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  1. Fuentes de variabilidad en el diagnóstico de gastritis atrófica multifocal asociada con la infección por Helicobacter pylori1

    PubMed Central

    Bravo, Luis Eduardo; Bravo, Juan Carlos; Realpe, José Luis; Zarama, Guillermo; Piazuelo, MarÍa Blanca; Correa, Pelayo

    2014-01-01

    RESUMEN Introducción El mapeo de las diferentes regiones del estómago y el número de fragmentos de mucosa gástrica disponibles para evaluación histopatológica son fuentes importantes de variación en el momento de clasificar y hacer la gradación de la gastritis crónica. Objetivos Estimar la sensibilidad del número de fragmentos de mucosa gástrica necesarios para establecer los diagnósticos de gastritis atrófica con metaplasia intestinal (MI), displasia y estado de infección por Helicobacter pylori. Además evaluar la variabilidad intra-observador en la clasificación de estas lesiones precursoras del cáncer gástrico. Materiales y métodos En una cohorte de 6 años de seguimiento se evaluaron 1,958 procedimientos de endoscopia realizados por dos gastroenterólogos. En cada procedimiento y de cada participante se obtuvieron 5 biopsias de mucosa gástrica que representaban antro, incisura angularis y cuerpo. Un único patólogo hizo la interpretación histológica de las 5 biopsias y proporcionó un diagnóstico definitivo global que se utilizó como patrón de referencia. Cada fragmento de mucosa gástrica examinado condujo a un diagnóstico individual para cada biopsia que se comparó con el patrón de referencia. La variabilidad intra-observador se evaluó en 127 personas que corresponden a una muestra aleatoria de 20% del total de endoscopias hechas a los 72 meses de seguimiento. Resultados La sensibilidad del diagnóstico de MI y displasia gástrica aumentó de manera significativa con el número de fragmentos de mucosa gástrica evaluados El sitio anatómico de mayor sensibilidad para el diagnóstico de MI y displasia fue la incisura angularis. Para descubrir H. pylori se logró alta sensibilidad con el estudio de un solo fragmento de mucosa gástrica (95.9%) y fue independiente del sitio de obtención de la biopsia. El acuerdo intra-observador para el diagnóstico de gastritis crónica fue 86.1% con valor kappa de 0.79 IC 95% (0.76-0.85). Las

  2. FUENTES Infrarrojas EN 2.2 lim EN la Region Asociada AL GLOBULO ORI-1-2

    NASA Astrophysics Data System (ADS)

    Cruz-Gonzalez, J.; Carrasco, L.; Ramos, M. P.

    1987-05-01

    Se ha mapeado en el cercano infrarrojo a 2.2 micras, una región de 2 x 5 minutos de arco asociada al glóbulo ORI-I-2. Se ha detectado emisión infrarroja de fuentes puntuales y emisión extendida de bajo brillo superficial. Se discute la asociación de fuentes de 2.2 micras con la emisión detectada en IRAS y en moléculas de radio frecuencias.

  3. Poblacion estelar joven embebida en la nube molecular galactica asociada a la fuente IRAS 18236-1205

    NASA Astrophysics Data System (ADS)

    Romero, Ricardo Retes

    2008-06-01

    En esta tesis presento una metodología de seleccion y estudio de la población estelar embebida en la nube molecular galactica asociada a la fuente IRAS 18236-1205. La fuente IRAS posee colores de region Ultra Compacta HII (UCHII) y tiene deteccióon en monosulfuro de carbono (CS), trazador molecular de alta densidad, lo cual da la posibilidad de definir la nube molecular asociada hacia esta region. Lo anterior muestra que esta es buena candidata a región de formación estelar masiva. La metodología de seleccion de la población embebida, est à basada por una parte, en la distribución del gas molecular monoxido de carbono (13CO) asociado a la fuente IRAS, nube molecular seleccionada del mapeo Galactic Ring Survey (GRS) realizado en 13CO. Otros pasos de la seleccion, se basan en los diagramas color-color y color-magnitud con datos del cercano infrarrrojo de 2MASS. Para el estudio de la componente estelar se usaron los catalogos de fuentes puntuales en el cercano, medio y lejano infrarrojo de 2MASS, SPITZER e IRAS, respectivamente. De los diagramas color-color y color-magnitud, usando datos de 2MASS, se construyo un criterio fotométrico para identificar los objetos estelares j ovenes embebidos en la region molecular. Aplicando modelos a la distribución espectral de energía (SED) de algunos ellos, se encontraron parametros estelares de objetos estelares j ovenes embebidos de masa intermedia y alta. Adicionalmente, se encontro un objeto de masa ´ intermedia no identifiado por el catalogo de 2MASS y su efecto sobre el medio interestelar, emision en la banda de [4.5] μm de IRAC-Spitzer asociado a un outflow. Dos de los objetos seleccionados por el criterio fotometrico resultaron ser objetos estelares jovenes de alta e intermedia masa (B1V/B2V y B8V/A0V respectivamente), los cuales deben estar asociados a la emision radiativa responsable de los colores de región UC HII. Otro objeto estelar joven de baja masa (F0V/F5V) fue encontrado en la region de estudio

  4. A-4 scientific results

    NASA Technical Reports Server (NTRS)

    Matteson, J.

    1979-01-01

    Observations of galactic sources, extragalactic sources and gamma bursts with the A-4 instrument at energy 1 energies of between 0.1 to 10 MeV are discussed. Aximuthal scans are presented. The Crab Nebula and its spectrum and the spectrum of Cygnus Z-1 are described.

  5. ConSCRIPT

    PubMed Central

    Mottarella, Scott E.; Rosa, Mario; Bangura, Abdul; Bernstein, Herbert J.; Craig, Paul A.

    2011-01-01

    The aim of the Structural Biology Extensible Visualization Scripting Language (SBEVSL) project is to allow users who are experts in one scripting language to use that language in a second molecular visualization environment without requiring the user to learn a new scripting language. ConSCRIPT, the first SBEVSL release, is a plug-in for PyMOL that accepts RasMol scripting commands either as premade scripts or as line-by-line entries from PyMOL's own command line. The plug-in is available for download at http://sourceforge.net/projects/sbevsl/files in the ConSCRIPT folder. PMID:21567873

  6. The Con Test

    ERIC Educational Resources Information Center

    Fletcher, Michael

    2009-01-01

    In this article, the author describes the format of the Con Test, an Australian television game show which followed the same general rules and game play as the UK show PokerFace. At the end of each round a contestant needs to decide whether or not he or she should fold. A contestant needs to know how likely it is that he or she is in last place.…

  7. Nam Con Son Basin

    SciTech Connect

    Tin, N.T.; Ty, N.D.; Hung, L.T.

    1994-07-01

    The Nam Con Son basin is the largest oil and gas bearing basin in Vietnam, and has a number of producing fields. The history of studies in the basin can be divided into four periods: Pre-1975, 1976-1980, 1981-1989, and 1990-present. A number of oil companies have carried out geological and geophysical studies and conducted drilling activities in the basin. These include ONGC, Enterprise Oil, BP, Shell, Petro-Canada, IPL, Lasmo, etc. Pre-Tertiary formations comprise quartz diorites, granodiorites, and metamorphic rocks of Mesozoic age. Cenozoic rocks include those of the Cau Formation (Oligocene and older), Dua Formation (lower Miocene), Thong-Mang Cau Formation (middle Miocene), Nam Con Son Formation (upper Miocene) and Bien Dong Formation (Pliocene-Quaternary). The basement is composed of pre-Cenozoic formations. Three fault systems are evident in the basin: north-south fault system, northeast-southwest fault system, and east-west fault system. Four tectonic zones can also be distinguished: western differentiated zone, northern differentiated zone, Dua-Natuna high zone, and eastern trough zone.

  8. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  9. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  10. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  11. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  12. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  13. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Meetings. 1912a.4 Section 1912a.4 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.4 Meetings. (a) The Committee...

  14. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority to...

  15. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  16. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority to...

  17. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  18. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority to...

  19. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  20. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority to...

  1. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority to...

  2. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  3. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  4. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to...

  5. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to...

  6. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to investigate and...

  7. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to...

  8. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to investigate and...

  9. 44 CFR Appendix A(4) to Part 61 - Appendix A(4) to Part 61

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Appendix A(4) to Part 61 A(4) Appendix A(4) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY... COVERAGE AND RATES Pt. 61, App. A(4) Appendix A(4) to Part 61 Federal Emergency Management Agency, Federal...

  10. 44 CFR Appendix A(4) to Part 61 - Appendix A(4) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(4) to Part 61 A(4) Appendix A(4) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY... COVERAGE AND RATES Pt. 61, App. A(4) Appendix A(4) to Part 61 Federal Emergency Management Agency,...

  11. Determinación de la masa evacuada en una región de oscurecimiento coronal y su relación con la masa de su CME asociada

    NASA Astrophysics Data System (ADS)

    López, F. M.; Cremades, H.; Nuevo, F. A.; Balmaceda, L.; Vásquez, A. M.

    2016-08-01

    Coronal dimmings are regions in the low corona characterized by depletions in the coronal EUV and X-ray intensity. Dimmings are usually related to the loss of plasma and magnetic fields asociated with the eruption of a Coronal Mass Ejection (CME). In this work we present a study of the temporal evolution for the mass loss of a dimming event observed in EUV wavelengths on 23 May 2010. The study of the mass loss was performed using EUV images obtained by the Atmospheric Imaging Assembly instrument on board the Solar Dynamics Observatory (AIA/SDO). For the estimation of the plasma electronic density in the low corona, we used a differential emission measure technique. On the other hand, we used coronographic data from the STEREO mission to estimate the temporal evolution of the mass for the asociated CME in white light. The obtained results show that the mass loss of the dimming represents 67.5 of the associated CME mass determined using white light data, which accounts for a considerable amount of the CME mass.

  12. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees. (a... at the same cost we charge for duplication of records and/or production of computer output under...

  13. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees. (a... at the same cost we charge for duplication of records and/or production of computer output under...

  14. Caffe con Troll: Shallow Ideas to Speed Up Deep Learning.

    PubMed

    Hadjis, Stefan; Abuzaid, Firas; Zhang, Ce; Ré, Christopher

    2015-01-01

    We present Caffe con Troll (CcT), a fully compatible end-to-end version of the popular framework Caffe with rebuilt internals. We built CcT to examine the performance characteristics of training and deploying general-purpose convolutional neural networks across different hardware architectures. We find that, by employing standard batching optimizations for CPU training, we achieve a 4.5× throughput improvement over Caffe on popular networks like CaffeNet. Moreover, with these improvements, the end-to-end training time for CNNs is directly proportional to the FLOPS delivered by the CPU, which enables us to efficiently train hybrid CPU-GPU systems for CNNs.

  15. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  16. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  17. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  18. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  19. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  20. Charge symmetry breaking in A = 4 hypernuclei

    NASA Astrophysics Data System (ADS)

    Achenbach, P.

    2016-11-01

    Charge symmetry breaking in the A = 4 hypernuclear system is reviewed. The data on binding energies of the mirror nuclei and hypernuclei are examined. At the Mainz Microtron MAMI the high-resolution spectroscopy of decay-pions in strangeness electro-production is used to extract the Λ hyperon ground state binding energy in 4ΛH. This binding energy is used together with the 4ΛHe ground state binding energy from nuclear emulsion experiments and with energy levels of the 1+ excited state for both hypernuclei from γ-ray spectroscopy to address the charge symmetry breaking in the strong interaction. The binding energy difference of the ground states in the mirror pair is reduced from its long accepted value ΔB4Λ(0+g.s.) ≈ 0.35MeV to ≈ 0.24MeV. The energy difference of the excited states becomes ΔB4Λ(1+exc) ≈ -0.08MeV, for the first time with opposite sign. These values were not reproduced by theoretical calculations with the exception of very recent approaches, although with a large systematic dependence. The full understanding of the charge symmetry breaking in the A = 4 hypernuclei still remains one of the open issues of hypernuclear physics.

  1. Mincle Signaling Promotes Con A Hepatitis.

    PubMed

    Greco, Stephanie H; Torres-Hernandez, Alejandro; Kalabin, Aleksandr; Whiteman, Clint; Rokosh, Rae; Ravirala, Sushma; Ochi, Atsuo; Gutierrez, Johana; Salyana, Muhammad Atif; Mani, Vishnu R; Nagaraj, Savitha V; Deutsch, Michael; Seifert, Lena; Daley, Donnele; Barilla, Rocky; Hundeyin, Mautin; Nikifrov, Yuriy; Tejada, Karla; Gelb, Bruce E; Katz, Steven C; Miller, George

    2016-10-01

    Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle(-/-), and Dectin-1(-/-) mice. The role of C/EBPβ and hypoxia-inducible factor-1α (HIF-1α) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ-related signaling intermediates C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPβ and HIF-1α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.

  2. Mincle Signaling Promotes Con-A Hepatitis

    PubMed Central

    Greco, Stephanie H.; Torres-Hernandez, Alejandro; Kalabin, Aleksandr; Whiteman, Clint; Rokosh, Rae; Ravirala, Sushma; Ochi, Atsuo; Gutierrez, Johana; Salyana, Muhammad Atif; Mani, Vishnu R.; Nagaraj, Savitha V.; Deutsch, Michael; Seifert, Lena; Daley, Donnele; Barilla, Rocky; Hundeyin, Mautin; Nikifrov, Yuriy; Tejada, Karla; Gelb, Bruce E.; Katz, Steven C.; Miller, George

    2016-01-01

    Concanavalin-A (Con-A) hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor (CLR) that is critical in the immune response to mycobacteria and fungi, but does not have a well-defined role in pre-clinical models of non-pathogen mediated inflammation. Since Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con-A hepatitis. Acute liver injury was assessed in the murine Con-A hepatitis model using C57BL/6, Mincle−/−, and Dectin-1−/− mice. The role of C/EBPβ and HIF-1α signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con-A hepatitis. Most significantly, Mincle deletion or blockade protected against Con-A hepatitis whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other CLRs did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ related signaling intermediates, C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con-A hepatitis and inhibition of both C/EBPβ and HIF1-α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con-A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation. PMID:27559045

  3. Galaxias australes con núcleo doble

    NASA Astrophysics Data System (ADS)

    Gimeno, G.; Díaz, R.; Carranza, G.

    Se estudia una muestra de galaxias australes con núcleo doble a partir de una búsqueda extensiva en la literatura. Se analizan las características morfológicas, fotométricas y espectroscópicas de la muestra. Para algunas galaxias se han realizado observaciones con el espectrógrafo multifunción (EMF) de la Estación Astrofísica de Bosque Alegre a partir de las cuales se determinaron parámetros cinemáticos.

  4. GeConT: gene context analysis.

    PubMed

    Ciria, R; Abreu-Goodger, C; Morett, E; Merino, E

    2004-09-22

    The fact that adjacent genes in bacteria are often functionally related is widely known. GeConT (Gene Context Tool) is a web interface designed to visualize genome context of a gene or a group of genes and their orthologs in all the completely sequenced genomes. The graphical information of GeConT can be used to analyze genome annotation, functional ortholog identification or to verify the genomic context congruence of any set of genes that share a common property. http://www.ibt.unam.mx/biocomputo/gecont.html

  5. Caffe con Troll: Shallow Ideas to Speed Up Deep Learning

    PubMed Central

    Hadjis, Stefan; Abuzaid, Firas; Zhang, Ce; Ré, Christopher

    2016-01-01

    We present Caffe con Troll (CcT), a fully compatible end-to-end version of the popular framework Caffe with rebuilt internals. We built CcT to examine the performance characteristics of training and deploying general-purpose convolutional neural networks across different hardware architectures. We find that, by employing standard batching optimizations for CPU training, we achieve a 4.5× throughput improvement over Caffe on popular networks like CaffeNet. Moreover, with these improvements, the end-to-end training time for CNNs is directly proportional to the FLOPS delivered by the CPU, which enables us to efficiently train hybrid CPU-GPU systems for CNNs. PMID:27314106

  6. InterCon Travel Health: Case B

    ERIC Educational Resources Information Center

    Truman, Gregory E.; Pachamanova, Dessislava A.; Goldstein, Michael A.

    2010-01-01

    InterCon provides services to health insurers of foreign tourists who travel to the United States and Canada. Management wants to implement a new information system that will deal with several operational problems, but it is having difficulty securing the capital resources to fund the system's development. After an initial failure, the chief…

  7. InterCon Travel Health: Case B

    ERIC Educational Resources Information Center

    Truman, Gregory E.; Pachamanova, Dessislava A.; Goldstein, Michael A.

    2010-01-01

    InterCon provides services to health insurers of foreign tourists who travel to the United States and Canada. Management wants to implement a new information system that will deal with several operational problems, but it is having difficulty securing the capital resources to fund the system's development. After an initial failure, the chief…

  8. Ependimoma myxopapilar sacro gigante con osteolisis

    PubMed Central

    Ajler, Pablo; Landriel, Federico; Goldschmidt, Ezequiel; Campero, Álvaro; Yampolsky, Claudio

    2014-01-01

    Objetivo: la presentación de un caso de una paciente con un ependimoma sacro con extensa infiltración y destrucción ósea local. Descripción del caso: una mujer de 53 años acudió a la consulta por dolor lumbosacro y alteraciones sensitivas perineales y esfinterianas. La imágenes por Resonancia Magnética (IRM) y la Tomografía Axial Computada (TAC) mostraron una lesión expansiva gigante a nivel S2-S4 con extensa osteólisis e invasión de tejidos adyacentes. Se realizó una exéresis tumoral completa con mejoría del estatus funcional. La anatomía patológica informó ependimoma mixopapilar. Discusión: la extensión de la resección quirúrgica es el mejor predictor de buen pronóstico. El tratamiento radiante se reserva como opción adyuvante para las resecciones incompletas y recidiva tumoral. La quimioterapia sólo debería utilizarse en casos en que la cirugía y la radioterapia estén contraindicadas. Conclusión: Los ependimomas mixopapilares sacros con destrucción ósea y presentación intra y extradural son muy infrecuentes y deben ser tenidos en cuenta entre los diagnósticos diferenciales preoperatorios. Su resección total, siempre que sea posible, es la mejor alternativa terapéutica. PMID:25165615

  9. Conserva a Puerto Rico con bosques maderables

    Treesearch

    Frank H. Wadsworth

    2009-01-01

    [article in Spanish] Puerto Rico consume muchos productos forestales costosos de importar. También tiene bosques extensos con maderas explotables. Además, existen condiciones físicas favorables para la producción de madera útil. No obstante, hoy día no se utiliza la madera de los bosques actuales ocurre la deforestación para cualquier fin. Los Bosques productivos de...

  10. Somatic cell nuclear transfer: pros and cons.

    PubMed

    Sumer, Huseyin; Liu, Jun; Tat, Pollyanna; Heffernan, Corey; Jones, Karen L; Verma, Paul J

    2009-01-01

    Even though the technique of mammalian SCNT is just over a decade old it has already resulted in numerous significant advances. Despite the recent advances in the reprogramming field, SCNT remains the bench-mark for the generation of both genetically unmodified autologous pluripotent stem cells for transplantation and for the production of cloned animals. In this review we will discuss the pros and cons of SCNT, drawing comparisons with other reprogramming methods.

  11. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall contain...

  12. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall contain...

  13. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall contain...

  14. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall contain...

  15. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of meat...

  16. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall...

  17. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  18. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  19. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  20. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  1. 26 CFR 1.401(a)(4)-12 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... Ancillary benefit. Ancillary benefit is defined in § 1.401(a)(4)-4(e)(2). Average annual compensation. Average annual compensation is defined in § 1.401(a)(4)-3(e)(2). Base benefit percentage. Base benefit... §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. Accumulation plan. Accumulation plan means a defined benefit...

  2. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4 How...

  3. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  4. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  5. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  6. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  7. 22 CFR 3a.4 - Procedure for requesting approval.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Procedure for requesting approval. 3a.4 Section 3a.4 Foreign Relations DEPARTMENT OF STATE GENERAL ACCEPTANCE OF EMPLOYMENT FROM FOREIGN GOVERNMENTS BY MEMBERS OF THE UNIFORMED SERVICES § 3a.4 Procedure for requesting approval. (a) An applicant must...

  8. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

  9. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

  10. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

  11. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

  12. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Calculation of time. 260.7a-4 Section 260.7a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-4 Calculation...

  13. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  14. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  15. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  16. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  17. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  18. S100A4 protects the myocardium against ischemic stress.

    PubMed

    Doroudgar, Shirin; Quijada, Pearl; Konstandin, Mathias; Ilves, Kelli; Broughton, Kathleen; Khalafalla, Farid G; Casillas, Alexandria; Nguyen, Kristine; Gude, Natalie; Toko, Haruhiro; Ornelas, Luis; Thuerauf, Donna J; Glembotski, Christopher C; Sussman, Mark A; Völkers, Mirko

    2016-11-01

    Myocardial infarction is followed by cardiac dysfunction, cellular death, and ventricular remodeling, including tissue fibrosis. S100A4 protein plays multiple roles in cellular survival, and tissue fibrosis, but the relative role of the S100A4 in the myocardium after myocardial infarction is unknown. This study aims to investigate the role of S100A4 in myocardial remodeling and cardiac function following infarct damage. S100A4 expression is low in the adult myocardium, but significantly increased following myocardial infarction. Deletion of S100A4 increased cardiac damage after myocardial infarction, whereas cardiac myocyte-specific overexpression of S100A4 protected the infarcted myocardium. Decreased cardiac function in S100A4 Knockout mice was accompanied with increased cardiac remodeling, fibrosis, and diminished capillary density in the remote myocardium. Loss of S100A4 caused increased apoptotic cell death both in vitro and in vivo in part mediated by decreased VEGF expression. Conversely, S100A4 overexpression protected cells against apoptosis in vitro and in vivo. Increased pro-survival AKT-signaling explained reduced apoptosis in S100A4 overexpressing cells. S100A4 expression protects cardiac myocytes against myocardial ischemia and is required for stabilization of cardiac function after MI. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Significance of the S100A4 protein in psoriasis.

    PubMed

    Zibert, John R; Skov, Lone; Thyssen, Jacob P; Jacobsen, Grete K; Grigorian, Mariam

    2010-01-01

    The S100A4 protein is reported as a pivotal player in the tumor microenvironment with a metastasis-promoting function. Moreover, the upregulation of S100A4 is found in other non-malignant human disorders as cardiac and pulmonary systems and rheumatoid arthritis. In this study, we investigated the expression and significance of S100A4 in psoriasis. We found significant upregulation of S100A4 in the dermis of psoriatic skin compared with normal skin. This pattern of S100A4 expression differs considerably from that of other S100 proteins, S100A7 and S100A8/9, with predominant expression in the epidermis of psoriasis. Furthermore, we revealed a massive release of the biologically active forms of S100A4 from psoriatic skin. Interestingly, we found stabilization (increase) of p53 in the basal layer of epidermis in close proximity to cells expressing S100A4. To examine the possible implication of S100A4 in the pathogenesis of psoriasis, we analyzed the effect of S100A4 blocking antibodies in a human psoriasis xenograft SCID mouse model and observed a significant reduction of the epidermal thickness and impairment in cell proliferation and dermal vascularization. In conclusion, we showed strong upregulation and release of S100A4 in the upper dermis of psoriatic skin and found evidence indicating that S100A4 might actively contribute to the pathogenesis of psoriasis.

  20. Energy Star program benefits Con Edison

    SciTech Connect

    1995-05-01

    Impressed with savings in energy costs achieved after upgrading the lighting and air conditioning systems at its Manhattan headquarters, Home Box Office (HBO) wanted to do more, James Flock, vice president for computer and office systems, contacted Con Edison Co. of New York in March 1991 to determine what the company could do to save money by reducing energy consumed by personal computers. Arthur Kressner, Con Edison Research and Development manager contacted industry organizations and manufacturers for advice, but was told only to shut off computers at night and on weekends. Kressner arranged a series of meetings with IBM and the Electric Power Research Institute (EPRI) to discuss the issue, then approached the U.S. Environmental Protection Agency (EPA), which was designing a program to promote the introduction and use of energy-efficient office equipment. In 1992, the EPA announced the Energy Star program for PCs, enabling manufacturers to display the Energy Star logo on machines meeting program criteria, including the ability to enter a sleep mode in which neither the computer nor monitor consume more than 30 W or electricity. Industry experts estimate national energy consumption by office equipment could double by the year 2000, but Energy Star equipment is expected to improve efficiency and help maintain electric loads.

  1. Plexin a4 expression in adult rat cranial nerves.

    PubMed

    Gutekunst, Claire-Anne; Gross, Robert E

    2014-11-01

    PlexinsA1-A4 participate in class 3 semaphorin signaling as co-receptors to neuropilin 1 and 2. PlexinA4 is the latest member of the PlexinA subfamily to be identified. In previous studies, we described the expression of PlexinA4 in the brain and spinal cord of the adult rat. Here, antibodies to PlexinA4 were used to reveal immunolabeling in most of the cranial nerve surveyed. Labeling was found in the olfactory, optic, oculomotor, trochlear, trigeminal, abducens, facial, vestibulocochlear, glossopharyngeal, vagus, and hypoglossal nerves. This is the first detailed description of the cellular and subcellular distribution of PlexinA4 in the adult cranial nerves. The findings will set the basis for future studies on the potential role of PlexinA4 in regeneration and repair of the adult central and peripheral nervous system. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Cervical disc arthroplasty: Pros and cons

    PubMed Central

    Moatz, Bradley; Tortolani, P. Justin

    2012-01-01

    Background: Cervical disc arthroplasty has emerged as a promising potential alternative to anterior cervical discectomy and fusion (ACDF) in appropriately selected patients. Despite a history of excellent outcomes after ACDF, the question as to whether a fusion leads to adjacent segment degeneration remains unanswered. Numerous US investigational device exemption trials comparing cervical arthroplasty to fusion have been conducted to answer this question. Methods: This study reviews the current research regarding cervical athroplasty, and emphasizes both the pros and cons of arthroplasty as compared with ACDF. Results: Early clinical outcomes show that cervical arthroplasty is as effective as the standard ACDF. However, this new technology is also associated with an expanding list of novel complications. Conclusion: Although there is no definitive evidence that cervical disc replacement reduces the incidence of adjacent segment degeneration, it does show other advantages; for example, faster return to work, and reduced need for postoperative bracing. PMID:22905327

  3. Plexin-A4 negatively regulates T lymphocyte responses.

    PubMed

    Yamamoto, Midori; Suzuki, Kazuhiro; Okuno, Tatsusada; Ogata, Takehiro; Takegahara, Noriko; Takamatsu, Hyota; Mizui, Masayuki; Taniguchi, Masahiko; Chédotal, Alain; Suto, Fumikazu; Fujisawa, Hajime; Kumanogoh, Atsushi; Kikutani, Hitoshi

    2008-03-01

    Semaphorins and their receptors play crucial roles not only in axon guidance during neuronal development but also in the regulation of immune responses. Plexin-A4, a member of the plexin-A subfamily, forms a receptor complex with neuropilins and transduces signals for class III semaphorins in the nervous system. Although plexin-A4 is also expressed in the lymphoid tissues, the involvement of plexin-A4 in immune responses remains unknown. To explore the role of plexin-A4 in the immune system, we analyzed immune responses in plexin-A4-deficient (plexin-A4-/-) mice. Among immune cells, plexin-A4 mRNA was detected in T cells, dendritic cells and macrophages but not in B cells and NK cells. Plexin-A4-/- mice had normal numbers and cell surface markers for each lymphocyte subset, suggesting that plexin-A4 is not essential for lymphocyte development. However, plexin-A4-/- mice exhibited enhanced antigen-specific T cell responses and heightened sensitivity to experimental autoimmune encephalomyelitis. Plexin-A4-/- T cells exhibited hyperproliferative responses to anti-CD3 stimulation and to allogeneic dendritic cells in vitro. Furthermore, this hyperproliferation was also observed in both T cells from neuropilin-1 mutant (npn-1(Sema-)) mice, in which the binding site of class III semaphorins is disrupted, and T cells from Sema3A-deficient (Sema-3A-/-) mice. Collectively, these results suggest that plexin-A4, as a component of the receptor complex for class III semaphorins, negatively regulates T cell-mediated immune responses.

  4. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Lifetime Learning Credit. 1.25A-4 Section 1.25A-4... Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1) Taxable years beginning before January 1, 2003. Subject to the phaseout of the education tax credit described in...

  5. CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing.

    PubMed

    Wang, Danxin; Sadee, Wolfgang

    2016-01-01

    Cytochrome P450 3A4 (CYP3A4) metabolizes 30-50% of clinically used drugs. Large interperson variability in CYP3A4 activity affects response to CYP3A4 substrate drugs. We had demonstrated that an intronic single nucleotide polymorphism rs35599367 (CYP3A4*22, located in intron 6) reduces mRNA/protein expression; however, the underlying mechanism remained unknown. Here we show that CYP3A4*22 is associated with a two-fold or greater increase in formation of a nonfunctional CYP3A4 alternative splice variant with partial intron 6 retention in human liver (P=0.006), but not in small intestines. Consistent with this observation, in-vitro transfection experiments with a CYP3A4 minigene (spanning from intron 5 to intron 7) demonstrated that plasmids carrying the rs35599367 minor T allele caused significantly greater intron 6 retention than the C allele in liver derived HepG2 cells, but not in intestine-derived LS-174T cells. These results indicate that tissue-specific increased formation of nonfunctional alternative splice variant causes reduced CYP3A4 mRNA/protein expression in CYP3A4*22 carriers.

  6. 26 CFR 1.167(a)-4 - Leased property.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Leased property. 1.167(a)-4 Section 1.167(a)-4... property. Capital expenditures made by a lessee for the erection of buildings or the construction of other permanent improvements on leased property are recoverable through allowances for depreciation or...

  7. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy...

  8. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Responsibilities and functions. 352a.4 Section...) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense Finance and Accounting Service (DFAS), is the principal DoD executive...

  9. 42 CFR 65a.4 - What are the program requirements?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What are the program requirements? 65a.4 Section 65a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  10. 42 CFR 65a.4 - What are the program requirements?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What are the program requirements? 65a.4 Section 65a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  11. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the Securities...

  12. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  13. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  14. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  15. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  16. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry...

  17. Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin.

    PubMed

    Ma, Zhong-lin; Yan, Xiao-jing; Zhao, Lei; Zhou, Jiu-jiu; Pang, Wan; Kai, Zhen-peng; Wu, Fan-hong

    2016-02-03

    Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management.

  18. Homotropic cooperativity of monomeric cytochrome P450 3A4

    SciTech Connect

    Baas, Bradley J.; Denisov, Ilia G.; Sligar, Stephen G.

    2010-11-16

    Mechanistic studies of mammalian cytochrome P450s are often obscured by the phase heterogeneity of solubilized preparations of membrane enzymes. The various protein-protein aggregation states of microsomes, detergent solubilized cytochrome or a family of aqueous multimeric complexes can effect measured substrate binding events as well as subsequent steps in the reaction cycle. In addition, these P450 monooxygenases are normally found in a membrane environment and the bilayer composition and dynamics can also effect these catalytic steps. Here, we describe the structural and functional characterization of a homogeneous monomeric population of cytochrome P450 3A4 (CYP 3A4) in a soluble nanoscale membrane bilayer, or Nanodisc [Nano Lett. 2 (2002) 853]. Cytochrome P450 3A4:Nanodisc assemblies were formed and purified to yield a 1:1 ratio of CYP 3A4 to Nanodisc. Solution small angle X-ray scattering was used to structurally characterize this monomeric CYP 3A4 in the membrane bilayer. The purified CYP 3A4:Nanodiscs showed a heretofore undescribed high level of homotropic cooperativity in the binding of testosterone. Soluble CYP 3A4:Nanodisc retains its known function and shows prototypic hydroxylation of testosterone when driven by hydrogen peroxide. This represents the first functional characterization of a true monomeric preparation of cytochrome P450 monooxygenase in a phospholipid bilayer and elucidates new properties of the monomeric form.

  19. Plasma levels of S100A4 in portopulmonary hypertension.

    PubMed

    Peng, Tien; Zamanian, Roham; Krowka, Michael J; Benza, Raymond L; Roberts, Kari E; Taichman, Darren B; Rybak, Debbie; Trotter, James F; Brown, Robert S; Fallon, Michael B; Kawut, Steven M

    2009-05-01

    We previously showed that a single nucleotide polymorphism in S100A4 was associated with portopulmonary hypertension (PPHTN) in patients with advanced liver disease. We aimed to determine the association between plasma levels of S100A4 and PPHTN. We performed a case-control study of patients with advanced liver disease. Cases with PPHTN had mean pulmonary artery pressure >25 mmHg, pulmonary vascular resistance >240 dynes s cm(-5) and pulmonary capillary wedge pressure A4. The study sample included 14 cases with PPHTN and 32 controls with liver disease. There was no difference in mean age between cases and controls (p = 0.52). Seventy-nine percent of cases were female compared with 44% of controls (p = 0.03). There was no difference in S100A4 levels between cases and controls (p = 0.58). Both groups had significantly higher S100A4 levels than healthy volunteers (p <0.05). There was no significant difference in plasma levels of S100A4 between PPHTN patients and controls with liver disease, although liver disease itself was associated with increased S100A4 levels.

  20. Plasma Levels of S100A4 in Portopulmonary Hypertension

    PubMed Central

    Peng, Tien; Zamanian, Roham; Krowka, Michael J.; Benza, Raymond L.; Roberts, Kari E.; Taichman, Darren B.; Rybak, Debbie; Trotter, James F.; Brown, Robert S.; Fallon, Michael B.; Kawut, Steven M.

    2010-01-01

    We previously showed that a single nucleotide polymorphism in S100A4 was associated with developing portopulmonary hypertension (PPHTN) in patients with advanced liver disease. We aimed to determine the association between plasma levels of S100A4 and PPHTN. We performed a case-control study of patients with advanced liver disease. Cases with PPHTN had mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes-sec · cm−5, and pulmonary capillary wedge pressure ≤15 mm Hg. Controls with liver disease had right ventricular systolic pressure < 40 mm Hg and normal right atrial and ventricular morphology by echocardiography. Plasma samples were assayed for S100A4. The study sample included 14 cases with PPHTN and 32 liver disease controls. The mean age for both cases and controls was 52 ± 9 yrs. Eighty percent of cases were female compared to 42% of controls (p = 0.02). There was no difference in S100A4 levels between cases and controls (p = 0.53). Both groups had significantly higher S100A4 levels than healthy volunteers (p < 0.05). There was no significant difference in plasma levels of S100A4 between PPHTN patients and controls with liver disease, although liver disease itself was associated with increased S100A4 levels. PMID:19399660

  1. Pros and cons of phage therapy

    PubMed Central

    Loc-Carrillo, Catherine

    2011-01-01

    Many publications list advantages and disadvantages associated with phage therapy, which is the use of bacterial viruses to combat populations of nuisance or pathogenic bacteria. The goal of this commentary is to discuss many of those issues in a single location. In terms of “Pros,” for example, phages can be bactericidal, can increase in number over the course of treatment, tend to only minimally disrupt normal flora, are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria, often are easily discovered, seem to be capable of disrupting bacterial biofilms, and can have low inherent toxicities. In addition to these assets, we consider aspects of phage therapy that can contribute to its safety, economics, or convenience, but in ways that are perhaps less essential to the phage potential to combat bacteria. For example, autonomous phage transfer between animals during veterinary application could provide convenience or economic advantages by decreasing the need for repeated phage application, but is not necessarily crucial to therapeutic success. We also consider possible disadvantages to phage use as antibacterial agents. These “Cons,” however, tend to be relatively minor. PMID:22334867

  2. INTERIOR VIEW WITH CASTING MACHINE AND A 4' DUCTILE IRON ...

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

    INTERIOR VIEW WITH CASTING MACHINE AND A 4' DUCTILE IRON PIPE BEING CENTRIFUGALLY CAST, AS OPERATOR WATCHES TO ENSURE QUALITY. - McWane Cast Iron Pipe Company, Pipe Casting Area, 1201 Vanderbilt Road, Birmingham, Jefferson County, AL

  3. Games Con Men Play: The Semiosis of Deceptive Interaction.

    ERIC Educational Resources Information Center

    Hankiss, Agnes

    1980-01-01

    Analyzes some of the most frequent deceptive interactions as rendered through case histories of male con artists and their victims taken from police records. Discusses the recurrent elements in both the con-games strategies and victims' way of interpreting those strategies. (JMF)

  4. Breath Analysis Science at PittCon 2012, Orlando, Florida

    EPA Science Inventory

    Breath analysis science was featured in three organized sessions at this year’s Pittsburgh Conference and Exposition, or ‘PittCon 2012’ (http://www.pittcon.org/). As described in previous meeting reports, PittCon is one of the largest international conferences for analytical chem...

  5. Trazando la materia oscura con cúmulos globulares

    NASA Astrophysics Data System (ADS)

    Forte, J. C.

    Se describe la estrategia adoptada para mapear la distribución de materia oscura y bariónica en galaxias elípticas cuyos cúmulos globulares están siendo observados con los telescopios VLT y Gemini. Se ejemplifican los resultados con los datos obtenidos en el cúmulo de Fornax.

  6. Breath Analysis Science at PittCon 2012, Orlando, Florida

    EPA Science Inventory

    Breath analysis science was featured in three organized sessions at this year’s Pittsburgh Conference and Exposition, or ‘PittCon 2012’ (http://www.pittcon.org/). As described in previous meeting reports, PittCon is one of the largest international conferences for analytical chem...

  7. RoboCon: A general purpose telerobotic control center

    SciTech Connect

    Draper, J.V.; Noakes, M.W.; Schempf, H.; Blair, L.M.

    1997-02-01

    This report describes human factors issues involved in the design of RoboCon, a multi-purpose control center for use in US Department of Energy remote handling applications. RoboCon is intended to be a flexible, modular control center capable of supporting a wide variety of robotic devices.

  8. Pro/con a precessional geodynamo

    NASA Astrophysics Data System (ADS)

    Vanyo, J.

    2003-04-01

    The modest amount of research that exists on the ability, or lack of ability, of mantle precession to power a geodynamo developed mostly during the last half of the 1900s. Papers by Roberts and Stewartson (1965) and by Busse (1968) studied precession generally without a pro/con conclusion. Malkus in the late 1960s attempted to advance a positive role for precession through experiments and analysis. His experiments have survived criticism, but his analyses were discounted, especially by Rochester, Jacobs, Smylie, and Chong (1975) and by Loper (1975). Rochester, et al. critiqued existing analyses of precession, including those of Malkus, but did not reach a strong position either pro or con a precessional geodynamo. Loper argued emphatically that precession was not capable of powering the geodynamo. Explicit analyses that either critique or support Loper’s arguments have yet to appear in the literature. During the 1970s, Vanyo and associates studied energy dissipation during precession of satellite liquid fuels and its effect on satellite attitude stability. Engineers and scientists in every country that has launched satellites completed similar research. Some is published in the aerospace literature, more is available in company and government reports. Beginning in 1981, Vanyo and associates applied this knowledge to the very similar problem of energy dissipation and flow patterns in precessing mechanical models scaled geometrically and dynamically to the Earth’s liquid core. Energy experiments indicate massive amounts of mechanical energy are dissipated at the CMB, and flow experiments show complex motions within the boundary layer and axial flows with helicity throughout the interior. Analysis of Earth core precession also advanced, especially in several papers by Kerswell and by Tilgner in the late 1990s. Detail numerical models have yet to appear. Although progress in understanding the role of precession in Earth core motions has advanced, there remains a

  9. Human Liver Cytochrome P450 3A4 Ubiquitination

    PubMed Central

    Wang, YongQiang; Kim, Sung-Mi; Trnka, Michael J.; Liu, Yi; Burlingame, A. L.; Correia, Maria Almira

    2015-01-01

    CYP3A4 is an abundant and catalytically dominant human liver endoplasmic reticulum-anchored cytochrome P450 enzyme engaged in the biotransformation of endo- and xenobiotics, including >50% of clinically relevant drugs. Alterations of CYP3A4 protein turnover can influence clinically relevant drug metabolism and bioavailability and drug-drug interactions. This CYP3A4 turnover involves endoplasmic reticulum-associated degradation via the ubiquitin (Ub)-dependent 26 S proteasomal system that relies on two highly complementary E2 Ub-conjugating-E3 Ub-ligase (UBC7-gp78 and UbcH5a-C terminus of Hsc70-interacting protein (CHIP)-Hsc70-Hsp40) complexes, as well as protein kinases (PK) A and C. We have documented that CYP3A4 Ser/Thr phosphorylation (Ser(P)/Thr(P)) by PKA and/or PKC accelerates/enhances its Lys ubiquitination by either of these E2-E3 systems. Intriguingly, CYP3A4 Ser(P)/Thr(P) and ubiquitinated Lys residues reside within the cytosol-accessible surface loop and/or conformationally assembled acidic Asp/Glu clusters, leading us to propose that such post-translational Ser/Thr protein phosphorylation primes CYP3A4 for ubiquitination. Herein, this possibility was examined through various complementary approaches, including site-directed mutagenesis, chemical cross-linking, peptide mapping, and LC-MS/MS analyses. Our findings reveal that such CYP3A4 Asp/Glu/Ser(P)/Thr(P) surface clusters are indeed important for its intermolecular electrostatic interactions with each of these E2-E3 subcomponents. By imparting additional negative charge to these Asp/Glu clusters, such Ser/Thr phosphorylation would generate P450 phosphodegrons for molecular recognition by the E2-E3 complexes, thereby controlling the timing of CYP3A4 ubiquitination and endoplasmic reticulum-associated degradation. Although the importance of phosphodegrons in the CHIP targeting of its substrates is known, to our knowledge this is the first example of phosphodegron involvement in gp78-substrate

  10. Interactions between CYP3A4 and Dietary Polyphenols

    PubMed Central

    Kerem, Zohar

    2015-01-01

    The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols. PMID:26180597

  11. Molecular modeling of cytochrome P450 3A4

    NASA Astrophysics Data System (ADS)

    Szklarz, Grazyna D.; Halpert, James R.

    1997-05-01

    The three-dimensional structure of human cytochrome P450 3A4 was modeled based on crystallographic coordinates of four bacterial P450s: P450 BM-3, P450cam, P450terp, and P450eryF. The P450 3A4 sequence was aligned to those of the known proteins using a structure-based alignment of P450 BM-3, P450cam, P450terp, and P450eryF. The coordinates of the model were then calculated using a consensus strategy, and the final structure was optimized in the presence of water. The P450 3A4 model resembles P450 BM-3 the most, but the B' helix is similar to that of P450eryF, which leads to an enlarged active site when compared with P450 BM-3, P450cam, and P450terp. The 3A4 residues equivalent to known substrate contact residues of the bacterial proteins and key residues of rat P450 2B1 are located in the active site or the substrate access channel. Docking of progesterone into the P450 3A4 model demonstrated that the substrate bound in a 6β-orientation can interact with a number of active site residues, such as 114, 119, 301, 304, 305, 309, 370, 373, and 479, through hydrophobic interactions. The active site of the enzyme can also accommodate erythromycin, which, in addition to the residues listed for progesterone, also contacts residues 101, 104, 105, 214, 215, 217, 218, 374, and 478. The majority of 3A4 residues which interact with progesterone and/or erythromycin possess their equivalents in key residues of P450 2B enzymes, except for residues 297, 480 and 482, which do not contact either substrate in P450 3A4. The results from docking of progesterone and erythromycin into the enzyme model make it possible to pinpoint residues which may be important for 3A4 function and to target them for site-directed mutagenesis.

  12. Structure and nucleosome interaction of the yeast NuA4 and Piccolo-NuA4 histone acetyltransferase complexes

    PubMed Central

    Chittuluru, Johnathan R.; Chaban, Yuriy; Monnet-Saksouk, Julie; Carrozza, Michael J.; Sapountzi, Vasileia; Selleck, William; Huang, Jiehuan; Utley, Rhea T.; Cramet, Myriam; Allard, Stephane; Cai, Gang; Workman, Jerry L.; Fried, Michael G.; Tan, Song; Côté, Jacques; Asturias, Francisco J.

    2011-01-01

    We have used electron microscopy (EM) and biochemistry to characterize the structure and nucleosome core particle (NCP) interaction of NuA4, an essential yeast histone acetyltransferase (HAT) complex conserved throughout eukaryotes. The ATM-related Tra1 subunit, shared with the SAGA coactivator, forms a large domain joined to a second portion that accommodates the Piccolo catalytic subcomplex and other NuA4 subunits. EM analysis of an NuA4–NCP complex shows the NCP bound at NuA4's periphery. EM characterization of Piccolo and Piccolo–NCP provided further information about subunit organization and confirmed that histone acetylation requires minimal contact with the NCP. A small conserved region at the N-terminus of Piccolo subunit Epl1 is essential for NCP interaction, whereas subunit Yng2 apparently positions Piccolo for efficient acetylation of H4 or H2A tails. Taken together, these results provide an understanding of NuA4 subunit organization and NCP interactions. PMID:21984211

  13. 26 CFR 1.509(a)-4 - Supporting organizations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... different publicly supported organizations within the class or classes of organizations designated by the... grant made by P to T is specifically earmarked for the training of social workers and teachers... grants to the individual social workers and teachers under section 4945(d)(3) and § 53.4945-4(a)(4...

  14. 12 CFR 708a.4 - Disclosures and communications to members.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... any conversion-related economic benefit a director or senior management official will or may receive... information about the communication process with its 90-day notice. (10) A group of members may make a joint... (f)(3) of this section, the credit union will use the group name provided by the group. § 708a.4,...

  15. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of applications...

  16. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... research project and the general research methods to be used. (e) The date on which research will begin or... PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other... confidentiality for a research project shall contain: (a) The name and address of the individual primarily...

  17. 26 CFR 1.411(a)-4 - Forfeitures, suspensions, etc.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... benefit plans). (3) Retroactive plan amendment. In the case of a participant's right to his employer...(a)-4 Forfeitures, suspensions, etc. (a) Nonforfeitability. Certain rights in an accrued benefit must... right to an accrued benefit is considered to be nonforfeitable at a particular time if, at that time...

  18. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of applications...

  19. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of applications...

  20. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of applications...

  1. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have been...

  2. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have been...

  3. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have been...

  4. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have been...

  5. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have been...

  6. 26 CFR 48.4161(a)-4 - Use considered sale.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Use considered sale. 48.4161(a)-4 Section 48... sale. For provisions relating to the tax on use of taxable articles by the manufacturer, producer, or importer thereof, see section 4218 relating to use by a manufacturer being considered a sale, and...

  7. Severe unilateral buphthalmos in a 4-month-old kitten.

    PubMed

    Finnie, Gillian

    2017-03-01

    A 4-month-old kitten was presented with unilateral buphthalmos. The eye was blind with no menace response, but intraocular pressure was normal. A trans-palpebral enucleation was performed on the affected eye and the globe was submitted for histology. There was a suppurative, lympho-plasmacytic panophthalmitis with inflammatory exudate in the iridocorneal angle.

  8. Framing Retention for Institutional Improvement: A 4 Ps Framework

    ERIC Educational Resources Information Center

    Kalsbeek, David H.

    2013-01-01

    A 4 Ps framework for student retention strategy is a construct for reframing the retention discussion in a way that enables institutional improvement by challenging some conventional wisdom and prevailing perspectives that have characterized retention strategy for years. It opens new possibilities for action and improvement by suggesting that…

  9. Framing Retention for Institutional Improvement: A 4 Ps Framework

    ERIC Educational Resources Information Center

    Kalsbeek, David H.

    2013-01-01

    A 4 Ps framework for student retention strategy is a construct for reframing the retention discussion in a way that enables institutional improvement by challenging some conventional wisdom and prevailing perspectives that have characterized retention strategy for years. It opens new possibilities for action and improvement by suggesting that…

  10. Novel mutations in the SLC26A4 gene.

    PubMed

    Busi, Micol; Castiglione, Alessandro; Taddei Masieri, Marina; Ravani, Anna; Guaran, Valeria; Astolfi, Laura; Trevisi, Patrizia; Ferlini, Alessandra; Martini, Alessandro

    2012-09-01

    Mutations in the SLC26A4 gene (7q22.3-7q31.1) are considered one of the most common causes of genetic hearing loss. There are two clinical forms related to these mutations: syndromic and non-syndromic deafness. The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present. Both are transmitted as an autosomal recessive trait, but simple heterozygotes can develop both forms of deafness. Actually it is thought that Pendred Syndrome occurs when both alleles of SLC26A4 gene are mutated; DFNB4 seems due to monoallelic mutations. PS and DFNB4 can be associated with inner ear malformations. In most of the cases (around 80%), these consist in Enlarged Vestibular Aqueduct (EVA). EVA can also be present without SLC26A4 mutations. Understanding the role of new SLC26A4 variants should facilitate clinical assessment, as well as diagnostic and therapeutic approaches. This investigation aims to detect and report genetic causes of two unrelated Italian boys with hearing loss. Patients and family members underwent clinical, audiological and genetic evaluations. To identify genetic mutations, DNA sequencing of SLC26A4 gene (including all 21 exons, exon-intron boundaries and promoter region) was carried out. Both probands were affected by congenital, progressive and fluctuating mixed hearing loss. Temporal bone imaging revealed a bilateral EVA with no other abnormalities in both cases. Probands were heterozygotes for previously undescribed mutations in the SLC26A4 gene: R409H/IVS2+1delG (proband 1) and L236P/K590X (proband 2). No other mutations were detected in GJB2, GJB6 genes or mitochondrial DNA (mit-DNA). The IVS2+1delG and K590X mutations have not yet been described in literature but there is some evidence to suggest that they have a pathological role. The results underlined the importance of considering the complete DNA sequencing of the SLC26A4 gene for differential molecular

  11. Effect of alpha lipoic acid on leukotriene A4 hydrolase.

    PubMed

    Torres, María José; Fierro, Angélica; Pessoa-Mahana, C David; Romero-Parra, Javier; Cabrera, Gonzalo; Faúndez, Mario

    2017-03-15

    Leukotriene A4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A4 to leukotriene B4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A4 Hydrolase. Alpha lipoic acid inhibited both activities of the enzyme at concentrations lower than 10μM. The 5-lipoxygenase inhibitor zileuton, or the 5-lipoxygenase activating protein inhibitor MK-886, were unable to inhibit the activity of the enzyme. Acute promyelocytic leukaemia HL-60 cells were differentiated to leukotriene A4 hydrolase expressing neutrophil-like cells. Alpha lipoic acid inhibited the aminopeptidase activity of the cytosolic fraction from neutrophil-like cells but had no effect on the cytosolic fraction from undifferentiated cells. Docking and molecular dynamic approximations revealed that alpha lipoic acid participates in electrostatic interactions with K-565 and R-563, which are key residues for the carboxylate group recognition of endogenous substrates by the enzyme. Alpha lipoic acid is a compound widely used in clinical practice, most of its therapeutic effects are associated with its antioxidants properties, however, antioxidant effect alone is unable to explain all clinical effects observed with alpha lipoic acid. Our results invite to evaluate the significance of the inhibitory effect of alpha lipoic acid on the catalytic activity of leukotriene A4 hydrolase using in vivo models.

  12. [Cement augmentation of pedicle screws : Pros and cons].

    PubMed

    Schnake, K J; Blattert, T R; Liljenqvist, U

    2016-09-01

    Cement augmentation of pedicle screws biomechanically increases screw purchase in the bone. However, clinical complications may occur. The pros and cons of the technique are discussed from different clinical perspectives.

  13. [Significance and progress of DIAN/A4/API].

    PubMed

    Shimada, Hiroyuki

    2016-03-01

    The DIAN observational study compared the pathophysiological markers between mutation carriers and non-carriers for autosomal dominant Alzheimer's disease. It has revealed the biomarker changes in the mutation carrier's brain started as early as 20, even 25 years prior to symptoms. The researchers of DIAN started the prevention trial(DIAN-TU) with two monoclonal antibodies. The API study is the clinical trial of the anti-amyloid monoclonal antibody therapy to the kindred of early onset familial AD (EOAD) who carry the PSEN1 E280A mutation. This study has also shown the same biomarker changes that were reported in the DIAN study. Anti-Amyloid Treatment in Asymptomatic AD (A4) is a prevention trial aimed at treating cognitive normal older individuals at risk of developing Alzheimer's disease dementia on the basis of having biomarker evidence of amyloid (pre-clinical AD). Solanezumab was selected for the anti-amyloid treatment for A4.

  14. Rotordynamic and Leakage Characteristics of a 4-Stage Brush Seal

    DTIC Science & Technology

    1992-12-01

    AD-A266 012 WL-TR-92-2125 .AP ROTORDYNAMIC AND LEAKAGE CHARACTERISTICS OF A 4-STAGE BRUSH SEAL K. J. CONNER D. W. CHILDS TURBOMACHINERY LABORATORIES...pre-rotation, and seal spacing. Direct damping is shown to increase with running speed; otherwise, the rotordynamic coefficients are relatively...test results for the 4-stage brush seal with an 8-cavity labyrinth showed superior rotordynamics performance for the brush seal; viz., larger values for

  15. A 4 K FTS demonstrator for future cooled space telescopes

    NASA Astrophysics Data System (ADS)

    Naylor, David; Veenendaal, Ian; Gom, Brad; Ade, Peter

    2016-07-01

    A commercial Fourier transform spectrometer scanning mechanism has been modified for operation at cryogenic temperatures. When installed in a 4 K cryostat with a multiple component blackbody calibration source and sensitive sub-Kelvin detector, the spectrometer will allow the evaluation of different scanning methods, metrology options and data compression techniques. It will also enable the study of the performance of critical optical components such as beam splitters and filters at their intended operating temperatures.

  16. Planificación Neuroquirúrgica con Software Osirix

    PubMed Central

    Jaimovich, Sebastián Gastón; Guevara, Martin; Pampin, Sergio; Jaimovich, Roberto; Gardella, Javier Luis

    2014-01-01

    Introducción: La individualidad anatómica es clave para reducir el trauma quirúrgico y obtener un mejor resultado. Actualmente, el avance en las neuroimágenes ha permitido objetivar esa individualidad anatómica, permitiendo planificar la intervención quirúrgica. Con este objetivo, presentamos nuestra experiencia con el software Osirix. Descripción de la técnica: Se presentan 3 casos ejemplificadores de 40 realizados. Caso 1: Paciente con meningioma de la convexidad parasagital izquierda en área premotora; Caso 2: Paciente con macroadenoma hipofisario, operada previamente por vía transeptoesfenoidal en otra institución con una resección parcial; Caso 3: Paciente con lesiones en pedúnculo cerebeloso medio bilateral. Se realizó la planificación prequirúrgica con el software OsiriX, fusionando y reconstruyendo en 3D las imágenes de TC e IRM, para analizar relaciones anatómicas, medir distancias, coordenadas y trayectorias, entre otras funciones. Discusión: El software OsiriX de acceso libre y gratuito permite al cirujano, mediante la fusión y reconstrucción en 3D de imágenes, analizar la anatomía individual del paciente y planificar de forma rápida, simple, segura y económica cirugías de alta complejidad. En el Caso 1 se pudo analizar las relaciones del tumor con las estructuras adyacentes para minimizar el abordaje. En el Caso 2 permitió comprender la anatomía post-operatoria previa del paciente, para determinar la trayectoria del abordaje transnasal endoscópico y la necesidad de ampliar su exposición, logrando la resección tumoral completa. En el Caso 3 permitió obtener las coordenadas estereotáxicas y trayectoria de una lesión sin representación tomográfica. Conclusión: En casos de no contar con costosos sistemas de neuronavegación o estereotáxia el software OsiriX es una alternativa a la hora de planificar la cirugía, con el objetivo de disminuir el trauma y la morbilidad operatoria. PMID:25165617

  17. Towards a complete A4 × SU(5) SUSY GUT

    NASA Astrophysics Data System (ADS)

    Björkeroth, Fredrik; de Anda, Francisco J.; de Medeiros Varzielas, Ivo; King, Stephen F.

    2015-06-01

    We propose a renormalisable model based on A 4 family symmetry with an SU(5) grand unified theory (GUT) which leads to the minimal supersymmetric standard model (MSSM) with a ℤ9 × ℤ6 symmetry provides the fermion mass hierarchy in both the quark and lepton sectors, while ℤ {4/ R } symmetry is broken to ℤ {2/ R }, identified as usual R-parity. Proton decay is highly sup-pressed by these symmetries. The strong CP problem is solved in a similar way to the Nelson-Barr mechanism. We discuss both the A 4 and SU(5) symmetry breaking sectors, including doublet-triplet splitting, Higgs mixing and the origin of the μ term. The model provides an excellent fit (better than one sigma) to all quark and lepton (including neu-trino) masses and mixing with spontaneous CP violation. With the A 4 vacuum alignments, (0, 1, 1) and (1, 3, 1), the model predicts the entire PMNS mixing matrix with no free pa-rameters, up to a relative phase, selected to be 2π/3 from a choice of the nine complex roots of unity, which is identified as the leptogenesis phase. The model predicts a normal neutrino mass hierarchy with leptonic angles θ{13/ ι } ≈ 8.7∘, θ{12/ ι } ≈ 34∘, θ{23/ ι } ≈ 46∘ and an oscillation phase δ ι ≈ - 87∘.

  18. Solution structure of leptospiral LigA4 Big domain

    SciTech Connect

    Mei, Song; Zhang, Jiahai; Zhang, Xuecheng; Tu, Xiaoming

    2015-11-13

    Pathogenic Leptospiraspecies express immunoglobulin-like proteins which serve as adhesins to bind to the extracellular matrices of host cells. Leptospiral immunoglobulin-like protein A (LigA), a surface exposed protein containing tandem repeats of bacterial immunoglobulin-like (Big) domains, has been proved to be involved in the interaction of pathogenic Leptospira with mammalian host. In this study, the solution structure of the fourth Big domain of LigA (LigA4 Big domain) from Leptospira interrogans was solved by nuclear magnetic resonance (NMR). The structure of LigA4 Big domain displays a similar bacterial immunoglobulin-like fold compared with other Big domains, implying some common structural aspects of Big domain family. On the other hand, it displays some structural characteristics significantly different from classic Ig-like domain. Furthermore, Stains-all assay and NMR chemical shift perturbation revealed the Ca{sup 2+} binding property of LigA4 Big domain. - Highlights: • Determining the solution structure of a bacterial immunoglobulin-like domain from a surface protein of Leptospira. • The solution structure shows some structural characteristics significantly different from the classic Ig-like domains. • A potential Ca{sup 2+}-binding site was identified by strains-all and NMR chemical shift perturbation.

  19. Solution structure of leptospiral LigA4 Big domain.

    PubMed

    Mei, Song; Zhang, Jiahai; Zhang, Xuecheng; Tu, Xiaoming

    2015-11-13

    Pathogenic Leptospiraspecies express immunoglobulin-like proteins which serve as adhesins to bind to the extracellular matrices of host cells. Leptospiral immunoglobulin-like protein A (LigA), a surface exposed protein containing tandem repeats of bacterial immunoglobulin-like (Big) domains, has been proved to be involved in the interaction of pathogenic Leptospira with mammalian host. In this study, the solution structure of the fourth Big domain of LigA (LigA4 Big domain) from Leptospira interrogans was solved by nuclear magnetic resonance (NMR). The structure of LigA4 Big domain displays a similar bacterial immunoglobulin-like fold compared with other Big domains, implying some common structural aspects of Big domain family. On the other hand, it displays some structural characteristics significantly different from classic Ig-like domain. Furthermore, Stains-all assay and NMR chemical shift perturbation revealed the Ca(2+) binding property of LigA4 Big domain. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Short-term effects of amelogenin gene splice products A+4 and A-4 implanted in the exposed rat molar pulp

    PubMed Central

    Jegat, Nadège; Septier, Dominique; Veis, Arthur; Poliard, Anne; Goldberg, Michel

    2007-01-01

    In order to study the short-time effects of two bioactive low-molecular amelogenins A+4 and A-4, half-moon cavities were prepared in the mesial aspect of the first maxillary molars, and after pulp exposure, agarose beads alone (controls) or beads soaked in A+4 or A-4 (experimental) were implanted into the pulp. After 1, 3 or 7 days, the rats were killed and the teeth studied by immunohistochemistry. Cell proliferation was studied by PCNA labeling, positive at 3 days, but decreasing at day 7 for A+4, whilst constantly high between 3 and 7 days for A-4. The differentiation toward the osteo/odontoblast lineage shown by RP59 labeling was more apparent for A-4 compared with A+4. Osteopontin-positive cells were alike at days 3 and 7 for A-4. In contrast, for A+4, the weak labeling detected at day 3 became stronger at day 7. Dentin sialoprotein (DSP), an in vivo odontoblast marker, was not detectable until day 7 where a few cells became DSP positive after A-4 stimulation, but not for A+4. These results suggest that A +/- 4 promote the proliferation of some pulp cells. Some of them further differentiate into osteoblast-like progenitors, the effects being more precocious for A-4 (day 3) compared with A+4 (day 7). The present data suggest that A +/- 4 promote early recruitment of osteogenic progenitors, and evidence functional differences between A+4 and A-4. PMID:18154672

  1. Experimental validation of a 4D elastic registration algorithm.

    PubMed

    Leung, Corina; Hashtrudi-Zaad, Keyvan; Foroughi, Pezhman; Abolmaesumi, Purang

    2008-01-01

    This paper presents an extensive validation study of an elastic registration algorithm for dynamic 3D ultrasound images (also known as a 4D image). The registration algorithm uses attribute vectors from both a fixed and previous moving images to perform feature-based alignment of a series of images. The 4D method reduces computational requirements and increases the effective search space for the location of corresponding features, resulting in enhanced registration speed when compared to a static 3D registration technique. Experimental analysis revealed up to 32% improvement in speed when using the 4D method, which makes the algorithm attractive for real-time applications.

  2. A 4D representation of DNA sequences and its application

    NASA Astrophysics Data System (ADS)

    Liao, Bo; Tan, Mingshu; Ding, Kequan

    2005-02-01

    A 4D representation of DNA sequences has been derived for mathematical denotation of DNA sequence. The 4D representation also avoids loss of information accompanying alternative 2D and 3D representation. The geometrical centers of the 4D graph of DNA sequences indicate the distribution of base frequencies. A interesting phenomenon is observed for Goat and Gallus β-globin genomes with high G + C content. The examination of similarities/dissimilarities among the coding sequences of the first exon of β-globin gene of different species illustrates the utility of the approach.

  3. Cytochrome P450 3A4 activity after surgical stress.

    PubMed

    Haas, Curtis E; Kaufman, David C; Jones, Carolyn E; Burstein, Aaron H; Reiss, William

    2003-05-01

    To evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. Prospective, open-label study with each patient serving as his or her own control. University-affiliated, acute care, general hospital. A total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n = 5), complete or partial colectomy (n = 6), or peripheral vascular surgery with graft (n = 5). Cytochrome P450 3A4 activity was estimated using the carbon-14 [14C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. ERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p =.06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (r(s) = -.541, p =.03) and log interleukin-6 area under the curve from 0 to 72 hrs (r(s) = -.597, p =.014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% +/- 5.2% vs. 74.7% +/- 5.1%, p <.001). Acute inflammation after

  4. A 4MM-Wave composite mode multimode conical feedhorn

    NASA Astrophysics Data System (ADS)

    Lin, Zhisheng; Du, Zhengmi; Chen, Shener

    1996-10-01

    A 4MM-Wave composite mode multimode conical feedhorn has been developed. Its mode-ratios are calculated and its formulas of the radiation patterns are derived. The measurement results of one and two dimension radiation patterns, measured by the automatic measurement system which we had researched, and the properties of band width and sidelobe are given. Theoretical analyses and measurements show that at the centre frequency 69.1GHZ, down to -23dB, the radiation pattern is rotationally symmetric, in this range there is not any sidelobe existing, the band width is 4.5 GHZ. The multimode feedhorn is thus of certain practical using value.

  5. Effects of metronidazole on hepatic CYP3A4 activity.

    PubMed

    Haas, C E; Kaufman, D C; DiCenzo, R C

    2001-10-01

    To evaluate the effect of a short course of oral metronidazole, commonly used for bowel-preparation regimens, on hepatic cytochrome P450 (CYP) 3A4 activity, as measured by the [14C N-methyl]-erythromycin breath test (ERMBT) in healthy volunteers. Prospective, nonrandomized, interventional study University-affiliated, community, teaching hospital. Five healthy male volunteers. Subjects underwent a baseline ERMBT in the morning before receiving three oral doses of metronidazole 500 mg administered at 3 P.M., 7 P.M., and 11 P.M. Repeat ERMBTs were performed at 24, 72, and 96 hours after the initial ERMBT. Changes in ERMBT values were compared with baseline results using Freidman's repeated-measures analysis of variance on ranks. The ERMBT values did not change significantly compared with baseline (p=0.82). Median (range) ERMBT values expressed as a percentage of baseline at 24, 72, and 96 hours were 110.3 (96.2-136.9), 101.3 (99.3-115.0), and 101.8 (95.5-116.3), respectively A short course of oral metronidazole does not result in a significant change in hepatic CYP3A4 activity as measured by the ERMBT.

  6. Charge symmetry breaking in the A = 4 hypernuclei

    NASA Astrophysics Data System (ADS)

    Gazda, Daniel; Gal, Avraham

    2016-10-01

    Charge symmetry breaking (CSB) in the Λ-nucleon strong interaction generates a charge dependence of Λ separation energies in mirror hypernuclei, which in the case of the A = 4 mirror hypernuclei 0+ ground states is sizable, ΔBΛJ=0 ≡BΛJ=0 (He4Λ) -BΛJ=0 (H4Λ) = 230 ± 90 keV, and of opposite sign to that induced by the Coulomb repulsion in light hypernuclei. Recent ab initio calculations of the (H4Λ, He4Λ) mirror hypernuclei 0g.s.+ and 1exc+ levels have demonstrated that a Λ -Σ0 mixing CSB model due to Dalitz and von Hippel (1964) is capable of reproducing this large value of ΔBΛJ=0. These calculations are discussed here with emphasis placed on the leading-order chiral EFT hyperon-nucleon Bonn-Jülich strong-interaction potential model used and the no-core shell-model calculational scheme applied. The role of one-pion exchange in producing sizable CSB level splittings in the A = 4 mirror hypernuclei is discussed.

  7. Rectal bleeding in a 4-month-old boy

    SciTech Connect

    Dutro, J.A.; Santanello, S.A.; Unger, F.; Goodwin, C.D.

    1986-10-24

    A case of bleeding Meckel's diverticulum is described in an infant. A 4-month-old boy was seen initially with a 24-hour history of painless hematochezia. His parents had noted two episodes of maroon-colored stool that did not appear to be associated with any abdominal distress. His medical history was unremarkable, with normal growth and development. Physical examination revealed a well-nourished, well-hydrated infant in no apparent distress. Vital signs were normal. Rectal examination revealed no masses, but bright-red blood was noted on the examining finger. Findings from the remainder of the examination were normal. An upright roentgenogram of the abdomen was obtained and demonstrated no abnormalities. The abdominal technetium scan was abnormal. An exploratory laparotomy was performed later on the day of admission.

  8. Lyapunov exponent diagrams of a 4-dimensional Chua system.

    PubMed

    Stegemann, Cristiane; Albuquerque, Holokx A; Rubinger, Rero M; Rech, Paulo C

    2011-09-01

    We report numerical results on the existence of periodic structures embedded in chaotic and hyperchaotic regions on the Lyapunov exponent diagrams of a 4-dimensional Chua system. The model was obtained from the 3-dimensional Chua system by the introduction of a feedback controller. Both the largest and the second largest Lyapunov exponents were considered in our colorful Lyapunov exponent diagrams, and allowed us to characterize periodic structures and regions of chaos and hyperchaos. The shrimp-shaped periodic structures appear to be malformed on some of Lyapunov exponent diagrams, and they present two different bifurcation scenarios to chaos when passing the boundaries of itself, namely via period-doubling and crisis. Hyperchaos-chaos transition can also be observed on the Lyapunov exponent diagrams for the second largest exponent.

  9. Multifocal tumoral calcinosis in a 4-year-old girl

    PubMed Central

    Sayar, Ilyas; Peker, Kemal; Kapısız, Alparslan; Bostancı, Isıl Esen; Gürbüzel, Mehmet; Isik, Arda; Peker, Necla Aydın

    2014-01-01

    Patient: Female, 4 Final Diagnosis: Tumoral calcinosis Symptoms: Hard immobile mass Medication: — Clinical Procedure: — Specialty: Surgery Objective: Congenital defects Background: Tumoral calcinosis is an uncommon condition associated with the deposition of painless calcific masses. It is more common in childhood or early adolescence of African-American females. Case Report: We present a case of a 4-year-old girl with tumoral calcinosis treated surgically. The case is rather rare in terms of the age of the patient and the localization of the masses (gluteal site). In our patient, the biochemical findings were normal, except for hyperphosphatemia and elevated alkaline phosphatase. Conclusions: Total excision appears to lead to a good clinical outcome and a low incidence of local relapse. PMID:24644527

  10. Efficient helium recondensing using a 4 K pulse tube cryocooler

    NASA Astrophysics Data System (ADS)

    Wang, Chao

    2005-12-01

    This paper introduces helium recondensing in a 4000 l dewar using a 4 K pulse tube cryocooler at Amundsen-Scott research station at the South Pole. The helium dewar has a normal boil-off rate of 14 l/day. Two features of cooling the dewar neck by helium vapor and precooling helium gas to be liquefied ensured high efficiency of the pulse tube recondenser in this application. The liquefier/recondenser has being successfully operating in the dewar at South Pole station since February 2005. It not only maintains zero boil-off of the dewar, but also liquefies helium gas supplied from outside of the dewar with a rate around 2.7 l/day.

  11. Organising evidence for environmental management decisions: a '4S' hierarchy.

    PubMed

    Dicks, Lynn V; Walsh, Jessica C; Sutherland, William J

    2014-11-01

    Making decisions informed by the best-available science is an objective for many organisations managing the environment or natural resources. Yet, available science is still not widely used in environmental policy and practice. We describe a '4S' hierarchy for organising relevant science to inform decisions. This hierarchy has already revolutionised clinical practice. It is beginning to emerge for environmental management, although all four levels need substantial development before environmental decision-makers can reliably and efficiently find the evidence they need. We expose common bypass routes that currently lead to poor or biased representation of scientific knowledge. We argue that the least developed level of the hierarchy is that closest to decision-makers, placing synthesised scientific knowledge into environmental decision support systems. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Pneumococcal sacroiliitis in a 4-year-old boy.

    PubMed

    Perez, A; Padilla, E; Marco, A; De Otero, J; Bandiera, D; Marimón, I

    2008-01-01

    Pyogenic sacroiliitis is an extremely rare manifestation of invasive pneumococcal disease in childhood as only four cases have been described to date. We report and comment on a case of pneumococcal sacroiliitis in a 4-year-old boy. This patient was diagnosed promptly on account of the symptom triad of fever, buttock pain, and limping gait, along with characteristic findings in magnetic resonance imaging (MRI) and bone scans, and recovered fully after 6 weeks of antimicrobial therapy. Pyogenic sacroiliitis is an uncommon disease in which the diagnosis is often delayed because of nonspecific clinical presentation. The key to successful management is early diagnosis in which MRI and bone scan findings play a crucial role. If the diagnosis is established promptly, most patients can be managed successfully following the therapeutic principles used in other osteoarticular infections.

  13. Acoustic noise reduction in a 4 T MRI scanner.

    PubMed

    Mechefske, Chris K; Geris, Ryan; Gati, Joseph S; Rutt, Brian K

    2002-01-01

    High-field, high-speed magnetic resonance imaging (MRI) can generate high levels of noise. There is ongoing concern in the medical and imaging research communities regarding the detrimental effects of high acoustic levels on auditory function, patient anxiety, verbal communication between patients and health care workers and ultimately MR image quality. In order to effectively suppress the noise levels inside MRI scanners, the sound field needs to be accurately measured and characterized. This paper presents the results of measurements of the sound radiation from a gradient coil cylinder within a 4 T MRI scanner under a variety of conditions. These measurement results show: (1) that noise levels can be significantly reduced through the use of an appropriately designed passive acoustic liner; and (2) the true noise levels that are experienced by patients during echo planar imaging.

  14. Detail of conning tower atop the submarine. Note the wire ...

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

    Detail of conning tower atop the submarine. Note the wire rope wrapped around the base of the tower, which may have been used in an attempt to pull the submarine offshore. - Sub Marine Explorer, Located along the beach of Isla San Telmo, Pearl Islands, Isla San Telmo, Former Panama Canal Zone, CZ

  15. Canceling Some d-CON Mouse and Rat Control Products

    EPA Pesticide Factsheets

    EPA has reached agreement with the manufacturer, to cancel 12 d-CON products that do not meet our testing protocols that better protect children, pets and non-target wildlife from accidental exposure to the pesticide. These products will be phased out.

  16. Providers debate pros and cons of pneumonia vaccination at discharge.

    PubMed

    2001-02-01

    When to vaccinate against pneumonia? Does it makes sense when patients are in the hospital? Or should patients wait for the first post-op visit with the PCP? Office-based and hospital-based physicians weigh the pros and cons of each.

  17. Three dimensional boundary layers on submarine conning towers and rudders

    NASA Astrophysics Data System (ADS)

    Gleyzes, C.

    1988-01-01

    Solutions for the definition of grids adapted to the calculation of three-dimensional boundary layers on submarine conning towers and on submarine rudders and fins are described. The particular geometry of such bodies (oblique shaped hull, curved fins) required special adaptations. The grids were verified on examples from a test basin.

  18. Utilice en forma segura los productos con cebo para roedores

    EPA Pesticide Factsheets

    Si se usan de manera inadecuada, los productos con veneno para ratas y ratones podrían hacerle daño a usted, a sus hijos o a sus mascotas. Siempre que use pesticidas lea la etiqueta del producto y siga todas las indicaciones.

  19. Teaching after Retirement: The Pros and the Cons

    ERIC Educational Resources Information Center

    Sommer, Robert

    2014-01-01

    Having enjoyed teaching during my active career, I continued to teach summer school following retirement. Self-observed sensory and cognitive impairments, although not mentioned by students in their evaluations, induced me to consider the pros and cons of continuing to teach. My hope is that this list of benefits and problems will be of assistance…

  20. Opioid analgesics in the substance abuser: pros and cons.

    PubMed

    Ineck, Joseph R; Rule, Ann M

    2006-01-01

    The pros and cons of using opioid analgesics to help manage pain in patient with a history of substance abuse are presented. Topics discussed include ethical constructs, efficacy, and safety relating to the use of opioids in patients with substance abuse histories.

  1. Teaching after Retirement: The Pros and the Cons

    ERIC Educational Resources Information Center

    Sommer, Robert

    2014-01-01

    Having enjoyed teaching during my active career, I continued to teach summer school following retirement. Self-observed sensory and cognitive impairments, although not mentioned by students in their evaluations, induced me to consider the pros and cons of continuing to teach. My hope is that this list of benefits and problems will be of assistance…

  2. Improved postural control in response to a 4-week balance training with partially unloaded bodyweight.

    PubMed

    Freyler, K; Weltin, E; Gollhofer, A; Ritzmann, R

    2014-06-01

    Balance training (BT) is successfully implemented in therapy as a countermeasure against postural dysfunctions. However, patients suffering from motor impairments may not be able to perform balance rehabilitation with full body load. The purpose of this study was to investigate whether partial unloading leads to the same functional and neuromuscular adaptations. The impact on postural control of a 4-week BT intervention has been compared between full and partial body load. 32 subjects were randomly assigned to a CON (conventional BT) or a PART group (partially unloaded BT). BT comprised balance exercises addressing dynamic stabilization in mono- and bipedal stance. Before and after training, centre of pressure (COP) displacement and electromyographic activity of selected muscles were monitored during different balance tasks. Co-contraction index (CCI) of soleus (SOL)/tibialis (TA) was calculated. SOL H-reflexes were elicited to evaluate changes in the excitability of the spinal reflex circuitry. Adaptations in response to the training were in a similar extent for both groups: (i) after the intervention, the COP displacement was reduced (P<0.05). This reduction was accompanied by (ii) a decreased CCI of SOL/TA (P<0.05) and (iii) a decrease in H-reflex amplitude (P<0.05). BT under partial unloading led to reduced COP displacements comparable to conventional BT indicating improved balance control. Moreover, decreased co-contraction of antagonistic muscles and reduced spinal excitability of the SOL motoneuron pool point towards changed postural control strategies generally observed after full body load training. Thus, BT considering partial unloading is an appropriate alternative for patients unable to conduct BT under full body load. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. LunGradCon: The Lunar Graduate Conference

    NASA Astrophysics Data System (ADS)

    Dove, A.; Poppe, A.; Neish, C.; Fagan, A.; Fuqua, H.; Kramer, G. Y.; Horanyi, M.

    2011-12-01

    Members of the Colorado Center for Lunar Dust and Atmospheric Studies (CCLDAS) initiated the Lunar Graduate Conference (LunGradCon), modeled after the highly successful Astrobiology Graduate Conference (AbGradCon). The purpose of this conference is to enhance the professional development of graduate students and early postdoctoral researchers by providing an opportunity to present and discuss scientific research in an environment of their peers. For the first two years, LunGradCon has been held as a one-day conference in conjunction with the NASA Lunar Science Institue's (NLSI) Lunar Science Forum at the NASA Ames Research Center. Activities include an invited overview talk on each of the NASA Lunar Science Institute's three main research areas (OF the Moon, ON the Moon, and FROM the Moon), submitted oral presentations from graduate students and postdoctoral researchers, and networking opportunities with established member of the lunar science community and the NLSI. In each of the first two years of LunGradCon, there have been 20-25 attendees, with about 15 of those presenting submitted talks. Each speaker received feedback forms from the other participants in order to improve on their presentation techniques. Participants also provided feedback on the conference as a whole in order to evaluate the content and provide suggestions for improvement in following years. Overall, the feedback has been extremely positive. This talk will summarize the achievements of past LunGradCons and plans for expansion of the conference to ensure a long-term positive impact on the early careers of future lunar, planetary and space science researchers.

  4. Effects of a 4-Week Biomechanical Ankle Platform System Protocol on Balance in High School Athletes With Chronic Ankle Instability.

    PubMed

    Cain, Mary Spencer; Garceau, Stacy Watt; Linens, Shelley W

    2017-01-01

    Chronic ankle instability (CAI) describes the residual symptoms present after repetitive ankle sprains. Current rehabilitation programs in the high school population focus on a multistation approach or general lower-extremity injury-prevention program. Specific rehabilitation techniques for CAI have not been established. To determine the effectiveness of a 4-wk biomechanical ankle platform system (BAPS) board protocol on the balance of high school athletes with CAI. Randomized control trial. Athletic training facility. Twenty-two high school athletes with "giving way" and a history of ankle sprains (ie, CAI) were randomized into a rehabilitation (REH) (166.23 ± 0.93 cm, 67.0 ± 9.47 kg, 16.45 ± 0.93 y) or control (CON) (173.86 ± 8.88 cm, 84.51 ± 21.28 kg, 16.55 ± 1.29 y) group. After baseline measures, the REH group completed a progressive BAPS rehabilitation program (3 times/wk for 4 wk), whereas the CON group had no intervention. Each session consisted of 5 trials of clockwise/counterclockwise rotations changing direction every 10 s during each 40-s trial. After 4 wk, baseline measurements were repeated. Dependent measures included longest time (time-in-balance test), average number of errors (foot lift test), average reach distance (cm) normalized to leg length for each reach direction (Star Excursion Balance Test [SEBT]), and fastest time (side hop test [SHT]). Significant group-by-time interactions were found for TIB (F1,20 = 9.89, P = .005), FLT (F1,20 = 41.18, P < .001), SEBT-anteromedial (F1,20 = 5.34, P = .032), SEBT-medial (F1,20 = 7.51, P = .013), SEBT-posteromedial (F1,20 = 12.84, P = .002), and SHT (F1,20 = 7.50, P = .013). Post hoc testing showed that the REH group improved performance on all measures at posttest, whereas the CON group did not. A 4-wk BAPS rehabilitation protocol improved balance in high school athletes suffering from CAI. These results can allow clinicians to rehabilitate in a focused manner by using 1 rehabilitation tool that

  5. 106-17 Telemetry Standards. Annex A.4. Asynchronous Recorder Multiplexer Output Re-Constructor (ARMOR)

    DTIC Science & Technology

    2017-07-01

    Telemetry Standards, RCC Standard 106-17 Annex A.4, July 2017 ANNEX A.4 Asynchronous Recorder Multiplexer Output Re-Constructor (ARMOR...A.4-10 Telemetry Standards, RCC Standard 106-17 Annex A.4, July 2017 A.4-ii This page...intentionally left blank. Telemetry Standards, RCC Standard 106-17 Annex A.4, July 2017 A.4-iii Acronyms ARMOR Asynchronous Recorder

  6. Can a $4 drug stop vertical HIV transmission?

    PubMed

    1999-11-01

    Researchers have determined that a $4 dose of Nevirapine, which is 70 times cheaper than a short course of AZT therapy, is more effective than the AZT treatment in reducing the transmission of HIV from mother to baby. About 1,800 infants are born each day with HIV infection, and an estimated 45 percent of pregnant women in South Africa will be infected by the end of the year. The Nevirapine therapy still remains too expensive for much of the world, and there are still many women who are not tested during pregnancy and do not know they are at risk of transmitting the disease. Because of the stigma, many African women decline testing even when it is free and treatment is available. A study in Uganda found that Nevirapine lowers the risk of HIV transmission by breast feeding by nearly 50 percent during a baby's first four months. Vertical transmission remains a difficult issue, especially where contaminated water supplies could put an infant at risk for other infections when they are fed formula mixed with contaminated water.

  7. Aerodynamic analysis of Audi A4 Sedan using CFD

    NASA Astrophysics Data System (ADS)

    Birwa, S. K.; Rathi, N.; Gupta, R.

    2013-04-01

    This paper presents the aerodynamic influence of velocity and ground clearance for Audi A4 Sedan. The topology of the test vehicle was modeled using CATIA P3 V5 R17. ANSYS FLUENT 12 was the CFD solver employed in this study. The distribution of pressure and velocity was obtained. The velocities were 30, 40, 50 and 60 m/s and ground clearances were 76.2 mm,101.6 mm,127 mm and 152.4 mm. The simulation results were compared with the available resources. It was found that the drag coefficient decreases with the velocity increasing from 30 to 60 m/s and increases with the ground clearance from 101.6 mm to 152.4 mm. Further decrease in ground clearance showed no effect on the value of coefficient of drag. The lift coefficient was found to decrease firstly with ground clearance from 152.4 mm to 101.6 mm, and then increase from 101.6 mm to 76.2 mm. Both the lift coefficient and drag coefficient was found to be minimum for the ground clearance of 101.6 mm as designed by the company.

  8. Genetic regulation of expression of leukotriene A4 hydrolase

    PubMed Central

    Castaldi, Peter; Cho, Michael H.; Blalock, J. Edwin; Gaggar, Amit

    2016-01-01

    In chronic inflammatory lung disorders such as chronic obstructive pulmonary disease (COPD), the concurrent organ-specific and systemic inflammatory responses lead to airway remodelling and vascular dysfunction. Although a major common risk factor for COPD, cigarette smoke alone cannot explain the progression of this disease; there is increasing evidence that genetic predisposition also plays a role in COPD susceptibility and progression. A key enzyme in chronic lung inflammation is leukotriene A4 hydrolase (LTA4H). With its aminopeptidase activity, LTA4H degrades the neutrophil chemoattractant tripeptide PGP. In this study, we used the luciferase reporter gene analysis system and quantitative trait locus analysis to explore the impact of single-nucleotide polymorphisms (SNPs) in the putative promoter region of LTA4H on LTA4H expression. We show that not only is the putative promoter of LTA4H larger than previously reported but also that SNPs in the expanded promoter region regulate expression of LTA4H both in cell-based systems and in peripheral blood samples from human subjects. These findings provide significant evidence for an active region upstream of the previously reported LTA4H promoter, which may have implications related to ongoing inflammatory processes in chronic lung disease. PMID:27730172

  9. Rotordynamic and leakage characteristics of a 4-stage brush seal

    NASA Astrophysics Data System (ADS)

    Conner, K. J.; Childs, D. W.

    1992-12-01

    Experimental results are presented for the direct and cross-coupled stiffness and damping coefficients as well as the leakage performance for a 4-stage brush seal. Variable test parameters include the inlet pressure, pressure ratio, shaft speed, fluid prerotation, and seal spacing. Direct damping is shown to increase with running speed; otherwise, the rotordynamic coefficients are relatively insensitive to changes in the test parameters. Cross-coupled stiffness is generally unchanged by increasing the inlet tangential velocity to the seals, suggesting that the brush seal is not affected by inlet swirl. Direct stiffness is shown to increase with frequency; however, the magnitudes of direct stiffness are always positive. Cross-coupled stiffness increases slightly with frequency; yet not as drastically as direct stiffness. Comparisons of test results for the 4-stage brush seal with an 8-cavity labyrinth showed superior rotordynamics performance for the brush seal; viz., large values for direct stiffness and lower values for the (destabilizing) cross-coupled stiffness coefficient. The damping for brush seals is smaller, but comparable to labyrinth seals. The whirl-frequency ratio is always smaller for the brush seal.

  10. Combretastatin A4 disodium phosphate-induced myocardial injury

    PubMed Central

    Tochinai, Ryota; Nagata, Yuriko; Ando, Minoru; Hata, Chie; Suzuki, Tomo; Asakawa, Naoyuki; Yoshizawa, Kazuhiko; Uchida, Kazumi; Kado, Shoichi; Kobayashi, Toshihide; Kaneko, Kimiyuki; Kuwahara, Masayoshi

    2016-01-01

    Histopathological and electrocardiographic features of myocardial lesions induced by combretastatin A4 disodium phosphate (CA4DP) were evaluated, and the relation between myocardial lesions and vascular changes and the direct toxic effect of CA4DP on cardiomyocytes were discussed. We induced myocardial lesions by administration of CA4DP to rats and evaluated myocardial damage by histopathologic examination and electrocardiography. We evaluated blood pressure (BP) of CA4DP-treated rats and effects of CA4DP on cellular impedance-based contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). The results revealed multifocal myocardial necrosis with a predilection for the interventricular septum and subendocardial regions of the apex of the left ventricular wall, injury of capillaries, morphological change of the ST junction, and QT interval prolongation. The histopathological profile of myocardial lesions suggested that CA4DP induced a lack of myocardial blood flow. CA4DP increased the diastolic BP and showed direct effects on hiPS-CMs. These results suggest that CA4DP induces dysfunction of small arteries and capillaries and has direct toxicity in cardiomyocytes. Therefore, it is thought that CA4DP induced capillary and myocardial injury due to collapse of the microcirculation in the myocardium. Moreover, the direct toxic effect of CA4DP on cardiomyocytes induced myocardial lesions in a coordinated manner. PMID:27559241

  11. Combination of vascular targeting PDT with combretastatin A4 phosphate

    NASA Astrophysics Data System (ADS)

    He, Chong; Fateye, Babasola; Chen, Bin

    2009-06-01

    Tumor vasculature is an attractive target for cancer therapy due to its accessibility to blood-borne therapeutic agents and the dependence of tumor cells on a functional blood supply for survival and growth. Vascular targeting photodynamic therapy (vPDT) is a novel modality based on the selective laser light activation of photosensitizers localized inside tumor vasculature to shutdown tumor vascular function. Although this vascular targeting therapy is showing great promise for cancer treatment, tumor recurrence has been observed in both preclinical and clinical studies. In this study, we intend to enhance the therapeutic outcome of vascular targeting PDT by combining it with combretastatin A4 phosphate (CA4P), a blood flow inhibitor. We found that the combination of CA4P and vPDT significantly increased endothelial cell apoptosis than each single therapy. Western blot analysis suggests that myosin light chain kinase (MLCK) is a common target of CA4P and vPDT. In a PC-3 prostate tumor model, we found that CA4P was able to greatly enhance tumor response to vPDT. These results demonstrate that CA4P and vPDT can be combined to enhance the therapeutic effect.

  12. A 4 GHz digital receiver using the Uniboard platform

    NASA Astrophysics Data System (ADS)

    Comoretto, Giovanni; Russo, Antonietta; Quertier, Benjamin; Cais, Philippe; Camino, Pascal

    2012-09-01

    The Uniboard is a general purpose board, developed as a part of the Radionet FP7 program, that hosts 8 Altera StratixIV FPGAs interconnected by high speed links. It can be used standalone or as a part of a more complex system. The Digital receiver application uses a single Uniboard to implement a flexible packetization of a wideband signal in the frequency domain. It accepts a 4 GHz (8 GS/s) input bandwidth and provides up to 64 output bands. The bandwidth and position of each output band can be independently adjusted. The input signal is first analyzed by a polyphase filterbank, that splits the input band into 32 sub-bands with a bandwidth of 190 MHz and a spacing of 128 MHz. The overlap among adjacent bands allows the positioning of the output bands without dead regions. This filterbank is followed by an array of digitally defined downconverters, each one composed of a mixer/LO and a variable decimation filter. The filter band can be adjusted in binary steps from 1 to 128 MHz. Using tap recirculation, the filter shape remains constant over this whole range, with about 60 dB of stopband rejection and 90% usable passband. The output bands are packetized according to the VDIF VLBI standard, over eight 10G Ethernet links. Further processing can be done either on board, or in a cluster of conventional PCs. In addition, high speed ADC are in-house developed (ASIC 65nm CMOS STmicroelectronics) to feed the Uniboard card with 8GS/s, 4GHz BW, 3bits samples.

  13. UNIT 14A.4 Generation of Recombinant Vaccinia Viruses

    PubMed Central

    Earl, Patricia L.; Moss, Bernard; Wyatt, Linda S.

    2016-01-01

    This unit describes how to infect cells with vaccinia virus and then transfect them with a plasmid-transfer vector or PCR fragment to generate a recombinant virus. Selection and screening methods used to isolate recombinant viruses and a method for the amplification of recombinant viruses are described. Finally, a method for live immunostaining that has been used primarily for detection of recombinant modified vaccinia virus Ankara (MVA) is presented. This unit first describes how to infect cells with vaccinia virus and then transfect them with a plasmid-transfer vector or PCR fragment to generate a recombinant virus (see Basic Protocol 1). Also presented are selection and screening methods used to isolate recombinant viruses (see Basic Protocol 2) and a method for the amplification of recombinant viruses (see Basic Protocol 3). Finally, a method for live immunostaining that has been used primarily for detection of recombinant modified vaccinia virus Ankara (MVA) is presented (see Basic Protocol 4). HeLa S3 cells are recommended for large-scale growth of vaccinia virus. BS-C-1 cells may be used for xanthine-guanine phosphoribosyltransferase (XGPRT) and plaque size selection, fluorescent protein screening, transfection and determination of virus titer (UNIT 14A.3). For thymidine kinase (TK) selection, HuTK− 143B cells are used. With MVA, all steps are carried out in CEF or BHK-21 cells (UNIT 14A.3). CAUTION Proceed carefully and follow biosafety level 2 (BL-2) practices when working with standard vaccinia virus (see UNIT 14A.3 for safety precautions). [*Copy Editor: The original CPMB unit referenced CPMB Unit 16.15 for safety. The chapter editor asked that the authors include some of the safety information in the revised units – CPMB 16.16 and 16.17 – which are now CPMC Unit 14A.3 and 14A.4. As a result, the authors changed the safety citation here to “Unit 14A.3”, which doesn’t have nearly as much information as the original CPMB Unit 16.15. Perhaps the

  14. ConStrains identifies microbial strains in metagenomic datasets.

    PubMed

    Luo, Chengwei; Knight, Rob; Siljander, Heli; Knip, Mikael; Xavier, Ramnik J; Gevers, Dirk

    2015-10-01

    An important fraction of microbial diversity is harbored in strain individuality, so identification of conspecific bacterial strains is imperative for improved understanding of microbial community functions. Limitations in bioinformatics and sequencing technologies have to date precluded strain identification owing to difficulties in phasing short reads to faithfully recover the original strain-level genotypes, which have highly similar sequences. We present ConStrains, an open-source algorithm that identifies conspecific strains from metagenomic sequence data and reconstructs the phylogeny of these strains in microbial communities. The algorithm uses single-nucleotide polymorphism (SNP) patterns in a set of universal genes to infer within-species structures that represent strains. Applying ConStrains to simulated and host-derived datasets provides insights into microbial community dynamics.

  15. Tailoring a ConOps for NASA LSP Integrated Operations

    NASA Technical Reports Server (NTRS)

    Owens, Skip Clark V., III

    2017-01-01

    An integral part of the Systems Engineering process is the creation of a Concept of Operations (ConOps) for a given system, with the ConOps initially established early in the system design process and evolved as the system definition and design matures. As Integration Engineers in NASA's Launch Services Program (LSP) at Kennedy Space Center (KSC), our job is to manage the interface requirements for all the robotic space missions that come to our Program for a Launch Service. LSP procures and manages a launch service from one of our many commercial Launch Vehicle Contractors (LVCs) and these commercial companies are then responsible for developing the Interface Control Document (ICD), the verification of the requirements in that document, and all the services pertaining to integrating the spacecraft and launching it into orbit. However, one of the systems engineering tools that have not been employed within LSP to date is a Concept of Operations. The goal of this paper is to research the format and content that goes into these various aerospace industry ConOps and tailor the format and content into template form, so the template may be used as an engineering tool for spacecraft integration with future LSP procured launch services. This tailoring effort was performed as the authors final Masters Project in the Spring of 2016 for the Stevens Institute of Technology and modified for publication with INCOSE (Owens, 2016).

  16. Orthologs of the class A4 heat shock transcription factor HsfA4a confer cadmium tolerance in wheat and rice.

    PubMed

    Shim, Donghwan; Hwang, Jae-Ung; Lee, Joohyun; Lee, Sichul; Choi, Yunjung; An, Gynheung; Martinoia, Enrico; Lee, Youngsook

    2009-12-01

    Cadmium (Cd) is a widespread soil pollutant; thus, the underlying molecular controls of plant Cd tolerance are of substantial interest. A screen for wheat (Triticum aestivum) genes that confer Cd tolerance to a Cd hypersensitive yeast strain identified Heat shock transcription factor A4a (HsfA4a). Ta HsfA4a is most similar to the class A4 Hsfs from monocots. The most closely related rice (Oryza sativa) homolog, Os HsfA4a, conferred Cd tolerance in yeast, as did Ta HsfA4a, but the second most closely related rice homolog, Os HsfA4d, did not. Cd tolerance was enhanced in rice plants expressing Ta HsfA4a and decreased in rice plants with knocked-down expression of Os HsfA4a. An analysis of the functional domain using chimeric proteins constructed from Ta HsfA4a and Os HsfA4d revealed that the DNA binding domain (DBD) of HsfA4a is critical for Cd tolerance, and within the DBD, Ala-31 and Leu-42 are important for Cd tolerance. Moreover, Ta HsfA4a-mediated Cd resistance in yeast requires metallothionein (MT). In the roots of wheat and rice, Cd stress caused increases in HsfA4a expression, together the MT genes. Our findings thus suggest that HsfA4a of wheat and rice confers Cd tolerance by upregulating MT gene expression in planta.

  17. [A 4-week oral toxicity study of prulifloxacin (NM441) in rats followed by a 4-week recovery test].

    PubMed

    Nishimura, N; Fukuda, K; Yamazaki, S; Tamura, K; Shindo, Y; Iwakura, K; Sumi, N

    1996-06-01

    A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats. Male and female rats were given the test material orally for 4 weeks at doses of 0 (control), 30, 300 and 3000 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted. There was one case of death in the 3000 mg/kg group. Grayish green and soft feces, unkempt fur, transient deep respiration and decreased body weight gain were observed in the 3000 mg/kg group. Decreased food consumption and increased water intake were seen in the 300 and 3000 mg/kg groups. Ophthalmoscopic examination failed to show any abnormalities related to the treatment. In urinalysis, crystalline substance in the urinary sediments, cloudy urine and decreased Na+ excretion were observed in the 300 and 3000 mg/kg groups. Increased urine volume, lowered urine specific gravity and decreased K+ and Cl- excretions were seen in the 3000 mg/kg group. Hematologic examination showed decreased Hb, Ht, MCV and MCH and increased WBC in the 3000 mg/kg group. Blood chemical examination revealed increased BUN and decreased K+ and Cl- in the 3000 mg/kg group, and decreased K+ and gamma-globulin in the 300 mg/kg group. Pathological changes caused by the treatment were as follows. Cecal weight was increased in all dose groups. Cecal distention and swelling of its absorptive cells were seen in the 300 and 3000 mg/kg groups. In kidney, tubular nephrosis with crystalline substance was observed in the 300 and 3000 mg/kg groups, and its organ weight was increased in the 3000 mg/kg group. The above-mentioned changes were reversible except for decreased gamma-globulin, increased BUN and urine volume, and lowered urine specific gravity. Ulcer and small cavities associated with proliferation of fibrous tissue in the femoral articular cartilage were observed in the 3000 mg/kg group at the end of recovery period of 4 weeks. Plasma levels and urinary concentrations of active

  18. Ligand Diversity of Human and Chimpanzee CYP3A4: Activation of Human CYP3A4 by Lithocholic Acid Results from Positive SelectionS⃞

    PubMed Central

    Kumar, Santosh; Qiu, Huan; Oezguen, Numan; Herlyn, Holger; Halpert, James R.; Wojnowski, Leszek

    2009-01-01

    For currently unknown reasons, the evolution of CYP3A4 underwent acceleration in the human lineage after the split from chimpanzee. We investigated the significance of this event by comparing Escherichia coli-expressed CYP3A4 from humans, chimpanzee, and their most recent common ancestor. The expression level of chimpanzee CYP3A4 was ∼50% of the human CYP3A4, whereas ancestral CYP3A4 did not express in E. coli. Steady-state kinetic analysis with 7-benzyloxyquinoline, 7-benzyloxy-4-(trifluoromethyl)coumarin (7-BFC), and testosterone showed no significant differences between human and chimpanzee CYP3A4. Upon addition of α-naphthoflavone (25 μM), human CYP3A4 showed a slightly decreased substrate concentration at which 50% of the maximal rate Vmax is reached for 7-BFC, whereas chimpanzee CYP3A4 showed a >2-fold increase. No significant differences in inhibition/activation were found for a panel of 43 drugs and endogenous compounds, suggesting that the wide substrate spectrum of human CYP3A4 precedes the human-chimpanzee split. A striking exception was the hepatotoxic secondary bile acid lithocholic acid, which at saturation caused a 5-fold increase in 7-BFC debenzylation by human CYP3A4 but not by chimpanzee CYP3A4. Mutagenesis of human CYP3A4 revealed that at least four of the six amino acids positively selected in the human lineage contribute to the activating effect of lithocholic acid. In summary, the wide functional conservation between chimpanzee and human CYP3A4 raises the prospect that phylogenetically more distant primate species such as rhesus and squirrel monkey represent suitable models of the human counterpart. Positive selection on the human CYP3A4 may have been triggered by an increased load of dietary steroids, which led to a novel defense mechanism against cholestasis. PMID:19299527

  19. High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine.

    PubMed

    Saito, Takuro; Wada, Hisashi; Yamasaki, Makoto; Miyata, Hiroshi; Nishikawa, Hiroyoshi; Sato, Eiichi; Kageyama, Shinichi; Shiku, Hiroshi; Mori, Masaki; Doki, Yuichiro

    2014-10-14

    We conducted a cancer vaccine clinical trial with MAGE-A4 protein. Safety, clinical response, and antigen-specific immune responses were analyzed and the prognostic factors by vaccination were investigated. Twenty patients with advanced esophageal, stomach or lung cancer were administered MAGE-A4 vaccine containing 300μg protein subcutaneously once every 2 weeks in six doses. Primary endpoints of this study were safety and MAGE-A4 immune responses. The vaccine was well tolerated. Fifteen of 20 patients completed one cycle of vaccination and two patients showed SD. A MAGE-A4-specific humoral immune response was observed in four patients who had high expression of MAGE-A4 and MHC class I on tumor cells. These four patients showed significantly longer overall survival than patients without an antibody response after vaccination (p=0.009). Patients with tumor cells expressing high MAGE-A4 or MHC class I antigen showed significantly longer overall survival than those with low expression. Induction of CD4 and CD8T cell responses was observed in three and six patients, respectively, and patients with induction of MAGE-A4-specific IFNγ-producing CD8T cells, but not CD4T cells, lived longer than those without induction. The CHP-MAGE-A4 vaccine was safe. Expression of MAGE-A4 and MHC class I in tumor tissue and the induction of a MAGE-A4-specific immune response after vaccination would be feasible prognostic markers for patients vaccinated with MAGE-A4. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Association of EphA4 polymorphism with swine reproductive traits and mRNA expression of EphA4 during embryo implantation.

    PubMed

    Fu, Yanfeng; Fu, Jinluan; Wang, Aiguo

    2012-03-01

    The swine erythropoietin-producing hepatocellular A4 (EphA4) gene, which was detected in the endometrium during embryo implantation in pigs, was one of the potential candidate genes for reproductive traits. In the study, two single nucleotide polymorphism (SNP) loci (EphA4_1 and EphA4_2) in exon 3 of EphA4 gene were analyzed to determine whether EphA4 influenced total number born (TNB) and number born alive (NBA). Association of two diallelic polymorphisms with reproductive traits was assessed in Landrace, Yorkshire and Duroc populations with 2,014 litter records of 765 sows. The results showed that G allele at EphA4_1 locus or C allele at EphA4_2 locus seemed to have advantageous effects on litter size. And the combined analyzed results demonstrated that genotype AGTC, AGCC and GGCC are better than genotype AATT, AATC and AGTT for TNB and NBA in either single parity or all parities. The results in this study demonstrated that EphA4 gene was significantly associated with litter size in pigs. In addition, a high mRNA expression of EphA4 was found in small intestine, large intestine, stomach and endometrium, and the expression decreased during implantation in pigs. Further studies were needed to confirm these preliminary researches.

  1. A complex photoreceptor system mediates the regulation by light of the conidiation genes con-10 and con-6 in Neurospora crassa.

    PubMed

    Olmedo, María; Ruger-Herreros, Carmen; Luque, Eva M; Corrochano, Luis M

    2010-04-01

    Genes con-10 and con-6 in Neurospora crassa are activated during conidiation or after illumination of vegetative mycelia. Light activation requires the white-collar complex (WCC), a transcription factor complex composed of the photoreceptor WC-1 and its partner WC-2. We have characterized the photoactivation of con-10 and con-6, and we have identified 300bp required for photoactivation in the con-10 promoter. A complex stimulus-response relationship for con-10 and con-6 photoactivation suggested the activity of a complex photoreceptor system. The WCC is the key element for con-10 activation by light, but we suggest that other photoreceptors, the cryptochrome CRY-1, the rhodopsin NOP-1, and the phytochrome PHY-2, modify the activity of the WCC for con-10 photoactivation, presumably through a repressor. In addition we show that the regulatory protein VE-1 is required for full photocarotenogenesis. We propose that these proteins may modulate the WCC in a gene-specific way.

  2. Molecular diagnostics: Molecular Med Tri-Con 2013.

    PubMed

    Klein, Roger D

    2013-07-01

    The 20th annual Molecular Med Tri-Con conference, sponsored by Cambridge Health Institute (MA, USA), consisted of over 250 presentations within five parallel 'channels': 'Diagnostics, Therapeutics, Clinical, Informatics and Cancer', along with five preliminary symposia, 15 short courses, a plenary keynote session entitled 'Personalized Oncology - Fulfilling the Promise for Today's Patients' and a keynote panel entitled, 'Emerging Technologies and Industry Perspectives'. Over 3000 individuals from academia, clinical laboratories and industry were in attendance. This article will focus on the Keynote Session of 'Molecular Diagnostics' track within the Diagnostics Channel.

  3. Apoyo a Estudios Geodinamicos con GPS en Guatemala

    NASA Astrophysics Data System (ADS)

    Robles, V. R.

    2013-05-01

    El Instituto Geografico Nacional de Guatemala implemento 17 estaciones GNSS en el año 2009, como un proyecto de credito mixto de donacion de equipamiento del Gobierno de Suiza, el cual, este equipamiento de estaciones CORS GNSS es un sistema de recepción y transmisión de datos crudos GPS RInex que utiliza la tecnologia Spider Web de Leica, asi mismo este sistema esta sirviendo para el espablecimiento de un marco geodesico nacional de coordenadas geodesicas oficiales, el cual se calculan u obtienen las velocidades en tiempos temporales programados de las 17 Estaciones CORS. La infraestructura del marco geodesico de Guatemala esta sirviendo de base para las aplicaciones de estudios geodinamicos como el monitoreo de del desplazamiento de las placas tectonicas por medio de un estudio que se inicio en el año de 1999, llamado medicion con GPS el sistema de Fallas de los rios Polochic Motagua de Guatemala, tambien para un estudio que se implemento para deformación de corteza terrestre local en un Volcan Activo de Guatemala llamado Pacaya. Para el estudio de medicion con GPS en el sistema de falla de los Rios del polochic Motagua se implementaron 16 puntos para medir con GPS de dos frecuencias en el año de 1999, el cual, tres puntos son estaciones geodesicas CORS IGS llamados GUAT, ELEN y HUEH, despues en el año de 2003 se hizo otra medicion en un total de 20 puntos, que permitió calcular las velocidades de desplazamieinto de los puntos en mención, usando como referencia el modelo NUVEL 1A de DeMets de la placa de Norteamerica. Este estudio fue en cooperación internacional por la universidad de Nice de Francia y el IGNde Francia. Para el estudio del monitoreo con GPS del volcan activo de Guatemala, se implementaron cuatro puntos al rededor del volcan, el cual, se realizan cuatro mediciones al año, que permiten determinar axialmente la distancias entre los puntos, y rebisar estadisticamente cual es el comportamiento de las distancias en funcion del tiempo, si

  4. Conning the conmen: Intelligence and female desire in Dedh Ishqiya.

    PubMed

    Singh, Shailendra Kumar

    2017-04-11

    This article investigates the ostensibly paradoxical relationship that exists between the theme of excessive love, as suggested by the title of Abhishek Chaubey's film Dedh Ishqiya (2014), and the actual representation of it in the movie, which is not only restrained and disproportionate, but is also looked at with suspicion and contempt. It examines the logic of this seeming contradiction through the other two related themes that Chaubey's chef-d'œuvre foregrounds, namely that of intelligence and female desire. The quest for financial autonomy that the female protagonists of the movie are involved in-a necessary pre-condition for leading independent lives-is so inextricably intertwined with manipulation, dexterity, and subterfuge, that any overt expression of homoerotic female desire can only jeopardize their existing possibilities of self-aggrandizement. The heteronormative arrangements of Begum Para's palace thus constitute the elaborate mise en scène, behind which female desire is enacted through a politics of intelligence, resourcefulness, discretion, and anonymity. Through this strategic negotiation, which is also a tactical necessity, the female protagonists are not only able to con the con men in the movie, but also imagine alternative subject positions that recognize the need for both pragmatism and expediency as well as deconstructing heteropatriarchal economies of desire.

  5. Glucuronidation of Dihydrotestosterone and trans-Androsterone by Recombinant UDP-Glucuronosyltransferase (UGT) 1A4: Evidence for Multiple UGT1A4 Aglycone Binding Sites

    PubMed Central

    Zhou, Jin; Tracy, Timothy S.

    2010-01-01

    UDP-glucuronosyltransferase (UGT) 1A4-catalyzed glucuronidation is an important drug elimination pathway. Although atypical kinetic profiles (nonhyperbolic, non-Michaelis-Menten) of UGT1A4-catalyzed glucuronidation have been reported occasionally, systematic kinetic studies to explore the existence of multiple aglycone binding sites in UGT1A4 have not been conducted. To this end, two positional isomers, dihydrotestosterone (DHT) and trans-androsterone (t-AND), were used as probe substrates, and their glucuronidation kinetics with HEK293-expressed UGT1A4 were evaluated both alone and in the presence of a UGT1A4 substrate [tamoxifen (TAM) or lamotrigine (LTG)]. Coincubation with TAM, a high-affinity UGT1A4 substrate, resulted in a concentration-dependent activation/inhibition effect on DHT and t-AND glucuronidation, whereas LTG, a low-affinity UGT1A4 substrate, noncompetitively inhibited both processes. The glucuronidation kinetics of TAM were then evaluated both alone and in the presence of different concentrations of DHT or t-AND. TAM displayed substrate inhibition kinetics, suggesting that TAM may have two binding sites in UGT1A4. However, the substrate inhibition kinetic profile of TAM became more hyperbolic as the DHT or t-AND concentration was increased. Various two-site kinetic models adequately explained the interactions between TAM and DHT or TAM and t-AND. In addition, the effect of TAM on LTG glucuronidation was evaluated. In contrast to the mixed effect of TAM on DHT and t-AND glucuronidation, TAM inhibited LTG glucuronidation. Our results suggest that multiple aglycone binding sites exist within UGT1A4, which may result in atypical kinetics (both homotropic and heterotropic) in a substrate-dependent fashion. PMID:20007295

  6. Glucuronidation of dihydrotestosterone and trans-androsterone by recombinant UDP-glucuronosyltransferase (UGT) 1A4: evidence for multiple UGT1A4 aglycone binding sites.

    PubMed

    Zhou, Jin; Tracy, Timothy S; Remmel, Rory P

    2010-03-01

    UDP-glucuronosyltransferase (UGT) 1A4-catalyzed glucuronidation is an important drug elimination pathway. Although atypical kinetic profiles (nonhyperbolic, non-Michaelis-Menten) of UGT1A4-catalyzed glucuronidation have been reported occasionally, systematic kinetic studies to explore the existence of multiple aglycone binding sites in UGT1A4 have not been conducted. To this end, two positional isomers, dihydrotestosterone (DHT) and trans-androsterone (t-AND), were used as probe substrates, and their glucuronidation kinetics with HEK293-expressed UGT1A4 were evaluated both alone and in the presence of a UGT1A4 substrate [tamoxifen (TAM) or lamotrigine (LTG)]. Coincubation with TAM, a high-affinity UGT1A4 substrate, resulted in a concentration-dependent activation/inhibition effect on DHT and t-AND glucuronidation, whereas LTG, a low-affinity UGT1A4 substrate, noncompetitively inhibited both processes. The glucuronidation kinetics of TAM were then evaluated both alone and in the presence of different concentrations of DHT or t-AND. TAM displayed substrate inhibition kinetics, suggesting that TAM may have two binding sites in UGT1A4. However, the substrate inhibition kinetic profile of TAM became more hyperbolic as the DHT or t-AND concentration was increased. Various two-site kinetic models adequately explained the interactions between TAM and DHT or TAM and t-AND. In addition, the effect of TAM on LTG glucuronidation was evaluated. In contrast to the mixed effect of TAM on DHT and t-AND glucuronidation, TAM inhibited LTG glucuronidation. Our results suggest that multiple aglycone binding sites exist within UGT1A4, which may result in atypical kinetics (both homotropic and heterotropic) in a substrate-dependent fashion.

  7. 26 CFR 1.401(a)(4)-13 - Effective dates and fresh-start rules.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... for five years, and has compensation equal to $60,000 in 1993. The amount of employer contribution to... otherwise provided in this section, §§ 1.401(a)(4)-1 through 1.401(a)(4)-13 apply to plan years beginning on...)(i) (nonelective plans), §§ 1.401(a)(4)-1 through 1.401(a)(4)-13 apply to plan years beginning on or...

  8. 26 CFR 1.401(a)(4)-13 - Effective dates and fresh-start rules.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... for five years, and has compensation equal to $60,000 in 1993. The amount of employer contribution to.... Except as otherwise provided in this section, §§ 1.401(a)(4)-1 through 1.401(a)(4)-13 apply to plan years... section 403(b)(12)(A)(i) (nonelective plans), §§ 1.401(a)(4)-1 through 1.401(a)(4)-13 apply to plan years...

  9. Cannabinoids and cancer: pros and cons of an antitumour strategy

    PubMed Central

    Bifulco, Maurizio; Laezza, Chiara; Pisanti, Simona; Gazzerro, Patrizia

    2006-01-01

    In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called ‘endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiproliferative actions of cannabinoid agonists on several tumour cells in vitro and in animal models. In this article, we will review the principal molecular pathways modulated by cannabinoids on cancer and summarize pros and cons evidence on the possible future use of endocannabinoid-based drugs in cancer therapy. PMID:16501583

  10. Balancing Ethical Pros and Cons of Stem Cell Derived Gametes.

    PubMed

    Segers, Seppe; Mertes, Heidi; de Wert, Guido; Dondorp, Wybo; Pennings, Guido

    2017-07-01

    In this review we aim to provide an overview of the most important ethical pros and cons of stem cell derived gametes (SCD-gametes), as a contribution to the debate about reproductive tissue engineering. Derivation of gametes from stem cells holds promising applications both for research and for clinical use in assisted reproduction. We explore the ethical issues connected to gametes derived from embryonic stem cells (both patient specific and non-patient specific) as well as those related to gametes derived from induced pluripotent stem cells. The technology of SCD-gametes raises moral concerns of how reproductive autonomy relates to issues of embryo destruction, safety, access, and applications beyond clinical infertility.

  11. Endoscopic scoring systems for inflammatory bowel disease: pros and cons.

    PubMed

    Tontini, Gian Eugenio; Bisschops, Raf; Neumann, Helmut

    2014-07-01

    Endoscopy plays a pivotal role for diagnosis and assessment of disease activity and extent in patients with inflammatory bowel diseases. International guidelines recommend the use of endoscopic scoring systems for evaluation of the prognosis and efficacy of medical treatments. Ideal scoring systems are easy to use, reproducible, reliable, responsive to changes, and validated in different clinical settings in order to guide therapeutic strategies. However, currently available endoscopic scoring systems often appear as complex for routine endoscopy and suffer from insufficient interobserver agreement and lack of formal validation which often limit their use in clinical trials. Here, we describe the role of endoscopic scoring systems in inflammatory bowel diseases focusing on pros and cons in the era of advanced endoscopic imaging and mucosal healing.

  12. Gradient Optimization for Analytic conTrols - GOAT

    NASA Astrophysics Data System (ADS)

    Assémat, Elie; Machnes, Shai; Tannor, David; Wilhelm-Mauch, Frank

    Quantum optimal control becomes a necessary step in a number of studies in the quantum realm. Recent experimental advances showed that superconducting qubits can be controlled with an impressive accuracy. However, most of the standard optimal control algorithms are not designed to manage such high accuracy. To tackle this issue, a novel quantum optimal control algorithm have been introduced: the Gradient Optimization for Analytic conTrols (GOAT). It avoids the piecewise constant approximation of the control pulse used by standard algorithms. This allows an efficient implementation of very high accuracy optimization. It also includes a novel method to compute the gradient that provides many advantages, e.g. the absence of backpropagation or the natural route to optimize the robustness of the control pulses. This talk will present the GOAT algorithm and a few applications to transmons systems.

  13. RoboCon: Operator interface for robotic applications

    SciTech Connect

    Schempf, H.; Warwick, J.; Fung, M.; Chemel, B.; Blackwell, M.

    1996-12-31

    Carnegie Mellon U. and ORNL`s Robotics and Process Systems Division are developing a state-of-the-art robot operator control station (RoboCon) with standardized hardware and software control interfaces to be adaptable to a variety of remote and robotic equipment currently funded by DOE`s Office of Science & Technology Robotics Technology Development Program. The human operation and telerobotic and supervisory control of sophisticated and remote and robotic systems is a complex, tiring, and non-intuitive activity. Since decontamination & decommissioning, selective equipment removal, mixed waste operations, and in-tank cleanup are going to be a major future activity in DOE environmental restoration and waste management cleanup agenda, it seems necessary to utilize an operator control station and interface which maximizes operator comfort and productivity.

  14. [Modern tribology in total hip arthroplasty: pros and cons].

    PubMed

    Gómez-García, F

    2014-01-01

    The wear products and adverse reactions that occur on bearing surfaces represent one of the greatest challenges in prosthetic replacements, as the latter experience increasing demands due to the large number of young and older adult patients that have a long life expectancy and remarkable activity. The purpose of this review is to analyze the pros and cons of the new advances in the bearing components of the articular surfaces of current total hip arthroplasties. We also discuss the strategies used historically, their problems, results and the surgeon's role in prescribing the tribologic couple that best fits each patient's needs. We conclude with practical recommendations for the prescription and management of the latest articular couples for total hip arthroplasty.

  15. Cannabinoids and cancer: pros and cons of an antitumour strategy.

    PubMed

    Bifulco, Maurizio; Laezza, Chiara; Pisanti, Simona; Gazzerro, Patrizia

    2006-05-01

    In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called 'endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiproliferative actions of cannabinoid agonists on several tumour cells in vitro and in animal models. In this article, we will review the principal molecular pathways modulated by cannabinoids on cancer and summarize pros and cons evidence on the possible future use of endocannabinoid-based drugs in cancer therapy.

  16. Neogene sequence stratigraphy, Nam Con Son Basin, offshore Vietnam

    SciTech Connect

    McMillen, K.J. ); Do Van Luu; Lee, E.K.; Hong, S.S. )

    1996-01-01

    An integrated well log, biostratigraphic, and seismic stratigraphic study of Miocene to Recent deltaic sediments deposited in the Nam Con Son Basin offshore from southern Vietnam shows the influence of eustacy and tectonics on sequence development. Sediments consist of Oligocene non-marine rift-basin fill (Cau Formation), early to middle Miocene tide-dominated delta plain to delta front sediments (TB 1.5 to TB 2.5, Due and Thong Formations), and late Miocene to Recent marine shelf sediments (TB. 2.6 to TB 3.1 0, Mang Cau, Nam Con Son, and Bien Dong Formations). Eustacy controlled the timing of key surfaces and sand distribution in the tectonically-quiet early Miocene. Tectonic effects on middle to late Miocene sequence development consist of thick transgressive systems tracts due to basin-wide subsidence and transgression, sand distribution in the basin center, and carbonate sedimentation on isolated fault blocks within the basin. Third-order sequence boundaries (SB) are identified by spore peaks, sand stacking patterns, and channel incision. In the basin center, widespread shale beds with coal occur above sequence boundaries followed by transgressive sandstone units. These TST sandstones merge toward the basin margin where they lie on older HST sandstones. Maximum flooding surfaces (MFS) have abundant marine microfossils and mangrove pollen, a change in sand stacking pattern, and often a strong seismic reflection with downlap. Fourth-order genetic-type sequences are also interpreted. The MFS is the easiest marker to identify and correlate on well logs. Fourth-order SB occur within these genetic units but are harder to identify and correlate.

  17. Neogene sequence stratigraphy, Nam Con Son Basin, offshore Vietnam

    SciTech Connect

    McMillen, K.J.; Do Van Luu; Lee, E.K.; Hong, S.S.

    1996-12-31

    An integrated well log, biostratigraphic, and seismic stratigraphic study of Miocene to Recent deltaic sediments deposited in the Nam Con Son Basin offshore from southern Vietnam shows the influence of eustacy and tectonics on sequence development. Sediments consist of Oligocene non-marine rift-basin fill (Cau Formation), early to middle Miocene tide-dominated delta plain to delta front sediments (TB 1.5 to TB 2.5, Due and Thong Formations), and late Miocene to Recent marine shelf sediments (TB. 2.6 to TB 3.1 0, Mang Cau, Nam Con Son, and Bien Dong Formations). Eustacy controlled the timing of key surfaces and sand distribution in the tectonically-quiet early Miocene. Tectonic effects on middle to late Miocene sequence development consist of thick transgressive systems tracts due to basin-wide subsidence and transgression, sand distribution in the basin center, and carbonate sedimentation on isolated fault blocks within the basin. Third-order sequence boundaries (SB) are identified by spore peaks, sand stacking patterns, and channel incision. In the basin center, widespread shale beds with coal occur above sequence boundaries followed by transgressive sandstone units. These TST sandstones merge toward the basin margin where they lie on older HST sandstones. Maximum flooding surfaces (MFS) have abundant marine microfossils and mangrove pollen, a change in sand stacking pattern, and often a strong seismic reflection with downlap. Fourth-order genetic-type sequences are also interpreted. The MFS is the easiest marker to identify and correlate on well logs. Fourth-order SB occur within these genetic units but are harder to identify and correlate.

  18. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  19. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  20. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  1. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  2. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  3. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  4. 42 CFR 51a.4 - How is application made for Federal funding?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How is application made for Federal funding? 51a.4 Section 51a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.4 How is application made for Federal funding? An application...

  5. 17 CFR 260.10a-4 - Consent of trustee to service of process.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... address in the United States as agent upon whom may be served any process, pleadings, subpoenas or other... of process. 260.10a-4 Section 260.10a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... § 260.10a-4 Consent of trustee to service of process. At the time of filing an application pursuant to...

  6. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  7. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  8. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  9. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  10. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  11. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  12. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  13. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  14. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  15. Human Cytochrome P450 3A4 as a Biocatalyst: Effects of the Engineered Linker in Modulation of Coupling Efficiency in 3A4-BMR Chimeras

    PubMed Central

    Degregorio, Danilo; D'Avino, Serena; Castrignanò, Silvia; Di Nardo, Giovanna; Sadeghi, Sheila J.; Catucci, Gianluca; Gilardi, Gianfranco

    2017-01-01

    Human liver cytochrome P450 3A4 is the main enzyme involved in drug metabolism. This makes it an attractive target for biocatalytic applications, such as the synthesis of pharmaceuticals and drug metabolites. However, its poor solubility, stability and low coupling have limited its application in the biotechnological context. We previously demonstrated that the solubility of P450 3A4 can be increased by creating fusion proteins between the reductase from Bacillus megaterium BM3 (BMR) and the N-terminally modified P450 3A4 (3A4-BMR). In this work, we aim at increasing stability and coupling efficiency by varying the length of the loop connecting the two domains to allow higher inter-domain flexibility, optimizing the interaction between the domains. Starting from the construct 3A4-BMR containing the short linker Pro-Ser-Arg, two constructs were generated by introducing a 3 and 5 glycine hinge (3A4-3GLY-BMR and 3A4-5GLY-BMR). The three fusion proteins show the typical absorbance at 450 nm of the reduced heme-CO adduct as well as the correct incorporation of the FAD and FMN cofactors. Each of the three chimeric proteins were more stable than P450 3A4 alone. Moreover, the 3A4-BMR-3-GLY enzyme showed the highest NADPH oxidation rate in line with the most positive reduction potential. On the other hand, the 3A4-BMR-5-GLY fusion protein showed a Vmax increased by 2-fold as well as a higher coupling efficiency when compared to 3A4-BMR in the hydroxylation of the marker substrate testosterone. This protein also showed the highest rate value of cytochrome c reduction when this external electron acceptor is used to intercept electrons from BMR to P450. The data suggest that the flexibility and the interaction between domains in the chimeric proteins is a key parameter to improve turnover and coupling efficiency. These findings provide important guidelines in engineering catalytically self-sufficient human P450 for applications in biocatalysis. PMID:28377716

  16. Human Cytochrome P450 3A4 as a Biocatalyst: Effects of the Engineered Linker in Modulation of Coupling Efficiency in 3A4-BMR Chimeras.

    PubMed

    Degregorio, Danilo; D'Avino, Serena; Castrignanò, Silvia; Di Nardo, Giovanna; Sadeghi, Sheila J; Catucci, Gianluca; Gilardi, Gianfranco

    2017-01-01

    Human liver cytochrome P450 3A4 is the main enzyme involved in drug metabolism. This makes it an attractive target for biocatalytic applications, such as the synthesis of pharmaceuticals and drug metabolites. However, its poor solubility, stability and low coupling have limited its application in the biotechnological context. We previously demonstrated that the solubility of P450 3A4 can be increased by creating fusion proteins between the reductase from Bacillus megaterium BM3 (BMR) and the N-terminally modified P450 3A4 (3A4-BMR). In this work, we aim at increasing stability and coupling efficiency by varying the length of the loop connecting the two domains to allow higher inter-domain flexibility, optimizing the interaction between the domains. Starting from the construct 3A4-BMR containing the short linker Pro-Ser-Arg, two constructs were generated by introducing a 3 and 5 glycine hinge (3A4-3GLY-BMR and 3A4-5GLY-BMR). The three fusion proteins show the typical absorbance at 450 nm of the reduced heme-CO adduct as well as the correct incorporation of the FAD and FMN cofactors. Each of the three chimeric proteins were more stable than P450 3A4 alone. Moreover, the 3A4-BMR-3-GLY enzyme showed the highest NADPH oxidation rate in line with the most positive reduction potential. On the other hand, the 3A4-BMR-5-GLY fusion protein showed a Vmax increased by 2-fold as well as a higher coupling efficiency when compared to 3A4-BMR in the hydroxylation of the marker substrate testosterone. This protein also showed the highest rate value of cytochrome c reduction when this external electron acceptor is used to intercept electrons from BMR to P450. The data suggest that the flexibility and the interaction between domains in the chimeric proteins is a key parameter to improve turnover and coupling efficiency. These findings provide important guidelines in engineering catalytically self-sufficient human P450 for applications in biocatalysis.

  17. Modulation of ConA-induced inflammatory ascites by histamine - short communication.

    PubMed

    Baintner, Károly

    2015-03-01

    The early phase of the ConA-induced inflammatory ascites was studied, with special reference to histamine. Concanavalin A (ConA), a cell-surface binding lectin was injected i.p. (25 mg/kg bw) to mice. After 1 h the animals were killed, the ascitic fluid collected and measured. Other agents were injected s.c., 10 min before the ConA-challenge. Exogenous histamine markedly inhibited the ConA-induced ascites. Release of endogenous vasoactive agents from the mast cells by Compound 48/80 had a similar, but slight effect. Cromolyn, a mast cell stabilizing agent, and chloropyramine, a histamine H1 receptor antagonist was ineffective. Although histamine increases endothelial permeability, it did not enhance the formation of ascitic fluid, on the contrary, it inhibited the ConA-induced ascites, presumably due to its known hypotonic effect. It is concluded that ConA-induced ascites is not mediated by mast cell histamine.

  18. Conversation with Lara about the Earth and Land. (Spanish Title: Conversando con Lara sobre la Tierra y la Teirra.) Conversando com Lara sobre a Terra e a Terra

    NASA Astrophysics Data System (ADS)

    da Conceição Barbosa-Lima, Maria

    2010-12-01

    en que vive es el planeta Tierra y que, probablemente por ese motivo, distingue con precisión, dentro de los limites de comprensión de la edad y madurez asociada, la tierra y la Tierra. O presente artigo analisa uma entrevista livre enquanto uma menina de quatro anos e quatro meses, matriculada na educação infantil, desenhava a Terra. A entrevista se realizou fora do ambiente escolar e sem qualquer outra pessoa por perto que pudesse interferir. De acordo com Ferreira & Silva (2004), para que o pesquisador conheça realmente o que uma criança põe no papel através de grafismos e/ou desenhos, é necessário ouvi-la durante o processo de criação do desenho. A menina apresenta, em relação à Terra, o tradicional desenho plano com o 'céu' paralelo ao solo, conforme já apresentaram Nardi & Carvalho (1996). Mas quando solicitada a desenhar o Mundo - palavra empregada em um trabalho por Butterworth et al. (2002), com intenção de não provocar 'confusões' desnecessárias para seus pesquisados - o representa de forma circular, colocando-se sobre sua superfície. Seus desenhos levaram à conclusão que esta criança ainda não tem conhecimento de que o Mundo em que vive é o Planeta Terra e que, provavelmente por este motivo, diferencia com precisão, dentro dos limites impostos por sua idade e consequente maturidade, a terra e a Terra.

  19. Cardiac CON Regulations and the Availability and Use of Revascularization Services

    PubMed Central

    Ho, Vivian; Ross, Joseph S.; Nallamothu, Brahmajee K.; Krumholz, Harlan M.

    2007-01-01

    Background Many states enforce Certificate of Need (CON) regulations for cardiac procedures, but little is known about how CON affects utilization. We assessed the association between cardiac CON regulations, availability of revascularization facilities, and revascularization rates. Methods We determined when state cardiac CON regulations were active and obtained data for Medicare beneficiaries ages 65 and older who received coronary artery bypass graft surgery (CABG) or a percutaneous coronary intervention (PCI) between 1989 and 2002. We compared the number of hospitals performing revascularization and patient utilization in states with and without CON regulations, and in states which discontinued CON regulations during 1989-2002. Results Each year, the per capita number of hospitals performing CABG and PCI was higher in states without CON (3.7 per 100,000 elderly for CABG, 4.5 for PCI in 2002), compared with CON states (2.5 for CABG, 3.0 for PCI in 2002). Multivariate regressions that adjusted for market and population characteristics found no difference in CABG utilization rates between states with and without CON (p=.7). However, CON was associated with 19.2 percent fewer PCIs per 1,000 elderly (p=.01), equivalent to 322,526 fewer PCIs for 1989-2002. Among most states that discontinued CON, the number of hospitals performing PCI rose in the mid 1990s, but there were no consistent trends in the number of hospitals performing CABG or in PCIs or CABGs per capita. Conclusions CON restricts the number of cardiac facilities, but its effect on utilization rates may vary by procedure. PMID:17893007

  20. The S100A4 Oncoprotein Promotes Prostate Tumorigenesis in a Transgenic Mouse Model

    PubMed Central

    Siddique, Hifzur R.; Adhami, Vaqar M.; Parray, Aijaz; Johnson, Jeremy J.; Siddiqui, Imtiaz A.; Shekhani, Mohammad T.; Murtaza, Imtiyaz; Ambartsumian, Noona; Konety, Badrinath R.; Mukhtar, Hasan

    2013-01-01

    S100A4, a calcium-binding protein, is known for its role in the metastatic spread of tumor cells, a late event of cancer disease. This is the first report showing that S100A4 is not merely a metastatic protein but also an oncoprotein that plays a critical role in the development of tumors. We earlier showed that S100A4 expression progressively increases in prostatic tissues with the advancement of prostate cancer (CaP) in TRAMP, an autochthonous mouse model. To study the functional significance of S100A4 in CaP, we generated a heterozygously deleted S100A4 (TRAMP/S100A4+/−) genotype by crossing TRAMP with S100A4−/− mice. TRAMP/S100A4+/− did not show a lethal phenotype, and transgenes were functional. As compared to age-matched TRAMP littermates, TRAMP/S100A4+/− mice exhibited 1) an increased tumor latency period (P < 0.001), 2) a 0% incidence of metastasis, and 3) reduced prostatic weights (P < 0.001). We generated S100A4-positive clones from S100A4-negative CaP cells and tested their potential. S100A4-positive tumors grew at a faster rate than S100A4-negative tumors in vitro and in a xenograft mouse model. The S100A4 protein exhibited growth factor–like properties in multimode (intracellular and extracellular) forms. We observed that 1) the growth-promoting effect of S100A4 is due to its activation of NFκB, 2) S100A4-deficient tumors exhibit reduced NFκB activity, 3) S100A4 regulates NFκB through the RAGE receptor, and 4) S100A4 and RAGE co-localize in prostatic tissues of mice. Keeping in view its growth-promoting role, we suggest that S100A4 qualifies as an excellent candidate to be exploited for therapeutic agents to treat CaP in humans. PMID:24069509

  1. CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

    PubMed

    Boulenc, Xavier; Nicolas, Olivier; Hermabessière, Stéphanie; Zobouyan, Isabelle; Martin, Valérie; Donazzolo, Yves; Ollier, Céline

    2016-02-01

    The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.

  2. Cellular localization and functional significance of CYP3A4 in the human epileptic brain

    PubMed Central

    Ghosh, Chaitali; Marchi, Nicola; Desai, Nirav K.; Puvenna, Vikram; Hossain, Mohammed; Gonzalez-Martinez, Jorge; Alexopoulos, Andreas V.; Janigro, Damir

    2011-01-01

    Summary Purpose Compelling evidence supports the presence of P450 enzymes (CYPs) in the central nervous system (CNS). However, little information is available on the localization and function of CYPs in the drug-resistant epileptic brain. We have evaluated the pattern of expression of the specific enzyme CYP3A4 and studied its co-localization with MDR1. We also determined whether an association exists between CYP3A4 expression and cell survival. Methods Brain specimens were obtained from eight patients undergoing resection to relieve drug-resistant seizures or to remove a cavernous angioma. Each specimen was partitioned for either immunostaining or primary culture of human endothelial cells and astrocytes. Immunostaining was performed using anti-CYP3A4, MDR1, GFAP, or NeuN antibodies. High performance liquid chromatography–ultraviolet (HPLC-UV) analysis was used to quantify carbamazepine (CBZ) metabolism by these cells. CYP3A4 expression was correlated to DAPI condensation, a marker of cell viability. Human embryonic kidney (HEK) cells were transfected with CYP3A4 to further evaluate the link between CYP3A4 levels, CBZ metabolism, and cell viability. Key Findings CYP3A4 was expressed by blood–brain barrier (BBB) endothelial cells and by the majority of neurons (75 ± 10%). Fluorescent immunostaining showed coexpression of CYP3A4 and MDR1 in endothelial cells and neurons. CYP3A4 expression inversely correlated with DAPI nuclear condensation. CYP3A4 overexpression in HEK cells conferred resistance to cytotoxic levels of carbamazepine. CYP3A4 levels positively correlated with the amount of CBZ metabolized. Significance CYP3A4 brain expression is not only associated with drug metabolism but may also represent a cytoprotective mechanism. Coexpression of CYP3A4 and MDR1 may be involved in cell survival in the diseased brain. PMID:21294720

  3. Involvement of S100A4 in stromal fibroblasts of the regenerating cornea.

    PubMed

    Ryan, David G; Taliana, Lavinia; Sun, Lijie; Wei, Zhi-Gang; Masur, Sandra K; Lavker, Robert M

    2003-10-01

    S100A4 is a member of the S100 family of calcium-binding proteins. Members of the S100 family have been implicated in a variety of cellular events, including growth, signaling, differentiation, and motility. It has been suggested that S100A4 modulates cell shape and motility by interacting with components of the cytoskeleton. In the present study, the distribution patterns of S100A4 were investigated in normal and regenerating mouse corneas. Rabbit cDNA libraries were prepared from cultures of corneal fibroblasts. S100A4 was identified as the most abundant message present. Expression of S100A4 in the cornea was determined using Northern blot analysis, in situ hybridization, and immunohistochemistry. Distribution patterns of S100A4 in primary corneal fibroblast cultures treated with either FGF-2/heparin or TGFbeta1 were analyzed by immunofluorescence. S100A4 mRNA was rarely detected in keratocytes or epithelial cells of the normal rabbit cornea. Likewise, S100A4 antigen was not found in normal mouse corneas. However, after removal of the corneal epithelium, fibroblasts are activated and had readily detectable S100A4 expression 6 days after wounding. In the in vitro equivalent of activated keratocytes, cultured rabbit corneal fibroblasts, S100A4 was restricted to the cytoplasm. In contrast, in cultures treated with TGFbeta1, which induces a myofibroblast phenotype, more than 90% of the cells showed a nuclear localization of S100A4. The findings show that S100A4 is expressed in the keratocyte phenotypes that appear in stromal tissue of corneas recovering from damage, the fibroblasts, and myofibroblasts. Its expression and distinct subcellular redistribution patterns suggest that S100A4 may be involved in the interconversions that occur between keratocytes, fibroblasts, and myofibroblasts during corneal wound healing.

  4. Laparoscopy for inflammatory bowel disease: pros and cons.

    PubMed

    Sardinha, T C; Wexner, S D

    1998-04-01

    The role of laparoscopic surgery in the treatment of colorectal malignancies is still under investigation, although it can offer significant benefits to many patients with inflammatory bowel disease (IBD). The aim of this study was to assess the pros and cons of the laparoscopic management of IBD. Data were obtained from a review of the literature published since 1992, when the first report of laparoscopic surgery for IBD appeared in print. From 1992 to 1997 several series of laparoscopic colorectal surgery for the management of IBD have been reported. A close evaluation of these studies revealed that laparoscopy in patients with terminal ileal Crohn's disease or anal Crohn's disease in need of fecal diversion offers significant advantages compared to laparotomy, including decreased pain, length of hospitalization, and disability. An additional bonus is improved cosmesis and a reduction in symptomatic postoperative adhesions. These many benefits can be achieved without any increase in morbidity or expense. Conversely, the use of this technology for restorative proctocolectomy in patients with mucosal ulcerative colitis is associated with a longer operative time and an increased incidence of both intra- and postoperative complications compared to laparotomy. Laparoscopic colorectal surgery can thus be advantageous for treatment of terminal ileal Crohn's disease but cannot be routinely justified for the treatment of mucosal ulcerative colitis.

  5. Pros and cons of circumcision: an evidence-based overview.

    PubMed

    Friedman, B; Khoury, J; Petersiel, N; Yahalomi, T; Paul, M; Neuberger, A

    2016-09-01

    Based on three large randomized controlled trials (RCTs) conducted in Africa, it can clearly be stated that circumcision lowers the risk of infection with the human immunodeficiency virus (HIV) and some sexually transmitted infections (STIs) among males in settings of high HIV and STI endemicity. Similar effects on STI risk may exist for females, although this may result from an indirect effect of decreasing risk of infection among male partners. It is unknown whether circumcision prevents HIV acquisition in men who have sex with men (MSM), although there might be a protective effect for men who engage mainly in insertive anal intercourse. When the effects of adult circumcision on sexual function and satisfaction of men are examined, high-quality evidence strongly supports lack of harm. Whether circumcision alters sexual satisfaction of female partners is not known as fewer and smaller studies reported conflicting results. Circumcision rarely causes serious complications if practiced by trained practitioners, in a sterile setting, and with a proper follow-up. These conclusions are limited by the lack of high-quality data from areas outside of Africa. RCTs have not been conducted to assess the effects of circumcising infants or MSM. Circumcision has well-proven benefits for people residing in areas with high prevalence of STIs, including HIV, and is not unethical for those who choose to be circumcised or have their children circumcised on religious, social, or cultural grounds. For many others, a definite pro or con recommendation, based on a risk-benefit ratio, cannot be made.

  6. Percutaneous coronary intervention in nonagenarians: pros and cons

    PubMed Central

    Biondi Zoccai, Giuseppe; Abbate, Antonio; D'Ascenzo, Fabrizio; Presutti, Davide; Peruzzi, Mariangela; Cavarretta, Elena; Marullo, Antonino G.M.; Lotrionte, Marzia; Frati, Giacomo

    2013-01-01

    Percutaneous coronary intervention is a mainstay in the management of symptomatic or high-risk coronary artery disease. The bulk of clinical evidence and experience underlying this fact relies, however, on relatively young patients. Indeed, few data of very limited quality are available which adequately define the risk-benefit and cost-benefit profile of coronary angioplasty and stenting in very old subjects, such as those of 90 years of age or older (i.e., nonagenarians). The aim of this review is to provide a concise, yet practical, synthesis of the available evidence on percutaneous coronary revascularization in the very elderly. The main arguments elaborated upon are to what extent we can extrapolate findings from studies including younger patients to nonagenarians, whether we should provide higher priority to prognosis or quality of life in such patients, and whether we can afford to allocate vast resources to care for such subjects in an era of financial constraints. Our review of 18 studies and 1082 patients suggest that percutaneous coronary intervention is feasible and associated with acceptable short- and long-term results in this population, which is nonetheless fraught with a high mortality risk irrespective of the revascularization procedure. Accordingly, the pros and cons of percutaneous coronary intervention should be carefully weighed when considering this treatment in nonagenarians. PMID:23610578

  7. Immune cascades in human intervertebral disc: the pros and cons

    PubMed Central

    Sun, Zhen; Zhang, Ming; Zhao, Xu-Hong; Liu, Zhi-Heng; Gao, Yang; Samartzis, Dino; Wang, Hai-Qiang; Luo, Zhuo-Jing

    2013-01-01

    The unique structural hallmark of the intervertebral disc has made its central composition, the nucleus pulposus (NP), excluded from the immunologic tolerance. Consequently, the intervertebral disc is identified as an immune-privileged organ. Traditionally, local detrimental immune activities caused by NP at the lesion sites of the disc are noted as a significant factor contributing to disc degeneration. However, given the beneficial activities of immune cells in other immune-privileged sites on basis of current evidence, the degenerate disc might need the assistance of a subpopulation of immune cells to restore its structure and lessen inflammation. In addition, the beneficial impact of immune cells can be seen in the absorption of the herniated NP, which is an important factor causes the mechanical compression of nerve roots. Consequently, a modulated immune network in degenerate disc is essential for the restoration of this immune-privileged organ. Until now, the understandings of immune response in disc degeneration still rest on the harmful aspect. Further studies are needed to explore its beneficial influence. Accordingly, there are no absolutely the pros and cons in terms of immune reactions caused by NP. PMID:23696917

  8. Immune cascades in human intervertebral disc: the pros and cons.

    PubMed

    Sun, Zhen; Zhang, Ming; Zhao, Xu-Hong; Liu, Zhi-Heng; Gao, Yang; Samartzis, Dino; Wang, Hai-Qiang; Luo, Zhuo-Jing

    2013-01-01

    The unique structural hallmark of the intervertebral disc has made its central composition, the nucleus pulposus (NP), excluded from the immunologic tolerance. Consequently, the intervertebral disc is identified as an immune-privileged organ. Traditionally, local detrimental immune activities caused by NP at the lesion sites of the disc are noted as a significant factor contributing to disc degeneration. However, given the beneficial activities of immune cells in other immune-privileged sites on basis of current evidence, the degenerate disc might need the assistance of a subpopulation of immune cells to restore its structure and lessen inflammation. In addition, the beneficial impact of immune cells can be seen in the absorption of the herniated NP, which is an important factor causes the mechanical compression of nerve roots. Consequently, a modulated immune network in degenerate disc is essential for the restoration of this immune-privileged organ. Until now, the understandings of immune response in disc degeneration still rest on the harmful aspect. Further studies are needed to explore its beneficial influence. Accordingly, there are no absolutely the pros and cons in terms of immune reactions caused by NP.

  9. Pros and cons of screening for occult Cushing syndrome.

    PubMed

    Tabarin, Antoine; Perez, Paul

    2011-03-22

    Systematic screening studies performed mainly in patients with diabetes mellitus have revealed an unexpectedly high prevalence of occult Cushing syndrome. Such studies may provide a rationale for systematically screening obese patients with type 2 diabetes mellitus. However, a screening strategy is only justified if it is supported by enough evidence of its efficacy and if the benefits will outweigh drawbacks. To date, the natural history of occult Cushing syndrome and its possible effect on long-term morbidity are unknown. The clinical spectrum of occult Cushing syndrome and its relatively low prevalence may potentially negatively affect the performance of endocrine tests used to diagnose overt Cushing syndrome and generate false positives. Whether the cure of occult Cushing syndrome favorably influences clinical outcomes and is more beneficial than treatment of diabetes mellitus and cardiovascular risk factors with currently available pharmacological tools remains to be demonstrated. Last, the acceptability of a screening program by professionals and the health-care system in terms of workload and costs is highly questionable. Thus, an assessment of the indications for and against screening for occult Cushing syndrome on the basis of currently available data suggests that, to date, the cons surpass the pros.

  10. Pros and Cons of Medical Management of Ulcerative Colitis

    PubMed Central

    Navaneethan, Udayakumar; Shen, Bo

    2010-01-01

    Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffuse mucosal inflammation limited to the colon and rectum. Although a complete medical cure may not be possible, UC can be treated with medications that induce and maintain remission. The medical management of this disease continues to evolve with a goal to avoid colectomy and ultimately alter the natural history of UC. Emergence of antitumor necrosis factor-α (TNF-α) agents has expanded the medical armamentarium. 5-Aminosalicylates continue to be used in mild to moderate UC and corticosteroids are mainly used for induction of remission with immunomodulators (6-mercaptopurine/azathiopurine/methotrexate) being applied as steroid-sparing agents for maintenance therapy. Infliximab has been approved by the U.S. Food and Drug Administration and used in the treatment of moderate to severe UC; nevertheless, its use may be associated with significant adverse effects and have a negative impact on the postoperative course should the patients undergo restorative proctocolectomy. In addition, there is always a concern about patients' compliance to medical therapy, cost of medications, and risk for UC-associated dysplasia. The authors discuss the pros and cons of medications used in the treatment of UC. PMID:22131893

  11. Pros, Cons, and Alternatives to Weight Based Cost Estimating

    NASA Technical Reports Server (NTRS)

    Joyner, Claude R.; Lauriem, Jonathan R.; Levack, Daniel H.; Zapata, Edgar

    2011-01-01

    Many cost estimating tools use weight as a major parameter in projecting the cost. This is often combined with modifying factors such as complexity, technical maturity of design, environment of operation, etc. to increase the fidelity of the estimate. For a set of conceptual designs, all meeting the same requirements, increased weight can be a major driver in increased cost. However, once a design is fixed, increased weight generally decreases cost, while decreased weight generally increases cost - and the relationship is not linear. Alternative approaches to estimating cost without using weight (except perhaps for materials costs) have been attempted to try to produce a tool usable throughout the design process - from concept studies through development. This paper will address the pros and cons of using weight based models for cost estimating, using liquid rocket engines as the example. It will then examine approaches that minimize the impct of weight based cost estimating. The Rocket Engine- Cost Model (RECM) is an attribute based model developed internally by Pratt & Whitney Rocketdyne for NASA. RECM will be presented primarily to show a successful method to use design and programmatic parameters instead of weight to estimate both design and development costs and production costs. An operations model developed by KSC, the Launch and Landing Effects Ground Operations model (LLEGO), will also be discussed.

  12. In vitro inhibition of cytochrome P450 3A4 by Aronia melanocarpa constituents.

    PubMed

    Bräunlich, Marie; Christensen, Hege; Johannesen, Siri; Slimestad, Rune; Wangensteen, Helle; Malterud, Karl E; Barsett, Hilde

    2013-01-01

    Extracts, subfractions, isolated anthocyanins and procyanidins, and two phenolic acids from aronia [Aronia melanocarpa] were investigated for their CYP3A4 inhibitory effects, using midazolam as the probe substrate and recombinant insect cell microsomes expressing CYP3A4 as the enzyme source. Procyanidin B5 was a considerably stronger CYP3A4 inhibitor in vitro than the isomeric procyanidin B2 and comparable to bergamottin, a known CYP3A4 inhibitor from grapefruit juice. The inhibitory activity of proanthocyanidin-containing fractions was correlated to the degree of polymerization. Among the anthocyanins, cyanidin 3-arabinoside showed stronger CYP3A4 inhibition than cyanidin 3-galactoside and cyanidin 3-glucoside. Thus, the ability to inhibit CYP3A4 in vitro seems to be influenced by the sugar unit linked to the anthocyanidin. Georg Thieme Verlag KG Stuttgart · New York.

  13. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 8 2013-07-01 2013-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method 6...

  14. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 8 2014-07-01 2014-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method 6...

  15. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 8 2012-07-01 2012-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method 6...

  16. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Table of contents. 1.401(a)(4)-0 Section 1.401(a)(4)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table of contents. This section contains a listing of...

  17. 26 CFR 1.401(a)-4 - Optional forms of benefit (before 1994).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Optional forms of benefit (before 1994). 1.401(a)-4 Section 1.401(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)-4 Optional forms of benefit (before 1994)....

  18. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2010 CFR

    2015-07-01

    ... 40 Protection of Environment 8 2015-07-01 2015-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  19. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2010 CFR

    2005-07-01

    ... 40 Protection of Environment 7 2005-07-01 2005-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  20. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2010 CFR

    2016-07-01

    ... 40 Protection of Environment 9 2016-07-01 2016-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  1. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2010 CFR

    2007-07-01

    ... 40 Protection of Environment 7 2007-07-01 2007-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  2. Isolation of CYP3A4 Inhibitors from the Black Cohosh (Cimicifuga racemosa)

    PubMed Central

    2005-01-01

    Recent investigation on drug interaction has shown that some foods and herbal medicines increase the oral availability of a variety of CYP3A4 substrates, which is caused by the reduction of CYP3A4 in intestinal epithelium. During the course of our investigation on CYP3A4 interaction, we found that the commercially available dietary supplement made from black cohosh (Cimicifuga racemosa) showed CYP3A4 inhibition. Black cohosh has been used for the treatment of menopausal and post-menopausal symptoms as a dietary supplement. Bioassay-guided isolation from the supplement afforded six active principles, which were identified as cycloartanoid triterpene glycosides. PMID:15937564

  3. S100A4 interacts with p53 in the nucleus and promotes p53 degradation.

    PubMed

    Orre, L M; Panizza, E; Kaminskyy, V O; Vernet, E; Gräslund, T; Zhivotovsky, B; Lehtiö, J

    2013-12-05

    S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.

  4. In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients.

    PubMed

    Engdal, Silje; Nilsen, Odd Georg

    2009-07-01

    The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P-450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c-DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6-beta-OH-testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC(50): 73 microg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 microg/mL, respectively). All IC(50) values were high compared with those determined for crude extracts of other herbal remedies. The IC(50)/IC(25) ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non-inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. Copyright 2009 John Wiley & Sons, Ltd.

  5. Meeting Report: Breath Biomarkers Networking Sessions at PittCon 2010, Orlando, Florida

    EPA Science Inventory

    The Pittsburgh Conference and Exposition, or "PittCon" (www.pittcon.org/), is one of the largest international conferences for analytical chemistry and instrumentation typically attracting about 25,000 attendees and 1,000 commercial exhibitors. PittCon began in 1950 as a small sp...

  6. Gestational surrogacy: could be a way to be a way to reproduction? Pros and cons.

    PubMed

    Clementina, Peris

    2011-06-01

    The aim of this article was to address pros and cons of gestational surrogacy, the social and psychological issues involved in surrogate motherhood triads. Pros and cons of surrogacy, the possible insurgence of a hematologic disease in the fetus, hemolytic disease of the newborn, naturally acquired microchimerism in surrogacy cases, ethical, medical, psychologic, legal and religious issues of a problem are discussed.

  7. Meeting Report: Breath Biomarkers Networking Sessions at PittCon 2010, Orlando, Florida

    EPA Science Inventory

    The Pittsburgh Conference and Exposition, or "PittCon" (www.pittcon.org/), is one of the largest international conferences for analytical chemistry and instrumentation typically attracting about 25,000 attendees and 1,000 commercial exhibitors. PittCon began in 1950 as a small sp...

  8. ConSearch: An Electronic Document Research and Retrieval Utility for Windows from Management Information Technologies.

    ERIC Educational Resources Information Center

    Combs, Joseph, Jr.

    1995-01-01

    Reviews ConSearch 3.0, a product that provides flexible searching of electronic files, allowing the location of related meanings as well as exact matches. ConSearch 3.0 differs from other file retrieval approaches by relating words in search phrases of questions to the "meaning" of the words, which are stored in a "conceptual…

  9. PRAME promotes in vitro leukemia cells death by regulating S100A4/p53 signaling.

    PubMed

    Xu, Y; Rong, L-J; Meng, S-L; Hou, F-L; Zhang, J-H; Pan, G

    2016-01-01

    PRAME (Preferentially Expressed Antigen in Melanoma) is a tumor-associated antigen recognized by immunocytes, and it induces cytotoxic T cell-mediated responses in melanoma. PRAME is expressed in a wide variety of tumors, but in contrast with most other tumor-associated antigens, it is also expressed in leukemias. The physiologic role of PRAME remains elusive. Recently, it has found PRAME could be involved in the regulation of cell death in leukemias, but the mechanism of the function is unclear. Here, we confirm that PRAME induces leukemias cell death by regulation of S100A4/p53 signaling. The pCDNA3-PRAME plasmid and its control were transfected with the KG-1 cells. The pCDNA3-PRAME transfected KG-1 cells were then transiently transfected with S100A4 cDNA or wt-p53 siRNA. The PRAME siRNA and its control were transfected with the K562 cells. The PRAME siRNA transfected K562 cells were then transiently transfected with S100A4 siRNA or pGMp53-Lu. PRAME, S100A4 and P53 were detected by Western blot assay in different time point. Annexin V/propidium iodide and MTT methods were used to detect apoptosis and cell survival rate. KG-1 cells overexpressing the PRAME gene significantly induces apoptosis and decreases proliferation in vitro, followed by down-regulation of S100A4 and up-regulation of p53. Up-regulation of S100A4 by S100A4 transfection inhibits PRAME-induced p53 up-regulation. Furthermore, up-regulation of S100A4 by S100A4 transfection or down-regulation of p53 by p53 siRNA transfection reduces apoptosis and increases proliferation in vitro. Knockdown of PRAME in K562 cells significantly increases proliferation in vitro, followed by up-regulation of S100A4 and down-regulation of p53. The downregulation of S100A4 by S100A4 siRNA transfection increased p53 expression. Furthermore, downregulation of S100A4 by S100A4 siRNA transfection or up-regulation of p53 by p53 transfection decreases proliferation in vitro. Our results suggest that the leukemias expressing

  10. Holotoxin Activity of Botulinum Neurotoxin Subtype A4 Originating from a Nontoxigenic Clostridium botulinum Expression System.

    PubMed

    Bradshaw, Marite; Tepp, William H; Whitemarsh, Regina C M; Pellett, Sabine; Johnson, Eric A

    2014-12-01

    Clostridium botulinum subtype A4 neurotoxin (BoNT/A4) is naturally expressed in the dual-toxin-producing C. botulinum strain 657Ba at 100× lower titers than BoNT/B. In this study, we describe purification of recombinant BoNT/A4 (rBoNT/A4) expressed in a nonsporulating and nontoxigenic C. botulinum expression host strain. The rBoNT/A4 copurified with nontoxic toxin complex components provided in trans by the expression host and was proteolytically cleaved to the active dichain form. Activity of the recombinant BoNT/A4 in mice and in human neuronal cells was about 1,000-fold lower than that of BoNT/A1, and the recombinant BoNT/A4 was effectively neutralized by botulism heptavalent antitoxin. A previous report using recombinant truncated BoNT/A4 light chain (LC) expressed in Escherichia coli has indicated reduced stability and activity of BoNT/A4 LC compared to BoNT/A1 LC, which was surmounted by introduction of a single-amino-acid substitution, I264R. In order to determine whether this mutation would also affect the holotoxin activity of BoNT/A4, a recombinant full-length BoNT/A4 carrying this mutation as well as a second mutation predicted to increase solubility (L260F) was produced in the clostridial expression system. Comparative analyses of the in vitro, cellular, and in vivo activities of rBoNT/A4 and rBoNT/A4-L260F I264R showed 1,000-fold-lower activity than BoNT/A1 in both the mutated and nonmutated BoNT/A4. This indicates that these mutations do not alter the activity of BoNT/A4 holotoxin. In summary, a recombinant BoNT from a dual-toxin-producing strain was expressed and purified in an endogenous clostridial expression system, allowing analysis of this toxin.

  11. Effect of Chinese herbs on CYP3A4 activity and expression in vitro.

    PubMed

    Lau, C; Mooiman, K D; Maas-Bakker, R F; Beijnen, J H; Schellens, J H M; Meijerman, I

    2013-09-16

    Traditional Chinese Medicine (TCM) has become more popular among cancer patients in the Western world, who often use Chinese herbs as adjuvant therapy to reduce the adverse effects of conventional chemotherapy. However, pharmacokinetic (PK) interactions between Chinese herbs and anticancer drugs can occur and have dramatic consequences for these patients. Currently, only a few possible PK interactions between Chinese herbs and conventional Western drugs have been documented. Since the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) contributes to most of the PK interactions with (anticancer) drugs, the effect of four Chinese herbs (Oldenlandia diffusa, Codonopsis tangshen, Rehmannia glutinosa and Astragalus propinquus) on the activity and expression of CYP3A4 was investigated in vitro. Ethanol and water-ethanol extracts of the four Chinese herbs were prepared from raw material. CYP3A4 inhibition was assessed by the use of Supersomes™ in a fluorescence assay. Furthermore, CYP3A4 induction was evaluated in a human pregnane X receptor (hPXR)-mediated CYP3A4 reporter gene assay and a quantitative real time PCR assay, both in human colon adenocarcinoma-derived LS180 cells (LS180). Extracts of Oldenlandia diffusa, Codonopsis tangshen, Rehmannia glutinosa and Astragalus propinquus inhibited CYP3A4 in human CYP3A4 Supersomes™ (IC50 values: 17-83 µg/mL). Oldenlandia diffusa and Rehmannia glutinosa significantly induced PXR-mediated CYP3A4 (p<0.001). Oldenlandia diffusa also significantly induced CYP3A4 mRNA levels (p<0.001 at 250 µg/mL). Concomitant use of Oldenlandia diffusa and Rehmannia glutinosa could result in induction of CYP3A4, leading to a reduced efficacy of drugs that are CYP3A4 substrates and have a narrow therapeutic window. Because of the possible enhanced toxicity caused by CYP3A4 inhibition, clinical effects of CYP3A4 inhibition by Astragalus propinquus and Codonopsis tangshen must also be taken into account. In conclusion, herb-drug interactions

  12. Self-Exfoliated Guanidinium-Based Ionic Covalent Organic Nanosheets (iCONs).

    PubMed

    Mitra, Shouvik; Kandambeth, Sharath; Biswal, Bishnu P; Khayum M, Abdul; Choudhury, Chandan K; Mehta, Mihir; Kaur, Gagandeep; Banerjee, Subhrashis; Prabhune, Asmita; Verma, Sandeep; Roy, Sudip; Kharul, Ulhas K; Banerjee, Rahul

    2016-03-02

    Covalent organic nanosheets (CONs) have emerged as functional two-dimensional materials for versatile applications. Although π-π stacking between layers, hydrolytic instability, possible restacking prevents their exfoliation on to few thin layered CONs from crystalline porous polymers. We anticipated rational designing of a structure by intrinsic ionic linker could be the solution to produce self-exfoliated CONs without external stimuli. In an attempt to address this issue, we have synthesized three self-exfoliated guanidinium halide based ionic covalent organic nanosheets (iCONs) with antimicrobial property. Self-exfoliation phenomenon has been supported by molecular dynamics (MD) simulation as well. Intrinsic ionic guanidinium unit plays the pivotal role for both self-exfoliation and antibacterial property against both Gram-positive and Gram-negative bacteria. Using such iCONs, we have devised a mixed matrix membrane which could be useful for antimicrobial coatings with plausible medical benefits.

  13. Amelogenin gene splice products A+4 and A-4 implanted in soft tissue determine the reorientation of CD45-positive cells to an osteo-chondrogenic lineage.

    PubMed

    Lacerda-Pinheiro, S; Septier, D; Tompkins, K; Veis, A; Goldberg, M; Chardin, H

    2006-12-15

    Several molecules such as bone morphogenetic protein-7, bone sialoprotein (BSP), or amelogenin gene splice products (A+4 or A-4) have been shown to induce reparative dentin formation in a rat model. However, at the moment, the origin and the mechanism of differentiation of the pulp cells stimulated by the bioactive molecules remain poorly understood. The present investigation was undertaken to validate an ectopic oral mucosal mouse model to evaluate the effects of amelogenin gene splice product implantation in a non-mineralizing tissue. Agarose beads, alone or coated with amelogenin gene splice products, were implanted in the mucosa of the cheeks in mouse. An immunohistochemical characterization of the recruited cells was undertaken for 3 days, 8 days, and 30 days after the implantation. The results showed that the implantation of agarose beads in mucosa induced the recruitment of inflammatory CD45 positive cells. When the beads were coated with amelogenin gene splice products (A+4 or A-4), the expression of osteo-chondrogenic markers (RP59, Sox9, or BSP) was also observed. However, no mineralization nodule was observed, even after 30 days of implantation. The present investigation suggests that amelognin gene splice products have the capacity of recruiting among inflammatory cell mesenchymal progenitors that eventually differentiate into osteo-chondrogenic cells. Altogether, the results obtained in the pulp model and the present data suggest the existence of different pathways of cell recruitment and differentiation in different cellular environments.

  14. Surgical animal models of neuropathic pain: Pros and Cons.

    PubMed

    Challa, Siva Reddy

    2015-03-01

    One of the biggest challenges for discovering more efficacious drugs for the control of neuropathic pain has been the diversity of chronic pain states in humans. It is now acceptable that different mechanisms contribute to normal physiologic pain, pain arising from tissue damage and pain arising from injury to the nervous system. To study pain transmission, spot novel pain targets and characterize the potential analgesic profile of new chemical entities, numerous experimental animal pain models have been developed that attempt to simulate the many human pain conditions. Among the neuropathic pain models, surgical models have paramount importance in the induction of pain states. Many surgical animal models exist, like the chronic constriction injury (CCI) to the sciatic nerve, partial sciatic nerve ligation (pSNL), spinal nerve ligation (SNL), spared nerve injury (SNI), brachial plexus avulsion (BPA), sciatic nerve transaction (SNT) and sciatic nerve trisection. Most of these models induce responses similar to those found in causalgia, a syndrome of sustained burning pain often seen in the distal extremity after partial peripheral nerve injury in humans. Researchers most commonly use these surgical models in both rats and mice during drug discovery to screen new chemical entities for efficacy in the area of neuropathic pain. However, there is scant literature that provides a comparative discussion of all these surgical models. Each surgical model has its own benefits and limitations. It is very difficult for a researcher to choose a suitable surgical animal model to suit their experimental set-up. Therefore, particular attention has been given in this review to comparatively provide the pros and cons of each model of surgically induced neuropathic pain.

  15. Synergistic hemolysins of coagulase-negative staphylococci (CoNS).

    PubMed

    Różalska, Małgorzata; Derczyńska, Anna; Maszewska, Agnieszka

    2015-01-01

    A total of 104 coagulase negative staphylococci, belonging to S. capitis, S. hominis, S. haemolyticus and S. warneri, originating from the collection of the Department of Pharmaceutical Microbiology (ZMF), Medical University of Lodz, Poland, were tested for their synergistic hemolytic activity. 83% of strains produced δ-hemolysin, however, the percentage of positive strains of S. haemolyticus, S. warneri, S. capitis and S. hominis was different - 98%, 78%, 75% and 68%, respectively. Highly pure hemolysins were obtained from culture supernatants by protein precipitation with ammonium sulphate (0-70% of saturation) and extraction by using a mixture of organic solvents. The purity and molecular mass of hemolysins was determined by TRIS/Tricine PAGE. All CoNS hemolysins were small peptides with a molar mass of about 3.5 kDa; they possessed cytotoxic activity against the line of human foreskin fibroblasts ATCC Hs27 and lysed red cells from different mammalian species, however, the highest activity was observed when guinea pig, dog and human red blood cells were used. The cytotoxic effect on fibroblasts occurred within 30 minutes. The S. cohnii ssp. urealyticus strain was used as a control. The antimicrobial activity was examined using hemolysins of S. capitis, S. hominis, S. cohnii ssp. cohnii and S. cohnii ssp. urealyticus. Hemolysins of the two S. cohnii subspecies did not demonstrate antimicrobial activity. Cytolysins of S. capitis and S. hominis had a very narrow spectrum of action; out of 37 examined strains, the growth of only Micrococcus luteus, Corynebacterium diphtheriae and Pasteurella multocida was inhibited.

  16. Effect of pyrazole, cobalt and phenobarbital on mouse liver cytochrome P-450 2a-4/5 (Cyp2a-4/5) expression.

    PubMed Central

    Hahnemann, B; Salonpää, P; Pasanen, M; Mäenpää, J; Honkakoski, P; Juvonen, R; Lang, M A; Pelkonen, O; Raunio, H

    1992-01-01

    Pyrazole, cobalt and phenobarbital increase the activity of coumarin 7-hydroxylase (COH) in mouse liver. To study the mechanism of this increase, we measured the expression of the cytochrome P-450 2a-4/5 (Cyp2a-4/5) complex, which mediates testosterone 15 alpha-hydroxylase and COH activities, as a function of dose and time after the treatment of C57BL/6 (B6) and DBA/2 (D2) male mice with the inducers. COH activity and Cyp2a-4/5 steady-state mRNA levels were increased in both strains in response to the inducers. No marked effect occurred with testosterone 15 alpha-hydroxylase or activities associated with Cyp1a-1 or Cyp2e-1. A 2-7-fold increase in response to the inducers was seen in the amount of P-450Coh (cytochrome P-450 isoenzyme catalysing coumarin 7-hydroxylation) protein in Western immunoblots. PCR amplification of a 1 kb region in Cyp2a-4/5-mRNA-derived cDNA, followed by cutting at the diagnostic PstI site, showed that most of the steady-state mRNA consisted of Cyp2a-5, which is also the form most affected by pyrazole. Nuclear run-off analysis revealed no increase in the transcription rate of Cyp2a-4/5 after pyrazole or cobalt treatment, whereas a 2-3-fold increase occurred after phenobarbital pretreatment in B6 mice. Together with previous reports [Aida & Negishi (1991) Biochemistry 30, 8041-8045], the current data suggest that both pyrazole and cobalt increase COH catalytic activity by affecting Cyp2a-5 by post-transcriptional mechanisms in mice. Images Fig. 1. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 7. PMID:1520280

  17. 26 CFR 1.668(a)-4 - Tax attributable to throwback.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax attributable to throwback. 1.668(a)-4...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.668(a)-4 Tax attributable to throwback. (a) The...

  18. 26 CFR 1.263A-4 - Rules for property produced in a farming business.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... business of growing and harvesting wheat and other grains. Individual B also processes grain that... business. 1.263A-4 Section 1.263A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... property produced in a farming business. (a) Introduction—(1) In general. This section provides...

  19. 26 CFR 1.401(a)(4)-6 - Contributory defined benefit plans.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Contributory defined benefit plans. 1.401(a)(4.... § 1.401(a)(4)-6 Contributory defined benefit plans. (a) Introduction. This section provides rules... attained ages at least equal to the average attained age of the HCEs in the plan. For this purpose, a plan...

  20. Performance oriented packaging report for charge, demolition, shaped, 15 pound, M2A4. Final report

    SciTech Connect

    Sniezek, F.M.

    1992-11-02

    This POP report is for the Charge, Demolition, Shaped, 15 Pound, M2A4 which is packaged 4 charges/Mil-B-2427 wood box. This report describes the results of testing conducted. Performance Oriented Packaging, POP, Charge, Demolition, Shaped, 15 Pound, M2A4, Mil-B-2427 Wood box.

  1. Lipoxin A4 promotes lung epithelial repair whilst inhibiting fibroblast proliferation

    PubMed Central

    Zheng, Shengxing; Dancer, Rachel C.A.; Parekh, Dhruv; Naidu, Babu; Gao-Smith, Fang; Wang, Qian; Jin, Shengwei; Lian, Qingquan

    2016-01-01

    Therapy that promotes epithelial repair whilst protecting against fibroproliferation is critical for restoring lung function in acute and chronic respiratory diseases. Primary human alveolar type II cells were used to model the effects of lipoxin A4 in vitro upon wound repair, proliferation, apoptosis and transdifferention. Effects of lipoxin A4 upon primary human lung fibroblast proliferation, collagen production, and myofibroblast differentiation were also assessed. Lipoxin A4 promoted type II cell wound repair and proliferation, blocked the negative effects of soluble Fas ligand/tumour necrosis factor α upon cell proliferation, viability and apoptosis, and augmented the epithelial cell proliferative response to bronchoaveolar lavage fluid (BALF) from acute respiratory distress syndrome (ARDS). In contrast, Lipoxin A4 reduced fibroblast proliferation, collagen production and myofibroblast differentiation induced by transforming growth factor β and BALF from ARDS. The effects of Lipoxin A4 were phosphatidylinositol 3′-kinase dependent and mediated via the lipoxin A4 receptor. Lipoxin A4 appears to promote alveolar epithelial repair by stimulating epitheial cell wound repair, proliferation, reducing apoptosis and promoting trans-differentiation of alveolar type II cells into type I cells. Lipoxin A4 reduces fibroblast proliferation, collagen production and myofibroblast differentiation. These data suggest that targeting lipoxin actions may be a therapeutic strategy for treating the resolution phase of ARDS. PMID:27957484

  2. Lipoxin A4 promotes lung epithelial repair whilst inhibiting fibroblast proliferation.

    PubMed

    Zheng, Shengxing; D'Souza, Vijay K; Bartis, Domokos; Dancer, Rachel C A; Parekh, Dhruv; Naidu, Babu; Gao-Smith, Fang; Wang, Qian; Jin, Shengwei; Lian, Qingquan; Thickett, David R

    2016-07-01

    Therapy that promotes epithelial repair whilst protecting against fibroproliferation is critical for restoring lung function in acute and chronic respiratory diseases. Primary human alveolar type II cells were used to model the effects of lipoxin A4in vitro upon wound repair, proliferation, apoptosis and transdifferention. Effects of lipoxin A4 upon primary human lung fibroblast proliferation, collagen production, and myofibroblast differentiation were also assessed. Lipoxin A4 promoted type II cell wound repair and proliferation, blocked the negative effects of soluble Fas ligand/tumour necrosis factor α upon cell proliferation, viability and apoptosis, and augmented the epithelial cell proliferative response to bronchoaveolar lavage fluid (BALF) from acute respiratory distress syndrome (ARDS). In contrast, Lipoxin A4 reduced fibroblast proliferation, collagen production and myofibroblast differentiation induced by transforming growth factor β and BALF from ARDS. The effects of Lipoxin A4 were phosphatidylinositol 3'-kinase dependent and mediated via the lipoxin A4 receptor. Lipoxin A4 appears to promote alveolar epithelial repair by stimulating epitheial cell wound repair, proliferation, reducing apoptosis and promoting trans-differentiation of alveolar type II cells into type I cells. Lipoxin A4 reduces fibroblast proliferation, collagen production and myofibroblast differentiation. These data suggest that targeting lipoxin actions may be a therapeutic strategy for treating the resolution phase of ARDS.

  3. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Plan amendments and plan terminations. 1.401(a)(4... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan terminations. (a) Introduction—(1) Overview. This...

  4. 26 CFR 1.401(a)(4)-11 - Additional rules.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Additional rules. 1.401(a)(4)-11 Section 1.401(a)(4)-11 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... employee's benefit under Plan B. However, Plan A provides for no similar recognition of service or...

  5. The cell adhesion molecule EphA4 is involved in circadian clock functions.

    PubMed

    Kiessling, S; O'Callaghan, E K; Freyburger, M; Cermakian, N; Mongrain, V

    2017-04-20

    Circadian (∼24 h) rhythms of cellular network plasticity in the central circadian clock, the suprachiasmatic nucleus (SCN), have been described. The neuronal network in the SCN regulates photic resetting of the circadian clock as well as stability of the circadian system during both entrained and constant conditions. EphA4, a cell adhesion molecule regulating synaptic plasticity by controlling connections of neurons and astrocytes, is expressed in the SCN. To address whether EphA4 plays a role in circadian photoreception and influences the neuronal network of the SCN, we have analyzed circadian wheel-running behavior of EphA4 knockout (EphA4(-/-) ) mice under different light conditions and upon photic resetting, as well as their light-induced protein response in the SCN. EphA4(-/-) mice exhibited reduced wheel-running activity, longer endogenous periods under constant darkness and shorter periods under constant light conditions, suggesting an effect of EphA4 on SCN function. Moreover, EphA4(-/-) mice exhibited suppressed phase delays of their wheel-running activity following a light pulse during the beginning of the subjective night (CT15). Accordingly, light-induced c-FOS (FBJ murine osteosarcoma viral oncogene homolog) expression was diminished. Our results suggest a circadian role for EphA4 in the SCN neuronal network, affecting the circadian system and contributing to the circadian response to light. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  6. S100A4 Elevation Empowers Expression of Metastasis Effector Molecules in Human Breast Cancer

    PubMed Central

    Ismail, Thamir M.; Bennett, Daimark; Platt-Higgins, Angela M.; Al-Medhity, Morteta; Barraclough, Roger; Rudland, Philip S.

    2017-01-01

    Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers, where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12 and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9, and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes. PMID:27927689

  7. Should Community College Students Earn an Associate Degree before Transferring to a 4-Year Institution?

    ERIC Educational Resources Information Center

    Kopko, Elizabeth M.; Crosta, Peter M.

    2016-01-01

    Using data on over 41,000 students in one state who entered community college before transferring to a 4-year institution, this study examines the following question: Are community college students who earn an associate degree before transferring to a 4-year college more likely to earn a bachelor's degree? Due to the causal nature surrounding this…

  8. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Calculation of income inclusion. 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME... of income inclusion. ...

  9. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2010 CFR

    2001-07-01

    ... 40 Protection of Environment 7 2001-07-01 2001-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (Continued) Appendix A-4 to Part 60—Test Methods 6 through 10B Method 6—Determination of...

  10. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Calculation of income inclusion. 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME... Calculation of income inclusion. ...

  11. Lattice equations arising from discrete Painlevé systems: II. {A}_{4}^{(1)} case

    NASA Astrophysics Data System (ADS)

    Joshi, Nalini; Nakazono, Nobutaka; Shi, Yang

    2016-12-01

    In this paper, we construct two lattices from the τ functions of {A}4(1)-surface q-Painlevé equations, on which quad-equations of ABS type appear. Moreover, using the reduced hypercube structure, we obtain the Lax pairs of the {A}4(1)-surface q-Painlevé equations.

  12. Cree antidiabetic plant extracts display mechanism-based inactivation of CYP3A4.

    PubMed

    Tam, Teresa W; Liu, Rui; Arnason, John T; Krantis, Anthony; Staines, William A; Haddad, Pierre S; Foster, Brian C

    2011-01-01

    Seventeen Cree antidiabetic medicinal plants were studied to determine their potential to inhibit cytochrome P450 3A4 (CYP3A4) through mechanism-based inactivation (MBI). The ethanolic extracts of the medicinal plants were studied for their inhibition of CYP3A4 using the substrates testosterone and dibenzylfluorescein (DBF) in high pressure liquid chromatography (HPLC) and microtiter fluorometric assays, respectively. Using testosterone as a substrate, extracts of Alnus incana, Sarracenia purpurea, and Lycopodium clavatum were identified as potent CYP3A4 MBIs, while those from Abies balsamea, Picea mariana, Pinus banksiana, Rhododendron tomentosum, Kalmia angustifolia, and Picea glauca were identified as less potent inactivators. Not unexpectedly, the other substrate, DBF, showed a different profile of inhibition. Only A. balsamea was identified as a CYP3A4 MBI using DBF. Abies balsamea displayed both NADPH- and time-dependence of CYP3A4 inhibition using both substrates. Overall, several of the medicinal plants may markedly deplete CYP3A4 through MBI and, consequently, decrease the metabolism of CYP3A4 substrates including numerous medications used by diabetics.

  13. 26 CFR 1.401(a)-4 - Optional forms of benefit (before 1994).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Optional forms of benefit (before 1994). 1.401(a.... § 1.401(a)-4 Optional forms of benefit (before 1994). Q-1: How does section 401(a)(4) apply to... January 30, 1986, and do not apply to plan years beginning on or after January 1, 1994. For rules...

  14. 26 CFR 1.401(a)-4 - Optional forms of benefit (before 1994).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Optional forms of benefit (before 1994). 1.401(a.... § 1.401(a)-4 Optional forms of benefit (before 1994). Q-1: How does section 401(a)(4) apply to... January 30, 1986, and do not apply to plan years beginning on or after January 1, 1994. For rules...

  15. 26 CFR 1.401(a)-4 - Optional forms of benefit (before 1994).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Optional forms of benefit (before 1994). 1.401(a.... § 1.401(a)-4 Optional forms of benefit (before 1994). Q-1: How does section 401(a)(4) apply to... January 30, 1986, and do not apply to plan years beginning on or after January 1, 1994. For rules...

  16. 26 CFR 1.401(a)-4 - Optional forms of benefit (before 1994).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Optional forms of benefit (before 1994). 1.401(a.... § 1.401(a)-4 Optional forms of benefit (before 1994). Q-1: How does section 401(a)(4) apply to... January 30, 1986, and do not apply to plan years beginning on or after January 1, 1994. For rules...

  17. Structure of the S100A4/myosin-IIA complex.

    PubMed

    Ramagopal, Udupi A; Dulyaninova, Natalya G; Varney, Kristen M; Wilder, Paul T; Nallamsetty, Sridevi; Brenowitz, Michael; Weber, David J; Almo, Steven C; Bresnick, Anne R

    2013-11-20

    S100A4, a member of the S100 family of Ca2+-binding proteins, modulates the motility of both non-transformed and cancer cells by regulating the localization and stability of cellular protrusions. Biochemical studies have demonstrated that S100A4 binds to the C-terminal end of the myosin-IIA heavy chain coiled-coil and disassembles myosin-IIA filaments; however, the mechanism by which S100A4 mediates myosin-IIA depolymerization is not well understood. We determined the X-ray crystal structure of the S100A4Δ8C/MIIA(1908-1923) peptide complex, which showed an asymmetric binding mode for the myosin-IIA peptide across the S100A4 dimer interface. This asymmetric binding mode was confirmed in NMR studies using a spin-labeled myosin-IIA peptide. In addition, our NMR data indicate that S100A4Δ8C binds the MIIA(1908-1923) peptide in an orientation very similar to that observed for wild-type S100A4. Studies of complex formation using a longer, dimeric myosin-IIA construct demonstrated that S100A4 binding dissociates the two myosin-IIA polypeptide chains to form a complex composed of one S100A4 dimer and a single myosin-IIA polypeptide chain. This interaction is mediated, in part, by the instability of the region of the myosin-IIA coiled-coil encompassing the S100A4 binding site. The structure of the S100A4/MIIA(1908-1923) peptide complex has revealed the overall architecture of this assembly and the detailed atomic interactions that mediate S100A4 binding to the myosin-IIA heavy chain. These structural studies support the idea that residues 1908-1923 of the myosin-IIA chain heavy represent a core sequence for the S100A4/myosin-IIA complex. In addition, biophysical studies suggest that structural fluctuations within the myosin-IIA coiled-coil may facilitate S100A4 docking onto a single myosin-IIA polypeptide chain.

  18. Novel European SLC1A4 variant: infantile spasms and population ancestry analysis.

    PubMed

    Conroy, Judith; Allen, Nicholas M; Gorman, Kathleen; O'Halloran, Eoghan; Shahwan, Amre; Lynch, Bryan; Lynch, Sally A; Ennis, Sean; King, Mary D

    2016-08-01

    SLC1A4 deficiency is a recently described neurodevelopmental disorder associated with microcephaly, global developmental delay, abnormal myelination, thin corpus callosum and seizures. It has been mainly reported in the Ashkenazi-Jewish population with affected individuals homozygous for the p.Glu256Lys variant. Exome sequencing performed in an Irish proband identified a novel homozygous nonsense SLC1A4 variant [p.Trp453*], confirming a second case of SLC1A4-associated infantile spasms. As this is the first European identified, population ancestry analysis of the Exome Aggregation Consortium database was performed to determine the wider ethnic background of SLC1A4 deficiency carriers. p.Glu256Lys was found in Hispanic and South Asian populations. Other potential disease-causing variants were also identified. Investigation for SLC1A4 deficiency should be performed regardless of ethnicity and extend to include unexplained early-onset epileptic encephalopathy.

  19. Multiple links between the NuA4 histone acetyltransferase complex and epigenetic control of transcription.

    PubMed

    Galarneau, L; Nourani, A; Boudreault, A A; Zhang, Y; Héliot, L; Allard, S; Savard, J; Lane, W S; Stillman, D J; Côté, J

    2000-06-01

    NuA4 is an essential histone H4/H2A acetyltransferase complex that interacts with activators and stimulates transcription in vitro. We have identified three novel NuA4 subunits: Act3/Arp4, an actin-related protein implicated in epigenetic control of transcription, Act1, and Epl1, a protein homologous to Drosophila Enhancer of Polycomb. Act3/Arp4 binds nucleosomes in vitro and is required for NuA4 integrity in vivo. Mutations in ACT3 and acetyltransferase-encoding ESA1 cause gene-specific transcription defects. Accordingly, NuA4 is localized in precise loci within the nucleus and does not overlap with the silent chromatin marker Sir3. These data along with the known epigenetic roles of Act3/Arp4 and homologs of Epl1 and Esa1 strongly support an essential role for chromatin structure modification by NuA4 in transcription regulation in vivo.

  20. Feasibility of partial A2 and A4 pulley excision: effect on finger flexor tendon biomechanics.

    PubMed

    Mitsionis, G; Bastidas, J A; Grewal, R; Pfaeffle, H J; Fischer, K J; Tomaino, M M

    1999-03-01

    We investigated the effect of partial excision of the A2 and A4 digital pulleys, separately and in combination, on finger angular rotation and the energy for finger flexion. Statistically significant decreases in angular rotation resulted only after 50% and 75% excision of A2, A4, or A2 and A4 in combination. Work of flexion trends were weak and none of the changes were statistically significant. Although optimal finger function relies on the integrity of the A2 and A4 pulleys to maintain the efficiency of the digital flexor system, these data suggest that the A2 and A4 pulleys can be excised up to 25%, either separately or in combination, without significant effects on angular rotation. Decreases in total angular range of motion after 50% and 75% pulley excision were small, even for combined pulley excision (9 degrees +/- 3 degrees and 15 degrees +/- 5 degrees [mean +/- SD], respectively), and may be clinically acceptable.

  1. Critical role of EphA4 in early brain injury after subarachnoid hemorrhage in rat.

    PubMed

    Fan, Ruiming; Enkhjargal, Budbazar; Camara, Richard; Yan, Feng; Gong, Lei; ShengtaoYao; Tang, Jiping; Chen, Yangmei; Zhang, John H

    2017-10-01

    Early brain injury (EBI) is reported as a primary cause of mortality in subarachnoid hemorrhage (SAH) patients. Eph receptor A4 (EphA4) has been associated with blood-brain barrier integrity and pro-apoptosis. We aimed to investigate a role of EphA4 in EBI after SAH. One hundred and seventy-nine male adult Sprague-Dawley rats were randomly divided into sham versus endovascular perforation model of SAH groups. SAH grade, neurological score, Evans blue dye extravasation, brain water content, mortality, Fluoro-Jade staining, immunofluorescence staining, and western blot experiments were performed after SAH. Small interfering RNA (siRNA) for EphA4, recombinant Ephexin-1 (rEphx-1), and Fasudil, a potent ROCK2 inhibitor, were used for intervention to study a role of EphA4 on EBI after SAH. The expression of EphA4, Ephexin-1, RhoA, and ROCK2 significantly increased after SAH. Knockdown of EphA4 using EphA4 siRNA injection intracerebroventricularly (i.c.v) reduced Evans blue extravasation, decreased brain water content, and alleviated neurobehavioral dysfunction after SAH. Additionally, the expression of Ephexin-1, RhoA, ROCK2 and cleaved caspase-3 were decreased. Tight junction proteins increased, and apoptotic neuron death decreased. The effects of EphA4 siRNA were abolished by rEphx-1. In contrast, Fasudil abolished the effects of rEphx-1. These results suggest that EphA4, a novel and promising target for treatment, exacerbates EBI through an Ephexin-1/ROCK2 pathway after SAH. Copyright © 2017. Published by Elsevier Inc.

  2. Molecular analysis of the human SLC13A4 sulfate transporter gene promoter

    SciTech Connect

    Jefferis, J.; Rakoczy, J.; Simmons, D.G.; Dawson, P.A.

    2013-03-29

    Highlights: ► Basal promoter activity of SLC13A4 −57 to −192 nt upstream of transcription initiation site. ► Human SLC13A4 5′-flanking region has conserved motifs with other placental species. ► Putative NFY, SP1 and KLF7 motifs in SLC13A4 5′-flanking region enhance transcription. -- Abstract: The human solute linked carrier (SLC) 13A4 gene is primarily expressed in the placenta where it is proposed to mediate the transport of nutrient sulfate from mother to fetus. The molecular mechanisms involved in the regulation of SLC13A4 expression remain unknown. To investigate the regulation of SLC13A4 gene expression, we analysed the transcriptional activity of the human SLC13A4 5′-flanking region in the JEG-3 placental cell line using luciferase reporter assays. Basal transcriptional activity was identified in the region −57 to −192 nucleotides upstream of the SLC13A4 transcription initiation site. Mutational analysis of the minimal promoter region identified Nuclear factor Y (NFY), Specificity protein 1 (SP1) and Krüppel like factor 7 (KLF7) motifs which conferred positive transcriptional activity, as well as Zinc finger protein of the cerebellum 2 (ZIC2) and helix–loop–helix protein 1 (HEN1) motifs that repressed transcription. The conserved NFY, SP1, KLF7, ZIC2 and HEN1 motifs in the SLC13A4 promoter of placental species but not in non-placental species, suggests a potential role for these putative transcriptional factor binding motifs in the physiological control of SLC13A4 mRNA expression.

  3. The Nuclear Factor-kB Pathway Regulates Cytochrome P450 3A4 Protein Stability

    SciTech Connect

    Zangar, Richard C.; Bollinger, Nikki; Verma, Seema; Karin, Norm J.; Lu, Yi

    2008-06-01

    We have previously observed that CYP3A4 protein levels are suppressed by inhibition of the proteasome in primary cultured hepatocytes. Because this result is opposite of what would be expected if CYP3A4 is degraded by the proteasome, it seems likely that there is another protein that is susceptible to proteasomal degradation that regulates CYP3A4 expression. In this study, we evaluate whether the nuclear factor kappa B (NF-kB) pathway is involved in that process. Our model system uses an adenovirus system to express CYP3A4 protein in HepG2 cells, which are derived from human cancer cells. Similar to results in primary hepatocytes, we found that inhibition of the proteasome with MG132 suppresses CYP3A4. Consistent with reports that proteasome inhibition suppresses the NF-kB pathway, we also observe a suppression of inhibitory kB kinase protein levels after treatment with MG132. Treatment of the HepG2 cells with NK-kB Activation Inhibitor also suppresses CYP3A4 proteins levels. In contrast, inhibition of either the proteasome or NF-kB pathways increases CYP3A4 mRNA levels. When the HepG2 cells are treated with cycloheximide, a general inhibitor of translation, the loss of CYP3A4 protein is accelerated by co-treatment with an NF-kB Activation Inhibitor. These results indicate that NF-kB activity regulates CYP3A4 protein stability and suggest that the NF-kB pathway is responsible for the decrease in CYP3A4 protein levels that results from the inhibition of proteasomal activity.

  4. Observaciones de la corona solar interior con un coronógrafo de espejo

    NASA Astrophysics Data System (ADS)

    Stenborg, G.; Schwenn, R.; Francile, C.; Rovira, M.

    El plasma de la corona solar es un buen indicador de las líneas de fuerza del campo magnético. Por lo tanto, el análisis de estructuras coronales cuasiestacionarias en la corona da importante información sobre el campo magnético y la actividad asociada. Se trata de poner límites a los modelos teóricos existentes mediante el estudio de distintas estructuras en la corona interior. En agosto de 1997 comenzó a operar el coronógrafo solar (MICA) en El Leoncito como parte del Observatorio Solar Alemán-Argentino. Desde su instalación obtiene imágenes de la corona solar (1.05 a 2.0 radios solares) en 2 líneas espectrales correspondientes a la emisión de Fe XIV y Fe X. El instrumento puede obtener imágenes cada minuto por lo que es ideal para estudiar procesos rápidos. Presentamos observaciones recientes que muestran la capacidad del coronógrafo así como la evolución de algunos eventos dinámicos observados por MICA.

  5. Antibiotic susceptibility of coagulase-negative staphylococci (CoNS): emergence of teicoplanin-non-susceptible CoNS strains with inducible resistance to vancomycin.

    PubMed

    Ma, Xiao Xue; Wang, En Hua; Liu, Yong; Luo, En Jie

    2011-11-01

    Coagulase-negative staphylococci (CoNS) have become increasingly recognized as important agents of nosocomial infection. One of the characteristics of CoNS is their resistance to multiple antimicrobial agents commonly used for the treatment of staphylococcal infections. CoNS strains (n = 745) isolated from a university teaching hospital in China between 2004 and 2009 were tested for antibiotic resistance. The antibiotics were placed into three categories based on resistance levels of the CoNS strains to these antibiotics: high resistance (resistance rate >70 %), including penicillin G, oxacillin and erythromycin; medium resistance (resistance rate between 30 and 70 %), including tetracycline, clindamycin, ciprofloxacin, trimethoprim/sulfamethoxazole and chloramphenicol; and low resistance (resistance rate <30 %), including rifampicin, ceftizoxime and gentamicin. We also found that the prevalence of strains non-susceptible to teicoplanin increased from 4.5 to 6.7 % between 2008 and 2009. A one-step vancomycin agar selection experiment and subsequent population analysis revealed potentially vancomycin-resistant subpopulations that have been selected from the teicoplanin-non-susceptible strains. Vigilant surveillance of nosocomial isolates of CoNS is needed to determine their resistance to glycopeptides.

  6. Potentiation of Methoxymorpholinyl Doxorubicin Anti-Tumor Activity by P450 3A4 Gene Transfer#

    PubMed Central

    Lu, Hong; Chen, Chong-Sheng; Waxman, David J.

    2008-01-01

    Summary Preclinical and clinical studies of CYP gene-directed enzyme-prodrug therapy have focused on anticancer prodrugs activated by CYP2B enzymes, which have low endogenous expression in human liver; however, the gene therapeutic potential of CYP3A enzymes, which are highly expressed in human liver, remains unknown. This study investigated methoxymorpholinyl-doxorubicin (MMDX), a novel CYP3A-activated anticancer prodrug. Retroviral transfer of CYP3A4 increased 9L gliosarcoma cell chemosensitivity to MMDX 120-fold (IC50=0.2nM). In CHO cells, overexpression of P450 reductase in combination with CYP3A4 enhanced chemosensitivity to MMDX, and to ifosfamide, another CYP3A4 prodrug, 11–23-fold compared to CYP3A4 expression alone. CYP3A4 expression and MMDX chemosensitivity were increased in human lung (A549) and brain (U251) tumor cells infected with replication-defective adenovirus encoding CYP3A4. Co-infection with Onyx-017, a replication-conditional adenovirus that co-amplifies and co-replicates the Adeno-3A4 virus, led to large increases in CYP3A4 RNA but only modest increases in CYP3A4 protein and activity. MMDX induced remarkable growth delay of 9L/3A4 tumors, but not 9L tumors, in immunodeficient mice administered low-dose MMDX either i.v. or by direct intratumoral injection (60µg/kg, every 7-days ×3), with the intratumoral route being substantially less toxic to the mouse host. No antitumor activity was observed with i.p. MMDX treatment, suggesting a substantial hepatic first pass effect, and with activated MMDX metabolites formed in the liver having poor access to the tumor site. These studies demonstrate that human CYP3A4 has strong potential for MMDX prodrug activation therapy, and suggest that endogenous tumor cell expression of CYP3A4, and not hepatic CYP3A4 activity, is a key determinant of responsiveness to MMDX therapy in cancer patients in vivo. PMID:19011599

  7. Project "Convective Wind Gusts" (ConWinG)

    NASA Astrophysics Data System (ADS)

    Mohr, Susanna; Richter, Alexandra; Kunz, Michael; Ruck, Bodo

    2017-04-01

    Convectively-driven strong winds usually associated with thunderstorms frequently cause substantial damage to buildings and other structures in many parts of the world. Decisive for the high damage potential are the short-term wind speed maxima with duration of a few seconds, termed as gusts. Several studies have shown that convectively-driven gusts can reach even higher wind speeds compared to turbulent gusts associated with synoptic-scale weather systems. Due to the small-scale and non-stationary nature of convective wind gusts, there is a considerable lack of knowledge regarding their characteristics and statistics. Furthermore, their interaction with urban structures and their influence on buildings is not yet fully understood. For these two reasons, convective wind events are not included in the present wind load standards of buildings and structures, which so far have been based solely on the characteristics of synoptically-driven wind gusts in the near-surface boundary layer (e. g., DIN EN 1991-1-4:2010-12; ASCE7). However, convective and turbulent gusts differ considerably, e.g. concerning vertical wind-speed profiles, gust factors (i.e., maximum to mean wind speed), or exceedance probability curves. In an effort to remedy this situation, the overarching objective of the DFG-project "Convective Wind Gusts" (ConWinG) is to investigate the characteristics and statistics of convective gusts as well as their interaction with urban structures. Based on a set of 110 climate stations of the German Weather Service (DWD) between 1992 and 2014, we analyzed the temporal and spatial distribution, intensity, and occurrence probability of convective gusts. Similar to thunderstorm activity, the frequency of convective gusts decreases gradually from South to North Germany. A relation between gust intensity/probability to orography or climate conditions cannot be identified. Rather, high wind speeds, e.g., above 30 m/s, can be expected everywhere in Germany with almost

  8. Clinical outcomes and management of mechanism-based inhibition of cytochrome P450 3A4

    PubMed Central

    Zhou, Shufeng; Chan, Eli; Li, Xiaotian; Huang, Min

    2005-01-01

    Mechanism-based inhibition of cytochrome P450 (CYP) 3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Such inhibition of CYP3A4 can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The inactivation of CYP3A4 by drugs has important clinical significance as it metabolizes approximately 60% of therapeutic drugs, and its inhibition frequently causes unfavorable drug–drug interactions and toxicity. The clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs, and patients. Clinical professionals should adopt proper approaches when using drugs that are mechanism-based CYP3A4 inhibitors. These include early identification of drugs behaving as CYP3A4 inactivators, rational use of such drugs (eg, safe drug combination regimen, dose adjustment, or discontinuation of therapy when toxic drug interactions occur), therapeutic drug monitoring, and predicting the risks for potential drug–drug interactions. A good understanding of CYP3A4 inactivation and proper clinical management are needed by clinical professionals when these drugs are used. PMID:18360537

  9. Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

    PubMed Central

    Poulos, Thomas L.

    2015-01-01

    Cytochrome P450 3A4 (CYP3A4) is the major and most important drug-metabolizing enzyme in humans that oxidizes and clears over a half of all administered pharmaceuticals. This is possible because CYP3A4 is promiscuous with respect to substrate binding and has the ability to catalyze diverse oxidative chemistries in addition to traditional hydroxylation reactions. Furthermore, CYP3A4 binds and oxidizes a number of substrates in a cooperative manner and can be both induced and inactivated by drugs. In vivo, CYP3A4 inhibition could lead to undesired drug-drug interactions and drug toxicity, a major reason for late-stage clinical failures and withdrawal of marketed pharmaceuticals. Owing to its central role in drug metabolism, many aspects of CYP3A4 catalysis have been extensively studied by various techniques. Here, we give an overview of experimental and theoretical methods currently used for investigation and prediction of CYP3A4-ligand interactions, a defining factor in drug metabolism, with an emphasis on the problems addressed and conclusions derived from the studies. PMID:26002732

  10. Molecular modelling of (A4T4NN)n and (T4A4NN)n: sequence elements responsible for curvature.

    PubMed Central

    Sanghani, S R; Zakrzewska, K; Harvey, S C; Lavery, R

    1996-01-01

    The molecular modelling program JUMNA has been used to investigate the origins of the strikingly different curvature of the two sequences, (A4T4NN)n and (T4A4NN)n. Gel electrophoresis and cyclisation studies have shown that only the former of these two sequences is significantly curved. By developing novel superhelical symmetry constraints we were able to study the energetic and structural aspects of polymeric DNA having a controlled curvature. The results obtained (which do not take into account specific hydration effects) correlate well with the experimental data and offer a molecular level explanation of curvature. Although curvature is found to be initiated by specific dinucleotide junctions, deformations spread to surrounding dinucleotide steps and, moreover, sequence effects beyond the dinucleotide level are observed. PMID:8649979

  11. Targeted Drug Delivery in Covalent Organic Nanosheets (CONs) via Sequential Postsynthetic Modification.

    PubMed

    Mitra, Shouvik; Sasmal, Himadri Sekhar; Kundu, Tanay; Kandambeth, Sharath; Illath, Kavya; Díaz Díaz, David; Banerjee, Rahul

    2017-03-29

    Covalent organic nanosheets (CONs) have emerged as a new class of functional two-dimensional (2D) porous organic polymeric materials with a high accessible surface, diverse functionality, and chemical stability. They could become versatile candidates for targeted drug delivery. Despite their many advantages, there are limitations to their use for target specific drug delivery. We anticipated that these drawbacks could be overturned by judicious postsynthetic modification steps to use CONs for targeted drug delivery. The postsynthetic modification would not only produce the desired functionality, it would also help to exfoliate to CONs as well. In order to meet this requirement, we have developed a facile, salt-mediated synthesis of covalent organic frameworks (COFs) in the presence of p-toluenesulfonic acid (PTSA). The COFs were subjected to sequential postsynthetic modifications to yield functionalized targeted CONs for targeted delivery of 5-fluorouracil to breast cancer cells. This postsynthetic modification resulted in simultaneous chemical delamination and functionalization to targeted CONs. Targeted CONs showed sustained release of the drug to the cancer cells through receptor-mediated endocytosis, which led to cancer cell death via apoptosis. Considering the easy and facile COF synthesis, functionality based postsynthetic modifications, and chemical delamination to CONs for potential advantageous targeted drug delivery, this process can have a significant impact in biomedical applications.

  12. Analyses of muscular dystrophy and Con A deficiency traits in testcross progeny of chickens.

    PubMed

    Kline, K; Sanders, B G

    1984-01-01

    Hereditary muscular dystrophic chickens of the Storrs strain possess two genetic disorders, muscular dystrophy (MD) and a deficient concanavalin A (Con A), a T-cell mitogen, mediated splenic lymphocyte blastogenic response. A possible amelioration of the MD phenotype in MD chickens expressing normal Con A was postulated on the basis of progeny segregating for these two traits in F2 genetic analyses. To test this possibility, testcross progeny were examined for segregation of MD and Con A deficiency traits, and for the degree of muscle destruction and Con A deficiency. The data show both traits to be inherited independently as autosomal recessive traits, and do not support any phenotypic modifications occurring in chickens expressing MD with normal Con A. In the testcross progeny, the Con A deficiency disorder is equally deficient in normal and MD progeny, and the degree of muscle destruction as measured by serum creatine phosphokinase levels is equally great in MD chickens with or without the Con A deficiency trait. The reduced numbers of MD chickens in the testcross progeny can be accounted for by chance and probably reflect losses during in ovo development.

  13. Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor.

    PubMed

    Takeshita, Akira; Igarashi-Migitaka, Junko; Koibuchi, Noriyuki; Takeuchi, Yasuhiro

    2013-03-01

    Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor prognosis. Mitotane alone or in combination with other cytotoxic drugs is a common therapeutic option for ACC. In addition to its adrenolytic function, mitotane has been known for decades to increase the metabolic clearance of glucocorticoids. It was recently shown that the tyrosine kinase inhibitor sunitinib is also rapidly metabolized in patients treated with mitotane, indicating that mitotane engages in clinically relevant drug interactions. Although the precise mechanism of these interactions is not well understood, cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is a key enzyme to inactivate both glucocorticoids and sunitinib. The nuclear receptor steroid and xenobiotic receptor (SXR (NR1I2)) is one of the key transcriptional regulators of CYP3A4 gene expression in the liver and intestine. A variety of xenobiotics bind to SXR and stimulate transcription of xenobiotic-response elements (XREs) located in the CYP3A4 gene promoter. In this study, we evaluated the effects of mitotane on SXR-mediated transcription in vitro by luciferase reporter analysis, SXR-steroid receptor coactivator 1 (SRC1) interactions, quantitative real-time PCR analysis of CYP3A4 expression, SXR knockdown, and CYP3A4 enzyme activity assays using human hepatocyte-derived cells. We found that mitotane activated SXR-mediated transcription of the XREs. Mitotane recruited SRC1 to the ligand-binding domain of SXR. Mitotane increased CYP3A4 mRNA levels, which was attenuated by SXR knockdown. Finally, we showed that mitotane increased CYP3A4 enzyme activity. We conclude that mitotane can induce CYP3A4 gene expression and suggest that mitotane is used cautiously due to its drug-drug interactions.

  14. Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation.

    PubMed

    Hosomi, Hiroko; Fukami, Tatsuki; Iwamura, Atsushi; Nakajima, Miki; Yokoi, Tsuyoshi

    2011-08-01

    Drug-induced hepatotoxicity, which is a rare but serious adverse reaction to a large number of pharmaceutical drugs, is sometimes associated with reactive metabolites produced by drug-metabolizing enzymes. In the present study, we constructed a cell-based system to evaluate the cytotoxicity of reactive metabolites produced by CYP3A4 using human hepatoma cells infected with an adenovirus vector expressing human CYP3A4 (AdCYP3A4). When seven hepatoma cell lines (HepG2, Hep3B, HLE, HLF, Huh6, Huh7, and Fa2N4 cells) were infected with AdCYP3A4, HepG2 cells showed the highest CYP3A4 protein expression and testosterone 6β-hydroxylase activity (670 pmol · min(-1) · mg(-1)). With the use of AdCYP3A4-infected HepG2 cells, the cytotoxicities of 23 drugs were evaluated by the 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, and the cell viability when treated with 11 drugs (amiodarone, desipramine, felbamate, isoniazid, labetalol, leflunomide, nefazodone, nitrofurantoin, tacrine, terbinafine, and tolcapone) was significantly decreased. Moreover, the transfection of siRNA for nuclear factor erythroid 2-related factor 2 (Nrf2) to decrease the cellular expression level of Nrf2 exacerbated the cytotoxicity of some drugs (troglitazone, flutamide, acetaminophen, clozapine, terbinafine, and desipramine), suggesting that the genes regulated by Nrf2 are associated with the detoxification of the cytotoxicities mediated by CYP3A4. We constructed a highly sensitive cell-based system to detect the drug-induced cytotoxicity mediated by CYP3A4. This system would be beneficial in preclinical screening in drug development and increase our understanding of the drug-induced cytotoxicity associated with CYP3A4.

  15. S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction

    PubMed Central

    Dahlmann, Mathias; Kobelt, Dennis; Walther, Wolfgang; Mudduluru, Giridhar; Stein, Ulrike

    2016-01-01

    The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success. PMID:27331819

  16. Ephrin-A4 inhibits sensory neurite outgrowth and is regulated by neonatal skin wounding.

    PubMed

    Moss, Andrew; Alvares, Debie; Meredith-Middleton, Jacqueta; Robinson, Michelle; Slater, Rebeccah; Hunt, Stephen P; Fitzgerald, Maria

    2005-11-01

    The mechanisms for directing and organising sensory axons within developing skin remain largely unknown. The present study provides the first evidence that signalling occurs between A-ephrins and Eph-A receptors during the development of rat cutaneous sensory innervation both during normal development and following skin injury. Specifically, our data indicate that ephrin-A4 mRNA and protein are expressed in the epidermis during late embryogenesis and the early postnatal period (E16-P3), and expression is significantly down-regulated postnatally. In addition, Eph-A receptors are expressed on dorsal root ganglia (DRG) cells at birth. The pattern of ephrin-A4 expression is mirrored by epidermal innervation, so that sensory terminals are restricted to epidermal regions devoid of ephrin-A4 but increase as ephrin-A4 expression subsides postnatally. Neonatal skin wounding causes sensory hyperinnervation and a differential screen of wounded vs. nonwounded skin revealed down-regulation of epidermal ephrin-A4 following neonatal skin wounding. Expression studies showed that this down-regulation is below the wound and coincides exactly with the onset of hyperinnervation. In vitro experiments show a function for ephrin-A4-Fc in inhibiting rat DRG neuronal growth and guidance when presented as either substratum-bound stripes of ephrin-A4-Fc or as soluble clustered proteins. In conclusion, these observations suggest that the Eph family ligand ephrin-A4 has an inhibitory influence on neonatal cutaneous nerve terminals from DRG sensory neurons in the hindlimb, and may serve to prevent inappropriate innervation of cutaneous regions. In addition, the absence of ephrin-A4 following neonatal skin wounding may play a critical permissive role in the sprouting response.

  17. Influence of lipophilicity on the interactions of hydroxy stilbenes with cytochrome P450 3A4.

    PubMed

    Regev-Shoshani, Gilly; Shoseyov, Oded; Kerem, Zohar

    2004-10-15

    Resveratrol, a polyphenol found in red wine, was recently suggested to act as an irreversible, mechanism-based inactivator of cytochrome P450 3A4 (CYP3A4). We found a significant inhibition of human CYP3A4-dependent transformation of cyclosporine by resveratrol, with IC50 = 4.5 microM. We studied the kinetics parameters of CYP3A4 transformation of resveratrol and structurally related, naturally occurring stilbenes. Resveratrol, piceid, resveratroloside, 5,4'-dihydroxy-3-O-methoxystilbene, and 5,3-dihydroxy-4'-O-methoxystilbene were all shown to inhibit hydroxylation of testosterone by CYP3A4. Both methoxy-stilbenes had lower IC50 values, ranging from 0.43 to 0.47 microM, suggesting that lipophilicity rather than number or positions of free hydroxyls (3,5 or 5,4') determines the CYP3A4 inhibition capacity of polyphenols. In line with these findings, both glucosyl-stilbenes were found to be weak inhibitors of CYP3A4. The affinity of the enzyme towards methoxy-stilbenes, expressed as apparent Km, was indeed higher than those for the parent resveratrol and its glucosides, in CYP3A4 reaction mixtures. Vmax values were similar, except for piceid. These results support the role of lipophilicity in the interaction of polyphenols with CYP3A4. It is suggested that selective structural modifications of substrates add significantly to knowledge acquired through molecular modifications of the enzyme. Copyright 2004 Elsevier Inc.

  18. Soft A4→Z3 symmetry breaking and cobimaximal neutrino mixing

    DOE PAGES

    Ma, Ernest

    2016-03-28

    In this study, I propose a model of radiative charged-lepton and neutrino masses with A4 symmetry. The soft breaking of A4 to Z3 lepton triality is accomplished by dimension-three terms. The breaking of Z3 by dimension-two terms allows cobimaximal neutrino mixing (θ13 ≠ 0, θ23 = π/4, δcp=π/2) to be realized with only very small finite calculable deviations from the residual Z3 lepton triality. This construction solves a long-standing technical problem inherent in renormalizable A4 models since their inception.

  19. Metabolomic profiling of liquid Echinacea medicinal products with in vitro inhibitory effects on cytochrome P450 3A4 (CYP3A4).

    PubMed

    Modarai, Maryam; Yang, Min; Suter, Andy; Kortenkamp, Andreas; Heinrich, Michael

    2010-03-01

    ECHINACEA is a popular and widely used herbal medicinal product and consequently, studies of its interactions with conventional drugs are of particular importance. We have shown that ECHINACEA preparations and some common alkylamides weakly inhibit several cytochrome P450 (CYP) isoforms, with considerable variation in potency. We now report a detailed analysis of six commercial ECHINACEA liquid preparations, with emphasis on the metabolomic characterisation of the ECHINACEA compounds responsible for inhibiting CYP3A4. We separated each preparation into its ethanol- and water-soluble components, and then used (1)H-NMR together with multivariate data analysis and partial least square regression analysis to investigate the nature of the compounds responsible for CYP3A4 inhibition. The results implicated alkylamides in the CYP3A4 inhibitory activity of ECHINACEA. One of the commercial preparations (Echinaforce(R)) was further fractionated using solid phase extraction. Analysis by (1)H-NMR and mass spectroscopy (LC/MS, tandem MS, accurate mass) identified dodeca-2 E,4 E,8 Z,10 E/Z-tetraenoic acid (alkylamide 1) and a new compound (putative molecular formula C (18)H (36) NO (+)) as major components of the inhibitory fractions. In addition, the alkylamide content of all six preparations was determined by reverse phase HPLC. Levels of alkylamides 1 and 3 (undeca-2 E,4 E/ Z-diene-8,10-diynoic acid isobutylamide), correlated well with CYP3A4 inhibition. The acetylene tetradeca-8 Z-ene-11,13-diyn-2-one was shown to be present in the E. PURPUREA as well as the E. PALLIDA extracts. E. PURPUREA unlike E. PALLIDA was thought to not contain significant amounts of acetylenes. Our results directly confirm the role of alkylamides in the inhibition of CYP3A4 by ECHINACEA and uncovered a new compound which may also be involved. Extensive differences in the composition of the commercially available preparations were found. This will inevitably impact on the product efficacy, safety and

  20. Abundancias químicas de estrellas de Mercurio-Manganeso obtenidas con espectros EBASIM

    NASA Astrophysics Data System (ADS)

    Pintado, O. I.; Adelman, S. J.

    Se determinan las abundancias químicas de estrellas de HgMn usando espectros obtenidos con EBASIM en CASLEO en un rango de longitud de onda comprendido entre los 400 y 890 nm. Los valores iniciales de temperatura efectiva y gravedad superficial se calculan con la fotometría uvbyβ. Las abundancias se calculan usando WIDTH9 y SYNTHE. Los resultados se comparan análisis realizados por los autores usando espectros obtenidos con el espectrógrado REOSC del CASLEO, el espectrógrafo echelle del Telescopio Anglo-Australiano y el espectrógrafo Coudé del Dominion Astrophysical Observatory.

  1. Exonal deletion of SLC24A4 causes hypomaturation amelogenesis imperfecta.

    PubMed

    Seymen, F; Lee, K-E; Tran Le, C G; Yildirim, M; Gencay, K; Lee, Z H; Kim, J-W

    2014-04-01

    Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3' UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis.

  2. Compartment A4 forward hold at midplatform level, view forward into ...

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

    Compartment A-4 forward hold at mid-platform level, view forward into lower section of hold. Note framing details, keep plate and stringers. (012A) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  3. Clinical relevance of antigen spreading pattern induced by CHP-MAGE-A4 cancer vaccination.

    PubMed

    Miyauchi, Kengo; Tsuchikawa, Takahiro; Wada, Masataka; Abiko, Takehiro; Kyogoku, Noriaki; Shichinohe, Toshiaki; Miyahara, Yoshihiro; Kageyama, Shinichi; Ikeda, Hiroaki; Shiku, Hiroshi; Hirano, Satoshi

    2016-05-01

    To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as a surrogate marker of patient survival. 12 patients who had been injected with 300 μg of CHP-MAGE-A4 and 0.5 Klinische Einheit of OK-432 in more than five vaccinations were analyzed. Increases in the anti-MAGE-A4-specific antibody response were observed in eight patients (66.7%), compared with six patients (50%) for anti-NY-ESO-1 and five patients (41.7%) for anti-MAGE-A3 after five vaccinations. We identified frequent antigen spreading following MAGE-A4 vaccinations without associations with the clinical response or patient prognosis. Antigen spreading pattern might reflect tumor shrinkage as a response to treatment and treatment history (clinical trial registration number: UMIN000001999).

  4. Development of the German A-4 guidance and control system, 1939 - 1945: A memoir

    NASA Technical Reports Server (NTRS)

    Steinhoff, E. A.

    1977-01-01

    The development by 1943 of a fully inertial navigational system for the German A-4 (V-2) missile is detailed. This flight control system used a triple-axis stabilized platform with two longitudinal accelerometers and one lateral accelerometer.

  5. Identification of a novel protein complex containing annexin A4, rabphilin and synaptotagmin.

    PubMed

    Willshaw, Angela; Grant, Karen; Yan, Jun; Rockliffe, Nichola; Ambavarapu, Sailaja; Burdyga, Galina; Varro, Andrea; Fukuoka, Shin-Ichi; Gawler, Debra

    2004-02-13

    Rabphilin is a synaptic vesicle-associated protein proposed to play a role in regulating neurotransmitter release. Here we report the isolation and identification of a novel protein complex containing rabphilin, annexin A4 and synaptotagmin 1. We show that the rabphilin C2B domain interacts directly with the N-terminus of annexin A4 and mediates the co-complexing of these two proteins in PC12 cells. Analyzing the cellular localisation of these co-complexing proteins we find that annexin A4 is located on synaptic membranes and co-localises with rabphilin at the plasma membrane in PC12 cells. Given that rabphilin and synaptotagmin are synaptic vesicle proteins involved in neurotransmitter release, the identification of this complex suggests that annexin A4 may play a role in synaptic exocytosis.

  6. 26 CFR 1.643(a)-4 - Extraordinary dividends and taxable stock dividends.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... B (section 651 and following) as a “simple trust,” there are excluded from distributable net income... TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.643(a)-4...

  7. 38 CFR 18a.4 - Duties of the Director, Contract Compliance Service.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 1964 § 18a.4 Duties of the Director, Contract Compliance Service. Upon referral by the Chief Medical...) Investigate and process all complaints arising under Title VI of the Civil Rights Act of 1964; (b) Conduct...

  8. 38 CFR 18a.4 - Duties of the Director, Contract Compliance Service.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 1964 § 18a.4 Duties of the Director, Contract Compliance Service. Upon referral by the Chief Medical...) Investigate and process all complaints arising under Title VI of the Civil Rights Act of 1964; (b) Conduct...

  9. 38 CFR 18a.4 - Duties of the Director, Contract Compliance Service.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 1964 § 18a.4 Duties of the Director, Contract Compliance Service. Upon referral by the Chief Medical...) Investigate and process all complaints arising under Title VI of the Civil Rights Act of 1964; (b) Conduct...

  10. 38 CFR 18a.4 - Duties of the Director, Contract Compliance Service.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 1964 § 18a.4 Duties of the Director, Contract Compliance Service. Upon referral by the Chief Medical...) Investigate and process all complaints arising under Title VI of the Civil Rights Act of 1964; (b) Conduct...

  11. 38 CFR 18a.4 - Duties of the Director, Contract Compliance Service.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 1964 § 18a.4 Duties of the Director, Contract Compliance Service. Upon referral by the Chief Medical...) Investigate and process all complaints arising under Title VI of the Civil Rights Act of 1964; (b) Conduct...

  12. S100A4 upregulation suppresses tissue ossification and enhances matrix degradation in experimental periodontitis models

    PubMed Central

    Zhou, Min; Li, Zhuo-quan; Wang, Zuo-lin

    2015-01-01

    Aim: S100A4, also known as fibroblast-specific protein 1 or metastasin 1, is not only highly expressed in growth-stimulated cultured cells and metastatic tumor cells, but also in the periodontal ligament. The aim of this study was to investigate the roles of S100A4 in the pathogenesis of periodontitis and its regulatory mechanisms in inflammatory milieu. Methods: Experimental periodontitis was induced in rats by submarginal silk ligatures. TRAP activity and S100A4 expression in periodontal ligaments were examined using immunohistochemistry and immunofluorescence methods. IL-1β-treated human periodontal ligament cells (hPDLCs) were used as in vitro model of experimental periodontitis. S100A4 mRNA and protein were assessed using qRT-PCR and Western blot, respectively. hPDLCs were transfected with either S100A4 overexpression plasmids or shRNAs plasmids. The mineralization in hPDLCs was evaluated with a 12-d osteogenic induction assay, and the expression of ALP, OCN, MMP-2 and MMP-13 was analyzed by qRT-PCR. Results: In the periodontal ligaments of rats with experimental periodontitis, TRAP activity and S100A4 protein staining were considerably more intense compared with those in the control rats. Treatment of hPDLCs with IL-1β (10, 50 and 100 ng/mL) dose-dependently increased the mRNA and protein levels of S100A4. Transfection with shRNAs markedly increased mineralized nodule formation and the osteogenic-related markers ALP and OCN levels in hPDLCs, whereas the overexpression of S100A4 significantly reduced mineralized nodule formation, and increased the matrix degradation enzymes MMP-2 and MMP-13 levels in hPDLCs. Conclusion: S100A4 is upregulated in the experimental rat periodontitis and in IL-1β-treated hPDLCs, where S100A4 suppresses osteogenic differentiation and enhances matrix degradation. Thus, S100A4 is a potential target for the treatment of periodontitis. PMID:26499072

  13. MicroRNAs regulate CYP3A4 expression via direct and indirect targeting.

    PubMed

    Pan, Yu-Zhuo; Gao, Wenqing; Yu, Ai-Ming

    2009-10-01

    CYP3A4 metabolizes many drugs on the market. Although transcriptional regulation of CYP3A4 is known to be tightly controlled by some nuclear receptors (NR) including vitamin D receptor (VDR/NR1I1), posttranscriptional regulation of CYP3A4 remains elusive. In this study, we show that noncoding microRNAs (miRNAs) may control posttranscriptional and transcriptional regulation of CYP3A4 by directly targeting the 3'-untranslated region (3'UTR) of CYP3A4 and indirectly targeting the 3'UTR of VDR, respectively. Luciferase reporter assays showed that CYP3A4 3'UTR-luciferase activity was significantly decreased in human embryonic kidney 293 cells transfected with plasmid that expressed microRNA-27b (miR-27b) or mouse microRNA-298 (mmu-miR-298), whereas the activity was unchanged in cells transfected with plasmid that expressed microRNA-122a or microRNA-328. Disruption of the corresponding miRNA response element (MRE) within CYP3A4 3'UTR led to a 2- to 3-fold increase in luciferase activity. Immunoblot analyses indicated that CYP3A4 protein was down-regulated over 30% by miR-27b and mmu-miR-298 in LS-180 and PANC1 cells. The decrease in CYP3A4 protein expression was associated with significantly decreased CYP3A4 mRNA levels, as determined by quantitative real-time PCR (qPCR) analyses. Likewise, interactions of miR-27b or mmu-miR-298 with VDR 3'UTR were supported by luciferase reporter assays. The mmu-miR-298 MRE site is well conserved within the 3'UTR of mouse, rat, and human VDR. Down-regulation of VDR by the two miRNAs was supported by immunoblot and qPCR analyses. Furthermore, overexpression of miR-27b or mmu-miR-298 in PANC1 cells led to a lower sensitivity to cyclophosphamide. Together, these findings suggest that CYP3A4 gene expression may be regulated by miRNAs at both the transcriptional and posttranscriptional level.

  14. 26 CFR 1.367(a)-4 - Special rules applicable to specified transfers of property.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 1.954-2(c)(2)(v). (d) through (h) For further guidance, see § 1.367-4T(d) through (h). (i) Effective....367(a)-4 Special rules applicable to specified transfers of property. (a) through (c)(2) For further guidance, see § 1.367(a)-4T(a) through (c)(2). (3) Aircraft and vessels leased in foreign commerce....

  15. State-Space Modeling, System Identification and Control of a 4th Order Rotational Mechanical System

    DTIC Science & Technology

    2009-12-01

    SYSTEM IDENTIFICATION AND CONTROL OF A 4th ORDER ROTATIONAL MECHANICAL SYSTEM by Jeremiah P. Anderson December 2009 Thesis Advisor...DATES COVERED Master’s Thesis 4. TITLE AND SUBTITLE State-space Modeling, System Identification and Control of a 4th Order Rotational Mechanical...Educational Control Products is modeled from first principles and represented in state-space form. Identification of the state-space parameters was

  16. Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the "Missing Heritability" Problem.

    PubMed

    Klein, Kathrin; Zanger, Ulrich M

    2013-01-01

    CYP3A4 is the most important drug metabolizing enzyme in adult humans because of its prominent expression in liver and gut and because of its broad substrate specificity, which includes drugs from most therapeutic categories and many endogenous substances. Expression and function of CYP3A4 vary extensively both intra- and interindividually thus contributing to unpredictable drug response and toxicity. A multitude of environmental, genetic, and physiological factors are known to influence CYP3A4 expression and activity. Among the best predictable sources of variation are drug-drug interactions, which are either caused by pregnane X-receptor (PXR), constitutive androstane receptor (CAR) mediated gene induction, or by inhibition through coadministered drugs or other chemicals, including also plant and food ingredients. Among physiological and pathophysiological factors are hormonal status, age, and gender, the latter of which was shown to result in higher levels in females compared to males, as well as inflammatory processes that downregulate CYP3A4 transcription. Despite the influence of these non-genetic factors, the genetic influence on CYP3A4 activity was estimated in previous twin studies and using information on repeated drug administration to account for 66% up to 88% of the interindividual variation. Although many single nucleotide polymorphisms (SNPs) within the CYP3A locus have been identified, genetic association studies have so far failed to explain a major part of the phenotypic variability. The term "missing heritability" has been used to denominate the gap between expected and known genetic contribution, e.g., for complex diseases, and is also used here in analogy. In this review we summarize CYP3A4 pharmacogenetics/genomics from the early inheritance estimations up to the most recent genetic and clinical studies, including new findings about SNPs in CYP3A4 (*22) and other genes (P450 oxidoreductase (POR), peroxisome proliferator-activated receptor

  17. Potential role of UGT1A4 promoter SNPs in anastrozole pharmacogenomics.

    PubMed

    Edavana, Vineetha Koroth; Dhakal, Ishwori B; Williams, Suzanne; Penney, Rosalind; Boysen, Gunnar; Yao-Borengasser, Aiwei; Kadlubar, Susan

    2013-04-01

    Anastrozole belongs to the nonsteroidal triazole-derivative group of aromatase inhibitors. Recently, clinical trials demonstrated improved antitumoral efficacy and a favorable toxicity with third-generation aromatase inhibitors, compared with tamoxifen. Anastrozole is predominantly metabolized by phase I oxidation with the potential for further phase II glucuronidation. It also, however, is subject to direct N-glucuronidation by UDP-glucuronosyltransferase 1A4 (UGT1A4). Anastrozole pharmacokinetics vary widely among patients, but pharmacogenomic studies of patients treated with anastrozole are sparse. In this study, we examined individual variability in the glucuronidation of anastrozole and its association with UGT1A4 promoter and coding region polymorphisms. In vitro assays using liver microsomal preparations from individual subjects (n = 96) demonstrated 235-fold variability in anastrozole glucuronidation. Anastrozole glucuronidation was correlated (r = 0.99; P < 0.0001) with lamotrigine glucuronidation (a diagnostic substrate for UGT1A4) and with UGT1A4 mRNA expression levels in human liver microsomes (r = 0.99; P < 0.0001). Recombinant UGT1A4 catalyzed anastrozole glucuronidation, which was inhibited by hecogenin (IC50 = 15 µM), a UGT1A4 specific inhibitor. The promoter region of UGT1A4 is polymorphic, and compared with those homozygous for the common allele, lower enzymatic activity was observed in microsomes from individuals heterozygous for -163G

  18. [Effects of isorhamnetin on CYP3A4 and herb-drug interaction].

    PubMed

    Ding, Li-li; Zhang, Jing-jing; Dou, Wei

    2012-08-01

    The study is to report the investigation of the effects of isorhamnetin on CYP3A4 and herb-drug interaction. A reporter gene assay is used to test pregnane X receptor transactivation action, qRT-PCR and a luminescence-based assay were applied to determine mRNA induction and enzyme activity of CYP3A4 after isorhamnetin treatment. The interaction of irinotecan and isorhamnetin was assessed by inhibition assay of cell proliferation. Isorhamnetin at 1, 10 and 25 micromol x L(-1) transactivated the CYP3A4 reporter construct and upregulated CYP3A4 mRNA as well in a dose-dependent manner. However, isorhamnetin had no effect on enzyme activity of CYP3A4 and irinotecan HepG2 cytotoxicity. In conclusion, activation of PXR by isorhamnetin played a role in the upregulation of CYP3A4 mRNA. Moreover, joint action of isorhamnetin with other drugs may not be associated with the herb-drug interaction.

  19. CYP3A4*18 polymorphisms and anti-hepatitis A virus seroprevalence.

    PubMed

    Ahmad, Fazlina; Che Hamzah, Nor Aizal; Mustaffa, Nazri; Hua, Gan Siew

    2011-01-01

    CYP3A4 is the major cytochrome in humans which shows reduced activity in chronic liver disease as well as in hepatic cirrhosis. The detection of this polymorphism may give an indication on the prognosis of patients having chronic viral hepatitis with superimposed hepatitis A infection. The aim of this study is to correlate the seroprevalence of anti-HAV antibodies in chronic liver disease patients having CYP3A4*18 polymorphisms. This is a prospective study where patients (n=119) blood was tested for anti-HAVIgG and CYP3A4*18 polymorphism. The overall anti-HAV seroprevalence was 88.2%. The etiology of CLD was hepatitis B in 96 patients (80.7%) and hepatitis C in 23 patients (19.3%). There was a significant increase in the age of the prevalence of this disease after 30 years of age (p=0.008). CYP3A4*18 polymorphism was detected in 3 (2.5%) of the patients with chronic liver disease. However, there was no significant association between CP3A4*18 mutation and anti-HAV serology. Age was the most important factor in determining anti-HAV positivity. It is concluded that CYP3A4*18 genetic polymorphism does not play a main role in influencing the seroprevalence of anti-hepatitis A among chronic viral hepatitis B and C liver disease patients.

  20. Automated extraction of information from the literature on chemical-CYP3A4 interactions.

    PubMed

    Feng, Chunlai; Yamashita, Fumiyoshi; Hashida, Mitsuru

    2007-01-01

    A text mining system is presented for automatically extracting information from the literature on chemical-CYP3A4 interactions (i.e., substrate, induction, inhibition). The system identifies chemicals and CYP3A4 forms according to a combination of name dictionaries and context features. In addition, it transforms sentences into multiple simple clauses each containing a single event and extracts information on chemical-CYP3A4 interactions using a simple but effective pattern matching method based on the order of three keywords (chemicals, CYP3A4, key verbs). Using this system, 2990 relations including 2700 identified interactions with CYP3A4 for 600 chemicals were extracted from a corpus of 2900 PubMed abstracts. In an evaluation test using 100 randomly selected abstracts, it achieved 87.4% recall and 92.3% precision for identification of the chemical name and 85.2% recall and 92.0% precision for the extraction of chemical-CYP3A4 interactions, respectively. This system will be applicable to interactions of chemicals with any functional proteins, such as enzymes and transporters, simply by changing the list of key verbs.

  1. Forster Distances of Ligand-Heme Pairs in Cytochrome P450 3A4

    NASA Astrophysics Data System (ADS)

    Fern, Joel; Guengerich, F. Peter; Marsch, Glenn A.

    2003-04-01

    Cytochrome P450 3A4 is a protein in the human intestine and liver which oxidizes over half of drugs in use today. Cytochrome P450 3A4 has proven resistant to structure determination by NMR or x-ray crystallography. Fluorescence Resonance Energy Transfer (FRET) studies of P450 3A4 can be used to compute distances between fluorophores in the protein, providing information on the structure of the protein. For a ligand to be suitably used as a probe its fluorescence must not be completely quenched by the heme cofactor in P450 3A4. By using quantum yields, fluorescence, and the absorption spectra of six P450 ligands, the following Forster distances between each ligand and the P450 heme moiety were obtained: pyrene 4.6 nm, aflatoxin B2 5.7 nm, alpha-naphthoflavone 3.7 nm, indinavir 2.6 nm, quinidine 3.5 nm, and terfenadine 2.8 nm. Having these distances should yield a better low-resolution cytochrome P450 3A4 structure. Using the Forster distances, FRET experiments on inter-ligand placement in P450 3A4 will be undertaken soon.

  2. Photoelectron spectroscopy and density functional theory study of ConO- (n = 1-3)

    NASA Astrophysics Data System (ADS)

    Li, Ren-Zhong; Liang, Jun; Xu, Xi-Ling; Xu, Hong-Guang; Zheng, Wei-Jun

    2013-06-01

    ConO- (n = 1-3) clusters were investigated with photoelectron spectroscopy and density functional calculations. The vertical detachment energies (VDEs) of ConO- (n = 1-3) were measured to be 1.54 ± 0.04, 1.43 ± 0.08, and 1.42 ± 0.08 eV respectively from their photoelectron spectra. The electron affinity and term energy of CoO were determined to be 1.54 ± 0.04 eV and 0.31 ± 0.04 eV respectively based on the vibrationally resolved photoelectron spectrum of CoO- and theoretical calculations. The structures of ConO- (n = 1-3) were determined by comparison of photoelectron experiments and calculations. The analysis of molecular orbitals shows that the HOMOs of ConO- (n = 1-3) cluster anions are mainly localized on the Co atoms.

  3. The International Consortium for the Investigation of Renal Malignancies (I-ConFIRM)

    Cancer.gov

    The International Consortium for the Investigation of Renal Malignancies (I-ConFIRM) was formed to promote international, multidisciplinary collaborations to advance our understanding of the etiology and outcomes of kidney cancer.

  4. iCon-TMA for control and quantitation of immunohistochemistry and in situ molecular pathology analysis.

    PubMed

    Petersen, Iver; Blind, Christiane; Koepenik, Axel; Dietel, Manfred; Krenn, Veit

    2007-01-01

    Reliable assessment of in situ pathology analyses like immunohistochemistry, RNA in situ hybridization, and FISH are critically important in diagnosis and treatment decisions. We describe the development of small tissue microarrays (TMA) for the internal control and quantitation of these techniques, the iCon-TMA. In its simple variant, these iCon-TMA (abbreviated from internal control TMA) consist of 2 tissue cylinders, one being clearly positive and the other clearly negative for a specific marker. In its more elaborate format, the iCon-TMAs carry additional tissue spots providing a scale for quantitatively assessable markers, e.g. representing scores of negative, weak, moderate, or strong positivity. The specimen with the yet unknown reactivity is then applied to the iCon-TMA section, and both are simultaneously processed and analyzed, thus providing a convenient measure for in situ quality control and quantitation.

  5. Stereospecific Metabolism of Itraconazole by CYP3A4: Dioxolane Ring Scission of Azole Antifungals

    PubMed Central

    Peng, Chi-Chi; Shi, Wei; Lutz, Justin D.; Kunze, Kent L.; Liu, Jun O.; Nelson, Wendel L.

    2012-01-01

    Itraconazole (ITZ) is a mixture of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. However, (2R,4S,2′R)-ITZ and (2R,4S,2′S)-ITZ also undergo stereoselective sequential metabolism by CYP3A4 at a site distant from the triazole ring to 3′-OH-ITZ, keto-ITZ, and N-desalkyl-ITZ. This stereoselective metabolism demonstrates specific interactions of ITZ within the CYP3A4 active site. To further investigate this process, the binding and metabolism of the four trans-ITZ stereoisomers by CYP3A4 were characterized. All four trans-ITZ stereoisomers were tight binding inhibitors of CYP3A4-mediated midazolam hydroxylation (IC50 16–26 nM), and each gave a type II spectrum upon binding to CYP3A4. However, instead of formation of 3′-OH-ITZ, they were oxidized at the dioxolane ring, leading to ring scission and formation of two new metabolites of ITZ. These two metabolites were also formed from the four cis-ITZ stereoisomers, although not as efficiently. The catalytic rates of dioxolane ring scission were similar to the dissociation rates of ITZ stereoisomers from CYP3A4, suggesting that the heme iron is reduced while the triazole moiety coordinates to it and no dissociation of ITZ is necessary before catalysis. The triazole containing metabolite [1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone] also inhibited CYP3A4 (IC50 >15 μM) and showed type II binding with CYP3A4. The dioxolane ring scission appears to be clinically relevant because this metabolite was detected in urine samples from subjects that had been administered the mixture of cis-ITZ isomers. These data suggest that the dioxolane ring scission is a metabolic pathway for drugs that contain this moiety. PMID:22106171

  6. Characterization of the effector cells in Con A-induced cytotoxicity against HEp 2 tumour targets.

    PubMed

    Pócsik, E; González-Cabello, R; Benedek, K; Perl, A; Láng, I; Gergely, P

    1983-01-01

    Con A-induced cytotoxic activity of human lymphocyte subpopulations obtained by cell fractionation procedures was studied in a test system using human epipharynx carcinoma cells (HEp 2) as targets. Only T lymphocytes were cytotoxic, non-T cells exerted no cytotoxic activity, but enhanced the adherence of the tumour cells. Tnon-G lymphocytes (Fc-receptor negative T cells) were more active than TG cells (Fc-receptor-positive T cells) in mediating the Con A-induced cytotoxic reaction.

  7. A role for lipoxin A4 as an anti-inflammatory mediator in the human endometrium

    PubMed Central

    Macdonald, Linsay J; Boddy, Sheila C; Denison, Fiona C; Sales, Kurt J; Jabbour, Henry N

    2011-01-01

    Lipoxin A4 is a lipid mediator that elicits anti-inflammatory and pro-resolution actions via its receptor, formyl peptide receptor 2 (FPR2/ALX). In this study, we aimed to investigate the expression and potential role of lipoxin A4 and FPR2/ALX in the regulation of inflammation associated with cyclical remodeling of the human endometrium across the menstrual cycle and during early pregnancy. Using quantitative RT-PCR analysis, we found that FPR2/ALX expression is upregulated during the menstrual phase of the cycle and in decidua tissue from the first trimester of pregnancy. We localized the site of expression of FPR2/ALX in menstrual phase endometrium and first-trimester decidua tissue to glandular epithelial cells and cells within the stromal compartment, including cells lining the blood vessels and immune cells. Measurement of serum lipoxin A4 by ELISA revealed no difference in its levels across the menstrual cycle but an elevation in early pregnancy (P<0.001). We found that lipoxin A4 was regulated by human chorionic gonadotrophin (hCG) during early pregnancy, because treatment of human decidua tissue with hCG increased lipoxin A4 release (P<0.01). Finally, we have shown that lipoxin A4 can suppress phorbol myristate acetate-induced expression of the inflammatory cytokines interleukin 6 and 8 in human endometrium and decidua tissue. These results demonstrate for the first time that lipoxin A4 and its receptor FPR2/ALX can regulate inflammatory events in the human endometrium and decidua of early pregnancy. PMID:21555360

  8. QSAR modeling of in vitro inhibition of cytochrome P450 3A4.

    PubMed

    Mao, Boryeu; Gozalbes, Rafael; Barbosa, Frédérique; Migeon, Jacques; Merrick, Sandra; Kamm, Kelly; Wong, Eric; Costales, Chester; Shi, Wei; Wu, Cheryl; Froloff, Nicolas

    2006-01-01

    We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drug-enzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.

  9. Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib

    PubMed Central

    Takakusa, Hideo; Wahlin, Michelle D.; Zhao, Chunsheng; Hanson, Kelsey L.; New, Lee Sun; Chan, Eric Chun Yong

    2011-01-01

    Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic intermediate complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib. PMID:21363997

  10. Jurkat/A4 cells with multidrug resistance exhibit reduced sensitivity to quercetin.

    PubMed

    Philchenkov, A; Zavelevich, M; Savinska, L; Blokhin, D

    2010-07-01

    While multidrug resistance of cancer cells is a well-known phenomenon, little is known on the cross resistance between cytotoxic chemotherapeutical agents and unrelated substances such as natural flavonoids. To compare the effects of cytotoxic drug, vepeside and natural flavonoid, quercetin in Jurkat cells and their multidrug-resistant subline Jurkat/A4, in particular to analyze the effector mechanisms of apoptosis and the profiles of several pro- and antiapoptotic proteins in these cells upon exposure to vepeside or quercetin. Apoptosis and poly (ADP-ribose) polymerase cleavage were assessed by flow cytometry. Expression of apoptosis-related proteins was analyzed by Western blotting. Jurkat/A4 cells are less sensitive to antiproliferative effects of quercetin as compared with the parental Jurkat cell line. While vepeside as well as quercetin initially induces apoptosis in both cell lines, the following survival of the exposed cells is essentially different. In resistant Jurkat/A4 cells, vepeside or quercetin treatment activates significantly less caspase-9 and -3 as compared with that in the parental cells. The expression of Bad and BNip1 proteins in Jurkat/A4 cells is lower than in the parental cell line. At the same time, XIAP and CAS levels in Jurkat/A4 cells increase. Upon apoptosis induction, XIAP and CAS levels in Jurkat cells decrease, this effect being negligible in resistant cells. Multidrug-resistant Jurkat/A4 cells exhibit reduced sensitivity to cytotoxic effects of quercetin. The expression profile of Jurkat/A4 cells is characterized by the increased levels of XIAP and CAS representing the endogenous inhibitors of apoptosis.

  11. EphA4 deficient mice maintain astroglial-fibrotic scar formation after spinal cord injury

    PubMed Central

    Herrmann, Julia E.; Shah, Ravi R.; Chan, Andrea F.; Zheng, Binhai

    2010-01-01

    One important aspect of recovery and repair after spinal cord injury (SCI) lies in the complex cellular interactions at the injury site that leads to the formation of a lesion scar. EphA4, a promiscuous member of the EphA family of repulsive axon guidance receptors, is expressed by multiple cell types in the injured spinal cord, including astrocytes and neurons. We hypothesized that EphA4 contributes to aspects of cell-cell interactions at the injury site after SCI, thus modulating the formation of the astroglial-fibrotic scar. To test this hypothesis, we studied tissue responses to a thoracic dorsal hemisection SCI in an EphA4 mutant mouse line. We found that EphA4 expression, as assessed by β-galactosidase reporter gene activity, is associated primarily with astrocytes in the spinal cord, neurons in the cerebral cortex and, to a lesser extent, spinal neurons, before and after SCI. However, we did not observe any overt reduction of glial fibrillary acidic protein (GFAP) expression in the injured area of EphA4 mutants in comparison with controls following SCI. Furthermore, there was no evident disruption of the fibrotic scar, and the boundary between reactive astrocytes and meningeal fibroblasts appeared unaltered in the mutants, as were lesion size, neuronal survival and inflammation marker expression. Thus, genetic deletion of EphA4 does not significantly alter the astroglial response or the formation of the astroglial-fibrotic scar following a dorsal hemisection SCI in mice. In contrast to what has been proposed, these data do not support a major role for EphA4 in reactive astrogliosis following SCI. PMID:20170651

  12. EphA4 deficient mice maintain astroglial-fibrotic scar formation after spinal cord injury.

    PubMed

    Herrmann, Julia E; Shah, Ravi R; Chan, Andrea F; Zheng, Binhai

    2010-06-01

    One important aspect of recovery and repair after spinal cord injury (SCI) lies in the complex cellular interactions at the injury site that leads to the formation of a lesion scar. EphA4, a promiscuous member of the EphA family of repulsive axon guidance receptors, is expressed by multiple cell types in the injured spinal cord, including astrocytes and neurons. We hypothesized that EphA4 contributes to aspects of cell-cell interactions at the injury site after SCI, thus modulating the formation of the astroglial-fibrotic scar. To test this hypothesis, we studied tissue responses to a thoracic dorsal hemisection SCI in an EphA4 mutant mouse line. We found that EphA4 expression, as assessed by beta-galactosidase reporter gene activity, is associated primarily with astrocytes in the spinal cord, neurons in the cerebral cortex and, to a lesser extent, spinal neurons, before and after SCI. However, we did not observe any overt reduction of glial fibrillary acidic protein (GFAP) expression in the injured area of EphA4 mutants in comparison with controls following SCI. Furthermore, there was no evident disruption of the fibrotic scar, and the boundary between reactive astrocytes and meningeal fibroblasts appeared unaltered in the mutants, as were lesion size, neuronal survival and inflammation marker expression. Thus, genetic deletion of EphA4 does not significantly alter the astroglial response or the formation of the astroglial-fibrotic scar following a dorsal hemisection SCI in mice. In contrast to what has been proposed, these data do not support a major role for EphA4 in reactive astrogliosis following SCI. Copyright (c) 2009 Elsevier Inc. All rights reserved.

  13. SLUDGE PARTICLE SEPAPATION EFFICIENCIES DURING SETTLER TANK RETRIEVAL INTO SCS-CON-230

    SciTech Connect

    DEARING JI; EPSTEIN M; PLYS MG

    2009-07-16

    The purpose of this document is to release, into the Hanford Document Control System, FA1/0991, Sludge Particle Separation Efficiencies for the Rectangular SCS-CON-230 Container, by M. Epstein and M. G. Plys, Fauske & Associates, LLC, June 2009. The Sludge Treatment Project (STP) will retrieve sludge from the 105-K West Integrated Water Treatment System (IWTS) Settler Tanks and transfer it to container SCS-CON-230 using the Settler Tank Retrieval System (STRS). The sludge will enter the container through two distributors. The container will have a filtration system that is designed to minimize the overflow of sludge fines from the container to the basin. FAI/09-91 was performed to quantify the effect of the STRS on sludge distribution inside of and overflow out of SCS-CON-230. Selected results of the analysis and a system description are discussed. The principal result of the analysis is that the STRS filtration system reduces the overflow of sludge from SCS-CON-230 to the basin by roughly a factor of 10. Some turbidity can be expected in the center bay where the container is located. The exact amount of overflow and subsequent turbidity is dependent on the density of the sludge (which will vary with location in the Settler Tanks) and the thermal gradient between the SCS-CON-230 and the basin. Attachment A presents the full analytical results. These results are applicable specifically to SCS-CON-230 and the STRS filtration system's expected operating duty cycles.

  14. Sport Concussion Management Using Facebook: A Feasibility Study of an Innovative Adjunct "iCon".

    PubMed

    Ahmed, Osman Hassan; Schneiders, Anthony G; McCrory, Paul R; Sullivan, S John

    2017-04-01

      Sport concussion is currently the focus of much international attention. Innovative methods to assist athletic trainers in facilitating management after this injury need to be investigated.   To investigate the feasibility of using a Facebook concussion-management program termed iCon (interactive concussion management) to facilitate the safe return to play (RTP) of young persons after sport concussion.   Observational study.   Facebook group containing interactive elements, with moderation and support from trained health care professionals.   Eleven participants (n = 9 men, n = 2 women; range, 18 to 28 years old) completed the study.   The study was conducted over a 3-month period, with participant questionnaires administered preintervention and postintervention. The primary focus was on the qualitative experiences of the participants and the effect of iCon on their RTP. Usage data were also collected.   At the completion of the study, all participants (100%) stated that they would recommend an intervention such as iCon to others. Their supporting quotes all indicated that iCon has the potential to improve the management of concussion among this cohort. Most participants (n = 9, 82%) stated they were better informed with regard to their RTP due to participating in iCon.   This interactive adjunct to traditional concussion management was appreciated among this participant group, which indicates the feasibility of a future, larger study of iCon. Athletic trainers should consider the role that multimedia technologies may play in assisting with the management of sport concussion.

  15. Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers

    PubMed Central

    Abel, Samantha; Jenkins, Timothy M; Whitlock, Lyndsey A; Ridgway, Caroline E; Muirhead, Gary J

    2008-01-01

    Aims To assess the potential of known CYP3A4 inducers, with and without CYP3A4 inhibitors, to alter the pharmacokinetic profile of maraviroc. Methods Two separate, open, randomized, placebo-controlled studies were conducted in healthy subjects. Study 1 was a 28-day parallel-group study with three treatment groups of 12 subjects each. On days 1–7, all subjects received maraviroc 100 mg b.i.d.; on days 8–21, subjects received maraviroc 100 mg b.i.d. plus either rifampicin 600 mg q.d., efavirenz (EFV) 600 mg q.d., or placebo q.d. as assigned; on days 22–28, the maraviroc dose was increased to 200 mg b.i.d. for patients receiving either rifampicin or EFV. Study 2 was a 21-day, two-way crossover study with three cohorts (12 subjects per cohort). On days 1–21, subjects received maraviroc 300 mg b.i.d. and boosted lopinavir (LPV/r, lopinavir 400 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 1, maraviroc 100 mg b.i.d. and boosted saquinavir (SQV/r, saquinavir 1000 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 2, and maraviroc 100 mg b.i.d. and 1000 mg saquinavir + LPV/r (400 mg/100 mg) or placebo b.i.d. in cohort 3. On days 8–21, subjects in all three cohorts also received EFV 600 mg or placebo q.d. Results Maraviroc (100 mg b.i.d.) exposure (AUC12 and Cmax) was reduced in the presence of rifampicin and EFV by approximately 70% and 50%, respectively. Maraviroc AUC12 and Cmax approached preinduction values when the maraviroc dose was increased to 200 mg b.i.d. for both the rifampicin-treated and EFV-treated groups. Co-administration of LPV/r with maraviroc (300 mg b.i.d.) resulted in geometric mean ratios (GMRs) of 395% and 197% for maraviroc AUC12 and Cmax, respectively, compared with placebo; addition of EFV resulted in GMRs of 253% and 125% for AUC12 and Cmax, respectively. Co-administration of SQV/r with maraviroc (100 mg b.i.d.) resulted in GMRs of 977% and 478% for maraviroc AUC12 and Cmax, respectively, compared with placebo; addition of EFV

  16. A 4-week choice foot speed and choice reaction training program improves agility in previously non-agility trained, but active men and women.

    PubMed

    Galpin, Andrew J; Li, Yuhua; Lohnes, Corey A; Schilling, Brian K

    2008-11-01

    Computerized agility training (CAT) products are frequently suggested to improve agility. However, these claims often are made without unbiased scientific support. Therefore, the purpose of this study was (a) to determine the reliability and effectiveness of a 4-week CAT training program on foot speed (FS) and choice reaction (REACT), and (b) to assess whether training on the CAT would facilitate the improvement of a separate change-of-direction (COD) test in non-agility-trained, but active, men and women. Twenty-three participants (15 men, 8 women) pre- and posttested on FS, REACT, and COD drills. Eleven of those participants (7 men, 4 women) engaged in 4 weeks of training on the FS and REACT drills (EX). The remaining 12 (8 men, 4 women) did not participate in the training and served as controls (CON). Coefficients of variation indicate strong precision for FS (6.9%) and REACT (2.6%). Test-retest reliability, as analyzed by intraclass correlations (ICC), were high for both FS and REACT (0.89). Significant test-by-group interactions were observed for all three tests: FS (p = 0.004), REACT (p = 0.011), and COD (p = 0.049). Post hoc analysis indicated that EX increased foot contacts for the FS drill (p = 0.006), whereas REACT and COD demonstrated decreases in time to completion (p = 0.013 and 0.038, respectively). The CON group did not improve on any of the tests. This study indicates that the chosen CAT is an accurate and reliable tool for measuring foot speed and reaction time. These data justify the use of this CAT in analyzing foot speed and reaction time. Altogether, 4 weeks of foot speed and reaction training on the chosen CAT produced improvements in overall agility in non-agility-trained, but active, men and women. These data warrant the integration of such a device into the training program of untrained athletes attempting to improve agility.

  17. Novel SLC37A4 Mutations in Korean Patients With Glycogen Storage Disease Ib.

    PubMed

    Choi, Rihwa; Park, Hyung Doo; Ko, Jung Min; Lee, Jeongho; Lee, Dong Hwan; Hong, Suk Jin; Ki, Chang Seok; Lee, Soo Youn; Kim, Jong Won; Song, Junghan; Choe, Yon Ho

    2017-05-01

    Molecular techniques are fundamental for establishing an accurate diagnosis and therapeutic approach of glycogen storage diseases (GSDs). We aimed to evaluate SLC37A4 mutation spectrum in Korean GSD Ib patients. Nine Korean patients from eight unrelated families with GSD Ib were included. SLC37A4 mutations were detected in all patients with direct sequencing using a PCR method and/or whole-exome sequencing. A comprehensive review of previously reported SLC37A4 mutations was also conducted. Nine different pathogenic SLC37A4 mutations were identified in the nine patients with GSD Ib. Among them, four novel mutations were identified: c.148G>A (pGly50Arg), c.320G>A (p.Trp107*), c.412T>C (p.Trp138Arg), and c.818G>A (p.Gly273Asp). The most common mutation type was missense mutations (66.7%, 6/9), followed by nonsense mutations (22.2%, 2/9) and small deletion mutations (11.1%, 1/9). The most common mutation identified in the Korean population was c.443C>T (p.Ala148Val), which comprised 39.9% (7/18) of all tested alleles. This mutation has not been reported in GSD Ib patients in other ethnic populations. This study expands knowledge of the SLC37A4 mutation spectrum in Korean patients with GSD Ib.

  18. EphA4 is Necessary for Spatially Selective Peripheral Somatosensory Topography

    PubMed Central

    North, HA; Karim, A; Jacquin, MF; Donoghue, MJ

    2009-01-01

    Somatosensation is the primary sensory modality employed by rodents in navigating their environments, and mystacial vibrissae on the snout are the primary conveyors of this information to the murine brain. The layout of vibrissae is spatially stereotyped and topographic connections faithfully maintain this layout throughout the neuraxis. Several factors have been shown to influence general vibrissal innervation by trigeminal neurons. Here, the role of a cell surface receptor, EphA4, in directing position-dependent vibrissal innervation is examined. EphA4 is expressed in the ventral region of the presumptive whisker pad and EphA4−/− mice lack the ventroposterior-most vibrissae. Analyses reveal that ventral trigeminal axons are abnormal, failing to innervate emerging vibrissae, and resulting in the absence of a select group of vibrissae in EphA4−/− mice. EphA4’s selective effect on a subset of whiskers implicates cell based signaling in the establishment of position-dependent connectivity and topography in the peripheral somatosensory system. PMID:20014408

  19. Pi-pi Stacking Mediated Cooperative Mechanism for Human Cytochrome P450 3A4.

    PubMed

    Fa, Botao; Cong, Shan; Wang, Jingfang

    2015-04-24

    Human Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 superfamily with responsibility for metabolizing ~50% of clinical drugs. Experimental evidence showed that CYP3A4 can adopt multiple substrates in its active site to form a cooperative binding model, accelerating substrate metabolism efficiency. In the current study, we constructed both normal and cooperative binding models of human CYP3A4 with antifungal drug ketoconazoles (KLN). Molecular dynamics simulation and free energy calculation were then carried out to study the cooperative binding mechanism. Our simulation showed that the second KLN in the cooperative binding model had a positive impact on the first one binding in the active site by two significant pi-pi stacking interactions. The first one was formed by Phe215, functioning to position the first KLN in a favorable orientation in the active site for further metabolism reactions. The second one was contributed by Phe304. This pi-pi stacking was enhanced in the cooperative binding model by the parallel conformation between the aromatic rings in Phe304 and the dioxolan moiety of the first KLN. These findings can provide an atomic insight into the cooperative binding in CYP3A4, revealing a novel pi-pi stacking mechanism for drug-drug interactions.

  20. Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A4.

    PubMed

    El-Sayed, Ramy; Bhattacharya, Kunal; Gu, Zonglin; Yang, Zaixing; Weber, Jeffrey K; Li, Hu; Leifer, Klaus; Zhao, Yichen; Toprak, Muhammet S; Zhou, Ruhong; Fadeel, Bengt

    2016-02-22

    We report a detailed computational and experimental study of the interaction of single-walled carbon nanotubes (SWCNTs) with the drug-metabolizing cytochrome P450 enzyme, CYP3A4. Dose-dependent inhibition of CYP3A4-mediated conversion of the model compound, testosterone, to its major metabolite, 6β-hydroxy testosterone was noted. Evidence for a direct interaction between SWCNTs and CYP3A4 was also provided. The inhibition of enzyme activity was alleviated when SWCNTs were pre-coated with bovine serum albumin. Furthermore, covalent functionalization of SWCNTs with polyethylene glycol (PEG) chains mitigated the inhibition of CYP3A4 enzymatic activity. Molecular dynamics simulations suggested that inhibition of the catalytic activity of CYP3A4 is mainly due to blocking of the exit channel for substrates/products through a complex binding mechanism. This work suggests that SWCNTs could interfere with metabolism of drugs and other xenobiotics and provides a molecular mechanism for this toxicity. Our study also suggests means to reduce this toxicity, eg., by surface modification.

  1. Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A4

    PubMed Central

    El-Sayed, Ramy; Bhattacharya, Kunal; Gu, Zonglin; Yang, Zaixing; Weber, Jeffrey K.; Li, Hu; Leifer, Klaus; Zhao, Yichen; Toprak, Muhammet S.; Zhou, Ruhong; Fadeel, Bengt

    2016-01-01

    We report a detailed computational and experimental study of the interaction of single-walled carbon nanotubes (SWCNTs) with the drug-metabolizing cytochrome P450 enzyme, CYP3A4. Dose-dependent inhibition of CYP3A4-mediated conversion of the model compound, testosterone, to its major metabolite, 6β-hydroxy testosterone was noted. Evidence for a direct interaction between SWCNTs and CYP3A4 was also provided. The inhibition of enzyme activity was alleviated when SWCNTs were pre-coated with bovine serum albumin. Furthermore, covalent functionalization of SWCNTs with polyethylene glycol (PEG) chains mitigated the inhibition of CYP3A4 enzymatic activity. Molecular dynamics simulations suggested that inhibition of the catalytic activity of CYP3A4 is mainly due to blocking of the exit channel for substrates/products through a complex binding mechanism. This work suggests that SWCNTs could interfere with metabolism of drugs and other xenobiotics and provides a molecular mechanism for this toxicity. Our study also suggests means to reduce this toxicity, eg., by surface modification. PMID:26899743

  2. Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A4

    NASA Astrophysics Data System (ADS)

    El-Sayed, Ramy; Bhattacharya, Kunal; Gu, Zonglin; Yang, Zaixing; Weber, Jeffrey K.; Li, Hu; Leifer, Klaus; Zhao, Yichen; Toprak, Muhammet S.; Zhou, Ruhong; Fadeel, Bengt

    2016-02-01

    We report a detailed computational and experimental study of the interaction of single-walled carbon nanotubes (SWCNTs) with the drug-metabolizing cytochrome P450 enzyme, CYP3A4. Dose-dependent inhibition of CYP3A4-mediated conversion of the model compound, testosterone, to its major metabolite, 6β-hydroxy testosterone was noted. Evidence for a direct interaction between SWCNTs and CYP3A4 was also provided. The inhibition of enzyme activity was alleviated when SWCNTs were pre-coated with bovine serum albumin. Furthermore, covalent functionalization of SWCNTs with polyethylene glycol (PEG) chains mitigated the inhibition of CYP3A4 enzymatic activity. Molecular dynamics simulations suggested that inhibition of the catalytic activity of CYP3A4 is mainly due to blocking of the exit channel for substrates/products through a complex binding mechanism. This work suggests that SWCNTs could interfere with metabolism of drugs and other xenobiotics and provides a molecular mechanism for this toxicity. Our study also suggests means to reduce this toxicity, eg., by surface modification.

  3. Novel pathogenic variants underlie SLC26A4-related hearing loss in a multiethnic cohort.

    PubMed

    Cengiz, Filiz Basak; Yilmazer, Rasim; Olgun, Levent; Sennaroglu, Levent; Kirazli, Tayfun; Alper, Hudaver; Olgun, Yuksel; Incesulu, Armagan; Atik, Tahir; Huesca-Hernandez, Fabiola; Domínguez-Aburto, Juan; González-Rosado, Garly; Hernandez-Zamora, Edgar; Arenas-Sordo, Maria de la Luz; Menendez, Ibis; Orhan, Kadir Serkan; Avci, Hakan; Mahdieh, Nejat; Bonyadi, Mortaza; Foster, Joseph; Duman, Duygu; Ozkinay, Ferda; Blanton, Susan H; Bademci, Guney; Tekin, Mustafa

    2017-10-01

    The genetics of sensorineural hearing loss is characterized by a high degree of heterogeneity. Despite this heterogeneity, DNA variants found within SLC26A4 have been reported to be the second most common contributor after those of GJB2 in many populations. Whole exome sequencing and/or Sanger sequencing of SLC26A4 in 117 individuals with sensorineural hearing loss with or without inner ear anomalies but not with goiter from Turkey, Iran, and Mexico were performed. We identified 27 unique SLC26A4 variants in 31 probands. The variants c.1673A > G (p.N558S), c.1708-1G > A, c.1952C > T (p.P651L), and c.2090-1G > A have not been previously reported. The p.N558S variant was detected in two unrelated Mexican families. A range of SLC26A4 variants without a common recurrent mutation underlies SLC26A4-related hearing loss in Turkey, Iran, and Mexico. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. A2 and A4 flexor pulley biomechanical analysis: comparison among gender and digit.

    PubMed

    Mallo, Gregory Charles; Sless, Yury; Hurst, Lawrence C; Wilson, Kevin

    2008-03-01

    Rock climbing has become increasingly more popular in the USA over the past two decades. Accordingly, with increased participation comes an increase in climbing-related injuries. Rooks et al noted that three-quarters of elite and recreational climbers will suffer upper extremity injuries, approximately 60% involving the hand or wrist and 40% divided evenly between the shoulder and elbow. Most of these injures will be strains, microtrauma, and tendonitis; however, 30-50% represent trauma to the proximal interphalangeal region. The purpose of this study was to investigate the biomechanical properties of the A2 and A4 pulley and compare biomechanical properties among gender and digit. A specially designed materials testing machine, shown in the included figure, measured maximum breaking load, displacement and stiffness of the A2 and A4 pulleys of ten cadaveric hands using an S hook to apply a steady force until complete pulley rupture. The A2 and A4 biomechanical properties of breaking load, displacement, and stiffness did not significantly differ among the index, middle, ring, and little fingers. Additionally, there was no significant difference in A2 or A4 pulley biomechanics between male and female specimens. The A2 and A4 pulleys among differing digits and genders have similar biomechanical properties in regards to maximum breaking load, displacement, and stiffness.

  5. A4 and CP symmetry and a model with maximal CP violation

    NASA Astrophysics Data System (ADS)

    Li, Cai-Chang; Lu, Jun-Nan; Ding, Gui-Jun

    2016-12-01

    We study a second CP symmetry compatible with the A4 flavor group, which interchanges the representations 1‧ and 1″. We analyze the lepton mixing patterns arising from the A4 and CP symmetry broken to residual subgroups Z3 and Z2 × CP in the charged lepton and neutrino sectors respectively. One phenomenologically viable mixing pattern is found, and it predicts maximal atmospheric mixing angle as well as maximal Dirac CP phase, trivial Majorana phases and the correlation sin2 ⁡θ12cos2 ⁡θ13 = 1 / 3. We construct a concrete model based on the A4 and CP symmetry, the above interesting mixing pattern is achieved, the observed charged lepton mass hierarchy is reproduced, and the reactor mixing angle θ13 is of the correct order.

  6. Hemopericardium with tamponade following rivaroxaban administration and its attenuation by CYP3A4 inhibitors

    PubMed Central

    Menendez, Denisse

    2016-01-01

    Novel oral anticoagulants including the factor Xa inhibitor rivaroxaban are important alternatives to warfarin for the prevention of thromboembolic stroke in patients with nonvalvular atrial fibrillation. The pharmacology and metabolism of these agents differ from those of the vitamin K antagonists used over the decades preceding their introduction. We present a case of spontaneous hemopericardium and cardiac tamponade following administration of rivaroxaban. A review of the patient's medications revealed a total of seven agents known to be metabolized through cytochrome P450 3A4 (CYP3A4), the major pathway for rivaroxaban metabolism. While most physicians are familiar with recommendations to monitor renal function in patients prescribed rivaroxaban, we suspect that many fail to evaluate possible interactions with other agents having CYP3A4 inhibitory or inducer activity. PMID:27695181

  7. Nonzero θ13 in SO (3 )→A4 lepton models

    NASA Astrophysics Data System (ADS)

    Grossman, Yuval; Ng, Wee Hao

    2015-04-01

    The simplest neutrino mass models based on A4 symmetry predict θ13=0 at tree level, a value that contradicts recent data. We study models that arise from the spontaneous breaking of an SO(3) symmetry to its A4 subgroup, and find that such models can naturally accommodate a nonzero θ13 at tree level. Standard Model charged leptons mix with additional heavy ones to generate a θ13 that scales with the ratio of the A4-breaking to SO(3)-breaking scales. A suitable choice of energy scales hence allows one to reproduce the correct lepton mixing angles. We also consider an alternative approach where we modify the alignment of flavons associated with the charged lepton masses, and find that the effects on θ13 are enhanced by a factor that scales as mτ/mμ.

  8. Intracellular accumulation and resistance to degradation of the Alzheimer amyloid A4/beta protein.

    PubMed Central

    Knauer, M F; Soreghan, B; Burdick, D; Kosmoski, J; Glabe, C G

    1992-01-01

    The A4 or beta protein is a peptide that constitutes the major protein component of senile plaques in Alzheimer disease. The A4/beta protein is derived from a larger, transmembrane amyloid precursor protein (APP). The putative abnormal processing events leading to amyloid accumulation are largely unknown. Here we report that a 42-residue synthetic peptide, beta 1-42, corresponding to one of the longer forms of the A4/beta protein, accumulates in cultured human skin fibroblasts and is stable for at least 3 days. The peptide appears to accumulate intracellularly, since it does not accumulate under conditions that prevent endocytosis and accumulation is correlated with the acquisition of resistance to removal by trypsin digestion. This intracellular accumulation is also correlated with the ability of the peptide to aggregate as determined by SDS/polyacrylamide gel electrophoresis. At low concentrations of the beta 1-42 peptide, which favor the nonaggregated state, no accumulation is observed. Shorter peptide analogs (28 or 39 residues) that are truncated at the C terminus, which lack the ability to aggregate in SDS gels, fail to accumulate. The accumulated intracellular beta 1-42 peptide is in an aggregated state and is contained in a dense organellar compartment that overlaps the distribution of late endosomes or secondary lysosomes. Immunofluorescence of the internalized peptide in permeabilized cells reveals that it is contained in granular deposits, consistent with localization in late endosomes or secondary lysosomes. Sequence analysis indicates that some of the internalized peptide is subject to N-terminal trimming. These results suggest that the aggregated A4/beta protein may be resistant to degradation and suggest that the A4/beta protein may arise, at least in part, by endosomal or lysosomal processing of APP. Our results also suggest that relatively nonspecific proteolysis may be sufficient to generate the A4/beta protein if this part of APP is selectively

  9. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

    PubMed Central

    de Graan, Anne-Joy M.; Elens, Laure; Sprowl, Jason A.; Sparreboom, Alex; Friberg, Lena E.; van der Holt, Bronno; de Raaf, Pleun J.; de Bruijn, Peter; Engels, Frederike K.; Eskens, Ferry A.L.M.; Wiemer, Erik A.C.; Verweij, Jaap; Mathijssen, Ron H.J.; van Schaik, Ron H.N.

    2013-01-01

    PURPOSE Paclitaxel is used for the treatment of several solid tumors and displays a high inter-individual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side-effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. EXPERIMENTAL DESIGN In an exploratory cohort of patients (n=261) treated with paclitaxel, neurotoxicity incidence and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by HPLC or LC-MS/MS, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by non-linear mixed effects modeling (NONMEM). Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n=239). RESULTS Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P <0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (odds ratio = 19.1; P = 0.001). CONCLUSIONS Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. PMID:23640974

  10. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity.

    PubMed

    de Graan, Anne-Joy M; Elens, Laure; Sprowl, Jason A; Sparreboom, Alex; Friberg, Lena E; van der Holt, Bronno; de Raaf, Pleun J; de Bruijn, Peter; Engels, Frederike K; Eskens, Ferry A L M; Wiemer, Erik A C; Verweij, Jaap; Mathijssen, Ron H J; van Schaik, Ron H N

    2013-06-15

    Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.

  11. Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability.

    PubMed

    Fasinu, Pius; Choonara, Yahya E; Khan, Riaz A; Du Toit, Lisa C; Kumar, Pradeep; Ndesendo, Valence M K; Pillay, Viness

    2013-02-01

    Molecular modeling computations were utilized to generate pharmaceutical grade CYP3A4-enzyme inhibitors. In vitro metabolism of felodipine in human intestinal and liver microsomes (HLM and HIM) was optimized yielding a Michaelis-Menten plot from where the K(m) and V(max) values were estimated by nonlinear regression. The flavonoids, naringin, naringenin, and quercetin, were subsequently incubated with felodipine at the determined K(m) value in HLM. Comparing results obtained from a known CYP3A4 inhibitor, verapamil, the flavonoids inhibited felodipine metabolism. In-depth computational analysis of these flavonoids in terms of CYP3A4 binding, sequencing, and affinity, computational biomimetism was employed to validate the potential CYP3A4 inhibitors. The modeled compounds were comparatively evaluated by incubation with felodipine in both HLM and HIM. Results showed that the polymers 8-arm-PEG, o-(2-aminoethyl)-o-methyl-PEG, 4-arm-PEG (molecular weight = 10,000 g/mol and 20,000 g/mol, respectively), and poly(l-lysine) were able to inhibit the felodipine metabolism with the half maximal inhibitory concentration (IC(50)) values ranging from 7.22 to 30.0 μM (HLM) and 5.78 to 41.03 μM (HIM). Molecular docking confirmed drug-enzyme interactions by computing the free energies of binding (ΔE) and inhibition constants (K(i)) of the docked compounds utilizing a Lamarckian Genetic Algorithm. Comparative correlations between the computed and experimental K(i) values were obtained. Computational modeling of CYP3A4 inhibitors provided a suitable strategy to screen pharmaceutical grade compounds that may potentially inhibit presystemic CYP3A4-dependent drug metabolism with the prospect of improving oral drug bioavailability. Copyright © 2012 Wiley Periodicals, Inc.

  12. An Inducible Cytochrome P450 3A4-Dependent Vitamin D Catabolic Pathway

    PubMed Central

    Wang, Zhican; Lin, Yvonne S.; Zheng, Xi Emily; Senn, Tauri; Hashizume, Takanori; Scian, Michele; Dickmann, Leslie J.; Nelson, Sidney D.; Baillie, Thomas A.; Hebert, Mary F.; Blough, David; Davis, Connie L.

    2012-01-01

    Vitamin D3 is critical for the regulation of calcium and phosphate homeostasis. In some individuals, mineral homeostasis can be disrupted by long-term therapy with certain antiepileptic drugs and the antimicrobial agent rifampin, resulting in drug-induced osteomalacia, which is attributed to vitamin D deficiency. We now report a novel CYP3A4-dependent pathway, the 4-hydroxylation of 25-hydroxyvitamin D3 (25OHD3), the induction of which may contribute to drug-induced vitamin D deficiency. The metabolism of 25OHD3 was fully characterized in vitro. CYP3A4 was the predominant source of 25OHD3 hydroxylation by human liver microsomes, with the formation of 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] dominating (Vmax/Km = 0.85 ml · min−1 · nmol enzyme−1). 4β,25(OH)2D3 was found in human plasma at concentrations comparable to that of 1α,25-dihydroxyvitamin D3, and its formation rate in a panel of human liver microsomes was strongly correlated with CYP3A4 content and midazolam hydroxylation activity. Formation of 4β,25(OH)2D3 in primary human hepatocytes was induced by rifampin and inhibited by CYP3A4-specific inhibitors. Short-term treatment of healthy volunteers (n = 6) with rifampin selectively induced CYP3A4-dependent 4β,25(OH)2D3, but not CYP24A1-dependent 24R,25-dihydroxyvitamin D3 formation, and altered systemic mineral homeostasis. Our results suggest that CYP3A4-dependent 25OHD3 metabolism may play an important role in the regulation of vitamin D3 in vivo and in the etiology of drug-induced osteomalacia. PMID:22205755

  13. The metastasis-promoting protein S100A4 regulates mammary branching morphogenesis

    PubMed Central

    Andersen, Kristin; Mori, Hidetoshi; Fata, Jimmie; Øyjord, Tove; Mælandsmo, Gunhild M.; Bissell, Mina

    2011-01-01

    High levels of the S100 calcium binding protein S100A4 also called fibroblast specific protein 1 (FSP1) have been established as an inducer of metastasis and indicator of poor prognosis in breast cancer. The mechanism by which S100A4 leads to increased cancer aggressiveness has yet to be established; moreover, the function of this protein in normal mammary gland biology has not been investigated. To address the role of S100A4 in normal mammary gland, its spatial and temporal expression patterns and possible function in branching morphogenesis were investigated. We show that the protein is expressed mainly in cells of the stromal compartment of adult humans, and during active ductal development, in pregnancy and in involution of mouse mammary gland. In 3D culture models, topical addition of S1004 induced significant increase in the TGFα mediated branching phenotype and a concomitant increase in expression of a previously identified branching morphogen, metalloproteinase-3 (MMP-3). These events were found to be dependent on MEK activation. Downregulation of S100A4 using shRNA significantly reduced TGFα induced branching and altered E-cadherin localization. These findings provide evidence that S100A4 is developmentally regulated and that it plays a functional role in mammary gland development by, in concert with TGFα, activating MMP-3, thereby increasing invasion into the fat pad during branching. We suggest that S100A4-mediated effects during branching morphogenesis provide a plausible mechanism for how it may function in breast cancer progression. PMID:21195708

  14. Metabolic-induced cytotoxicity of diosbulbin B in CYP3A4-expressing cells.

    PubMed

    Jiang, Ji-Zong; Yang, Bao-Hua; Ji, Li-Li; Yang, Li; Mao, Yu-Chang; Hu, Zhuo-Han; Wang, Zheng-Tao; Wang, Chang-Hong

    2017-02-01

    As a candidate antitumor agent, diosbulbin B (DB) can induce serious liver toxicity and other adverse reactions. DB is mainly metabolized by CYP3A4 in vitro and in vivo, but the cytotoxicity and anti-tumor mechanisms of DB have yet to be clarified. This study aimed to determine whether the cytotoxicity and anti-tumor effects of DB are related to the metabolism-induced activation of CYP3A4 in various cell models, including CYP-free NIH3T3 cells, primary rat hepatocytes, HepG2 and L02 cells of high CYP3A4 expression and wild-type. Results showed that DB did not markedly decrease the viability of NIH3T3 cells. DB metabolites, obtained from the metabolism by mouse liver microsomes, did not elicit cytotoxicity on NIH3T3 cells either. By contrast, DB could induce significant cytotoxicity on primary rat hepatocytes. The DB induced cytotoxicity on HepG2 or L02 cells with high CYP3A4 expression were stronger than those on wild-type cells. As a metabolic biomarker, the metabolite conjugate (M31) of DB with GSH was detected in the incubation system. A higher amount of M31 was generated in the transfected HepG2 and L02 cells than in the wild-type cells at different time points. Ketoconazole, however, could restrain DB induced cytotoxicity on primary rat hepatocytes and in CYP3A4 transfected HepG2 and L02 cells. Therefore, the cytotoxicity of DB was closely related to CYP3A4-metabolized reactive DB metabolites.

  15. Case report: delirium due to a diltiazem-fentanyl CYP3A4 drug interaction.

    PubMed

    Levin, Tomer T; Bakr, Mohamed Hussien; Nikolova, Tanya

    2010-01-01

    Fentanyl and diltiazem are frequently used medications. Diltiazem inhibits cytochrome P450 3A4 isoenzymes. This can suppress fentanyl metabolism. We present a case of delirium after coadministration of fentanyl and diltiazem. Cautious use is warranted while concomitantly administering fentanyl and diltiazem as this can potentiate fentanyl toxicity. Other 3A4 inhibitors include ketoconazole, erythromycin, nefazodone, ritonavir, delavirdine, aprepitant and imatinib. Psychosomatic medicine psychiatrists, pain and palliative care physicians and cardiologists in particular should be aware of this interaction. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. Polymorphisms in COL4A3 and COL4A4 genes associated with keratoconus

    PubMed Central

    Štabuc-Šilih, Mirna; Ravnik-Glavač, Metka; Glavač, Damjan; Hawlina, Marko

    2009-01-01

    Purpose Alterations in collagen type IV, alpha-3 (COL4A3) and collagen type IV, alpha-4 (COL4A4) genes may be responsible for a decrease in collagen types I and III, a feature often detected in keratoconus (KC). To evaluate the significance of alterations in COL4A3 and COL4A4 genes in KC patients, we screened both genes and estimated the significance of polymorphisms in Slovenian patients with KC. Methods The study included 104 unrelated patients with KC and 157 healthy blood donors. Diagnosis was established by clinical examination, electronic refractometry, and keratometry. DNA was extracted from blood, and gene exons were amplified by PCR. Non-isotopic high-resolution single-stranded conformation analysis (SSCA) was used to screen COL4A3 and COL4A4 genes, and migration shifts detected by SSCA were subsequently sequenced. For statistical evaluation, control blood donors were chosen according to age, sex, and not having blood relationship. Neither patients nor control blood donors chosen for statistical analysis were in blood relationship. We used Fisher’s exact test for statistical evaluation, with p<0.05 considered significant. Results We detected eight polymorphisms in the COL4A3 gene and six in the COL4A4 gene. Allele differences in D326Y in COL4A3 and M1237V and F1644F in COL4A4 are significantly distinctive of KC patients (Fisher’s exact test, p<0.05). When analyzing different genotypes under three models (dominant, recessive, and additive), we established that P141L, D326Y, and G895G in COL4A3 and P482S, M1327V, V1516V, and F1644F in COL4A4 have significant differences in genotype distribution between KC patients and the control group. Conclusions This is the first mutational screening of COL4A3 and COL4A4 genes in KC patients to establish the status of these genes and compare them to a control population. Analysis of COL4A3 and COL4A4 revealed no mutations related to KC patients, but specific genotypes of seven previously described polymorphisms are

  17. The interaction with tubulin of a series of stilbenes based on combretastatin A-4.

    PubMed Central

    Woods, J. A.; Hadfield, J. A.; Pettit, G. R.; Fox, B. W.; McGown, A. T.

    1995-01-01

    A series of stilbenes, based on combretastatin A-4, were synthesised. A structure-activity study was carried out to characterise the interaction of these agents with tubulin. The substitution of small alkyl substituents for the 4'-methoxy group of combretastatin A-4 and the loss of the 3'-hydroxyl group does not have a major effect on the interaction with tubulin. trans-Stilbenes were shown to bind tubulin, but do not inhibit microtubule assembly. This work, together with previous studies, has been used to propose an idealised structure for a tubulin-binding agent of this type. Images Figure 7 PMID:7710932

  18. Pros and cons: prospective predictors of marijuana use on a college campus.

    PubMed

    Elliott, Jennifer C; Carey, Kate B

    2013-03-01

    Marijuana use on college campuses is prevalent and associated with high rates of abuse and dependence. The Marijuana Decisional Balance (MDB) scales measure perceived pros and cons toward marijuana use. Evidence supports reliability and concurrent validity of these scales, but the predictive validity has not yet been assessed. The current study evaluated the prospective predictive validity of pros and cons scales for marijuana use, as well as explored predictive validity for marijuana problem indicators. Secondary analyses included test-retest reliability and internal consistency, to provide additional evidence of psychometric properties. A total of 149 college students (57% recent marijuana users, 77% lifetime users) participated in a baseline survey, then completed a second survey one month later. All provided data on marijuana pros and cons, as well as use status in the past month. Users at each time point reported on use frequency, problems, and disorder symptoms. In the month between assessments, 55% of the students used marijuana. Both pros and cons subscales prospectively predicted use status in the subsequent month, but not use frequency. Pros prospectively predicted marijuana problems and dependence symptoms at follow-up, and remained a significant predictor of later dependence symptoms even after controlling for baseline dependence symptoms. In contrast, pros only marginally predicted abuse. Cons did not predict problems, abuse, or dependence symptoms. Pros and cons showed strong test-retest reliability (rs = 0.80-0.85) and internal consistency (alphas = 0.92-0.95). In a college sample, pros and cons of marijuana use demonstrated stability over one month, and prospectively predicted use. Pros may also have utility in predicting problems and dependence potential on college campuses.

  19. 26 CFR 1.401(a)(4)-8 - Cross-testing.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... other allocations under the plan for the plan year; and (4) The composition of the group of employees...). (vii) Special rules for target benefit plans qualified under prior law—(A) Service taken into account... plan year under the rules of § 1.401(a)(4)-13(e). (C) Satisfaction of prior law. In determining whether...

  20. 26 CFR 1.401(a)(4)-8 - Cross-testing.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... other allocations under the plan for the plan year; and (4) The composition of the group of employees...). (vii) Special rules for target benefit plans qualified under prior law—(A) Service taken into account... plan year under the rules of § 1.401(a)(4)-13(e). (C) Satisfaction of prior law. In determining whether...

  1. 26 CFR 1.401(a)(4)-8 - Cross-testing.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... other allocations under the plan for the plan year; and (4) The composition of the group of employees...). (vii) Special rules for target benefit plans qualified under prior law—(A) Service taken into account... plan year under the rules of § 1.401(a)(4)-13(e). (C) Satisfaction of prior law. In determining whether...

  2. 26 CFR 31.6011(a)-4 - Returns of income tax withheld.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... wages—(1) For further guidance, see § 31.6011(a)-4T(a)(1). (2) Wages paid for domestic service. Schedule... under section 3402(p), from wages paid for domestic service as defined in section 3510. Schedule H (Form... § 301.6361-1(d)(3)(iv). (3) Wages paid for agricultural labor. Every person shall make a return...

  3. Rice carotenoid β-ring hydroxylase CYP97A4 is involved in lutein biosynthesis.

    PubMed

    Lv, Ming-Zhu; Chao, Dai-Yin; Shan, Jun-Xiang; Zhu, Mei-Zhen; Shi, Min; Gao, Ji-Ping; Lin, Hong-Xuan

    2012-06-01

    Lutein is the most abundant plant carotenoid and plays essential roles in photosystem assembly and stabilization, as well as protection against photostress. To date, only a few lutein biosynthesis genes have been identified in crop plants. In this study, the rice Cyt P450 gene CYP97A4 encoding a carotenoid β-ring hydroxylase was shown to be involved in lutein biosynthesis. The results revealed that CYP97A4 was preferentially expressed in leaf compared with spikelet, sheath, stalk and root, and encoded a protein localized at the subcellular level to the chloroplasts. Compared with the wild type, the three allelic mutants of CYP97A4 displayed lutein reductions of 12-24% with substantially increased α-carotene, while Chl a/b levels were unaltered. The increased α-carotene in the mutants led to greater sensitivity under high light stress. Similarly, reactive oxygen species (ROS) imaging of leaves treated with intense light showed that the mutants generally accumulated greater levels of ROS compared with wild-type plants, which probably caused detrimental effects to the plant photosystem. In conclusion, this study demonstrated the important role of CYP97A4 in α-carotene hydroxylation in rice, and knock-out of the gene reduced lutein and increased α-carotene, contributing to sensitivity to intense light.

  4. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Plan amendments and plan terminations. 1.401(a... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan terminations. (a) Introduction—(1) Overview. This...

  5. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Plan amendments and plan terminations. 1.401(a... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan terminations. (a) Introduction—(1) Overview. This paragraph (a)...

  6. 26 CFR 1.401(a)(4)-9 - Plan aggregation and restructuring.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., however, provides special rules for determining whether a plan that consists of one or more defined contribution plans and one or more defined benefit plans (a DB/DC plan) satisfies section 401(a)(4) with... defined contribution plans that are part of the DB/DC plan as a single plan, and all defined benefit plans...

  7. 26 CFR 31.6011(a)-4 - Returns of income tax withheld.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... wages—(1) For further guidance, see § 31.6011(a)-4T(a)(1). (2) Wages paid for domestic service. Schedule... 1040) is generally filed as an attachment to an income tax return; however, if the employer does not... gambling winnings subject to withholding under section 3402(q); (2) Retirement pay for services in the...

  8. A 4D-optimization concept for scanned ion beam therapy.

    PubMed

    Graeff, Christian; Lüchtenborg, Robert; Eley, John Gordon; Durante, Marco; Bert, Christoph

    2013-12-01

    Scanned carbon beam therapy offers advantageous dose distributions and an increased biological effect. Treating moving targets is complex due to sensitivity to range changes and interplay. We propose a 4D treatment planning concept that considers motion during particle number optimization. The target was subdivided into sectors, one for each motion phase of a 4D-CT. Each sector was non-rigidly transformed to its motion phase and there targeted by a dedicated raster field (RST). Therefore, the resulting 4D-RST compensated target motion and range changes. A 4D treatment control system (TCS) was needed for synchronized delivery to the measured patient motion. 4D-optimized plans were simulated for 9 NSCLC lung cancer patients and compared to static irradiation at end-exhale. A prototype TCS was implemented and successfully tested in a film experiment. The 4D-optimized treatment plan resulted in only slightly lower dose coverage of the target compared to static optimization, with V 95% of 97.9% (median, range 96.5-99.4%) vs. 99.3% (98.5-99.8%), with negligible overdose. The conformity number was comparable at 88.2% (85.1-92.5%) vs. 85.2% (79.9-91.2%) for 4D and static, respectively. We implemented and tested a 4D treatment plan optimization method resulting in highly conformal dose delivery. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. 9. Naval Facilities (NAVFAC) Engineering Command Drawing 6100590 (814A4) (1978), ...

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

    9. Naval Facilities (NAVFAC) Engineering Command Drawing 6100590 (814-A-4) (1978), 'Various Repairs to Building 814, Site, Floor Plan, Roof Plan and Elevations' - Mare Island Naval Shipyard, Chemical Cleaning Facility, North of Fourteenth Street, between California & Railroad Avenue, Vallejo, Solano County, CA

  10. Hypomaturation amelogenesis imperfecta caused by a novel SLC24A4 mutation.

    PubMed

    Herzog, Curtis R; Reid, Bryan M; Seymen, Figen; Koruyucu, Mine; Tuna, Elif Bahar; Simmer, James P; Hu, Jan C-C

    2015-02-01

    In this case report of autosomal recessive pigmented hypomaturation amelogenesis imperfecta (AI), we identify a novel homozygous missense mutation (g.165151 T>G; c.1317 T>G; p.Leu436 Arg) in SLC24A4, a gene encoding a potassium-dependent sodium-calcium exchanger that is critical for hardening dental enamel during tooth development.

  11. Genetic Testing for Deafness--GJB2 and SLC26A4 as Causes of Deafness.

    ERIC Educational Resources Information Center

    Smith, Richard J. H.; Robin, Nathaniel H.

    2002-01-01

    This article introduces the concept of genetic testing for deafness. Two genes that make appreciable contributions to the autosomal recessive non-syndromic deafness (ARNSD) genetic load are reviewed, GJB2 and SLC26A4. In addition, the unique aspects of genetic counseling for deafness and recurrence chance estimates are explained. (Contains…

  12. Genetic Testing for Deafness--GJB2 and SLC26A4 as Causes of Deafness.

    ERIC Educational Resources Information Center

    Smith, Richard J. H.; Robin, Nathaniel H.

    2002-01-01

    This article introduces the concept of genetic testing for deafness. Two genes that make appreciable contributions to the autosomal recessive non-syndromic deafness (ARNSD) genetic load are reviewed, GJB2 and SLC26A4. In addition, the unique aspects of genetic counseling for deafness and recurrence chance estimates are explained. (Contains…

  13. EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From α-Cells

    PubMed Central

    Hutchens, Troy

    2015-01-01

    The loss of inhibition of glucagon secretion exacerbates hyperglycemia in type 1 and 2 diabetes. However, the molecular mechanisms that regulate glucagon secretion in unaffected and diabetic states remain relatively unexplained. We present evidence supporting a new model of juxtacrine-mediated regulation of glucagon secretion where neighboring islet cells negatively regulate glucagon secretion through tonic stimulation of α-cell EphA receptors. Primarily through EphA4 receptors, this stimulation correlates with maintenance of a dense F-actin network. In islets, additional stimulation and inhibition of endogenous EphA forward signaling result in inhibition and enhancement, respectively, of glucagon secretion, accompanied by an increase and decrease, respectively, in α-cell F-actin density. Sorted α-cells lack endogenous stimulation of EphA forward signaling from neighboring cells, resulting in enhanced basal glucagon secretion as compared with islets and the elimination of glucose inhibition of glucagon secretion. Restoration of EphA forward signaling in sorted α-cells recapitulates both normal basal glucagon secretion and glucose inhibition of glucagon secretion. Additionally, α-cell–specific EphA4−/− mice exhibit abnormal glucagon dynamics, and EphA4−/− α-cells contain less dense F-actin networks than EphA4+/+ α-cells. This juxtacrine-mediated model provides insight into the functional and dysfunctional regulation of glucagon secretion and opens up new therapeutic strategies for the clinical management of diabetes. PMID:26251403

  14. Ileal impaction and jejunal enterotomy in a 4-month-old Arabian filly.

    PubMed

    Davis, Heather A; Munsterman, Amelia

    2012-01-01

    A 4-month-old Arabian filly was treated by surgical correction of an ileal impaction. The impaction was resolved through a distal jejunal enterotomy. One-year follow-up showed no post-operative complications secondary to the enterotomy. Jejunal enterotomy may be a surgical option for resolution of an ileal impaction.

  15. Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole.

    PubMed

    Petitcollin, A; Crochette, R; Tron, C; Verdier, M-C; Boglione-Kerrien, C; Vigneau, C; Bellissant, E; Lemaitre, F

    2016-10-01

    Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension. Based on a case of sirolimus overdosage following posaconazole tablets administration, we modelled the inhibition of sirolimus clearance by posaconazole, and then simulated several dosage regimens of sirolimus taken together with posaconazole tablets. We were able to describe well the interaction, and found a value of IC50 of posaconazole towards sirolimus clearance of 0.68 μg/mL. The simulations showed that even a 80% decrease of the daily dose of sirolimus is unsuitable in many cases with trough concentrations of posaconazole of 2 μg/mL. A decrease of 40% of the dose with spacing administrations of 3 days may be considered. The clinicians and pharmacologists must be warned that the use of posaconazole tablets may result in an inhibition of CYP3A4 of greater magnitude than with the oral suspension.

  16. 22. Photographic copy enlargement from a 4x5 copy negative of ...

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

    22. Photographic copy enlargement from a 4x5 copy negative of a print. (Original print located on abandoned NASA site, currently owned by the City of Downey, Downey, California). 1954 USAF PLANT 16 AERIAL BUILDING 41 NORTH TO SOUTH. - NASA Industrial Plant, Missile Research Laboratory, 12214 Lakewood Boulevard, Downey, Los Angeles County, CA

  17. 15. Photographic copy englargement from a 4x5 copy negative (Original ...

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

    15. Photographic copy englargement from a 4x5 copy negative (Original drawing located on abandoned NASA site, currently owned by the City of Downey, Downey, California). 1980 BLDG 10, BLDG 42 FLOOR PLAN, NASA MARCH 15 1980. - NASA Industrial Plant, Maintenance Facility, 12214 Lakewood Boulevard, Downey, Los Angeles County, CA

  18. 9. Photographic copy enlargement from a 4x5 copy negative. (Original ...

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

    9. Photographic copy enlargement from a 4x5 copy negative. (Original drawing located on abandoned NASA site, currently owned by the City of Downey, Downey, California). 1976 BLDGS.25, 41 SITE PLAN. - NASA Industrial Plant, Storage Facility, 12214 Lakewood Boulevard, Downey, Los Angeles County, CA

  19. 14. Photographic copy englargement from a 4x5 copy negative (Original ...

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

    14. Photographic copy englargement from a 4x5 copy negative (Original photograph by original photographer located on abandoned NASA site, currently owned by the City of Downey, Downey, California). AERIAL PHOTOGRAPH 1935-1936 CONSOLIDATED VULTEE AIRCRAFT CORPORATION FROM WEST TO EAST - NASA Industrial Plant, Maintenance Facility, 12214 Lakewood Boulevard, Downey, Los Angeles County, CA

  20. 23. Photographic copy enlargement from a 4x5 copy negative of ...

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

    23. Photographic copy enlargement from a 4x5 copy negative of a drawing (Original drawing located on abandoned NASA site, currently owned by the City of Downey, Downey, Calfornia). JANUARY 1960 USAF PLANT 16 MASTER PLOT AND GRID PLAN. - NASA Industrial Plant, Missile Research Laboratory, 12214 Lakewood Boulevard, Downey, Los Angeles County, CA

  1. Fatal Methadone Toxicity: Potential Role of CYP3A4 Genetic Polymorphism

    PubMed Central

    Richards-Waugh, Lauren L.; Primerano, Donald A.; Dementieva, Yulia; Kraner, James C.; Rankin, Gary O.

    2014-01-01

    Methadone is difficult to administer as a therapeutic agent because of a wide range of interindividual pharmacokinetics, likely due to genetic variability of the CYP450 enzymes responsible for metabolism to its principal metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). CYP3A4 is one of the primary CYP450 isoforms responsible for the metabolism of methadone to EDDP in humans. The purpose of this study was to evaluate the role of CYP3A4 genetic polymorphisms in accidental methadone fatalities. A study cohort consisting of 136 methadone-only and 92 combined methadone/benzodiazepine fatalities was selected from cases investigated at the West Virginia and Kentucky Offices of the Chief Medical Examiner. Seven single nucleotide polymorphisms (SNPs) were genotyped within the CYP3A4 gene. Observed allelic and genotypic frequencies were compared with expected frequencies obtained from The National Center for Biotechnology Information dbSNP database. SNPs rs2242480 and rs2740574 demonstrated an apparent enrichment within the methadone-only overdose fatalities compared with the control group and the general population. This enrichment was not apparent in the methadone/benzodiazepine cases for these two SNPs. Our findings indicate that there may be two or more SNPs on the CYP3A4 gene that cause or contribute to the methadone poor metabolizer phenotype. PMID:25217544

  2. 26 CFR 1.669(a)-4 - Tax attributable to short-cut throwback method.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Tax attributable to short-cut throwback method... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(a)-4 Tax attributable to short-cut... the tax on the amounts deemed distributed under section 666 by the short-cut throwback method provided...

  3. 26 CFR 1.669(a)-4 - Tax attributable to short-cut throwback method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax attributable to short-cut throwback method... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(a)-4 Tax attributable to short-cut... the tax on the amounts deemed distributed under section 666 by the short-cut throwback method provided...

  4. 26 CFR 1.669(a)-4 - Tax attributable to short-cut throwback method.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax attributable to short-cut throwback method... Taxable Years Beginning Before January 1, 1969 § 1.669(a)-4 Tax attributable to short-cut throwback method... the amounts deemed distributed under section 666 by the short-cut throwback method provided in section...

  5. 26 CFR 1.669(a)-4 - Tax attributable to short-cut throwback method.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Tax attributable to short-cut throwback method... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(a)-4 Tax attributable to short-cut... the tax on the amounts deemed distributed under section 666 by the short-cut throwback method provided...

  6. 26 CFR 1.669(a)-4 - Tax attributable to short-cut throwback method.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Tax attributable to short-cut throwback method... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(a)-4 Tax attributable to short-cut... the tax on the amounts deemed distributed under section 666 by the short-cut throwback method provided...

  7. Emergency cardiac resynchronisation in a 4kg infant post surgical closure of ventricular septal defect.

    PubMed

    Yeong, Michael; Rumball, Elizabeth; Sinclair, Susan; Skinner, Jonathan R

    2013-04-01

    Cardiac resynchronisation therapy (CRT) is an established treatment for adult patients with cardiac failure due to mechanical and electrical dyssynchrony. Data on CRT in infants are scarce. We report the remarkable success of emergent CRT by epicardial pacing of the left ventricular apex in a 4kg infant with left ventricular failure due to LV dyssynchrony from left bundle branch block.

  8. Effects on Students of a 4 X 4 Junior High School Block Scheduling Program.

    ERIC Educational Resources Information Center

    Cobb, R. Brian; Abate, Stacey; Baker, Dennis

    1999-01-01

    Investigated the effects of a 4 X 4 block scheduling program on a variety of student measures in a middle school with 355 block-scheduled students, some of whom were in high school at the time of the study. Results of the block scheduling were generally consistent with existing literature and generally positive. (SLD)

  9. 26 CFR 1.408A-4 - Converting amounts to Roth IRAs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Converting amounts to Roth IRAs. 1.408A-4... amounts to Roth IRAs. This section sets forth the following questions and answers that provide rules applicable to Roth IRA conversions: Q-1. Can an individual convert an amount in his or her traditional IRA...

  10. 26 CFR 1.401(a)(4)-11 - Additional rules.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....401(a)(4)-4(b) for benefits, rights, or features, a corrective amendment may make a benefit, right, or... employee's rights and benefits under the plan, the corrective amendment must generally be effective as if... plan year. However, to the extent that an amendment makes a benefit, right, or feature available to...

  11. Hypomaturation Amelogenesis Imperfecta Caused By A Novel SLC24A4 Mutation

    PubMed Central

    Herzog, Curtis R.; Reid, Bryan M.; Seymen, Figen; Koruyucu, Mine; Tuna, Elif Bahar; Simmer, James P.; Hu, Jan C-C.

    2014-01-01

    In this case report of autosomal recessive pigmented hypomaturation amelogenesis imperfecta (AI), we identify a novel homozygous missense mutation (g.165151T>G; c.1317T>G; p.Leu436Arg) in SLC24A4, a gene encoding a potassium-dependent sodium-calcium exchanger that is critical for hardening dental enamel during tooth development. PMID:25442250

  12. 16. Photocopy of drawing enlarged from a 4x5 negative (from ...

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

    16. Photocopy of drawing enlarged from a 4x5 negative (from Cultural Resources plan files, Gateway National Recreation Area, New Jersey) U.S. Army Corps of Engineers, Designers, 1909 PLAN OF DRAINAGE AND ELECTRICAL SYSTEM OF BATTERY - Fort Hancock, Battery George Arrowsmith, Southwest edge of Sandy Point extending to Horseshoe Cove, Fort Hancock, Monmouth County, NJ

  13. Effect of Curriculum Change on Exam Performance in a 4-Week Psychiatry Clerkship

    ERIC Educational Resources Information Center

    Niedermier, Julie; Way, David; Kasick, David; Kuperschmidt, Rada

    2010-01-01

    Objective: The authors investigated whether curriculum change could produce improved performance, despite a reduction in clerkship length from 8 to 4 weeks. Methods: The exam performance of medical students completing a 4-week clerkship in psychiatry was compared to national data from the National Board of Medical Examiners' Psychiatry Subject…

  14. Effect of Curriculum Change on Exam Performance in a 4-Week Psychiatry Clerkship

    ERIC Educational Resources Information Center

    Niedermier, Julie; Way, David; Kasick, David; Kuperschmidt, Rada

    2010-01-01

    Objective: The authors investigated whether curriculum change could produce improved performance, despite a reduction in clerkship length from 8 to 4 weeks. Methods: The exam performance of medical students completing a 4-week clerkship in psychiatry was compared to national data from the National Board of Medical Examiners' Psychiatry Subject…

  15. 26 CFR 1.401(a)(4)-6 - Contributory defined benefit plans.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Contributory defined benefit plans. 1.401(a)(4...)-6 Contributory defined benefit plans. (a) Introduction. This section provides rules necessary for...) Excess plans with varying contribution rates. In the case of a defined benefit excess plan described in...

  16. Identification and characterization of a novel mouse plexin, plexin-A4.

    PubMed

    Suto, Fumikazu; Murakami, Yasunori; Nakamura, Fumio; Goshima, Yoshio; Fujisawa, Hajime

    2003-03-01

    Plexins belonging to the plexin-A subfamily form complexes with neuropilins and propagate signals of class 3 semaphorins into neurons, even though they do not directly bind the semaphorins. In this study, we identified a new member of the plexin-A subfamily in the mice, plexin-A4, and showed that it was expressed in the developing nervous system with a pattern different to that of other members of the plexin-A subfamily (plexin-A1, plexin-A2 and plexin-A3). COS-7 cells coexpressing plexin-A4 with neuropilin-1 were induced to contract by Sema3A, a member of the class 3 semaphorin. Ectopic expression of plexin-A4 in mitral cells that are originally insensitive to Sema3A resulted in the collapse of growth cones in the presence of Sema3A. These results suggest that plexin-A4 plays a role in the propagation of Sema3A activities.

  17. Lipoxin A4 ameliorates ischemia/reperfusion induced spinal cord injury in rabbit model

    PubMed Central

    Liu, Zhi-Qiang; Zhang, Hong-Bin; Wang, Jian; Xia, Li-Jian; Zhang, Wei

    2015-01-01

    Ischemia/reperfusion (I/R) induced spinal cord injury is an important pathologic mechanism leading to the paraplegia observed after surgery to repairaortic aneurysms. This study aims to investigate the neuroprotective effects of Lipoxin A4 and its potential mechanism in a rabbit model with I/R spinal cord injury. Forty-five rabbits were randomly divided into three groups: sham group, I/R group and Lipoxin A4 group. Rabbits were subject to 30 min aortic occlusion to induce transient spinal cord ischemia. All animals were sacrificed after neurological evaluation with modified Tarlov criteria at the 48th hour after reperfusion, and the spinal cord segments (L4-6) were harvested for histopathological examination, as well as local malondialdehyde (MDA) and total superoxide dismutase (SOD) activity analysis. All animals in the I/R group became paraplegic. While after 48-hour treatment, compared with I/R group, Lipoxin A4 significantly improved neurological function, reduced cell apoptosis and MDA levels as well as increased SOD activity (P < 0.05). These results suggest that Lipoxin A4 can ameliorate I/R induced spinal cord injury in Rabbit through its antiapoptosis and antioxidant activity. PMID:26550197

  18. 26 CFR 1.410(a)-4 - Maximum age conditions and time of participation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Maximum age conditions and time of participation.... § 1.410(a)-4 Maximum age conditions and time of participation. (a) Maximum age conditions—(1) General...) if the plan excludes from participation (on the basis of age) an employee who has attained an...

  19. 26 CFR 1.410(a)-4 - Maximum age conditions and time of participation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Maximum age conditions and time of participation.... § 1.410(a)-4 Maximum age conditions and time of participation. (a) Maximum age conditions—(1) General...) if the plan excludes from participation (on the basis of age) an employee who has attained an...

  20. 26 CFR 1.410(a)-4 - Maximum age conditions and time of participation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Maximum age conditions and time of participation.... § 1.410(a)-4 Maximum age conditions and time of participation. (a) Maximum age conditions—(1) General...) if the plan excludes from participation (on the basis of age) an employee who has attained an...

  1. 26 CFR 1.662(a)-4 - Amounts used in discharge of a legal obligation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... extent of his legal obligation under local law. In the case of a parent's obligation to support his child... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Amounts used in discharge of a legal obligation... Which Distribute Corpus § 1.662(a)-4 Amounts used in discharge of a legal obligation. Any amount...

  2. BALLISTIC DISPERSION OF MK 80 SERIES BOMBS DELIVERED IN STICKS BY THE A- 4 AIRCRAFT

    DTIC Science & Technology

    The ballistic dispersion of low drag bombs dropped in sticks from the A-4 aircraft is calculated from test data. The data are inadeque to permit...determination of whether dispersion depends on slant range or time of fall, but an estimate can be made for delivery parameters of interest.

  3. 26 CFR 1.408A-4 - Converting amounts to Roth IRAs.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Converting amounts to Roth IRAs. 1.408A-4... Converting amounts to Roth IRAs. This section sets forth the following questions and answers that provide rules applicable to Roth IRA conversions: Q-1. Can an individual convert an amount in his or...

  4. 26 CFR 1.408A-4 - Converting amounts to Roth IRAs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Converting amounts to Roth IRAs. 1.408A-4... Converting amounts to Roth IRAs. This section sets forth the following questions and answers that provide rules applicable to Roth IRA conversions: Q-1. Can an individual convert an amount in his or...

  5. 26 CFR 1.408A-4 - Converting amounts to Roth IRAs.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Converting amounts to Roth IRAs. 1.408A-4 Section... Converting amounts to Roth IRAs. This section sets forth the following questions and answers that provide rules applicable to Roth IRA conversions: Q-1. Can an individual convert an amount in his or...

  6. Ileal impaction and jejunal enterotomy in a 4-month-old Arabian filly

    PubMed Central

    Davis, Heather A.; Munsterman, Amelia

    2012-01-01

    A 4-month-old Arabian filly was treated by surgical correction of an ileal impaction. The impaction was resolved through a distal jejunal enterotomy. One-year follow-up showed no post-operative complications secondary to the enterotomy. Jejunal enterotomy may be a surgical option for resolution of an ileal impaction. PMID:22753967

  7. Fatal methadone toxicity: potential role of CYP3A4 genetic polymorphism.

    PubMed

    Richards-Waugh, Lauren L; Primerano, Donald A; Dementieva, Yulia; Kraner, James C; Rankin, Gary O

    2014-10-01

    Methadone is difficult to administer as a therapeutic agent because of a wide range of interindividual pharmacokinetics, likely due to genetic variability of the CYP450 enzymes responsible for metabolism to its principal metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). CYP3A4 is one of the primary CYP450 isoforms responsible for the metabolism of methadone to EDDP in humans. The purpose of this study was to evaluate the role of CYP3A4 genetic polymorphisms in accidental methadone fatalities. A study cohort consisting of 136 methadone-only and 92 combined methadone/benzodiazepine fatalities was selected from cases investigated at the West Virginia and Kentucky Offices of the Chief Medical Examiner. Seven single nucleotide polymorphisms (SNPs) were genotyped within the CYP3A4 gene. Observed allelic and genotypic frequencies were compared with expected frequencies obtained from The National Center for Biotechnology Information dbSNP database. SNPs rs2242480 and rs2740574 demonstrated an apparent enrichment within the methadone-only overdose fatalities compared with the control group and the general population. This enrichment was not apparent in the methadone/benzodiazepine cases for these two SNPs. Our findings indicate that there may be two or more SNPs on the CYP3A4 gene that cause or contribute to the methadone poor metabolizer phenotype.

  8. Eco-Challenge: A 4-Week Approach to Eco-Action.

    ERIC Educational Resources Information Center

    Raines, J. Thayer

    1991-01-01

    Describes Challenge Wilderness Camp (Bradford, Vermont), a 4-week residential program designed to teach boys, ages 9-16, environmental ethics through first-hand experiences. The camp incorporates land and waste management policies and procedures; programs in outdoor skills instruction; and wilderness trips including backpacking, off-trail hiking,…

  9. 8 CFR 213a.4 - Actions for reimbursement, public notice, and congressional reports.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.4 Actions for... immigrant wants to seek reimbursement from a sponsor, household member, or joint sponsor, the program... (this is the date the sponsored immigrant became a permanent resident), the sponsored immigrant's...

  10. 8 CFR 213a.4 - Actions for reimbursement, public notice, and congressional reports.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.4 Actions for... immigrant wants to seek reimbursement from a sponsor, household member, or joint sponsor, the program... (this is the date the sponsored immigrant became a permanent resident), the sponsored immigrant's...

  11. 8 CFR 213a.4 - Actions for reimbursement, public notice, and congressional reports.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.4 Actions for... immigrant wants to seek reimbursement from a sponsor, household member, or joint sponsor, the program... (this is the date the sponsored immigrant became a permanent resident), the sponsored immigrant's...

  12. 8 CFR 213a.4 - Actions for reimbursement, public notice, and congressional reports.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.4 Actions for... immigrant wants to seek reimbursement from a sponsor, household member, or joint sponsor, the program... commenced (this is the date the sponsored immigrant became a permanent resident), the sponsored...

  13. 8 CFR 213a.4 - Actions for reimbursement, public notice, and congressional reports.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.4 Actions for... immigrant wants to seek reimbursement from a sponsor, household member, or joint sponsor, the program... commenced (this is the date the sponsored immigrant became a permanent resident), the sponsored...

  14. N-Heterocyclic Carbene Capture by Cytochrome P450 3A4.

    PubMed

    Jennings, Gareth K; Ritchie, Caroline M; Shock, Lisa S; Lyons, Charles E; Hackett, John C

    2016-07-01

    Cytochrome P450 3A4 (CYP3A4) is the dominant P450 enzyme involved in human drug metabolism, and its inhibition may result in adverse interactions or, conversely, favorably reduce the systemic elimination rates of poorly bioavailable drugs. Herein we describe a spectroscopic investigation of the interaction of CYP3A4 with N-methylritonavir, an analog of ritonavir, widely used as a pharmacoenhancer. In contrast to ritonavir, the binding affinity of N-methylritonavir for CYP3A4 is pH-dependent. At pH <7.4, the spectra are definitively type I, whereas at pH ≥7.4 the spectra have split Soret bands, including a red-shifted component characteristic of a P450-carbene complex. Variable-pH UV-visible spectroscopy binding studies with molecular fragments narrows the source of this pH dependence to its N-methylthiazolium fragment. The C2 proton of this group is acidic, and variable-pH resonance Raman spectroscopy tentatively assigns it a pKa of 7.4. Hence, this fragment of N-methylritonavir is expected to be readily deprotonated under physiologic conditions to yield a thiazol-2-ylidene, which is an N-heterocyclic carbene that has high-affinity for and is presumed to be subsequently captured by the heme iron. This mechanism is supported by time-dependent density functional theory with an active site model that accurately reproduces distinguishing features of the experimental UV-visible spectra of N-methylritonavir bound to CYP3A4. Finally, density functional theory calculations support that this novel interaction is as strong as the tightest-binding azaheterocycles found in P450 inhibitors and could offer new avenues for inhibitor development. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  15. Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers.

    PubMed

    DeVane, C Lindsay; Donovan, Jennifer L; Liston, Heidi L; Markowitz, John S; Cheng, Kenneth T; Risch, S Craig; Willard, Lauren

    2004-02-01

    An antidepressant for use in the patient receiving concomitant drug treatment, over-the-counter medications, or herbal products should lack cytochrome P-450 (CYP) 3A4 inductive or inhibitory activity to provide the least likelihood of a drug-drug interaction. This study addresses the potential of 4 diverse antidepressants (venlafaxine, nefazodone, sertraline, and fluoxetine) to inhibit or induce CYP3A4. In a 4-way crossover design, 16 subjects received clinically relevant doses of venlafaxine, nefazodone, or sertraline for 8 days or fluoxetine for 11 days. Treatments were separated by a 7- to 14-day washout period and fluoxetine was always the last antidepressant taken. CYP3A4 activity was evaluated for each subject at baseline and following each antidepressant using the erythromycin breath test (EBT) and by the pharmacokinetics of alprazolam (ALPZ) after 2-mg dose of oral ALPZ. Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism (P > 0.05). For nefazodone, a statistically significant inhibition was observed (P < 0.0005). Nefazodone was also the only antidepressant that caused a significant change in ALPZ disposition, decreasing its area under the concentration-versus-time curve (AUC; P < 0.01), and increasing its elimination half-life (16.4 vs. 12.3 hours; P < 0.05) compared with values at baseline. No significant differences were found in the pharmacokinetics of ALPZ with any of the other antidepressants tested. These results demonstrate in vivo that, unlike nefazodone, venlafaxine, sertraline, and fluoxetine do not possess significant metabolic inductive or inhibitory effects on CYP3A4.

  16. Polychlorinated biphenyl (PCB) induction of CYP3A4 enzyme activity in healthy Faroese adults

    SciTech Connect

    Petersen, Maria Skaalum Halling, Jonrit; Damkier, Per; Nielsen, Flemming; Grandjean, Philippe; Weihe, Pal; Brosen, Kim

    2007-10-15

    The CYP3A4 enzyme is, along with other cytochrome P450 enzymes, involved in the metabolism of environmental pollutants and is highly inducible by these substances. A commercial polychlorinated biphenyl (PCB) mixture, 1,1,1,-trichloro-2-(o-chlorophenyl), 2-(p'-chlorophenyl)ethane (o,p'-DDT) and 1,1,-dichloro-2,2-bis (p-chlorophenyl)ethene (p,p'-DDE) are known to induce CYP3A4 activity through activation of nuclear receptors, such as the pregnane X receptor. However, this induction of CYP3A4 has not yet been investigated in humans. Thus, the aim of the study was to determine the variability of the CYP3A4 phenotype in regard to increased concentrations of PCBs and other persistent organohalogen pollutants (POPs) in healthy Faroese adults. In 310 randomly selected Faroese residents aged 18-60 years, the CYP3A4 activity was determined based on the urinary 6{beta}-hydroxycortisol/cortisol (6{beta}-OHC/FC) ratio. POP exposures were assessed by measuring their concentrations in serum lipid. The results showed a unimodal distribution of the 6{beta}-OHC/FC ratio with values ranging from 0.58 to 27.38. Women had a slightly higher 6{beta}-OHC/FC ratio than men (p = 0.07). Confounder-adjusted multiple regression analysis showed significant associations between 6{beta}-OHC/FC ratios and {sigma}PCB, PCB-TEQ and p,p'-DDE, o,p'-DDT and HCB, respectively, but the associations were statistically significant for men only.

  17. Evidences for CYP3A4 autoactivation in the desulfuration of dimethoate by the human liver.

    PubMed

    Buratti, Franca M; Testai, Emanuela

    2007-11-20

    Dimethoate (DIM) is an organophosphorothionate (OPT) pesticide used worldwide as a systemic insecticide and acaricide. It is characterized by low-to-moderate acute mammalian toxicity; similarly to the other OPT pesticides, its mode of action is mediated by the inhibition of acetylcholinesterase (AChE), exerted by its toxic metabolite dimethoate-oxon or omethoate (OME), which is also used as a direct acting pesticide. Human hepatic DIM bioactivation to the toxic metabolite OME has been characterized by using c-DNA expressed human CYPs and human liver microsomes (HLM) also in the presence of CYP-specific chemical inhibitors, with a method based on AChE inhibition. The obtained kinetic parameters and AChE IC(50) have been compared with those previously obtained with other OPTs, indicating a lower efficiency in DIM desulfuration reaction and a lower potency in inhibiting AChE. Results showed that, similarly to the other OPTs tested so far, at low DIM concentration OME formation is mainly catalysed by CYP1A2, while the role of 3A4 is relevant at high DIM levels. Differently from the other OPTs, DIM desulfuration reaction showed an atypical kinetic profile, likely due to CYP3A4 autoactivation. The sigmoidicity degree of the activity curve increased with the level of CYP3A4 in HLM or disappeared in the presence of a CYP3A4 chemical inhibitor. This atypical kinetic behaviour can be considered one of the possible explanations for the recent findings that among patients hospitalized following OPT intoxication, DIM ingestion gave different symptoms and more severe poisoning (23.1% of fatal cases versus total) than chlorpyrifos (8% of deaths), which has a lower LD(50) value. Since DIM-poisoned patients poorly responded to pralidoxime, the possibility to use CYP3A4 inhibitors could be considered as a complementary treatment.

  18. SubCons: a new ensemble method for improved human subcellular localization predictions.

    PubMed

    Salvatore, M; Warholm, P; Shu, N; Basile, W; Elofsson, A

    2017-08-15

    Knowledge of the correct protein subcellular localization is necessary for understanding the function of a protein. Unfortunately large-scale experimental studies are limited in their accuracy. Therefore, the development of prediction methods has been limited by the amount of accurate experimental data. However, recently large-scale experimental studies have provided new data that can be used to evaluate the accuracy of subcellular predictions in human cells. Using this data we examined the performance of state of the art methods and developed SubCons, an ensemble method that combines four predictors using a Random Forest classifier. SubCons outperforms earlier methods in a dataset of proteins where two independent methods confirm the subcellular localization. Given nine subcellular localizations, SubCons achieves an F1-Score of 0.79 compared to 0.70 of the second best method. Furthermore, at a FPR of 1% the true positive rate (TPR) is over 58% for SubCons compared to less than 50% for the best individual predictor. SubCons is freely available as a webserver (http://subcons.bioinfo.se) and source code from https://bitbucket.org/salvatore_marco/subcons-web-server. The golden dataset as well is available from http://subcons.bioinfo.se/pred/download. arne@bioinfo.se. Supplementary data are available at Bioinformatics online.

  19. ConA-based glucose sensing using the long-lifetime azadioxatriangulenium fluorophore

    NASA Astrophysics Data System (ADS)

    Cummins, Brian; Simpson, Jonathan; Gryczynski, Zygmunt; Sørensen, Thomas Just; Laursen, Bo W.; Graham, Duncan; Birch, David; Coté, Gerard

    2014-02-01

    Fluorescent glucose sensing technologies have been identified as possible alternatives to current continuous glucose monitoring approaches. We have recently introduced a new, smart fluorescent ligand to overcome the traditional problems of ConA-based glucose sensors. For this assay to be translated into a continuous glucose monitoring device where both components are free in solution, the molecular weight of the smart fluorescent ligand must be increased. We have identified ovalbumin as a naturally-occurring glycoprotein that could serve as the core-component of a 2nd generation smart fluorescent ligand. It has a single asparagine residue that is capable of displaying an N-linked glycan and a similar isoelectric point to ConA. Thus, binding between ConA and ovalbumin can potentially be monovalent and sugar specific. This work is the preliminary implementation of fluorescently-labeled ovalbumin in the ConA-based assay. We conjugate the red-emitting, long-lifetime azadioxatriangulenium (ADOTA+) dye to ovalbumin, as ADOTA have many advantageous properties to track the equilibrium binding of the assay. The ADOTA-labeled ovalbumin is paired with Alexa Fluor 647-labeled ConA to create a Förster Resonance Energy Transfer (FRET) assay that is glucose dependent. The assay responds across the physiologically relevant glucose range (0-500 mg/dL) with increasing intensity from the ADOTA-ovalbumin, showing that the strategy may allow for the translation of the smart fluorescent ligand concept into a continuous glucose monitoring device.

  20. ConsPred: a rule-based (re-)annotation framework for prokaryotic genomes.

    PubMed

    Weinmaier, Thomas; Platzer, Alexander; Frank, Jeroen; Hellinger, Hans-Jörg; Tischler, Patrick; Rattei, Thomas

    2016-11-01

    The rapidly growing number of available prokaryotic genome sequences requires fully automated and high-quality software solutions for their initial and re-annotation. Here we present ConsPred, a prokaryotic genome annotation framework that performs intrinsic gene predictions, homology searches, predictions of non-coding genes as well as CRISPR repeats and integrates all evidence into a consensus annotation. ConsPred achieves comprehensive, high-quality annotations based on rules and priorities, similar to decision-making in manual curation and avoids conflicting predictions. Parameters controlling the annotation process are configurable by the user. ConsPred has been used in the institutions of the authors for longer than 5 years and can easily be extended and adapted to specific needs. The ConsPred algorithm for producing a consensus from the varying scores of multiple gene prediction programs approaches manual curation in accuracy. Its rule-based approach for choosing final predictions avoids overriding previous manual curations. ConsPred is implemented in Java, Perl and Shell and is freely available under the Creative Commons license as a stand-alone in-house pipeline or as an Amazon Machine Image for cloud computing, see https://sourceforge.net/projects/conspred/. thomas.rattei@univie.ac.atSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

    PubMed

    Apellániz-Ruiz, M; Inglada-Pérez, L; Naranjo, M E G; Sánchez, L; Mancikova, V; Currás-Freixes, M; de Cubas, A A; Comino-Méndez, I; Triki, S; Rebai, A; Rasool, M; Moya, G; Grazina, M; Opocher, G; Cascón, A; Taboada-Echalar, P; Ingelman-Sundberg, M; Carracedo, A; Robledo, M; Llerena, A; Rodríguez-Antona, C

    2015-06-01

    Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.

  2. Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA

    PubMed Central

    Lu, Ya-Jie; Yao, Jun; Wei, Qin-Jun; Xing, Guang-Qian; Cao, Xin

    2015-01-01

    Abstract Many SLC26A4 mutations have been identified in patients with nonsyndromic enlarged vestibular aqueduct (EVA). However, the roles of SLC26A4 genotypes and phenotypes in hereditary deafness remain unexplained. This study aims to perform a meta-analysis based on the PRISMA statement to evaluate the diagnostic value of SLC26A4 mutant alleles and their correlations with multiethnic hearing phenotypes in EVA patients. The systematic literature search of the PubMed, Wiley Online Library, EMBASE, Web of Science, and Science Direct databases was conducted in English for articles published before July 15, 2015. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (ORs) with 95% confidence interval (CI). Twenty-five eligible studies involved 2294 cases with EVA data. A total of 272 SLC26A4 variations were found in deafness with EVA and 26 mutations of SCL26A4 had higher frequency. The overall OR was 646.71 (95% CI: 383.30–1091.15, P = 0.000). A total of 22 mutants were considered statistically significant in all ethnicities (ORs >1, P < 0.05). In particular, 8 mutants were specificity of EVA phenotypes in mutations of SLC26A4 for Asia deafness populations (ORs >1, P < 0.05), 4 mutants for Europe and North America (ORs >1, P < 0.05), and the IVS7-2A>G mutations in SLC26A4 were found to have the highest frequency in deafness individuals with EVA phenotype (62.42%). Moreover, subgroups for studies limited to cases with EVA phenotype, 11 mutants relevant risks (RRs) were P < 0.05, especially for IVS7-2A>G bi-allelic mutants assayed in a deafness population (RR = 0.880, P = 0.000). Diagnostic accuracy of SLC26A4 mutation results also

  3. ConTour: Data-Driven Exploration of Multi-Relational Datasets for Drug Discovery.

    PubMed

    Partl, Christian; Lex, Alexander; Streit, Marc; Strobelt, Hendrik; Wassermann, Anne-Mai; Pfister, Hanspeter; Schmalstieg, Dieter

    2014-12-01

    Large scale data analysis is nowadays a crucial part of drug discovery. Biologists and chemists need to quickly explore and evaluate potentially effective yet safe compounds based on many datasets that are in relationship with each other. However, there is a lack of tools that support them in these processes. To remedy this, we developed ConTour, an interactive visual analytics technique that enables the exploration of these complex, multi-relational datasets. At its core ConTour lists all items of each dataset in a column. Relationships between the columns are revealed through interaction: selecting one or multiple items in one column highlights and re-sorts the items in other columns. Filters based on relationships enable drilling down into the large data space. To identify interesting items in the first place, ConTour employs advanced sorting strategies, including strategies based on connectivity strength and uniqueness, as well as sorting based on item attributes. ConTour also introduces interactive nesting of columns, a powerful method to show the related items of a child column for each item in the parent column. Within the columns, ConTour shows rich attribute data about the items as well as information about the connection strengths to other datasets. Finally, ConTour provides a number of detail views, which can show items from multiple datasets and their associated data at the same time. We demonstrate the utility of our system in case studies conducted with a team of chemical biologists, who investigate the effects of chemical compounds on cells and need to understand the underlying mechanisms.

  4. A Con A- purified hydatid glycoprotein fraction effectively diagnoses human hydatidosis.

    PubMed

    Kamel, Manal M; Maher, Kesmat M; Rabia, Ibrahim; Helmy, Ahmed H; El-Adawi, Azza I; Mousa, Mousa A; Mahgoub, Abeer M

    2006-12-01

    Diagnosis and quantification of Echinococcus granulosus infection in man and animal hosts are centralized to feasible control. This study included 93 serum samples, 25 sure positive hydatid cases confirmed surgically, 7 suspected cases diagnosed by indirect haemagglutination IHA and 41 cases other parasitic infections (15 S. mansoni, 8 Fasciola, 7 Ascaris, 5 H. nana & 6 Ancylostoma) diagnosed by microscopic examination and were negative by ELISA and/or IHA for anti-hydatid antibody. Twenty negative serum samples served as healthy controls. Six types of hydatid fluid antigens (crude, host-free & Con-A purified) of human and camel origin were subjected to electrophoretic separation (SDS-PAGE) and immunoblotting (EITB). The anti-hydatid IgG was detected in sera of the different groups for evaluation of sensitivity, specificity and diagnostic efficacy of each type of antigens. Detection of circulating hydatid antigen (CAg) was performed using anti rabbit hyperimmune sera raised against Con-A purified either human or camel hydatid antigen. SDS-PAGE revealed several bands ranging from 55-185 kDa with 10 kDa band shared by all antigens. The specific bands revealed by EITB for Con-A purified camel and human antigens were at 80, 110 & 55, 110 kDa respectively. ELISA highest sensitivity (96.9%) was by using host-free Con-A purified glycoprotein fraction of human hydatid antigen. Highest specificity (98.4%) was recorded upon use of either Con-A purified camel or human antigen with 94.5% & 97.7% diagnostic efficacy respectively. Detection of circulating antigen by polyclonal antibodies against Con-A purified human hydatid antigen revealed 91.8% specificity.

  5. Physician Preparation for the American Board of Emergency Medicine ConCert Examination.

    PubMed

    Marco, Catherine A; Wahl, Robert P; Counselman, Francis L; Heller, Barry N; Kowalenko, Terry; Harvey, Anne L; Joldersma, Kevin B; Reisdorff, Earl J

    2016-02-01

    To maintain certification by the American Board of Emergency Medicine (ABEM), physicians are required to pass the Continuous Certification (ConCert) examination at least every 10 years. On the 2014 ConCert postexamination survey, ABEM sought to understand the manner in which ABEM diplomates prepared for the test and to identify associations between test preparation approaches and performance on the ConCert examination. This was a cross-sectional survey study. The survey was administered at the end of the 2014 ConCert examination. Analyses included chi-square and linear regression to determine the association of preparation methods with performance. Of the 2,431 on-time test-takers, 2,338 (96.2%) were included. The most commonly used study approach was the review of written materials designed for test preparation (1,585; 67.8%), followed by an online training course (1,006; 43.0%). There were 758 (32.4%) physicians who took a single onsite board review course, while 41 (1.8%) took two or more onsite courses. Most physicians (1,611; 68.9%) spent over 35 hours preparing for the ConCert examination. The study method that was most associated with favorable test scores was the review of written materials designed for test preparation (p < 0.001). Attending an onsite preparation course was associated with poorer performance (p < 0.001). There was a significant association between no additional preparation and failing the examination (chi-square with Yates correction; p = 0.001). A substantial majority (97.8%) of physicians taking the 2014 ABEM ConCert examination prepared for it. The majority of physicians used written materials specifically designed for test preparation. Reviewing written materials designed for test preparation was associated with the highest performance. © 2016 by the Society for Academic Emergency Medicine.

  6. Non-zero θ _{13} and leptonic CP phase with A_4 symmetry

    NASA Astrophysics Data System (ADS)

    Sruthilaya, M.; Mohanta, R.

    2017-03-01

    We consider a model based on A_4 symmetry to explain the phenomenon of neutrino mixing. The spontaneous symmetry breaking of A_4 symmetry leads to a co-bimaximal mixing matrix at leading order. We consider the effect of higher order corrections in neutrino sector and find that the mixing angles thus obtained, come well within the 3σ ranges of their experimental values. We study the implications of this formalism on the other phenomenological observables, such as CP violating phase, Jarlskog invariant and the effective Majorana mass |M_{ee}|. We also obtain the branching ratio of the lepton flavour violating decay μ → e γ in the context of this model and find that it can be less than its present experimental upper bound.

  7. 10 Gbps transmission of electroabsorption modulators integrated with a 4-channel distributed Bragg reflector laser array

    NASA Astrophysics Data System (ADS)

    Ryu, Sang-Wan; Sim, Jae-Sik; Kwan, Yong-Hwan; Kim, Sung-Bock; Baek, Yong-Soon

    2008-05-01

    10 Gbps data transmission was demonstrated with electroabsorption modulators integrated with a 4-channel wavelength division multiplexing transmitter composed of distributed Bragg reflector (DBR) lasers. A selective area growth technique was employed for the control of bandgap energy in the gain, modulator and passive sections. Then the laser and modulator stripes were fabricated by a buried heterostructure process. The DBR lasers showed uniform threshold currents between 5 and 10 mA, while the slope efficiency was around 0.11 W A-1. By controlling the DBR currents, a 4-channel transmitter was achieved for the channel spacing of 100 GHz (0.8 nm). The electroabsorption modulator showed clear eye openings under 10 Gbps non-return-to-zero modulation. It allowed 10 Gbps error-free operation over a 25 km long single-mode fiber.

  8. The Rif GTPase regulates cytoskeletal signaling from plexinA4 to promote neurite retraction.

    PubMed

    Fan, Lifei; Yan, Huijuan; Pellegrin, Stephanie; Morigen; Mellor, Harry

    2015-03-17

    The small GTPase Rif is required for the early stages of dendritic spine formation in neurons, acting through the formin mDia2 to control actin polymerization. Rif is expressed at high levels in the brain, suggesting broader roles in neuronal function. We screened a yeast two-hybrid cDNA library to identify additional binding partners for Rif of potential relevance to neuronal function. We found that Rif interacts with FARP1, a neuronal activator of the RhoA GTPase. We show that Rif has two separate roles in FARP1 regulation-in controlling its association with plexinA4, and in releasing active RhoA from a plexinA4/FARP1 complex. The regulation of FARP1 by Rif promotes neurite retraction in cells stimulated with the semaphorin Sema6A.

  9. Molecular cloning and amino acid sequence of leukotriene A4 hydrolase.

    PubMed Central

    Funk, C D; Rådmark, O; Fu, J Y; Matsumoto, T; Jörnvall, H; Shimizu, T; Samuelsson, B

    1987-01-01

    A cDNA clone corresponding to leukotriene A4 hydrolase was isolated from a human lung lambda gt11 expression library by immunoscreening with a polyclonal antiserum. Several additional clones from human lung and placenta cDNA lambda g11 libraries were obtained by plaque hybridization with the 32P-labeled lung cDNA clone. One of these clones has an insert of 1910 base pairs that contains the complete protein-coding region. From the deduced primary structure, leukotriene A4 hydrolase is a 610 amino and protein with a calculated molecular weight of 69,140. No apparent homologies with microsomal epoxide hydrolases were found. RNA blot analysis indicated substantial amounts of a discrete mRNA of approximately equal to 2250 nucleotides in lung tissue and leukocytes. Images PMID:2821541

  10. Soluciones analiticas AL problema de jets con velocidad de eyeccion variable EN EL tiempo.

    NASA Astrophysics Data System (ADS)

    Canto, J.; Raga, A. C.; D'Alessio, P.

    1998-11-01

    Se presenta un nuevo metodo que permite resolver de manera exacta y analitica las ecuaciones que describen un jet hipersonico con velocidad de eyeccion variable en el tiempo. El metodo se basa en consideraciones sencillas de conservacion de momento para las superficies de trabajo que se forman en el interior del jet. Como ejemplo, se presentan soluciones para jets con variacion sinusoidal en la velocidad de eyeccion, y tambien para el caso de un incremento lineal en el tiempo. Estas soluciones analiticas tienen una clara aplicacion en la interpretacion de las observaciones de jets asociados a objetos Herbig-Haro.

  11. GeConT 2: gene context analysis for orthologous proteins, conserved domains and metabolic pathways.

    PubMed

    Martinez-Guerrero, C E; Ciria, R; Abreu-Goodger, C; Moreno-Hagelsieb, G; Merino, E

    2008-07-01

    The Gene Context Tool (GeConT) allows users to visualize the genomic context of a gene or a group of genes and their orthologous relationships within fully sequenced bacterial genomes. The new version of the server incorporates information from the COG, Pfam and KEGG databases, allowing users to have an integrated graphical representation of the function of genes at multiple levels, their phylogenetic distribution and their genomic context. The sequence of any of the genes can be easily retrieved, as well as the 5' or 3' regulatory regions, greatly facilitating further types of analysis. GeConT 2 is available at: http://bioinfo.ibt.unam.mx/gecont.

  12. [A 4-week intravenous toxicity study of the active metabolite (NM394) of prulifloxacin (NM441) in rats followed by a 4-week recovery test].

    PubMed

    Ishida, S; Iketani, M; Yamazaki, S; Tamura, K; Shindo, Y; Iwakura, K; Sumi, N

    1996-06-01

    A repeated dose toxicity study of ( +/- )-6- fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (NM394), the active metabolite of a new antibacterial agent, prulifloxacin, was conducted in Sprague-Dawley rats. Male and female rats were given the test material intravenously for 4 weeks at doses of 0 (control), 3, 10 and 30 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted. There were no treatment-related effects on survival, clinical signs, body weight and food consumption. Ophthalmoscopic and hematologic examinations failed to show any abnormalities related to the treatment. Increased water consumption was observed in the 10 and 30 mg/kg groups. In these dose groups, increased urine volume and lowered urine specific gravity, and crystalline substance and small epithelial cells in urinary sediments were seen. Cloudy urine was also seen in the 30 mg/kg group. Blood chemical examination showed decreased gamma-globulin in the 10 and 30 mg/kg groups and increased BUN and creatinine in the 30 mg/kg group. Pathological changes caused by the treatment were as follows. In kidney, tubular nephrosis with crystalline substance was observed in the 10 and 30 mg/kg groups and its organ weight was increased in the 30 mg/kg group. Cecal weight was increased in the 30 mg/kg group. The above-mentioned changes were reversible except for decreased gamma-globulin. Plasma levels and urinary concentrations of the test material were increased in all dose groups with dose-related manner, whereby no sex differences were observed. No effects caused by the repeated dosing were seen in the plasma concentrations. Toxicological findings were not observed in the 3 mg/kg group. The results show that the NOAEL of NM394 is 3 mg/kg for 4-week repeated dose toxicity in rats.

  13. In vitro metabolism of piperaquine is primarily mediated by CYP3A4.

    PubMed

    Lee, Tina Ming-Na; Huang, Liusheng; Johnson, Marla K; Lizak, Patricia; Kroetz, Deanna; Aweeka, Francesca; Parikh, Sunil

    2012-11-01

    Piperaquine (PQ) is part of a first-line treatment regimen for Plasmodium falciparum malaria recommended by the World Health Organization (WHO). We aimed to determine the major metabolic pathway(s) of PQ in vitro. A reliable, validated tandem mass spectrometry method was developed. Concentrations of PQ were measured after incubation with both human liver microsomes (HLMs) and expressed cytochrome P450 enzymes (P450s). In pooled HLMs, incubations with an initial PQ concentration of 0.3 µM resulted in a 34.8 ± 4.9% loss of substrate over 60 min, corresponding to a turnover rate of 0.009 min(-1) (r(2) = 0.9223). Miconazole, at nonspecific P450 inhibitory concentrations, resulted in almost complete inhibition of PQ metabolism. The greatest inhibition was demonstrated with selective CYP3A4 (100%) and CYP2C8 (66%) inhibitors. Using a mixture of recombinant P450 enzymes, turnover for PQ metabolism was estimated as 0.0099 min(-1); recombinant CYP3A4 had a higher metabolic rate (0.017 min(-1)) than recombinant CYP2C8 (p < .0001). Inhibition of CYP3A4-mediated PQ loss was greatest using the selective inhibitor ketoconazole (9.1 ± 3.5% loss with ketoconazole vs 60.7 ± 5.9% with no inhibitor, p < .0001). In summary, the extent of inhibition of in vitro metabolism with ketoconazole (83%) denotes that PQ appears to be primarily catalyzed by CYP3A4. Further studies to support these findings through the identification and characterization of PQ metabolites are planned.

  14. In vitro metabolism of piperaquine is primarily mediated by CYP3A4

    PubMed Central

    Lee, Tina Ming-Na; Huang, Liusheng; Johnson, Marla K.; Lizak, Patricia; Kroetz, Deanna; Aweeka, Francesca; Parikh, Sunil

    2016-01-01

    Piperaquine (PQ) is part of a first-line treatment regimen for Plasmodium falciparum malaria recommended by the World Health Organization (WHO). We aimed to determine the major metabolic pathway(s) of PQ in vitro. A reliable, validated tandem mass spectrometry method was developed. Concentrations of PQ were measured after incubation with both human liver microsomes (HLMs) and expressed cytochrome P450 enzymes (P450s). In pooled HLMs, incubations with an initial PQ concentration of 0.3 µM resulted in a 34.8 ± 4.9% loss of substrate over 60 min, corresponding to a turnover rate of 0.009 min−1 (r2 = 0.9223). Miconazole, at nonspecific P450 inhibitory concentrations, resulted in almost complete inhibition of PQ metabolism. The greatest inhibition was demonstrated with selective CYP3A4 (100%) and CYP2C8 (66%) inhibitors. Using a mixture of recombinant P450 enzymes, turnover for PQ metabolism was estimated as 0.0099 min−1; recombinant CYP3A4 had a higher metabolic rate (0.017 min−1) than recombinant CYP2C8 (p < .0001). Inhibition of CYP3A4-mediated PQ loss was greatest using the selective inhibitor ketoconazole (9.1 ± 3.5% loss with ketoconazole vs 60.7 ± 5.9% with no inhibitor, p < .0001). In summary, the extent of inhibition of in vitro metabolism with ketoconazole (83%) denotes that PQ appears to be primarily catalyzed by CYP3A4. Further studies to support these findings through the identification and characterization of PQ metabolites are planned. PMID:22671777

  15. Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4.

    PubMed

    Chesné, C; Guyomard, C; Guillouzo, A; Schmid, J; Ludwig, E; Sauter, T

    1998-01-01

    1. The metabolism of Meloxicam (ME) and the cytochrome(s) P450 (CYPs) involved were analysed by using primary human hepatocytes, human liver microsomes and microsomes from recombinant human B-lymphoblastoid cell lines. 2. While human hepatocytes were capable of converting ME to a 5-hydroxymethyl metabolite (M7) and then to a 5-carboxyderivative (M5), human liver microsomes formed mostly only the 5-hydroxymethylderivative. The kinetics of the formation of M7 by human liver microsomes were biphasic with Km = 13.6 +/- 9.5 and 381 +/- 55.2 microM respectively. The corresponding Vmax were 33.7 +/- 24.2 and 143 +/- 83.9 pmol/min/mg protein respectively. 3. CYP2C9 and, to a much lesser extent, CYP3A4 were found to convert ME to M7. The involvement of 2C9 was demonstrated by inhibition of tolbutamide hydroxylase activity in the presence of ME, inhibition of ME metabolism by sulphaphenazole, correlation between ME metabolism and tolbutamide hydroxylase activity and active metabolism of ME by recombinant 2C9. The involvement of 3A4 was shown by inhibition of ME metabolism by ketoconazole, correlation between ME metabolism and nifedipine oxidase activity and metabolism of ME by recombinant 3A4. Kinetics of the formation of M7 by the individual enzymes resulted in a Km = 9.6 microM and Vmax = 8.4 pmol/min/mg protein for 2C9 and a Km = 475 microM and Vmax = 23 pmol/min/mg protein for 3A4.

  16. Inflammatory epidermolysis bullosa acquisita in a 4-year-old girl.

    PubMed

    Lazić-Mosler, Elvira; Jukić, Ines Lakoš; Murat-Sušić, Slobodna; Husar, Karmela; Skerlev, Mihael; Bukvić Mokos, Zrinka; Ishii, Norito; Hashimoto, Takashi; Marinović, Branka

    2015-11-01

    This study presents a case of linear immunoglobulin A dermatosis-like epidermolysis bullosa acquisita in a 4-year-old girl showing rapid, widespread and inflammatory skin lesions. The diagnosis was confirmed by histopathology, direct and indirect immunofluorescence, various immunoblotting analyses and enzyme-linked immunosorbent assays. Despite the severe clinical manifestations, the disease was successfully controlled by combination therapy of oral prednisolone and dapsone. © 2015 Japanese Dermatological Association.

  17. A Space Imaging Concept Based on a 4-meter Spun-Cast Borosilicate Monolithic Primary Mirror

    DTIC Science & Technology

    2010-06-01

    borosilicate monolithic primary mirror 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Steve West, S.H... Mirror Technology Days, Boulder, Colorado, USA, 7-9 June 2010. 14. ABSTRACT The goal of this effort is to produce the largest monolithic telescope...capable of being lifted by a Delta IV or Atlas V EELV to 500 km. A strategy using a 4 m borosilicate mirror is proposed. A preliminary architecture was

  18. Compartment A4 hold at midplatform level, view from starboard to ...

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

    Compartment A-4 hold at mid-platform level, view from starboard to port shows protective deck framing and underside of armor plate. Open wood ceiling aids in circulating air. Note ventilation duct for fresh air at center of photograph. Open hatch penetrates protective deck and leads to bread room, compartment A-102. (012) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  19. Application of PGNAA for bulk coal samples in a 4pi geometry.

    PubMed

    Borsaru, M; Jecny, Z

    2001-03-01

    A 4pi geometry bulk coal analyser using the Prompt gamma neutron activation analysis (PGNAA) technique was tested in the laboratory. The volume of the bulk samples was 270 litres. A 1.5 microg 252Cf neutron source and a 75 mm x 35 mm dia BGO detector were used for the measurements. The ash, Fe, Si and Al content of coal were determined with good accuracy.

  20. EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From α-Cells.

    PubMed

    Hutchens, Troy; Piston, David W

    2015-11-01

    The loss of inhibition of glucagon secretion exacerbates hyperglycemia in type 1 and 2 diabetes. However, the molecular mechanisms that regulate glucagon secretion in unaffected and diabetic states remain relatively unexplained. We present evidence supporting a new model of juxtacrine-mediated regulation of glucagon secretion where neighboring islet cells negatively regulate glucagon secretion through tonic stimulation of α-cell EphA receptors. Primarily through EphA4 receptors, this stimulation correlates with maintenance of a dense F-actin network. In islets, additional stimulation and inhibition of endogenous EphA forward signaling result in inhibition and enhancement, respectively, of glucagon secretion, accompanied by an increase and decrease, respectively, in α-cell F-actin density. Sorted α-cells lack endogenous stimulation of EphA forward signaling from neighboring cells, resulting in enhanced basal glucagon secretion as compared with islets and the elimination of glucose inhibition of glucagon secretion. Restoration of EphA forward signaling in sorted α-cells recapitulates both normal basal glucagon secretion and glucose inhibition of glucagon secretion. Additionally, α-cell-specific EphA4(-/-) mice exhibit abnormal glucagon dynamics, and EphA4(-/-) α-cells contain less dense F-actin networks than EphA4(+/+) α-cells. This juxtacrine-mediated model provides insight into the functional and dysfunctional regulation of glucagon secretion and opens up new therapeutic strategies for the clinical management of diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  1. Reversible hydrogen adsorption on Co/N4 cluster embedded in graphene: The role of charge manipulation

    NASA Astrophysics Data System (ADS)

    Omidvar, Akbar

    2017-08-01

    Electrical charging of Co/N4 cluster embedded in graphene (Co/N4/G) is proposed as an approach for electrocatalytically switchable hydrogen adsorption. Using density functional theory, we found that the H2 molecule is weakly adsorbed on the uncharged Co/N4/G cluster. Our results show that the adsorption energy of hydrogen molecule on Co/N4/G cluster is significantly increased by introducing extra positive charges into the cluster. Once the charges are removed, H2 molecule spontaneously desorb from the Co/N4/G absorbent. Therefore, this approach promises both facile reversibility and tunable kinetics without the need of specific catalysts. Our study indicates that the Co/N4/G nanomaterial is excellent absorbent for controllable and reversible adsorption and release of H2.

  2. Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor.

    PubMed

    Masubuchi, Yasuhiro; Kawaguchi, Yuki

    2013-11-01

    Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is the inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI, sertraline, is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline directly to inhibit hepatic drug metabolism is relatively weak compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. The study examined whether sertraline produces time-dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6β-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting the formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with the reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with MI complex formation. Copyright © 2013 John Wiley & Sons, Ltd.

  3. Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A4

    PubMed Central

    Brigatte, Patrícia; Faiad, Odair Jorge; Ferreira Nocelli, Roberta Cornélio; Landgraf, Richardt G.; Palma, Mario Sergio; Cury, Yara; Curi, Rui; Sampaio, Sandra Coccuzzo

    2016-01-01

    We investigated the effects of Crotoxin (CTX), the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, on Walker 256 tumor growth, the pain symptoms associated (hyperalgesia and allodynia), and participation of endogenous lipoxin A4. Treatment with CTX (s.c.), daily, for 5 days reduced tumor growth at the 5th day after injection of Walker 256 carcinoma cells into the plantar surface of adult rat hind paw. This observation was associated with inhibition of new blood vessel formation and decrease in blood vessel diameter. The treatment with CTX raised plasma concentrations of lipoxin A4 and its natural analogue 15-epi-LXA4, an effect mediated by formyl peptide receptors (FPRs). In fact, the treatment with Boc-2, an inhibitor of FPRs, abolished the increase in plasma levels of these mediators triggered by CTX. The blockage of these receptors also abolished the inhibitory action of CTX on tumor growth and blood vessel formation and the decrease in blood vessel diameter. Together, the results herein presented demonstrate that CTX increases plasma concentrations of lipoxin A4 and 15-epi-LXA4, which might inhibit both tumor growth and formation of new vessels via FPRs. PMID:27190493

  4. [Involvement of cytochromeP4503A4 in the metabolism of haloperidol and bromperidol].

    PubMed

    Furukori, H

    1998-02-01

    To clarify the involvement of cytochromeP450 (CYP) 3A4 in the metabolism of haloperidol and bromperidol in humans, the effects of itraconazole, a potent inhibitor of CYP3A4, on steady-state plasma concentrations of both drugs and their reduced metabolites were investigated using 21 schizophrenic patients. Patients treated with haloperidol 12 or 24 mg/day (n = 13) or bromperidol 12 or 24 mg/day (n = 8) for at least 2 weeks were then given itraconazole 200 mg/day for 7 days. Blood samplings were performed before administration, 1 week during itraconazole coadministration and 1 week after its discontinuation together with clinical assessments. Plasma concentrations of haloperidol and bromperidol and their reduced metabolites were significantly higher during itraconazole treatment (P < 0.01). Deterioration in the neurological side effects of haloperidol was observed during itraconazole coadministration. Thus, this study suggests that itraconazole inhibits the metabolism of haloperidol and bromperidol, and that CYP3A4 is involved in the metabolism of both drugs.

  5. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor

    PubMed Central

    Pamplona, Fabricio A.; Ferreira, Juliano; Menezes de Lima, Octávio; Duarte, Filipe Silveira; Bento, Allisson Freire; Forner, Stefânia; Villarinho, Jardel G.; Bellocchio, Luigi; Wotjak, Carsten T.; Lerner, Raissa; Monory, Krisztina; Lutz, Beat; Canetti, Claudio; Matias, Isabelle; Calixto, João Batista; Marsicano, Giovanni; Guimarães, Marilia Z. P.; Takahashi, Reinaldo N.

    2012-01-01

    Allosteric modulation of G-protein–coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A4 is an endogenous allosteric enhancer of the CB1 cannabinoid receptor. Lipoxin A4 was detected in brain tissues, did not compete for the orthosteric binding site of the CB1 receptor (vs. 3H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A4 displayed a CB1 receptor-dependent protective effect against β-amyloid (1–40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB1 receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders. PMID:23150578

  6. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.

    PubMed

    Pamplona, Fabricio A; Ferreira, Juliano; Menezes de Lima, Octávio; Duarte, Filipe Silveira; Bento, Allisson Freire; Forner, Stefânia; Villarinho, Jardel G; Bellocchio, Luigi; Bellochio, Luigi; Wotjak, Carsten T; Lerner, Raissa; Monory, Krisztina; Lutz, Beat; Canetti, Claudio; Matias, Isabelle; Calixto, João Batista; Marsicano, Giovanni; Guimarães, Marilia Z P; Takahashi, Reinaldo N

    2012-12-18

    Allosteric modulation of G-protein-coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A(4) is an endogenous allosteric enhancer of the CB(1) cannabinoid receptor. Lipoxin A(4) was detected in brain tissues, did not compete for the orthosteric binding site of the CB(1) receptor (vs. (3)H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A(4) displayed a CB(1) receptor-dependent protective effect against β-amyloid (1-40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB(1) receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.

  7. A 4.1-Mb Congenic Region of Rf-4 Contributes to Glomerular Permeability

    PubMed Central

    O’Meara, Caitlin C.; Lutz, Michelle M.; Sarkis, Allison B.; Xu, Haiyan; Kothinti, Rajendra K.; Hoffman, Matthew; Moreno, Carol; Tabatabai, Niloofar M.; Lazar, Jozef; Roman, Richard J.

    2012-01-01

    The combined transfer of two renal function quantitative trait loci (QTLs), Rf-1 (rat chromosome 1) and Rf-4 (rat chromosome 14), from the Fawn-hooded hypertensive rat onto the August Copenhagen Irish genetic background significantly increases proteinuria and demonstrates an interaction between these QTLs. Because the original Rf-4 congenic region is 61.9 Mbp, it is necessary to reduce this interval to feasibly search for variants responsible for renal susceptibility in this region. Here, we generated a minimal congenic line (Rf-1a+4_a) to identify a 4.1-Mb region of the Rf-4 QTL that significantly contributes to the severity of proteinuria in the Fawn-hooded hypertensive rat. Rf-1a+4_a animals have an increased glomerular permeability to albumin without significant changes in BP, indicating that at least one genetic element in this refined region directly affects renal function. Sequence analysis revealed no variants predicted to damage protein function, implying that regulatory elements are responsible for the Rf-4 phenotype. Multiple human studies, including recent genome-wide association studies, link the homologous human region with susceptibility to renal disease, suggesting that this congenic line is an important model for studying pathways that contribute to the progression of kidney disease. PMID:22343117

  8. NOS3 gene variants and male infertility: Association of 4a/4b with oligoasthenozoospermia.

    PubMed

    Vučić, N L J; Nikolić, Z Z; Vukotić, V D; Tomović, S M; Vuković, I I; Kanazir, S D; Savić-Pavićević, D L J; Brajušković, G N

    2017-05-03

    Results of recent studies confirmed that oxidative stress negatively affects sperm motility and causes sperm DNA damage. Produced by nitric oxide synthase 3 (NOS3), nitric oxide is considered to be one of the important mediators of oxidative stress in testis tissue. The aim of this study was to assess the possible association of three genetic variants (rs2070744, rs1799983 and intron variant 4a/4b) in NOS3 gene and infertility occurrence in two groups of infertile men (idiopathic azoospermia and oligoasthenozoospermia) and fertile controls. Genotypes for the single-nucleotide genetic variants rs1799983 and rs2070744 were determined by PCR-RFLP, while genotyping of intron 4 variant 4a/4b was performed by gel electrophoresis of PCR products. Statistical analysis was performed by SNPStats software. No significant association between the three genetic variants of the NOS3 gene and infertility risk was determined comparing allele and genotype frequencies among group of patients diagnosed with azoospermia and the control group. Nevertheless, there was a significant positive association between 4a/4b and infertility in the group of males diagnosed with oligoasthenozoospermia, under overdominant genetic model. Our findings suggest that tandem repeat variant within intron 4 of the NOS3 gene is associated with an increased risk of infertility in men diagnosed with idiopathic oligoasthenozoospermia. © 2017 Blackwell Verlag GmbH.

  9. A 4-meter wide field coronagraph space telescope for general astrophysics and exoplanet observations

    NASA Astrophysics Data System (ADS)

    Tenerelli, Domenick; Angel, Roger; Burge, Jim; Guyon, Olivier; Zabludoff, Ann; Belikov, Ruslan; Pluzhnik, Eugene; Egerman, Robert

    2010-07-01

    The Wide Field Coronagraph Telescope (WFCT) is a 4-meter space telescope for general astrophysics and exoplanet observations that meets the 2000 Decadal Committee requirements. This paper presents a design for a 4-m diameter, off-axis space telescope that offers high performance in both wide field and coronagraphic imaging modes. A 3.8 x 3.3-m unobstructed elliptical pupil is provided for direct coronagraphic imaging of exoplanets and a 4-m diameter pupil for wide-field imaging from far-ultraviolet (UV) to near-infrared (IR). The off-axis wide-field optics are all reflective and designed to deliver an average of 12 nm wavefront aberrations over a 6 x 24 arcminute field of view (FOV), therefore providing diffraction-limited images down to 300 nm wavelength and 15 mas images down to a wavelength limit set only by the mirror coatings. The coronagraph with phase-induced amplitude apodization (PIAA) provides diffraction suppression around a 360-degree field with high Strehl and sensitivity at the 1e-10 level to an inner working angle of 2 λ/D (or 50 mas at 500 nm wavelength). This paper focuses on the optical design that allows the above imaging features to be combined in single telescope, and gives a preliminary spacecraft design and costing, assuming a distant trailing orbit.

  10. The computational model to predict accurately inhibitory activity for inhibitors towards CYP3A4.

    PubMed

    Xie, Zhiyuan; Zhang, Tao; Wang, Jing-Fang; Chou, Kuo-Chen; Wei, Dong-Qing

    2010-01-01

    The cytochrome P450 (CYP) is a superfamily of enzymes with oxidative function responsible for the metabolism of xenobiotics especially drug metabolism. CYP3A4, an extensive studied CYP isoform, plays crucial role in the metabolism of structurally diverse drugs. Furthermore, the drug-drug interaction resulted from the inhibition of CYP3A4 activity is of extreme importance for the treatment of disease and the development of new drug. In this study, using the method of the support vector machine (SVM) and three descriptors selected from the 153 descriptors we construct the models that can predict accurately the inhibitory effect of a compound on the activity of CYP3A4. By optimizing the parameters related to SVM, the cross validation correlation efficient of the model can achieve 0.71, which is higher than those of other models obtained using Artifical Neutral Network (ANN) and Partial least square (PLS) methods to our knowledge, and thus our model can present the important application in assessment of the potential toxicity of a drug as well as prediction of drug-drug interactions. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. Development of a highly reproducible system to evaluate inhibition of cytochrome P450 3A4 activity by natural medicines.

    PubMed

    Sato, Yu; Sasaki, Takamitsu; Takahashi, Shogo; Kumagai, Takeshi; Nagata, Kiyoshi

    2015-01-01

    In recent years, a number of natural medicines have been reported to have inductive or inhibitive effects on the activity of drug metabolizing enzymes, upon co-administration with prescribed medicines. However, information regarding natural medicine-drug interactions that influence drug metabolism is limited owing to the lack of efficient screening method for such interactions. Therefore, to understand whether P450 activity is affected by natural medicine in small intestines, we have established frozen recombinant P450-expressing cells infected with human CYP3A4 expressing adenovirus (Ad-CYP3A4) to evaluate the effect of natural medicines on CYP3A4 activity. Ad-CYP3A4 cells were created by infecting HepG2 cells with Ad-CYP3A4 at 10 multiplicity of infection (MOI) and these cells were stored using cryopreservation medium (fAd-CYP3A4 cells) to obtain long-term consistent data and stable supplies of cells expressing a constant level of CYP3A4 activity. The CYP3A4 activity in fAd-CYP3A4 cells remained unaffected at the end of each frozen period (0, 1, 2, and 6 months). Inhibitory effect on CYP3A4 activity by typical inhibitors (ketoconazole, hyperforin) and natural medicines (Cat's Claw, Devil's Claw, Feverfew, Peppermint Oil, Red Clover, and Siberian Eleuthero) were evaluated. The inhibitors had nearly equal IC50 values in fAd-CYP3A4 cells, Ad-CYP3A4 cells and recombinant CYP3A4 microsomes. Cat's Claw, Peppermint Oil and Siberian Eleuthero inhibited CYP3A4 activity more potently than 0.1 μM ketoconazole in fAd-CYP3A4 cells. In the present study, we have successfully developed a highly reproducible system to evaluate CYP3A4 inhibition in small intestines by natural medicines.

  12. Fungal lactone ring opening of 6', 7'-dihydroxybergamottin diminishes cytochrome P450 3A4 inhibitory activity

    USDA-ARS?s Scientific Manuscript database

    Furanocoumarins (FCs) are a class of aromatic compounds in grapefruit that inhibit human intestinal cytochrome P450 3A4 (CYP3A4). Since fungi metabolize polycyclic aromatic hydrocarbons, we hypothesized that certain fungi might also metabolize FCs into forms that may be inactive as CYP3A4 inhibitors...

  13. Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.

    PubMed

    Akiyoshi, Takeshi; Saito, Takashi; Murase, Saori; Miyazaki, Mitsue; Murayama, Norie; Yamazaki, Hiroshi; Guengerich, F Peter; Nakamura, Katsunori; Yamamoto, Koujirou; Ohtani, Hisakazu

    2011-04-01

    CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.

  14. An in vitro system for measuring genotoxicity mediated by human CYP3A4 in Saccharomyces cerevisiae.

    PubMed

    Fasullo, Michael; Freedland, Julian; St John, Nicholas; Cera, Cinzia; Egner, Patricia; Hartog, Matthew; Ding, Xinxin

    2017-05-01

    P450 activity is required to metabolically activate many chemical carcinogens, rendering them highly genotoxic. CYP3A4 is the most abundantly expressed P450 enzyme in the liver, accounting for most drug metabolism and constituting 50% of all hepatic P450 activity. CYP3A4 is also expressed in extrahepatic tissues, including the intestine. However, the role of CYP3A4 in activating chemical carcinogens into potent genotoxins is unclear. To facilitate efforts to determine whether CYP3A4, per se, can activate carcinogens into potent genotoxins, we expressed human CYP3A4 in the DNA-repair mutant (rad4 rad51) strain of budding yeast Saccharomyces cerevisiae and tested the novel, recombinant yeast strain for ability to report CYP3A4-mediated genotoxicity of a well-known genotoxin, aflatoxin B1 (AFB1 ). Yeast microsomes containing human CYP3A4, but not those that do not contain CYP3A4, were active in hydroxylation of diclofenac, a known CYP3A4 substrate drug, a result confirming CYP3A4 activity in the recombinant yeast strain. In cells exposed to AFB1 , the expression of CYP3A4 supported DNA adduct formation, chromosome rearrangements, cell death, and expression of the large subunit of ribonucleotide reductase, Rnr3, a marker of DNA damage. Expression of CYP3A4 also conferred sensitivity in rad4 rad51 mutants exposed to colon carcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). These data confirm the ability of human CYP3A4 to mediate the genotoxicity of AFB1 , and illustrate the usefulness of the CYP3A4-expressing, DNA-repair mutant yeast strain for screening other chemical compounds that are CYP3A4 substrates, for potential genotoxicity. Environ. Mol. Mutagen. 58:217-227, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  15. S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility

    SciTech Connect

    Chen, Na; Sato, Daisuke; Saiki, Yuriko; Sunamura, Makoto; Fukushige, Shinichi; Horii, Akira

    2014-05-09

    Highlights: • We observed frequent overexpression of S100A4 in lung cancer cell lines. • Knockdown of S100A4 suppressed proliferation in lung cancer cells. • Forced expression of S100A4 accelerated cell motility in lung cancer cells. • PRDM2 was found to be one of the downstream suppressed genes of S100A4. - Abstract: S100A4, a small calcium-binding protein belonging to the S100 protein family, is commonly overexpressed in a variety of tumor types and is widely accepted to associate with metastasis by regulating the motility and invasiveness of cancer cells. However, its biological role in lung carcinogenesis is largely unknown. In this study, we found that S100A4 was frequently overexpressed in lung cancer cells, irrespective of histological subtype. Then we performed knockdown and forced expression of S100A4 in lung cancer cell lines and found that specific knockdown of S100A4 effectively suppressed cell proliferation only in lung cancer cells with S100A4-overexpression; forced expression of S100A4 accelerated cell motility only in S100A4 low-expressing lung cancer cells. PRDM2 and VASH1, identified as novel upregulated genes by microarray after specific knockdown of S100A4 in pancreatic cancer, were also analyzed, and we found that PRDM2 was significantly upregulated after S100A4-knockdown in one of two analyzed S100A4-overexpressing lung cancer cells. Our present results suggest that S100A4 plays an important role in lung carcinogenesis by means of cell proliferation and motility by a pathway similar to that in pancreatic cancer.

  16. Impact of the ConRed program on different cyberbulling roles.

    PubMed

    Del Rey, Rosario; Casas, José A; Ortega, Rosario

    2016-01-01

    This article presents results from an evaluation of the ConRed cyberbullying intervention program. The program's impacts were separately determined for the different roles within cyberbullying that students can take, i.e., cyber-victims, cyber-bullies, cyber-bully/victims, and bystanders. The ConRed program is a theory-driven program designed to prevent cyberbullying and improve cyberbullying coping skills. It involves students, teachers, and families. During a 3-month period, external experts conducted eight training sessions with students, two with teachers and one with families. ConRed was evaluated through a quasi-experimental design, in which students from three secondary schools were separated into experimental and control groups. The sample comprised 875 students, aged between 11 and 19 years. More students (n = 586) were allocated to the experimental groups at the specific insistence of the management of all schools; the remainder (n = 289) formed the control. Repeated measures MANOVA showed that cyber victims, cyber aggressors and cyberbully/victims reduced their involvement in cyberbullying. Moreover, cyber-victims and bystanders adjusted their perceptions about their control of personal information on the Internet, and cyber aggressors and bystanders reduced their Internet dependence. The ConRed program had stronger effects on male participants, especially in heightening their affective empathy. © 2015 Wiley Periodicals, Inc.

  17. Mandated Mental Health Insurance: A Complex Case of Pros and Cons. Human Resources Series.

    ERIC Educational Resources Information Center

    Paterson, Andrea

    1986-01-01

    The pros and cons of state laws mandating mental health insurance are discussed in this report. The history of a 1985 Supreme Court case which held that states could mandate mental health benefits introduces the report. In an overview of the issue, the long-standing argument between the insurance industry and the mental health establishment is…

  18. [(Con)natal teeth: a role for maternity care and dental care].

    PubMed

    Gambon, D L

    2014-02-01

    A baby was referred to a dentist by an obstetrician 18 days after birth in connection with the presence of 2 teeth in the mandibula which resembled incisors. It appeared to be a case of 2 (con)natal teeth with a high degree of mobility. Dental treatment in the form of 2 extractions was necessary.

  19. Non Invasive Biomedical Analysis - Breath Networking Session at PittCon 2011, Atlanta, Georgia

    EPA Science Inventory

    This was the second year that our breath colleagues organized a networking session at the Pittsburgh Conference and Exposition or ''PittCon'' (http://www.pincon.org/).This time it was called "Non-invasive Biomedical Analysis" to broaden the scope a bit, but the primary focus rema...

  20. Silence, Metaperformance, and Communication in Pedro Almodóvar's "Hable con ella"

    ERIC Educational Resources Information Center

    Fellie, Maria C.

    2016-01-01

    Many scenes in Pedro Almodóvar's "Hable con ella" (2002) include shots of metaperformances such as silent films, dances, television shows, concerts, and bullfights. Spectators often observe passive characters who are in turn observing. By presenting these performances within cinematic performance, Almodóvar highlights our role as viewers…

  1. Wilderness for science: pros and cons of using wilderness areas for biological research

    Treesearch

    Diana L. Six; Paul Alaback; Robert A. Winfree; Delia Snyder; Anne Hagele

    2000-01-01

    Research is one of the intended purposes of wilderness. The Wilderness Act states that “wilderness may contain ecological, geological, or other features of scientific, educational, scenic, or historical value.” This session specifically focuses on the pros and cons of conducting research in wilderness.

  2. Are You Ready to Go Digital?: The Pros and Cons of Electronic Portfolio Development

    ERIC Educational Resources Information Center

    Heath, Marilyn

    2005-01-01

    There is an increasing need for educators to have professional portfolios, which are considered to be authentic tools for evaluating the knowledge, skill, beliefs and attitudes of prospective educators. Electronic portfolios are gaining in popularity and their relative pros and cons are examined.

  3. Silence, Metaperformance, and Communication in Pedro Almodóvar's "Hable con ella"

    ERIC Educational Resources Information Center

    Fellie, Maria C.

    2016-01-01

    Many scenes in Pedro Almodóvar's "Hable con ella" (2002) include shots of metaperformances such as silent films, dances, television shows, concerts, and bullfights. Spectators often observe passive characters who are in turn observing. By presenting these performances within cinematic performance, Almodóvar highlights our role as viewers…

  4. Non Invasive Biomedical Analysis - Breath Networking Session at PittCon 2011, Atlanta, Georgia

    EPA Science Inventory

    This was the second year that our breath colleagues organized a networking session at the Pittsburgh Conference and Exposition or ''PittCon'' (http://www.pincon.org/).This time it was called "Non-invasive Biomedical Analysis" to broaden the scope a bit, but the primary focus rema...

  5. End-User Use of Data Base Query Language: Pros and Cons.

    ERIC Educational Resources Information Center

    Nicholes, Walter

    1988-01-01

    Man-machine interface, the concept of a computer "query," a review of database technology, and a description of the use of query languages at Brigham Young University are discussed. The pros and cons of end-user use of database query languages are explored. (Author/MLW)

  6. Mandated Mental Health Insurance: A Complex Case of Pros and Cons. Human Resources Series.

    ERIC Educational Resources Information Center

    Paterson, Andrea

    1986-01-01

    The pros and cons of state laws mandating mental health insurance are discussed in this report. The history of a 1985 Supreme Court case which held that states could mandate mental health benefits introduces the report. In an overview of the issue, the long-standing argument between the insurance industry and the mental health establishment is…

  7. Are You Ready to Go Digital?: The Pros and Cons of Electronic Portfolio Development

    ERIC Educational Resources Information Center

    Heath, Marilyn

    2005-01-01

    There is an increasing need for educators to have professional portfolios, which are considered to be authentic tools for evaluating the knowledge, skill, beliefs and attitudes of prospective educators. Electronic portfolios are gaining in popularity and their relative pros and cons are examined.

  8. CHILES Con Pol: An ultra-deep JVLA survey probing galaxy evolution and cosmic magnetism

    NASA Astrophysics Data System (ADS)

    Hales, Christopher A.; Momjian, Emmanuel; van Gorkom, Jacqueline; Rupen, Michael P.; Greiner, Maksim; Ensslin, Torsten A.; Bonzini, Margherita; Padovani, Paolo; Harrison, Ian; Brown, Michael L.; Gim, Hansung; Yun, Min S.; Maddox, Natasha; Stewart, Adam; Fender, Rob P.; Tremou, Evangelia; Chomiuk, Laura; Peters, Charee; Wilcots, Eric M.; Lazio, Joseph

    2015-08-01

    We are undertaking a 1000 hour campaign with the Karl G. Jansky VLA to survey 0.2 square degrees of the COSMOS field in full polarization continuum at 1.4 GHz. Our observations are part of a joint program with the spectral line COSMOS HI Large Extragalactic Survey (CHILES). When complete, we expect our CHILES Continuum Polarization (CHILES Con Pol) survey to reach an SKA-era sensitivity of 500 nJy per 4 arcsecond resolving beam, the deepest view of the radio sky yet. CHILES Con Pol will open new and fertile parameter space, with sensitivity to star formation rates of 10 Msun per year out to an unprecedented redshift of z=2, and ultra-luminous infrared galaxies and sub-millimeter galaxies out to redshifts of z=8 and beyond. This rich resource will extend the utility of radio band studies beyond the usual radio quasar and radio galaxy populations, opening sensitivity to the starforming and radio-quiet AGN populations that form the bulk of extragalactic sources detected in the optical, X-ray, and infrared bands. In this talk I will outline the key science of CHILES Con Pol, including galaxy evolution and novel measurements of intergalactic magnetic fields. I will present initial results from the first 180 hours of the survey and describe our forthcoming Data Release 1. I invite the astronomical community to consider unique science that can be pursued with CHILES Con Pol radio data.

  9. Pros & Cons of Using Blackboard Collaborate for Blended Learning on Students' Learning Outcomes

    ERIC Educational Resources Information Center

    Hamad, Mona M.

    2017-01-01

    Blackboard Collaborate was introduced to King Khalid University recently in the last decade; instructors and students were trained to use it in an effective way. The objective of this study is to find pros and cons of using Blackboard Collaborate for Blended Learning and its effect on students' learning outcomes. The researcher used the…

  10. "Con todo mi corazón": Mentoring Latinas in Educational Leadership Doctoral Programs

    ERIC Educational Resources Information Center

    Rodríguez, Mariela A.

    2016-01-01

    Personal narrative essays were used to analyze the experiences of four Latina doctoral students who completed their first year in an educational leadership doctoral program in a Hispanic-Serving Institution (HSI) in the southwestern U.S. Four themes emerged from their "testimonios" 1) "Con todo el corazón"; 2) "Somos como…

  11. "Con todo mi corazón": Mentoring Latinas in Educational Leadership Doctoral Programs

    ERIC Educational Resources Information Center

    Rodríguez, Mariela A.

    2016-01-01

    Personal narrative essays were used to analyze the experiences of four Latina doctoral students who completed their first year in an educational leadership doctoral program in a Hispanic-Serving Institution (HSI) in the southwestern U.S. Four themes emerged from their "testimonios" 1) "Con todo el corazón"; 2) "Somos como…

  12. The Con Edison Emergency Child Care Plan for Management Employees: Summary Plan Description.

    ERIC Educational Resources Information Center

    Consolidated Edison Co., Brooklyn, NY.

    This summary plan description offers guidelines for participation in a pilot program that provides short-term emergency care for children of Con Edison managers who are under 13 years old. The plan offers professional, in-home child care that can be used when usual arrangements have collapsed. The summary plan description addresses the following…

  13. ConMap: Investigating New Computer-Based Approaches to Assessing Conceptual Knowledge Structure in Physics.

    ERIC Educational Resources Information Center

    Beatty, Ian D.

    There is a growing consensus among educational researchers that traditional problem-based assessments are not effective tools for diagnosing a student's knowledge state and for guiding pedagogical intervention, and that new tools grounded in the results of cognitive science research are needed. The ConMap ("Conceptual Mapping") project, described…

  14. A 4-week instructed minimalist running transition and gait-retraining changes plantar pressure and force.

    PubMed

    Warne, J P; Kilduff, S M; Gregan, B C; Nevill, A M; Moran, K A; Warrington, G D

    2014-12-01

    The purpose of this study is to compare changes in plantar pressure and force using conventional running shoes (CRS) and minimalist footwear (MFW) pre and post a 4-week MFW familiarization period. Ten female runners (age: 21 ± 2 years; stature: 165.8 ± 4.5 cm; mass: 55.9 ± 3.2 kg) completed two 11 km/h treadmill runs, 24 hours apart, in both CRS and MFW (pretest). Plantar data were measured using sensory insoles for foot strike patterns, stride frequency, mean maximum force ( M ⁢ F ¯ ), mean maximum pressure ( M ⁢ P ¯ ) and eight mean maximum regional pressures. Subjects then completed a 4-week familiarization period consisting of running in MFW and simple gait-retraining, before repeating the tests (posttest). During the pretests, 30% of subjects adopted a forefoot strike in MFW, following familiarization this increased to 80%; no change occurred in CRS. A significant decrease in M ⁢ F ¯ in both MFW and CRS (P = 0.024) was observed from pre-post, and a significant decrease in heel pressures in MFW. M ⁢ P ¯ was higher in MFW throughout testing (P < 0.001).A 4-week familiarization to MFW resulted in a significant reduction in M ⁢ F ¯ in both the CRS and MFW conditions, as well as a reduction in heel pressures. Higher M ⁢ P ¯ was observed throughout testing in the MFW condition.

  15. Conformational Mobility in Cytochrome P450 3A4 Explored by Pressure-Perturbation EPR Spectroscopy.

    PubMed

    Davydov, Dmitri R; Yang, Zhongyu; Davydova, Nadezhda; Halpert, James R; Hubbell, Wayne L

    2016-04-12

    We used high hydrostatic pressure as a tool for exploring the conformational landscape of human cytochrome P450 3A4 (CYP3A4) by electron paramagnetic resonance and fluorescence spectroscopy. Site-directed incorporation of a luminescence resonance energy transfer donor-acceptor pair allowed us to identify a pressure-dependent equilibrium between two states of the enzyme, where an increase in pressure increased the spatial separation between the two distantly located fluorophores. This transition is characterized by volume change (ΔV°) and P1/2 values of -36.8 ± 5.0 mL/mol and 1.45 ± 0.33 kbar, respectively, which corresponds to a Keq° of 0.13 ± 0.06, so that only 15% of the enzyme adopts the pressure-promoted conformation at ambient pressure. This pressure-promoted displacement of the equilibrium is eliminated by the addition of testosterone, an allosteric activator. Using site-directed spin labeling, we demonstrated that the pressure- and testosterone-sensitive transition is also revealed by pressure-induced changes in the electron paramagnetic resonance spectra of a nitroxide side chain placed at position 85 or 409 of the enzyme. Furthermore, we observed a pressure-induced displacement of the emission maxima of a solvatochromic fluorophore (7-diethylamino-3-((((2-maleimidyl)ethyl)amino)carbonyl) coumarin) placed at the same positions, which suggests a relocation to a more polar environment. Taken together, the results reveal an effector-dependent conformational equilibrium between open and closed states of CYP3A4 that involves a pronounced change at the interface between the region of α-helices A/A' and the meander loop of the enzyme, where residues 85 and 409 are located. Our study demonstrates the high potential of pressure-perturbation strategies for studying protein conformational landscapes.

  16. Screening of SLC26A4 gene in autoimmune thyroid diseases.

    PubMed

    Kallel, R; Niasme-Grare, M; Belguith-Maalej, S; Mnif, M; Abid, M; Ayadi, H; Masmoudi, S; Jonard, L; Hadj Kacem, H

    2013-08-01

    The Pendred syndrome (PS) gene, SLC26A4, was involved in the genetic susceptibility of autoimmune thyroid disease (AITD) in Tunisian population. Recently, functional assays have shown a differential expression of SLC26A4 gene between Graves' disease (GD) and Hashimoto's thyroiditis (HT). Here, by the mean of DHPLC and HRM, we explored the 21 exons and their flanking intronic sequences of 128 patients affected with GD (n = 64) or HT (n = 64). The pathogenic effect of identified variations on splice was investigated using the web server HSF. Eighteen allelic variations were identified and ranged on missense, sens and splice variations. Nine identified variations (c.-66C>G, c.898A>C, c.1002-9A>C, c.1061T>C, c.1544 + 9G>T, c.1545-5T>G, c.1790T>C, c.1826T>G, c.2139T>G) were previously reported in hearing impairment studies. Forty-seven per cent (30/64) of GD patients and 37,5% (24/64) of HT patients present at least one variant in the explored sequences. Moreover, the analysis of the variant distribution between HT (9 (5'UTR), 12 exonic and 13 intronic) and GD (18 (5'UTR), 13 exonic and 5 intronic) patients showed a significant difference (χ² = 6.54, 2df, P = 0.03). Interestingly, missense changes (I300L, p.M283I, F354S and p.L597S) affected conserved residues of pendrin. On the other hand, the HSF analyses ascertain that some variants identified in HT disease are predicted to have a pathogenic effect on splice. In conclusion, our analysis of SLC26A4 sequence variations suggested a distinct genetics basis between HT and GD patients, which should be confirmed on a large cohort.

  17. Conformational Mobility in Cytochrome P450 3A4 Explored by Pressure-Perturbation EPR Spectroscopy

    PubMed Central

    Davydov, Dmitri R.; Yang, Zhongyu; Davydova, Nadezhda; Halpert, James R.; Hubbell, Wayne L.

    2016-01-01

    We used high hydrostatic pressure as a tool for exploring the conformational landscape of human cytochrome P450 3A4 (CYP3A4) by electron paramagnetic resonance and fluorescence spectroscopy. Site-directed incorporation of a luminescence resonance energy transfer donor-acceptor pair allowed us to identify a pressure-dependent equilibrium between two states of the enzyme, where an increase in pressure increased the spatial separation between the two distantly located fluorophores. This transition is characterized by volume change (ΔV°) and P1/2 values of −36.8 ± 5.0 mL/mol and 1.45 ± 0.33 kbar, respectively, which corresponds to a Keq° of 0.13 ± 0.06, so that only 15% of the enzyme adopts the pressure-promoted conformation at ambient pressure. This pressure-promoted displacement of the equilibrium is eliminated by the addition of testosterone, an allosteric activator. Using site-directed spin labeling, we demonstrated that the pressure- and testosterone-sensitive transition is also revealed by pressure-induced changes in the electron paramagnetic resonance spectra of a nitroxide side chain placed at position 85 or 409 of the enzyme. Furthermore, we observed a pressure-induced displacement of the emission maxima of a solvatochromic fluorophore (7-diethylamino-3-((((2-maleimidyl)ethyl)amino)carbonyl) coumarin) placed at the same positions, which suggests a relocation to a more polar environment. Taken together, the results reveal an effector-dependent conformational equilibrium between open and closed states of CYP3A4 that involves a pronounced change at the interface between the region of α-helices A/A′ and the meander loop of the enzyme, where residues 85 and 409 are located. Our study demonstrates the high potential of pressure-perturbation strategies for studying protein conformational landscapes. PMID:27074675

  18. The a(4) Scheme-A High Order Neutrally Stable CESE Solver

    NASA Technical Reports Server (NTRS)

    Chang, Sin-Chung

    2009-01-01

    The CESE development is driven by a belief that a solver should (i) enforce conservation laws in both space and time, and (ii) be built from a nondissipative (i.e., neutrally stable) core scheme so that the numerical dissipation can be controlled effectively. To provide a solid foundation for a systematic CESE development of high order schemes, in this paper we describe a new high order (4-5th order) and neutrally stable CESE solver of a 1D advection equation with a constant advection speed a. The space-time stencil of this two-level explicit scheme is formed by one point at the upper time level and two points at the lower time level. Because it is associated with four independent mesh variables (the numerical analogues of the dependent variable and its first, second, and third-order spatial derivatives) and four equations per mesh point, the new scheme is referred to as the a(4) scheme. As in the case of other similar CESE neutrally stable solvers, the a(4) scheme enforces conservation laws in space-time locally and globally, and it has the basic, forward marching, and backward marching forms. Except for a singular case, these forms are equivalent and satisfy a space-time inversion (STI) invariant property which is shared by the advection equation. Based on the concept of STI invariance, a set of algebraic relations is developed and used to prove the a(4) scheme must be neutrally stable when it is stable. Numerically, it has been established that the scheme is stable if the value of the Courant number is less than 1/3

  19. Absence of a growth hormone effect on rat soleus atrophy during a 4-day spaceflight

    NASA Technical Reports Server (NTRS)

    Jiang, Bian; Roy, Roland R.; Navarro, Christine; Edgerton, V. R.

    1993-01-01

    The effect of a 4-day-long spaceflight on the size and the enzyme properties of soleus fibers of rats and the effects of exogenous growth hormone (GH) on the atrophic response of the soleus muscle were investigated in four groups of rats: (1) control, (2) control plus GH treatment, (3) flight, and (4) flight plus GH treatment. Results showed that the fiber size and the type of myosin heavy chain expressed fibers (but not the metabolic properties) of the soleus were affected by four days of weightlessness and that the effects were not ameliorated by the administration of growth hormone.

  20. An integrated map with cosmid/PAC contigs of a 4-Mb down syndrome critical region

    SciTech Connect

    Osoegawa, Kazutoyo; Susukida, Rie; Okano, Saishi

    1996-03-05

    The major phenotypic features of Down syndrome have been correlated with partial trisomies of chromosome 21, allowing us to define the candidate gene region to a 4-Mb segment on the 21q22.2 band. We present here a high resolution physical map with megabase-sized cosmid/PAC contigs. This ordered clone library has provided unique material for the integration of a variety of mappable objects, including exons, cDNAs, restriction sites etc. Furthermore, our results have emplified a strategy for the completion of the chromosome 21 map to sequencing. 42 refs., 5 figs.

  1. Rectal Bleeding and Abdominal Pain Following Vaccination in a 4-Month-Old Infant

    PubMed Central

    Posa, Molly R.; Kelly, Maria N.

    2017-01-01

    Intussusception is one of the most frequent causes of intestinal obstruction in infants. Rotavirus vaccination has been associated with intussusception in the medical literature. We report a case of a 4-month-old female with intussusception requiring hemicolectomy one week following rotavirus vaccination. We review the pathophysiology, presentation, and management of intussusception with a distinct focus on the history of rotavirus vaccination and risks of intussusception associated with timing of rotavirus vaccine administration. The discussion makes a strong case for rotavirus vaccine counseling regarding signs of intestinal obstruction and the importance of early recognition. PMID:28163948

  2. High-throughput fluorescence assay of cytochrome P450 3A4

    PubMed Central

    Cheng, Qian; Sohl, Christal D; Guengerich, F Peter

    2013-01-01

    Cytochrome P450 mono-oxygenases (P450s) are the principal enzymes involved in the oxidative metabolism of drugs and other xenobiotics. In this protocol, we describe a fluorescence-based, high-throughput assay for measuring the activity of P450 3A4, one of the key enzymes involved in drug metabolism. The assay involves the oxidative debenzylation of a substituted coumarin, yielding an increase in fluorescence on reaction. The entire procedure can be accomplished in 1 h or less. PMID:19661996

  3. Oxidase uncoupling in heme monooxygenases: Human cytochrome P450 CYP3A4 in Nanodiscs

    SciTech Connect

    Grinkova, Yelena V.; Denisov, Ilia G.; McLean, Mark A.; Sligar, Stephen G.

    2013-01-25

    Highlights: ► Substantial reducing equivalents are lost in human P450 CYP3A4 via an oxidase channel. ► Substrate binding has a pronounced effect on uncoupling in cytochrome P450. ► Anionic phospholipids improve the overall coupling in CYP3A4 Nanodiscs. -- Abstract: The normal reaction mechanism of cytochrome P450 operates by utilizing two reducing equivalents to reduce atmospheric dioxygen, producing one molecule of water and an oxygenated product in an overall stoichiometry of 2 electrons:1 dioxygen:1 product. However, three alternate unproductive pathways exist where the intermediate iron–oxygen states in the catalytic cycle can yield reduced oxygen products without substrate metabolism. The first involves release of superoxide from the oxygenated intermediate while the second occurs after input of the second reducing equivalent. Superoxide rapidly dismutates and hence both processes produce hydrogen peroxide that can be cytotoxic to the organism. In both cases, the formation of hydrogen peroxide involves the same overall stoichiometry as oxygenases catalysis. The key step in the catalytic cycle of cytochrome P450 involves scission of the oxygen–oxygen bond of atmospheric dioxygen to produce a higher valent iron-oxo state termed “Compound I”. This intermediate initiates a radical reaction in the oxygenase pathway but also can uptake two additional reducing equivalents from reduced pyridine nucleotide (NADPH) and the flavoprotein reductase to produce a second molecule of water. This non-productive decay of Compound I thus yields an overall oxygen to NADPH ratio of 1:2 and does not produce hydrocarbon oxidation. This water uncoupling reaction provides one of a limited means to study the reactivity of the critical Compound I intermediate in P450 catalysis. We measured simultaneously the rates of NADPH and oxygen consumption as a function of substrate concentration during the steady-state hydroxylation of testosterone catalyzed by human P450 CYP3A4

  4. Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity.

    PubMed

    Lv, Xuan; Pan, Liumeng; Wang, Jiaying; Lu, Liping; Yan, Weilin; Zhu, Yanye; Xu, Yiwen; Guo, Ming; Zhuang, Shulin

    2017-03-01

    Triazole fungicides are widely used as broad-spectrum fungicides, non-steroidal antiestrogens and for various industrial applications. Their residues have been frequently detected in multiple environmental and human matrices. The increasingly reported toxicity incidents have led triazole fungicides as emerging contaminants of environmental and public health concern. However, whether triazole fungicides behave as endocrine disruptors by directly mimicking environmental androgens/antiandrogens or exerting potential androgenic disruption indirectly through the inhibition of cytochrome P450 (CYP450) enzyme activity is yet an unresolved question. We herein evaluated five commonly used triazole fungicides including bitertanol, hexaconazole, penconazole, tebuconazole and uniconazole for the androgenic and anti-androgenic activity using two-hybrid recombinant human androgen receptor (AR) yeast bioassay and comparatively evaluated their effects on enzymatic activity of CYP3A4 by P450-Glo™ CYP3A4 bioassay. All five fungicides showed moderate anti-androgenic activity toward human AR with the IC50 ranging from 9.34 μM to 79.85 μM. The anti-androgenic activity remained no significant change after the metabolism mediated by human liver microsomes. These fungicides significantly inhibited the activity of CYP3A4 at the environmental relevant concentrations and the potency ranks as tebuconazole > uniconazole > hexaconazole > penconazole > bitertanol with the corresponding IC50 of 0.81 μM, 0.93 μM, 1.27 μM, 2.22 μM, and 2.74 μM, respectively. We found that their anti-androgenic activity and the inhibition potency toward CYP3A4 inhibition was significantly correlated (R(2) between 0.83 and 0.97, p < 0.001). Our results indicated that the risk assessment of triazole pesticides and structurally similar chemicals should fully consider potential androgenic disrupting effects and the influences on the activity of CYP450s.

  5. Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.

    PubMed

    Hsyu, Poe-Hirr; Pignataro, Daniela Soriano; Matschke, Kyle

    2017-01-01

    Bosutinib is an oral, dual Src and Abl tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to prior TKI therapy. Bosutinib is primarily metabolized by cytochrome P450 (CYP) 3A4, suggesting drug interaction potential with other CYP3A4 modulators. This open-label, randomized, 2-sequence, 2-period crossover study assessed the effect of single-dose aprepitant, a moderate CYP3A4 inhibitor, on the single-dose pharmacokinetic profile of oral bosutinib 500 mg. Nineteen healthy, fed adults received bosutinib (100 mg × 5) alone or coadministered with aprepitant (125 mg × 1) in each treatment period (with a ≥14-day washout); serial blood samples were analyzed. Safety was evaluated. Following coadministration of aprepitant with bosutinib, the area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) and maximum plasma concentration (C max) were higher than in bosutinib alone (AUCinf, 4719 and 2268 ng•h/mL; C max, 146.0 and 94.94 ng/mL). For bosutinib with aprepitant versus bosutinib alone, mean terminal elimination half-life was similar (25.99 vs 27.79 h), time to C max was longer (6.02 vs 4.15 h), and apparent oral clearance (CL/F) was decreased (105.9 vs 220.4 L/h). The ratio of adjusted geometric means of AUCinf and C max for bosutinib with aprepitant relative to bosutinib alone were 199 % (90 % confidence interval, 167-237 %) and 153 % (127-184 %), respectively. Both treatments were well tolerated. In healthy volunteers, administering a single dose of aprepitant increased the AUC and C max following a single dose of bosutinib by 99 and 53 %, respectively. These results are consistent with a moderate CYP3A4 inhibitor effect of aprepitant on bosutinib (Trial Registration: ClinicalTrials.gov NCT02058277).

  6. [Awake Nasotracheal Intubation for a 4-Year-old Boy with an Oral Penetrating Toothbrush Injury].

    PubMed

    Kobayashi, Naoya; Ando, Kokichi; Saito, Kazutomo; Toyama, Hiroaki; Fudeta, Hiroto; Yamauchi, Masanori

    2015-09-01

    We report a case of an oral penetrating injury caused by a toothbrush in a 4-year-old 17-kg boy. The toothbrush was lodged in the right cervical region through the oral cavity, and emergency surgery for removal was planned under general anesthesia. Although mask ventilation was not possible because of the protruding toothbrush handle, awake nasotracheal intubation was successfully performed with a fiber-scope and intravenous fentanyl 25 μg. We conclude that appropriate analgesics could facilitate awake intubation in pediatric patients.

  7. Cytotoxicities of a 4-META/MMA-TBBO resin against human pulp fibroblasts.

    PubMed

    Fujisawa, Seiichiro; Atsumi, Toshiko

    2004-06-01

    This study was designed to investigate the cytotoxicity of MMA (methyl methacrylate) and 4-META (4-methacryloyloxyethoxycarbonylphthalic anhydride)/MMA with or without TBBO (tri-n-butylborane partially oxide), an initiator and TBBO alone against human pulp fibroblasts (HPF). Cell viabilities were measured by MTT assay. The cytotoxicity of 4-META/MMA-TBBO was comparable with that of MMA-TBBO. TBBO showed higher cytotoxicity than 4-META/MMA. The cytotoxicity induction of a 4-META/MMA-TBBO resin may be preferably associated with TBBO.

  8. Noise Diode Stability Measurements Using a 4.3 GHz Laboratory Radiometer

    NASA Technical Reports Server (NTRS)

    Scherner, M. J.; Lawrence, R. W.

    1997-01-01

    The need for passive microwave radiometry using aperture synthesis and phased arrays for large apertures requiring more stability has generated several studies. The in-flight calibration and, therefore, the stability of such systems is an important design consideration. A 4.3 GHz laboratory radiometry operating in a balanced Dicke mode has been developed for making precise brightness (noise) temperature measurements. The stability of the noise diode source used in the noise-injection loop is of interest. A statistical Allan variance method to characterize the stability of the radiometer and the noise diode is presented in this paper. Noise measurements which demonstrate this approach are also included.

  9. Case Report: Traumatic anterior cerebral artery aneurysm in a 4-year old child

    PubMed Central

    Munakomi, Sunil; Tamrakar, Karuna; Chaudhary, Pramod; Bhattarai, Binod; Cherian, Iype

    2015-01-01

    Traumatic intracranial aneurysm in the proximal part of the anterior cerebral artery in the pediatric population has not been documented so far. Here we report the case of a 4 year-old child who developed a pseudo-aneurysm after minor head trauma and was managed successfully with trapping of the aneurysm. A ventriculo-peritoneal shunt was placed as the child became dependent on extraventricular drain during the post-operative period. The patient made excellent recovery in neurological status within 1 month of post-operative clinical follow up. PMID:27635218

  10. Hemophagocytosis in the Acute Phase of Fatal Kawasaki Disease in a 4 Month-Old Girl.

    PubMed

    Doğan, Vehbi; Karaaslan, Erhan; Özer, Samet; Gümüşer, Rüveyda; Yılmaz, Resul

    2016-07-01

    Kawasaki disease is a systemic vasculitis predominately affecting coronary arteries. Hemophagocytic lymphohistiocytosis can complicate the course of Kawasaki disease. Rare cases of secondary hemophagocytic lymphohistiocytosis occurring during the acute phase of Kawasaki disease have been reported. We report here a 4 month-old girl with diffuse coronary ectasia and secondary hemophagocytic lymphohistiocytosis occurring during the acute phase of incomplete Kawasaki disease. Due to the large overlap in clinical symptoms, the presence of atypical findings for Kawasaki disease should suggest the possible diagnosis of hemophagocytic lymphohistiocytosis in these patients.

  11. Absence of a growth hormone effect on rat soleus atrophy during a 4-day spaceflight

    NASA Technical Reports Server (NTRS)

    Jiang, Bian; Roy, Roland R.; Navarro, Christine; Edgerton, V. R.

    1993-01-01

    The effect of a 4-day-long spaceflight on the size and the enzyme properties of soleus fibers of rats and the effects of exogenous growth hormone (GH) on the atrophic response of the soleus muscle were investigated in four groups of rats: (1) control, (2) control plus GH treatment, (3) flight, and (4) flight plus GH treatment. Results showed that the fiber size and the type of myosin heavy chain expressed fibers (but not the metabolic properties) of the soleus were affected by four days of weightlessness and that the effects were not ameliorated by the administration of growth hormone.

  12. Ingestion of tea tree oil (Melaleuca oil) by a 4-year-old boy.

    PubMed

    Morris, Marilyn C; Donoghue, Aaron; Markowitz, Jennifer A; Osterhoudt, Kevin C

    2003-06-01

    A 4-year-old boy ingested a small quantity of tea tree oil. Within 30 minutes, he became ataxic and shortly thereafter progressed to unresponsiveness; he was endotracheally intubated by paramedics. His neurologic status improved gradually over 10 hours, and he remains well on follow-up. Tea tree oil is an increasingly popular topical antiseptic that is available in a wide variety of products, often without warning labels. Healthcare providers should be aware of the common uses of tea tree oil, as well as its potential toxicity.

  13. Where there's smoke there's fire--ear candling in a 4-year-old girl.

    PubMed

    Hornibrook, Jeremy

    2012-12-14

    It is estimated that one-third of the United States population subscribes to alternative medical therapies (Eisenberg et al, NEJM 1993;328:246-252). Ear candles are popular products promoted by alternative health practitioners, and sold by health shops and even over the Internet. They have been promoted for ear and sinus discomfort, rhinitis, sinusitis, glue ear, colds, flu, migraine, tinnitus, but particularly for removal of ear wax (cerumen). In this case report, a 4-year-old girl in New Zealand presents with otitis media and during the course of the ear examination white deposits were noticed on her eardrum; this was confirmed as being caused by ear candling.

  14. Optimizing Electrospray Interfaces Using Slowly Diverging Conical Duct (ConDuct) Electrodes

    PubMed Central

    Krutchinsky, Andrew N.; Padovan, Júlio C.; Cohen, Herbert; Chait, Brian T.

    2015-01-01

    We demonstrate that the efficiency of ion transmission from atmosphere to vacuum through stainless steel electrodes that contain slowly divergent conical duct (ConDuct) channels can be close to 100%. Here, we explore the properties of 2.5 cm long electrodes with angles of divergence of 0°, 1°, 2°, 3°, 5°, 8°, 13°, and 21°, respectively. The ion transmission efficiency was observed to jump from 10–20% for the 0° (straight) channels to 90–95% for channels with an angle of divergence as small as 1°. Furthermore, the 2–3° ConDuct electrodes produced extraordinarily low divergence ion beams that propagated in a laser-like fashion over long distances in vacuum. To take advantage of these newly discovered properties, we constructed a novel atmosphere-to-vacuum ion interface utilizing a 2° ConDuct as an inlet electrode and compared its ion transmission efficiency with that of the interface used in the commercial (Thermo) Velos Orbitrap and Q Exactive mass spectrometers. We observed that the ConDuct interface transmitted up to 17 times more ions than the commercial reference interface and also yielded improved signal-to-noise mass spectra of peptides. We infer from these results that the performance of many current atmosphere-tovacuum interfaces utilizing metal capillaries can be substantially improved by replacing them with 1° or 2° metal ConDuct electrodes, which should preserve the convenience of supplying ion desolvation energy by heating the electrode while greatly increasing the efficiency of ion transmission into the mass spectrometer. PMID:25667060

  15. Optimizing Electrospray Interfaces Using Slowly Diverging Conical Duct (ConDuct) Electrodes

    NASA Astrophysics Data System (ADS)

    Krutchinsky, Andrew N.; Padovan, Júlio C.; Cohen, Herbert; Chait, Brian T.

    2015-04-01

    We demonstrate that the efficiency of ion transmission from atmosphere to vacuum through stainless steel electrodes that contain slowly divergent conical duct (ConDuct) channels can be close to 100%. Here, we explore the properties of 2.5-cm-long electrodes with angles of divergence of 0°, 1°, 2°, 3°, 5°, 8°, 13°, and 21°, respectively. The ion transmission efficiency was observed to jump from 10-20% for the 0° (straight) channels to 90-95% for channels with an angle of divergence as small as 1°. Furthermore, the 2-3° ConDuct electrodes produced extraordinarily low divergence ion beams that propagated in a laser-like fashion over long distances in vacuum. To take advantage of these newly discovered properties, we constructed a novel atmosphere-to-vacuum ion interface utilizing a 2° ConDuct as an inlet electrode and compared its ion transmission efficiency with that of the interface used in the commercial (Thermo Fisher Scientific, San Jose, CA, USA) Velos Orbitrap and Q Exactive mass spectrometers. We observed that the ConDuct interface transmitted up to 17 times more ions than the commercial reference interface and also yielded improved signal-to-noise mass spectra of peptides. We infer from these results that the performance of many current atmosphere-to-vacuum interfaces utilizing metal capillaries can be substantially improved by replacing them with 1° or 2° metal ConDuct electrodes, which should preserve the convenience of supplying ion desolvation energy by heating the electrode while greatly increasing the efficiency of ion transmission into the mass spectrometer.

  16. ConMap - a new spatial data mining framework for terrain based digital soil mapping

    NASA Astrophysics Data System (ADS)

    Behrens, T.; Schmidt, K.; Scholten, T.

    2009-04-01

    In this talk, we present a new digital terrain analysis framework for digital soil mapping based on spatial data mining, referred to as the contextual elevation mapping (ConMap). Aiming at integrating different scales, which can be important at landscape scale level due to interrelations of topo- and climofunctions, it comprises local surface function approximations in terms of standard local terrain attributes as well as the incorporation of geomorphic arrangements within larger neighborhoods. In contrast to common digital terrain analysis of deriving multiple terrain attributes, ConMap is based on elevation differences from the center pixel to each pixel in a local neighborhood. These differences are then used as predictors in machine learning approaches such as Random Forests. Thus, it is not necessary to choose a specific set of terrain attributes. Additionally, possibly unknown surface functions can be taken into account, as well as larger geomorphic settings. We applied and validated the framework by predicting topsoil silt content for an area of 1150 km2 in Rhineland-Palatinate and Hesse, Germany, based on 342 samples, a 20 m resolution DEM, and neighborhood sizes up to 12 km. Cross-validation R2 values increase from 0.15 for standard digital terrain analysis to 0.61 using ConMap. This effect is due to a spatial trend in the data. As ConMap is able to map this trend and as it is based on the pedological concept of integrating scales it can be seen as a new entry to spatial prediction approaches such as Kriging or Geographically Weighted Regression. We conclude that ConMap shows a great potential for future digital soil mapping studies.

  17. Metastasin S100A4 is a mediator of sex hormone-dependent formation of the cortical bone.

    PubMed

    Erlandsson, Malin C; Bian, Li; Jonsson, Ing-Marie; Andersson, Karin M; Bokarewa, Maria I

    2013-08-01

    S100A4 is a Ca-binding protein participating in regulation of cell growth, survival, and motility. Here we studied the role of S100A4 protein in sex hormone-regulated bone formation. Bone mineral density in the trabecular and cortical compartments was evaluated in female S100A4 knockout (KO), in matched wild-type (WT) counterparts, and in WT mice treated with lentiviral small hairpin RNA construct inhibiting the S100A4 gene transcription or with a nontargeting construct, by peripheral quantitative computed tomography. The effect of sex hormones on bone was measured 5 weeks after ovariectomy (OVX) and/or dehydroepiadrosterone treatment. S100A4KO had an excessive trabecular and cortical bone formation compared with the age- and sex-matched WT mice. S100A4KO had an increased periosteal circumference (P = .001), cortical thickness (P = .056), and cortical area (P = .003), which predicted 20% higher bone strength in S100A4KO (P = .013). WT mice treated with small hairpin RNA-S100A4 showed an increase of the cortical bone parameters in a fashion identical with S100A4KO mice, indicating the key role of S100A4 in the changed bone formation. S100A4KO mice had higher serum levels of osteocalcin and a higher number of osteocalcin-positive osteoblasts under the periosteum. OVX-S100A4 resulted in the loss of the cortical bone supported by high CTX-I levels, whereas no such changes were observed in OVX-WT mice. S100A4KO mice resisted the dehydroepiadrosterone -induced bone formation observed in the WT counterparts. Our study indicates that S100A4 is a regulator of bone formation, which inhibits bone excess in the estrogen-sufficient mice and prevents the cortical bone loss in the estrogen-deprived mice.

  18. Moringa oleifera leaf extracts inhibit 6β-hydroxylation of testosterone by CYP3A4

    PubMed Central

    Monera, Tsitsi G.; Wolfe, Alan R.; Maponga, Charles C.; Benet, Leslie Z.; Guglielmo, Joseph

    2017-01-01

    Background Moringa oleifera is a tropical tree often used as a herbal medicine, including by people who test positive for HIV. Since herbal constituents may interact with drugs via inhibition of metabolizing enzymes, we investigated the effects of extracts of M. oleifera on the CYP3A4-mediated 6ß-hydroxylation of testosterone. Methods Methanolic and aqueous leaf and root of extracts of M. oleifera with concentrations between 0.01 and 10 mg/ml were incubated with testosterone and mixed-sex human liver microsomes in the presence of NADPH. Metabolite concentrations were determined by HPLC. The cytotoxicity of the extracts was tested with HepG2 cells using the MTT formazan assay. Results Significant CYP3A4 inhibitory effects were found, with IC50 values of 0.5 and 2.5 mg/ml for leaf-methanol and leaf-water extracts, respectively. Root extracts were less active. Cytotoxicity was observed only with the leaf-water extract (IC50 = 6 mg/ml). Conclusions Further investigation is warranted to elucidate the potential of M. oleifera for clinically significant interactions with antiretroviral and other drugs. PMID:19745507

  19. Protective Effects of Lipoxin A4 in Testis Injury following Testicular Torsion and Detorsion in Rats

    PubMed Central

    Zhou, Xian-Long; Yang, Qi-Sheng; Ni, Shao-Zhou; Tu, Xiao-Peng; Zhao, Yan; Xu, Bing; Pan, Zheng-Qi; Shen, Jun

    2014-01-01

    Purpose. To investigate the protective effects of lipoxin A4 (LXA4) in rat testis injury following testicular torsion/detorsion. Methods. A rat testicular torsion model has been established as described. Rats were randomly divided into 6 groups: sham group, torsion group, torsion/detorsion (T/D) group, and T/D plus LXA4-pretreated groups (3 subgroups). Rats in LXA4-pretreated groups received LXA4 injection (0.1, 1.0, and 10 μg/kg body weight in LXA4-pretreated subgroups 1–3, resp.) at a single dose 1 h before detorsion. Biochemical analysis, apoptosis assessment, and morphologic evaluation were carried out after orchiectomies. Results. GPx and SOD levels significantly increased and MDA levels significantly reduced in LXA4-pretreated groups compared to T/D group. LXA4 also reverted IL-2 and TNF-α to basal levels and improved the expression of IL-4 and IL-10 in LXA4-pretreated groups. Moreover, the expression of NF-κB was downregulated in LXA4-pretreated groups. LXA4 treatment also showed an improved testicular morphology and decreased apoptosis in testes. Conclusion. Lipoxin A4 protects rats against testes injury after torsion/detorsion via modulation of cytokines, oxidative stress, and NF-κB activity. PMID:24904198

  20. Mechanical Design of a 4-Stage ADR for the PIPER mission

    NASA Technical Reports Server (NTRS)

    James, Bryan L.; Kimball, Mark O.; Shirron, Peter J.; Sampson, Michael A.; Letmate, Richard V.; Jackson, Michael L.

    2017-01-01

    The four 1,280 bolometer detector arrays that will fly on the balloon borne PIPER mission will be cooled by a 4-stage adiabatic demagnetization refrigerator (ADR). Two of the three mechanically independent ADR assemblies provide thermal isolation to their salt pills through Kevlar suspensions while the other provides thermal isolation to its salt pill through the use of bellows and Vespel material. The ADR integrates with the detector arrays and it sits in a large bucket Dewar containing superfluid liquid helium. This paper will describe the complex mechanical design of the PIPER ADR, and summarize the mechanical analysis done to validate the design.The four 1,280 bolometer detector arrays that will fly on the balloon borne PIPER mission will be cooled by a 4-stage adiabatic demagnetization refrigerator (ADR). Two of the three mechanically independent ADR assemblies provide thermal isolation to their salt pills through Kevlar suspensions while the other provides thermal isolation to its salt pill through the use of bellows and Vespel material. The ADR integrates with the detector arrays and it sits in a large bucket Dewar containing superfluid liquid helium. This paper will describe the complex mechanical design of the PIPER ADR, and summarize the mechanical analysis done to validate the design.