, i.e., reduction of vesicular endocytosis without affecting synaptic release. This set of results addresses the issue of the geometrical arrangement of the Ca2+ sensor, allowing the C2B domain antibody to restrict Ca2+-dependent C2B self-oligomerization without modifying the Ca2+-dependent release process. PMID:15591349

  16. Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes.

    PubMed

    Arendt, Maja; Fall, Tove; Lindblad-Toh, Kerstin; Axelsson, Erik

    2014-10-01

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.

  17. SCF E3 ligase PP2-B11 plays a positive role in response to salt stress in Arabidopsis.

    PubMed

    Jia, Fengjuan; Wang, Chunyan; Huang, Jinguang; Yang, Guodong; Wu, Changai; Zheng, Chengchao

    2015-08-01

    Skp1-Cullin-F-box (SCF) E3 ligases are essential to the post-translational regulation of many important factors involved in cellular signal transduction. In this study, we identified an F-box protein from Arabidopsis thaliana, AtPP2-B11, which was remarkably induced with increased duration of salt treatment in terms of both transcript and protein levels. Transgenic Arabidopsis plants overexpressing AtPP2-B11 exhibited obvious tolerance to high salinity, whereas the RNA interference line was more sensitive to salt stress than wild-type plants. Isobaric tag for relative and absolute quantification analysis revealed that 4311 differentially expressed proteins were regulated by AtPP2-B11 under salt stress. AtPP2-B11 could upregulate the expression of annexin1 (AnnAt1) and function as a molecular link between salt stress and reactive oxygen species accumulation in Arabidopsis. Moreover, AtPP2-B11 influenced the expression of Na(+) homeostasis genes under salt stress, and the AtPP2-B11 overexpressing lines exhibited lower Na(+) accumulation. These results suggest that AtPP2-B11 functions as a positive regulator in response to salt stress in Arabidopsis.

  18. Acid-Sensing Ion Channel 2a (ASIC2a) Promotes Surface Trafficking of ASIC2b via Heteromeric Assembly

    PubMed Central

    Kweon, Hae-Jin; Kim, Dong-Il; Bae, Yeonju; Park, Jae-Yong; Suh, Byung-Chang

    2016-01-01

    Acid-sensing ion channels (ASICs) are proton-activated cation channels that play important roles as typical proton sensors during pathophysiological conditions and normal synaptic activities. Among the ASIC subunits, ASIC2a and ASIC2b are alternative splicing products from the same gene, ACCN1. It has been shown that ASIC2 isoforms have differential subcellular distribution: ASIC2a targets the cell surface by itself, while ASIC2b resides in the ER. However, the underlying mechanism for this differential subcellular localization remained to be further elucidated. By constructing ASIC2 chimeras, we found that the first transmembrane (TM1) domain and the proximal post-TM1 domain (17 amino acids) of ASIC2a are critical for membrane targeting of the proteins. We also observed that replacement of corresponding residues in ASIC2b by those of ASIC2a conferred proton-sensitivity as well as surface expression to ASIC2b. We finally confirmed that ASIC2b is delivered to the cell surface from the ER by forming heteromers with ASIC2a, and that the N-terminal region of ASIC2a is additionally required for the ASIC2a-dependent membrane targeting of ASIC2b. Together, our study supports an important role of ASIC2a in membrane targeting of ASIC2b. PMID:27477936

  19. IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response.

    PubMed

    Cohen, Heather B; Ward, Amanda; Hamidzadeh, Kajal; Ravid, Katya; Mosser, David M

    2015-10-15

    The priming of macrophages with IFN-γ prior to TLR stimulation results in enhanced and prolonged inflammatory cytokine production. In this study, we demonstrate that, following TLR stimulation, macrophages upregulate the adenosine 2b receptor (A2bR) to enhance their sensitivity to immunosuppressive extracellular adenosine. This upregulation of A2bR leads to the induction of macrophages with an immunoregulatory phenotype and the downregulation of inflammation. IFN-γ priming of macrophages selectively prevents the induction of the A2bR in macrophages to mitigate sensitivity to adenosine and to prevent this regulatory transition. IFN-γ-mediated A2bR blockade leads to a prolonged production of TNF-α and IL-12 in response to TLR ligation. The pharmacologic inhibition or the genetic deletion of the A2bR results in a hyperinflammatory response to TLR ligation, similar to IFN-γ treatment of macrophages. Conversely, the overexpression of A2bR on macrophages blunts the IFN-γ effects and promotes the development of immunoregulatory macrophages. Thus, we propose a novel mechanism whereby IFN-γ contributes to host defense by desensitizing macrophages to the immunoregulatory effects of adenosine. This mechanism overcomes the transient nature of TLR activation, and prolongs the antimicrobial state of the classically activated macrophage. This study may offer promising new targets to improve the clinical outcome of inflammatory diseases in which macrophage activation is dysregulated. PMID:26355158

  20. Synthesis and characterization of new quaternary borocarbides RRh{sub 2}B{sub 2}C (R = rare earth)

    SciTech Connect

    Ye, Jinhua; Matsumoto, Takehiko; Shishido, Toetsu

    1997-10-01

    Arc-melting syntheses of RRh{sub 2}B{sub 2}C were carried out for all lanthanide elements except promethium. X ray diffraction revealed that new compounds exit for R = Y, La-Er (except Eu), and the stability of RRh{sub 2}B{sub 2}C decreases for the smaller lanthanide. The tetragonal a-axis of RRh{sub 2}B{sub 2}C decreases for the smaller lanthanide. The tetragonal a-axis of RRh{sub 2}B{sub 2}C was found to contract as R goes from La to Er. The c-axis, however, expands slightly. In accordance with the lattice parameter change, interatomic distances between Rh atoms decrease significantly from 2.7623 {angstrom} in LaRh{sub 2}B{sub 2}C to 2.6552 {angstrom} in ErRh{sub 2}B{sub 2}C. The reduced stability of the RRh{sub 2}B{sub 2}C phase for the smaller rare earth is explained by the change in the crystallographic parameters with the size of R.

  1. Auxin and epigenetic regulation of SKP2B, an F-box that represses lateral root formation.

    PubMed

    Manzano, Concepción; Ramirez-Parra, Elena; Casimiro, Ilda; Otero, Sofía; Desvoyes, Bénédicte; De Rybel, Bert; Beeckman, Tom; Casero, Pedro; Gutierrez, Crisanto; C Del Pozo, Juan

    2012-10-01

    In plants, lateral roots originate from pericycle founder cells that are specified at regular intervals along the main root. Here, we show that Arabidopsis (Arabidopsis thaliana) SKP2B (for S-Phase Kinase-Associated Protein2B), an F-box protein, negatively regulates cell cycle and lateral root formation as it represses meristematic and founder cell divisions. According to its function, SKP2B is expressed in founder cells, lateral root primordia and the root apical meristem. We identified a novel motif in the SKP2B promoter that is required for its specific root expression and auxin-dependent induction in the pericycle cells. Next to a transcriptional control by auxin, SKP2B expression is regulated by histone H3.1/H3.3 deposition in a CAF-dependent manner. The SKP2B promoter and the 5' end of the transcribed region are enriched in H3.3, which is associated with active chromatin states, over H3.1. Furthermore, the SKP2B promoter is also regulated by H3 acetylation in an auxin- and IAA14-dependent manner, reinforcing the idea that epigenetics represents an important regulatory mechanism during lateral root formation.

  2. SCF E3 ligase PP2-B11 plays a positive role in response to salt stress in Arabidopsis

    PubMed Central

    Jia, Fengjuan; Wang, Chunyan; Huang, Jinguang; Yang, Guodong; Wu, Changai; Zheng, Chengchao

    2015-01-01

    Skp1–Cullin–F-box (SCF) E3 ligases are essential to the post-translational regulation of many important factors involved in cellular signal transduction. In this study, we identified an F-box protein from Arabidopsis thaliana, AtPP2-B11, which was remarkably induced with increased duration of salt treatment in terms of both transcript and protein levels. Transgenic Arabidopsis plants overexpressing AtPP2-B11 exhibited obvious tolerance to high salinity, whereas the RNA interference line was more sensitive to salt stress than wild-type plants. Isobaric tag for relative and absolute quantification analysis revealed that 4311 differentially expressed proteins were regulated by AtPP2-B11 under salt stress. AtPP2-B11 could upregulate the expression of annexin1 (AnnAt1) and function as a molecular link between salt stress and reactive oxygen species accumulation in Arabidopsis. Moreover, AtPP2-B11 influenced the expression of Na+ homeostasis genes under salt stress, and the AtPP2-B11 overexpressing lines exhibited lower Na+ accumulation. These results suggest that AtPP2-B11 functions as a positive regulator in response to salt stress in Arabidopsis. PMID:26041321

  3. Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes.

    PubMed

    Arendt, Maja; Fall, Tove; Lindblad-Toh, Kerstin; Axelsson, Erik

    2014-10-01

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus. PMID:24975239

  4. 1-, 3- and 8-substituted-9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor.

    PubMed

    Stefanachi, Angela; Brea, Jose Manuel; Cadavid, Maria Isabel; Centeno, Nuria B; Esteve, Cristina; Loza, Maria Isabel; Martinez, Ana; Nieto, Rosa; Raviña, Enrique; Sanz, Ferran; Segarra, Victor; Sotelo, Eddy; Vidal, Bernat; Carotti, Angelo

    2008-03-15

    A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA(2B) and hA(2A) receptor subtypes. Several ligands endowed with high binding affinity at hA(2B) receptors, excellent selectivity over hA(2A) and hA(3) and a significant, but lower, selectivity over hA(1) were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA(2B) (K(i)=11, 2 and 5.5 nM, respectively) and selective towards hA(2A) (hA(2A)/hA(2B) SI=912, 159 and 630, respectively), hA(3) (hA(3)/hA(2B) SI=>100, 3090 and >180, respectively) and hA(1) (hA(1)/hA(2B) SI=>100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. Structure-affinity and structure-selectivity relationships suggested that the binding potency at the hA(2B) receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at N1 larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA(2A)/hA(2B) SI. PMID:18226909

  5. Inoculation with Metal-Mobilizing Plant-Growth-Promoting Rhizobacterium Bacillus sp. SC2b and Its Role in Rhizoremediation.

    PubMed

    Ma, Ying; Oliveira, Rui S; Wu, Longhua; Luo, Yongming; Rajkumar, Mani; Rocha, Inês; Freitas, Helena

    2015-01-01

    A plant growth-promoting bacterial (PGPB) strain SC2b was isolated from the rhizosphere of Sedum plumbizincicola grown in lead (Pb)/zinc (Zn) mine soils and characterized as Bacillus sp. based on (1) morphological and biochemical characteristics and (2) partial 16S ribosomal DNA sequencing analysis. Strain SC2b exhibited high levels of resistance to cadmium (Cd) (300 mg/L), Zn (730 mg/L), and Pb (1400 mg/L). This strain also showed various plant growth-promoting (PGP) features such as utilization of 1-aminocyclopropane-1-carboxylate, solubilization of phosphate, and production of indole-3-acetic acid and siderophore. The strain mobilized high concentration of heavy metals from soils and exhibited different biosorption capacity toward the tested metal ions. Strain SC2b was further assessed for PGP activity by phytagar assay with a model plant Brassica napus. Inoculation of SC2b increased the biomass and vigor index of B. napus. Considering such potential, a pot experiment was conducted to assess the effects of inoculating the metal-resistant PGPB SC2b on growth and uptake of Cd, Zn and Pb by S. plumbizincicola in metal-contaminated agricultural soils. Inoculation with SC2b elevated the shoot and root biomass and leaf chlorophyll content of S. plumbizincicola. Similarly, plants inoculated with SC2b demonstrated markedly higher Cd and Zn accumulation in the root and shoot system, indicating that SC2b enhanced Cd and Zn uptake by S. plumbizincicola through metal mobilization or plant-microbial mediated changes in chemical or biological soil properties. Data demonstrated that the PGPB Bacillus sp. SC2b might serve as a future biofertilizer and an effective metal mobilizing bioinoculant for rhizoremediation of metal polluted soils.

  6. Effects of chronic NMDA-NR2b inhibition in the median eminence of the reproductive senescent female rat.

    PubMed

    Kermath, B A; Riha, P D; Sajjad, A; Gore, A C

    2013-10-01

    Gonadotrophin-releasing hormone (GnRH) neurones of the hypothalamic-pituitary-gonadal (HPG) axis drive reproductive function and undergo age-related decreases in activation during the transition to reproductive senescence. Decreased GnRH secretion from the median eminence (ME) partially arises from attenuated glutamatergic signalling via the NMDA receptor (NMDAR) and may be a result of changing NMDAR stoichiometry to favour NR2b over NR2a subunit expression with ageing. We have previously shown that the systemic inhibition of NR2b-containing receptors with ifenprodil, an NR2b-specific antagonist, stimulates parameters of luteinising hormone (used as a proxy for GnRH) release in both young and middle-aged females. In the present study, we chronically administered ifenprodil, an NR2b-specific antagonist, at the site of GnRH terminals in the ME or at GnRH perikarya in the preoptic area, in reproductively senescent middle-aged female rats, aiming to determine whether NR2b antagonism could restore aspects of reproductive functionality. Effects on oestrous cyclicity, serum hormones, and protein expression of GnRH, NR2b and phosphorylated NR2b (Tyr-1472) in the ME were measured. Chronic ifenprodil treatment in the ME (but not the preoptic area) altered oestrous cyclicity by increasing the percentage of days spent in pro-oestrus. This was accompanied by increased GnRH fluorescence intensity in the external ME zone and a greater proportion of GnRH terminals that co-labelled with pNR2b with treatment. We also observed changes in the relationships between protein immunofluorescence, serum hormone levels and other aspects of reproductive physiology in acyclic females, as revealed by bionetwork analysis. Together, these data support the hypothesis that NMDAR-NR2b expression and phosphorylation state play a role in reproductive senescence and highlight the ME as a major player in reproductive ageing.

  7. 5-HT2B antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation

    PubMed Central

    Hutcheson, Joshua D.; Ryzhova, Larisa M.; Setola, Vincent; Merryman, W. David

    2012-01-01

    Transforming growth factor-β1 (TGF-β1) induces myofibroblast activation of quiescent aortic valve interstitial cells (AVICs), a differentiation process implicated in calcific aortic valve disease (CAVD). The ubiquity of TGF-β1 signaling makes it difficult to target in a tissue specific manner; however, the serotonin 2B receptor (5-HT2B) is highly localized to cardiopulmonary tissues and agonism of this receptor displays pro-fibrotic effects in a TGF-β1-dependent manner. Therefore, we hypothesized that antagonism of 5-HT2B opposes TGF-β1-induced pathologic differentiation of AVICs and may offer a druggable target to prevent CAVD. To test this hypothesis, we assessed the interaction of 5-HT2B antagonism with canonical and non-canonical TGF-β1 pathways to inhibit TGF-β1-induced activation of isolated porcine AVICs in vitro. Here we show that AVIC activation and subsequent calcific nodule formation is completely mitigated by 5-HT2B antagonism. Interestingly, 5-HT2B antagonism does not inhibit canonical TGF-β1 signaling as identified by Smad3 phosphorylation and activation of a partial plasminogen activator inhibitor-1 promoter (PAI-1, a transcriptional target of Smad3), but prevents non-canonical p38 MAPK phosphorylation. It was initially suspected that 5-HT2B antagonism prevents Src tyrosine kinase phosphorylation; however, we found that this is not the case and time-lapse microscopy indicates that 5-HT2B antagonism prevents non-canonical TGF-β1 signaling by physically arresting Src tyrosine kinase. This study demonstrates the necessity of non-canonical TGF-β1 signaling in leading to pathologic AVIC differentiation. Moreover, we believe that the results of this study suggest 5-HT2B antagonism as a novel therapeutic approach for CAVD that merits further investigation. PMID:22940605

  8. Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis.

    PubMed

    El Oussini, Hajer; Bayer, Hanna; Scekic-Zahirovic, Jelena; Vercruysse, Pauline; Sinniger, Jérôme; Dirrig-Grosch, Sylvie; Dieterlé, Stéphane; Echaniz-Laguna, Andoni; Larmet, Yves; Müller, Kathrin; Weishaupt, Jochen H; Thal, Dietmar R; van Rheenen, Wouter; van Eijk, Kristel; Lawson, Roland; Monassier, Laurent; Maroteaux, Luc; Roumier, Anne; Wong, Philip C; van den Berg, Leonard H; Ludolph, Albert C; Veldink, Jan H; Witting, Anke; Dupuis, Luc

    2016-03-01

    Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT2B mRNA in spinal cord and displayed less pronounced degeneration of Iba1 positive cells than patients carrying two copies of the more common A allele. Thus, the 5-HT2B receptor limits degeneration of spinal cord mononuclear

  9. Inoculation with Metal-Mobilizing Plant-Growth-Promoting Rhizobacterium Bacillus sp. SC2b and Its Role in Rhizoremediation.

    PubMed

    Ma, Ying; Oliveira, Rui S; Wu, Longhua; Luo, Yongming; Rajkumar, Mani; Rocha, Inês; Freitas, Helena

    2015-01-01

    A plant growth-promoting bacterial (PGPB) strain SC2b was isolated from the rhizosphere of Sedum plumbizincicola grown in lead (Pb)/zinc (Zn) mine soils and characterized as Bacillus sp. based on (1) morphological and biochemical characteristics and (2) partial 16S ribosomal DNA sequencing analysis. Strain SC2b exhibited high levels of resistance to cadmium (Cd) (300 mg/L), Zn (730 mg/L), and Pb (1400 mg/L). This strain also showed various plant growth-promoting (PGP) features such as utilization of 1-aminocyclopropane-1-carboxylate, solubilization of phosphate, and production of indole-3-acetic acid and siderophore. The strain mobilized high concentration of heavy metals from soils and exhibited different biosorption capacity toward the tested metal ions. Strain SC2b was further assessed for PGP activity by phytagar assay with a model plant Brassica napus. Inoculation of SC2b increased the biomass and vigor index of B. napus. Considering such potential, a pot experiment was conducted to assess the effects of inoculating the metal-resistant PGPB SC2b on growth and uptake of Cd, Zn and Pb by S. plumbizincicola in metal-contaminated agricultural soils. Inoculation with SC2b elevated the shoot and root biomass and leaf chlorophyll content of S. plumbizincicola. Similarly, plants inoculated with SC2b demonstrated markedly higher Cd and Zn accumulation in the root and shoot system, indicating that SC2b enhanced Cd and Zn uptake by S. plumbizincicola through metal mobilization or plant-microbial mediated changes in chemical or biological soil properties. Data demonstrated that the PGPB Bacillus sp. SC2b might serve as a future biofertilizer and an effective metal mobilizing bioinoculant for rhizoremediation of metal polluted soils. PMID:26167758

  10. Improved electrochemical performance of nitrogen doped TiO2-B nanowires as anode materials for Li-ion batteries.

    PubMed

    Zhang, Yongquan; Fu, Qiang; Xu, Qiaoling; Yan, Xiao; Zhang, Rongyu; Guo, Zhendong; Du, Fei; Wei, Yingjin; Zhang, Dong; Chen, Gang

    2015-07-28

    N-doped TiO2-B nanowires are prepared by the solvothermal method using TiN nanoparticles as the starting material. X-ray photoelectron spectroscopy shows that the N dopants preferentially occupy the interstitial sites of TiO2-B up to a content of ∼0.55 at%. Above this critical value, the N dopants will substitute the oxygen atoms which improve the electronic conductivity of TiO2-B. The maximum proportion of substituted-N in the TiO2-B nanowires is ∼1.3 at%. Raman scattering shows that the substituted-N strengthens the Ti(1)-O1-Ti(2) and O1-Ti(1)-O3 bonds of TiO2-B. This improves the stability of the corresponding local structures, thus reducing the distortion of the Li(+) diffusion channel along the b-axis of TiO2-B. As a result, the substituted-N has more of an impact on the electrochemical properties of TiO2-B than the interstitial-N does. The TiO2-B nanowires containing substituted-N dopants exhibit a remarkably enhanced electrochemical performance compared to pure TiO2-B. They show a discharge capacity of 153 mA h g(-1) at the 20 C rate with a capacity retention of 76% after 1000 cycles. In addition, they can deliver a discharge capacity of 100 mA h g(-1) at an ultra-high rate of 100 C, indicating their great potential in high power lithium ion batteries.

  11. 3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists.

    PubMed

    Wei, Jing; Wang, Songqing; Gao, Shaofen; Dai, Xuedong; Gao, Qingzhi

    2007-01-01

    Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands. PMID:17330954

  12. 3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists.

    PubMed

    Wei, Jing; Wang, Songqing; Gao, Shaofen; Dai, Xuedong; Gao, Qingzhi

    2007-01-01

    Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.

  13. Trypanosoma brucei Co-opts NK Cells to Kill Splenic B2 B Cells.

    PubMed

    Frenkel, Deborah; Zhang, Fengqiu; Guirnalda, Patrick; Haynes, Carole; Bockstal, Viki; Radwanska, Magdalena; Magez, Stefan; Black, Samuel J

    2016-07-01

    After infection with T. brucei AnTat 1.1, C57BL/6 mice lost splenic B2 B cells and lymphoid follicles, developed poor parasite-specific antibody responses, lost weight, became anemic and died with fulminating parasitemia within 35 days. In contrast, infected C57BL/6 mice lacking the cytotoxic granule pore-forming protein perforin (Prf1-/-) retained splenic B2 B cells and lymphoid follicles, developed high-titer antibody responses against many trypanosome polypeptides, rapidly suppressed parasitemia and did not develop anemia or lose weight for at least 60 days. Several lines of evidence show that T. brucei infection-induced splenic B cell depletion results from natural killer (NK) cell-mediated cytotoxicity: i) B2 B cells were depleted from the spleens of infected intact, T cell deficient (TCR-/-) and FcγRIIIa deficient (CD16-/-) C57BL/6 mice excluding a requirement for T cells, NKT cell, or antibody-dependent cell-mediated cytotoxicity; ii) administration of NK1.1 specific IgG2a (mAb PK136) but not irrelevant IgG2a (myeloma M9144) prevented infection-induced B cell depletion consistent with a requirement for NK cells; iii) splenic NK cells but not T cells or NKT cells degranulated in infected C57BL/6 mice co-incident with B cell depletion evidenced by increased surface expression of CD107a; iv) purified NK cells from naïve C57BL/6 mice killed purified splenic B cells from T. brucei infected but not uninfected mice in vitro indicating acquisition of an NK cell activating phenotype by the post-infection B cells; v) adoptively transferred C57BL/6 NK cells prevented infection-induced B cell population growth in infected Prf1-/- mice consistent with in vivo B cell killing; vi) degranulated NK cells in infected mice had altered gene and differentiation antigen expression and lost cytotoxic activity consistent with functional exhaustion, but increased in number as infection progressed indicating continued generation. We conclude that NK cells in T. brucei infected mice

  14. Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

    PubMed Central

    Alonso, Pino; Gratacós, Mónica; Segalàs, Cinto; Escaramís, Georgia; Real, Eva; Bayés, Mónica; Labad, Javier; López-Solà, Clara; Estivill, Xavier; Menchón, José M.

    2012-01-01

    Background Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neurotransmission in the pathogenesis of obsessive–compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-d-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. Methods Between 2003 and 2008, we performed a case–control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. Results We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37–4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22–3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. Limitations Study limitations included the risk of population stratification associated with the case–control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B. Conclusion Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD

  15. Trypanosoma brucei Co-opts NK Cells to Kill Splenic B2 B Cells

    PubMed Central

    Frenkel, Deborah; Guirnalda, Patrick; Haynes, Carole; Bockstal, Viki; Magez, Stefan; Black, Samuel J.

    2016-01-01

    After infection with T. brucei AnTat 1.1, C57BL/6 mice lost splenic B2 B cells and lymphoid follicles, developed poor parasite-specific antibody responses, lost weight, became anemic and died with fulminating parasitemia within 35 days. In contrast, infected C57BL/6 mice lacking the cytotoxic granule pore-forming protein perforin (Prf1-/-) retained splenic B2 B cells and lymphoid follicles, developed high-titer antibody responses against many trypanosome polypeptides, rapidly suppressed parasitemia and did not develop anemia or lose weight for at least 60 days. Several lines of evidence show that T. brucei infection-induced splenic B cell depletion results from natural killer (NK) cell-mediated cytotoxicity: i) B2 B cells were depleted from the spleens of infected intact, T cell deficient (TCR-/-) and FcγRIIIa deficient (CD16-/-) C57BL/6 mice excluding a requirement for T cells, NKT cell, or antibody-dependent cell-mediated cytotoxicity; ii) administration of NK1.1 specific IgG2a (mAb PK136) but not irrelevant IgG2a (myeloma M9144) prevented infection-induced B cell depletion consistent with a requirement for NK cells; iii) splenic NK cells but not T cells or NKT cells degranulated in infected C57BL/6 mice co-incident with B cell depletion evidenced by increased surface expression of CD107a; iv) purified NK cells from naïve C57BL/6 mice killed purified splenic B cells from T. brucei infected but not uninfected mice in vitro indicating acquisition of an NK cell activating phenotype by the post-infection B cells; v) adoptively transferred C57BL/6 NK cells prevented infection-induced B cell population growth in infected Prf1-/- mice consistent with in vivo B cell killing; vi) degranulated NK cells in infected mice had altered gene and differentiation antigen expression and lost cytotoxic activity consistent with functional exhaustion, but increased in number as infection progressed indicating continued generation. We conclude that NK cells in T. brucei infected mice

  16. Trypanosoma brucei Co-opts NK Cells to Kill Splenic B2 B Cells.

    PubMed

    Frenkel, Deborah; Zhang, Fengqiu; Guirnalda, Patrick; Haynes, Carole; Bockstal, Viki; Radwanska, Magdalena; Magez, Stefan; Black, Samuel J

    2016-07-01

    After infection with T. brucei AnTat 1.1, C57BL/6 mice lost splenic B2 B cells and lymphoid follicles, developed poor parasite-specific antibody responses, lost weight, became anemic and died with fulminating parasitemia within 35 days. In contrast, infected C57BL/6 mice lacking the cytotoxic granule pore-forming protein perforin (Prf1-/-) retained splenic B2 B cells and lymphoid follicles, developed high-titer antibody responses against many trypanosome polypeptides, rapidly suppressed parasitemia and did not develop anemia or lose weight for at least 60 days. Several lines of evidence show that T. brucei infection-induced splenic B cell depletion results from natural killer (NK) cell-mediated cytotoxicity: i) B2 B cells were depleted from the spleens of infected intact, T cell deficient (TCR-/-) and FcγRIIIa deficient (CD16-/-) C57BL/6 mice excluding a requirement for T cells, NKT cell, or antibody-dependent cell-mediated cytotoxicity; ii) administration of NK1.1 specific IgG2a (mAb PK136) but not irrelevant IgG2a (myeloma M9144) prevented infection-induced B cell depletion consistent with a requirement for NK cells; iii) splenic NK cells but not T cells or NKT cells degranulated in infected C57BL/6 mice co-incident with B cell depletion evidenced by increased surface expression of CD107a; iv) purified NK cells from naïve C57BL/6 mice killed purified splenic B cells from T. brucei infected but not uninfected mice in vitro indicating acquisition of an NK cell activating phenotype by the post-infection B cells; v) adoptively transferred C57BL/6 NK cells prevented infection-induced B cell population growth in infected Prf1-/- mice consistent with in vivo B cell killing; vi) degranulated NK cells in infected mice had altered gene and differentiation antigen expression and lost cytotoxic activity consistent with functional exhaustion, but increased in number as infection progressed indicating continued generation. We conclude that NK cells in T. brucei infected mice

  17. Discovery of 3-Substituted Aminocyclopentanes as Potent and Orally Bioavailable NR2B Subtype-Selective NMDA Antagonists

    PubMed Central

    2011-01-01

    A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson’s disease in a dose dependent manner. PMID:22816022

  18. Identification of methyl violet 2B as a novel blocker of focal adhesion kinase signaling pathway in cancer cells

    SciTech Connect

    Kim, Hwan; Kim, Nam Doo; Lee, Jiyeon; Han, Gyoonhee; Sim, Taebo

    2013-07-26

    Highlights: •FAK signaling cascade in cancer cells is profoundly inhibited by methyl violet 2B. •Methyl violet 2B identified by virtual screening is a novel allosteric FAK inhibitor. •Methyl violet 2B possesses extremely high kinase selectivity. •Methyl violet 2B suppresses strongly the proliferation of cancer cells. •Methyl violet 2B inhibits focal adhesion, invasion and migration of cancer cells. -- Abstract: The focal adhesion kinase (FAK) signaling cascade in cancer cells was profoundly inhibited by methyl violet 2B identified with the structure-based virtual screening. Methyl violet 2B was shown to be a non-competitive inhibitor of full-length FAK enzyme vs. ATP. It turned out that methyl violet 2B possesses extremely high kinase selectivity in biochemical kinase profiling using a large panel of kinases. Anti-proliferative activity measurement against several different cancer cells and Western blot analysis showed that this substance is capable of suppressing significantly the proliferation of cancer cells and is able to strongly block FAK/AKT/MAPK signaling pathways in a dose dependent manner at low nanomolar concentration. Especially, phosphorylation of Tyr925-FAK that is required for full activation of FAK was nearly completely suppressed even with 1 nM of methyl violet 2B in A375P cancer cells. To the best of our knowledge, it has never been reported that methyl violet possesses anti-cancer effects. Moreover, methyl violet 2B significantly inhibited FER kinase phosphorylation that activates FAK in cell. In addition, methyl violet 2B was found to induce cell apoptosis and to exhibit strong inhibitory effects on the focal adhesion, invasion, and migration of A375P cancer cells at low nanomolar concentrations. Taken together, these results show that methyl violet 2B is a novel, potent and selective blocker of FAK signaling cascade, which displays strong anti-proliferative activities against a variety of human cancer cells and suppresses adhesion

  19. Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists.

    PubMed

    Lim, Chae Jo; Oh, Seung Ae; Lee, Byung Ho; Oh, Kwang-Seok; Yi, Kyu Yang

    2014-12-15

    The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability.

  20. Facile synthetic route towards nanostructured Fe-TiO2(B), used as negative electrode for Li-ion batteries

    NASA Astrophysics Data System (ADS)

    Grosjean, Remi; Fehse, Marcus; Pigeot-Remy, Stéphanie; Stievano, Lorenzo; Monconduit, Laure; Cassaignon, Sophie

    2015-03-01

    We present here a novel simple method for the synthesis of highly pure TiO2(B). The fast microwave-assisted synthetic route allows facile scale-up of the process. Aiming at an application of the titania polymorph as negative electrode for Li-ion batteries, we have prepared a Fe-containing TiO2(B) and tested the electrochemical performances of both pure and Fe-containing materials. Fe insertion in TiO2(B) allows enhancing capacity and rate capability.

  1. Visual Field Loss in a Case of Recurrent Cystic Craniopharyngioma During Concomitant Treatment With Pegylated Interferon α-2b.

    PubMed

    Tiedemann, Laura M; Manley, Peter; Smith, Edward R; Dagi, Linda R

    2016-01-01

    A 13-year-old male with suprasellar cystic craniopharyngioma initially controlled with sequential subtotal resections and proton-beam irradiation was later treated with intracystic pegylated interferon α-2b due to progression and a lack of further surgical options. After initial successful control of recurrent cyst enlargement and stabilization of the ophthalmic examination, progressive and irreversible visual field loss ensued. Imaging revealed intracranial leakage from the intracystic catheter, and direct administration of interferon α-2b was discontinued. Given the recent interest in interferon α-2b, oncologists are advised to vigilantly monitor patients for signs of local toxicity that may result from unintended leakage during intracystic delivery.

  2. Factors Affecting Phenotype Variability in a Family with CMT2B: Gender and LRSAM1 Genotype

    PubMed Central

    Peddareddygari, Leema Reddy; Oberoi, Kinsi; Vellore, Jaasrini Reddy; Grewal, Raji P.

    2016-01-01

    Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified. In this family, none of the individuals had ulceromutilating features, and there was a marked variability in the age of onset. We discuss the possible etiology of the observed phenotypic variability including the role of gender and possible RAB7A/LRSAM1 gene interactions. PMID:27462242

  3. Laboratory detection of a new interstellar free radical CH2CN(2B1)

    NASA Technical Reports Server (NTRS)

    Saito, Shuji; Yamamoto, Satoshi; Irvine, W. M.; Ziurys, L. M.; Suzuki, Hiroko

    1988-01-01

    An asymmetric-top free radical CH2CN with a 2B1 ground state was detected by laboratory microwave spectroscopy. The radical was produced in a free-space absorption cell by a DC glow discharge in pure CH3CN gas. About 60 fine-structure components were observed for the N = 11-10 to 14-13 a-type rotational transitions in the frequency region of 220-260 GHz. Hyperfine resolved components for the N = 4-3 and 5-4 transitions were resolved in the 80 and 100 GHz regions, respectively. Molecular constants were determined and U100602 and U80484 from Sgr B2, and U40240 and U20120 from TMC-1 were assigned to the N = 5-4, 4-3, 2-1, and 1-0 transitions with K(-1) = 0 of the CH2CN radical.

  4. Scanning Hall Probe Imaging of ErNi2B2C

    SciTech Connect

    Bluhm, Hendrik; Sebastian, Suchitra; Guikema, Janice W.; Fisher, I.R.; Moler, Kathryn A.; /Stanford U., Appl. Phys. Dept.

    2005-12-02

    We report scanning Hall probe imaging of ErNi{sub 2}B{sub 2}C in the superconducting, antiferromagnetic, and weakly ferromagnetic regimes in magnetic fields up to 20 Oe, well below H{sub c1}, with two results. First, imaging isolated vortices shows that they spontaneously rearrange on cooling through the antiferromagnetic transition temperature T{sub N} = 6 K to pin on twin boundaries, forming a striped pattern. Second, a weak, random magnetic signal appears in the ferromagnetic phase below T{sub WFM} = 2.3 K, and no spontaneous vortex lattice is present down to 1.9 K. We conclude that ferromagnetism coexists with superconductivity either by forming small ferromagnetic domains or with oscillatory variation of the magnetization on sub-penetration depth length scales.

  5. Iron abundance in the hot DA white dwarfs Feige 24 and G191 B2B

    NASA Technical Reports Server (NTRS)

    Vennes, Stephane; Chayer, Pierre; Thorstensen, John R.; Bowyer, Stuart; Shipman, Harry L.

    1992-01-01

    Attention is given to model calculations of the far- and extreme-UV line spectra of highly ionized Fe species (Fe IV, Fe V, and Fe VI) for hot high-gravity H-rich stars. A spectral analysis of 31 hr of exposure of the DA white dwarf Feige 24 with IUE in the echelle mode reveals the presence of Fe with an abundance relative to H by number of (5-10) x 10 exp -6 with an uncertainty dominated by the determination of stellar parameters. An analysis of IUE data from the white dwarf G191 B2B results in a similar Fe abundance if this star shares similar atmospheric parameters (Teff, g) with Feige 24. Fe is thus the second most abundant photospheric element in hot DA white dwarfs.

  6. Collision-induced absorption in the O2 B-band region near 670 nm.

    PubMed

    Spiering, Frans R; Kiseleva, Maria B; Filippov, Nikolay N; van Kesteren, Line; van der Zande, Wim J

    2011-05-28

    We have determined the collision-induced absorption (CIA) spectrum in the O(2) B-band in pure oxygen. We present absolute extinction coefficients of the minimums in between rotational lines using cavity ring-down spectroscopy. The measured extinction is corrected for the B-band magnetic dipole absorption using a model which includes line-mixing. The remaining extinction consists of collision-induced absorption and Rayleigh scattering. We retrieve the magnitude of the Rayleigh scattering and the CIA spectrum based on their individual different behavior with density. The CIA spectrum of the B-band resembles that of the oxygen A-band in shape but not in magnitude. The contribution of CIA to the total B-band absorption is 40% higher in comparison to that of the A-band.

  7. Localization of two potassium channel {beta} subunit genes, KCNA1B and KCNA2B

    SciTech Connect

    Schultz, D.; Smith, L.; Thayer, M.

    1996-02-01

    The gating properties and current amplitudes of mammalian voltage-activated Shaker potassium channels are modulated by at least two associated {beta} subunits (Kv{beta}1.1 and Kv{beta}1.2). The human Kv{beta}1.1 gene (KCNA1B) resides on chromosome 3, as indicated by somatic cell hybrid mapping. More precise localization of KCNA1B to 3q26.1 was obtained with fluorescence in situ hybridization (FISH) and was corroborated by PCR screening of the CEPH YAC library. The human Kv{beta}1.2 gene (KCNA2B) resides on chromosome 1, as indicated by somatic cell hybrid mapping, and has been localized by FISH to 1p36.3. 20 refs., 2 figs.

  8. Adenosine A2B Receptor: From Cell Biology to Human Diseases.

    PubMed

    Sun, Ying; Huang, Pingbo

    2016-01-01

    Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR's functions, including certain seemingly paradoxical functions of the receptor. Growing evidence indicates a critical role of A2BAR in cancer, renal disease, and diabetes, in addition to its importance in the regulation of vascular diseases, and lung disease. Here, we also discuss the role of A2BAR in cancer, renal disease, and diabetes and the potential of the receptor as a target for treating these three diseases. PMID:27606311

  9. Adenosine A2B receptor: from cell biology to human diseases

    NASA Astrophysics Data System (ADS)

    Sun, Ying; Huang, Pingbo

    2016-08-01

    Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR’s functions, including certain seemingly paradoxical functions of the receptor. Growing evidence indicates a critical role of A2BAR in cancer, renal disease, and diabetes, in addition to its importance in the regulation of vascular diseases and lung disease. Here, we also discuss the role of A2BAR in cancer, renal disease, and diabetes and the potential of the receptor as a target for treating these three diseases.

  10. Adenosine A2B Receptor: From Cell Biology to Human Diseases

    PubMed Central

    Sun, Ying; Huang, Pingbo

    2016-01-01

    Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR's functions, including certain seemingly paradoxical functions of the receptor. Growing evidence indicates a critical role of A2BAR in cancer, renal disease, and diabetes, in addition to its importance in the regulation of vascular diseases, and lung disease. Here, we also discuss the role of A2BAR in cancer, renal disease, and diabetes and the potential of the receptor as a target for treating these three diseases.

  11. Adenosine A2B Receptor: From Cell Biology to Human Diseases

    PubMed Central

    Sun, Ying; Huang, Pingbo

    2016-01-01

    Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR's functions, including certain seemingly paradoxical functions of the receptor. Growing evidence indicates a critical role of A2BAR in cancer, renal disease, and diabetes, in addition to its importance in the regulation of vascular diseases, and lung disease. Here, we also discuss the role of A2BAR in cancer, renal disease, and diabetes and the potential of the receptor as a target for treating these three diseases. PMID:27606311

  12. Fast hydrogen sorption from MgH2-VO2(B) composite materials

    NASA Astrophysics Data System (ADS)

    Milošević, Sanja; Kurko, Sandra; Pasquini, Luca; Matović, Ljiljana; Vujasin, Radojka; Novaković, Nikola; Novaković, Jasmina Grbović

    2016-03-01

    The hydrogen sorption kinetics of MgH2‒VO2(B) composites synthesised by mechanical milling have been studied. The microstructural properties of composites were characterized by means of X-ray diffraction (XRD), Raman spectroscopy, Scanning electron microscopy (SEM), Particle size analysis (PSD), while sorption behaviour was followed by differential scanning calorimetry (DSC) and Sievert measurements. Results have shown that although desorption temperature reduction is moderate; there is a substantial improvement in hydrogen sorption kinetics. The complete desorption of pure MgH2 at elevated temperature takes place in more than 30 min while the composite fully desorbs in less than 2 min even at lower temperatures. It has been shown that the metastable γ-MgH2 phase and the point defects have a decisive role in desorption process only in the first sorption cycle, while the second and the subsequent sorption cycles are affected by microstructural and morphological characteristics of the composite.

  13. Low level waste heat conversion by Organic Rankine Cycle. Task 2B report

    SciTech Connect

    Brandt, D.L.

    1981-01-01

    A Refinery Energy Profile Study identified the waste heat being rejected from process streams in air and water cooled heat exchangers as a potential area for the application of energy conservation technology. One technology for recovering energy in this area, when process stream temperatures are in the 200 to 400/sup 0/F range, is the Organic Rankine Cycle (ORC) System. The Rankine cycle is a thermodynamic process for converting heat energy into mechanical and/or electrical energy. The objective of Task 2B in this followup contract to the Profile Study is to evaluate ORC systems for recovering energy from air and water cooled process streams by analyzing specific applications within a refinery crude unit. The basis for this study is the data from the Refinery Energy Profile Study.

  14. Agile text mining for the 2014 i2b2/UTHealth Cardiac risk factors challenge.

    PubMed

    Cormack, James; Nath, Chinmoy; Milward, David; Raja, Kalpana; Jonnalagadda, Siddhartha R

    2015-12-01

    This paper describes the use of an agile text mining platform (Linguamatics' Interactive Information Extraction Platform, I2E) to extract document-level cardiac risk factors in patient records as defined in the i2b2/UTHealth 2014 challenge. The approach uses a data-driven rule-based methodology with the addition of a simple supervised classifier. We demonstrate that agile text mining allows for rapid optimization of extraction strategies, while post-processing can leverage annotation guidelines, corpus statistics and logic inferred from the gold standard data. We also show how data imbalance in a training set affects performance. Evaluation of this approach on the test data gave an F-Score of 91.7%, one percent behind the top performing system.

  15. High-temperature Raman spectroscopic study of vanadoborate Na3VO2B6O11

    NASA Astrophysics Data System (ADS)

    Ji, Zhang; De-Ming, Zhang; Qing-Li, Zhang; Shao-Tang, Yin

    2016-03-01

    Raman spectra of a vanadoborate (Na3VO2B6O11) crystal from room temperature up to the melting point have been recorded. The main internal vibrational modes of the crystal have been assigned. It was found that all the Raman bands exhibit decreases in frequency and the widths of the Raman bands increase with the increase of temperature. However, no phase transition was observed under 525 °C. The micro-structure of its melt was studied by quantum chemistry ab initio calculation. The continuous three-dimensional network of the crystal collapsed and transformed into VO4 and VBO6 clusters during the melting process with an isomerization reaction from four-coordinated boron to a three-coordinated species. Project supported by the National Natural Science Foundation of China (Grant Nos. 51302268 and 51102239) and the Natural Science Foundation of Anhui Province, China (Grant No. KJ2015A339).

  16. Flexibility in crosstalk between H2B ubiquitination and H3 methylation in vivo

    PubMed Central

    Vlaming, Hanneke; van Welsem, Tibor; de Graaf, Erik L; Ontoso, David; Altelaar, AF Maarten; San-Segundo, Pedro A; Heck, Albert JR; van Leeuwen, Fred

    2014-01-01

    Histone H2B ubiquitination is a dynamic modification that promotes methylation of histone H3K79 and H3K4. This crosstalk is important for the DNA damage response and has been implicated in cancer. Here, we show that in engineered yeast strains, ubiquitins tethered to every nucleosome promote H3K79 and H3K4 methylation from a proximal as well as a more distal site, but only if in a correct orientation. This plasticity indicates that the exact location of the attachment site, the native ubiquitin-lysine linkage and ubiquitination cycles are not critical for trans-histone crosstalk in vivo. The flexibility in crosstalk also indicates that other ubiquitination events may promote H3 methylation. PMID:25141862

  17. Factors Affecting Phenotype Variability in a Family with CMT2B: Gender and LRSAM1 Genotype.

    PubMed

    Peddareddygari, Leema Reddy; Oberoi, Kinsi; Vellore, Jaasrini Reddy; Grewal, Raji P

    2016-01-01

    Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified. In this family, none of the individuals had ulceromutilating features, and there was a marked variability in the age of onset. We discuss the possible etiology of the observed phenotypic variability including the role of gender and possible RAB7A/LRSAM1 gene interactions. PMID:27462242

  18. Creation of transgenic Brassica napus L. plants expressing human alpha 2b interferon gene.