EC galndular, Feb,2014gynonco
欧盟六价铬法规2014
II(Non-legislative acts)REGULATIONSCOMMISSION REGULATION (EU) No 301/2014of 25 March 2014amending Annex XVII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) asregards chromium VI compounds(Text with EEA relevance)THE EUROPEAN COMMISSION,Having regard to the Treaty on the Functioning of the European Union,Having regard to Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94, as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC,93/67/EEC, 93/105/EC and 2000/21/EC ( 1 ), and in particularArticle 68(1) thereof, Whereas:(1) On 19 January 2012, the Kingdom of Denmarksubmitted to the European Chemicals Agency (hereinafter‘Agency’) a dossier pursuant to Article 69(4) of Regu lation (EC) No 1907/2006, in order to initiate the restrictions process in accordance with Articles 69 to 73 of that Regulation (hereinafter ‘Annex XV dossier’). In that dossier, it was demonstrated that exposure to chromium VI, when contained in leather articles or leather parts of articles coming into contact with the skin, poses a risk to human health. Chromium VI compounds can induce new cases of sensitisation and elicit allergic response. The dossier demonstrates that action on a Union-wide basis is necessary.(2) Chromium VI compounds can be formed in leatherthrough the oxidation of chromium III compounds,which are added in some tanning processes to cross- link the collagen subunits in order to increase leather’s dimensional stability, as well as its resistance to mech anical action and heat. According to the Annex XV dossier, the mechanisms of and conditions under which chromium VI is formed are known and most tanneries inthe Union have already developed and widely imple mented measures in order to control and minimise its formation.(3) On 28 November 2012 the Committee for RiskAssessment (hereinafter ‘RAC’) adopted by consensusthe opinion on the restriction proposed in the Annex XV dossier. According to the RAC opinion, the restriction is the most appropriate Union-wide measure to address the identified risks posed by chromium VI compounds in leather, both in terms of effectiveness and practicability. However, in its opinion RAC proposed to modify the restriction by deleting the notion of direct and prolonged contact with the skin, originally included in the Annex XV dossier.(4) The proposed restriction focuses on the risk of inductionof skin sensitisation related to direct or indirect skin contact with leather articles or leather parts of articles containing chromium VI. In already sensitised people, such contacts may also elicit allergic response at lower concentrations than those needed for the induction of sensitisation.(5) Theproposed restriction should cover leather articles and articles containing leather parts used by consumers or workers, that under normal or reasonably foreseeable conditions of use come into contact with the skin.(6) TheEN ISO 17075 standard method is the only inter nationally recognised analytical method currently available to detect chromium VI in leather, including leather in articles. The determination limit of the EN ISO 17075 standard method is 3 mg/kg (0,0003 % by weight) of chromium VI content in the total dry weight of the leather. Fixing such threshold for the restriction of the placing on the market of leather articles or articles containing leather parts is therefore justified for monitor ability and enforceability purposes.Journal of the European UnionL 90/1( 1 ) OJ L 396, 30.12.2006, p. 1.(7)According to the RAC opinion, the threshold of 3 mg/kg(0,0003 % by weight) of chromium VI content in the total dry weight of the leather corresponds to exposures higher than the Lowest-Observed Adverse Effect Level for elicitation. According to the opinion of RAC, that threshold is expected to be 80 % effective in reducing the occurrence of new chromium VI-related allergic dermatitis cases due to chromium VI in leather articles.(8)The effectiveness of the restriction on the number of cases of chromium allergy can be determined by moni toring cases of chromium VI-related allergic dermatitis. Should the prevalence of the allergy not decrease, or should an analytical method to detect lower content of chromium VI become available and be recognised as reliable, this restriction should be reviewed.(9) On6 March 2013 the Committee for Socio-Economic Analysis (hereinafter ‘SEAC’) adopted by consensus the opinion on the restriction proposed in the Annex XV dossier. According to the SEAC opinion, the restriction, as modified by RAC, is the most appropriate Union-wide measure to address the identified risks in terms of the proportionality of its socioeconomic benefits to its socioeconomic costs.(10) TheForum for Exchange of Information on Enforcement was consulted during the restrictions process. (11) On8 April 2013 the Agency submitted to the Commission the opinions of RAC and SEAC based on which the Commission concluded that an unacceptable risk to human health arose where chromium VI compounds were present in leather articles and articles containing leather parts, coming into contact with the skin, which needs to be addressed on a Union-wide basis. The socioeconomic impacts of this restriction, including the availability of alternatives, have been taken into account.(12) The restriction on the placing on the market of second-hand articles would impose a disproportionate burden on the consumers re-selling these articles. Furthermore, due to the nature of those transactions, such restriction would be difficult to enforce. Therefore, this restriction should not apply to leather articles or articles containing leather parts which were in end-use in the Union before this Regulation applies.(13) Itis appropriate to provide for a period of 12 months after the entry into force of this Regulation for the stake holders concerned to take measures to comply with this Regulation, including addressing articles that are already in the supply chain, including in stocks.(14) Regulation(EC) No 1907/2006 should therefore be amended accordingly. (15) Themeasures provided for in this Regulation are in accordance with the opinion of the Committee estab lished under Article 133 of Regulation (EC) No 1907/2006,HAS ADOPTED THIS REGULATION:Article 1Annex XVII to Regulation (EC) No 1907/2006 is amended in accordance with the Annex to this Regulation.Article 2This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union .It shall apply from 1 May 2015.This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Brussels, 25 March 2014.For the Commission The PresidentJosé Manuel BARROSOL 90/2Official Journal of the European Union 26.3.2014ANNEXIn Annex XVII to Regulation (EC) No 1907/2006, the following paragraphs 5, 6 and 7 are added to column 2 ofentry 47:Journal of the European UnionL 90/3。
(EU) No 358 2014 欧盟化妆品法规修订
COMMISSION REGULATION (EU) No 358/2014of 9 April 2014amending Annexes II and V to Regulation (EC) No 1223/2009 of the European Parliament and ofthe Council on cosmetic products(Text with EEA relevance)THE EUROPEAN COMMISSION,Having regard to the Treaty on the Functioning of the European Union,Having regard to Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products (1), and in particular Article 31(1) thereof,Whereas:(1) Entry 25 of Annex V to Regulation (EC) No 1223/2009 specifies a maximum concentration of 0,3 % in relationto the use of triclosan as a preservative in cosmetic products.(2) The Scientific Committee on Consumer Products (SCCP), subsequently replaced by the Scientific Committee onConsumer Safety (SCCS) pursuant to Commission Decision 2008/721/EC (2), adopted an opinion on the safety of triclosan for human health in January 2009 (3), followed by an addendum of March 2011 (4).(3) The SCCP considered that the continued use of triclosan as a preservative at the current maximum concentrationlimit of 0,3 % in all cosmetic products is not safe for the consumer because of the magnitude of the aggregate exposure, and the SCCS confirmed this position. However, the SCCP considered that its use at a maximum concentration of 0,3 % in toothpastes, hand soaps, body soaps/shower gels and deodorants, face powders and blemish concealers is safe. In addition, the SCCS considered that other uses of triclosan in nail products where the intended use is to clean the fingernails and toenails before the application of artificial nail systems at a maximum concentration of 0,3 % and in mouthwashes at a maximum concentration of 0,2 % are safe for the consumer.(4) In light of the SCCS opinions mentioned above, the Commission considers that maintaining the restriction onthe use of triclosan at its current level would raise a potential risk to human health. The additional restrictions suggested by the SCCP and the SCCS should therefore be implemented in Annex V to Regulation (EC) No 1223/2009.(5) Entry 12 of Annex V to Regulation (EC) No 1223/2009 specifies a maximum concentration of 0,4 % for singleester and 0,8 % for mixtures of esters in relation to the use of parabens as preservatives in cosmetic products, under the denomination 4-hydroxybenzoic acid and its salts and esters.(6) The SCCS adopted an opinion on parabens in December 2010 (5), followed by a clarification of October 2011 (6)in response to a unilateral decision by Denmark to ban propylparaben and butylparaben, their isoforms and their salts in cosmetic products for children under three years of age based on their potential endocrine activity, taken in accordance with Article 12 of Council Directive 76/768/EEC (7).(7) The SCCS confirmed that methylparaben and ethylparaben are safe at the maximum authorised concentrations.In addition, the SCCS noted that limited or no information was submitted by industry for the safety evaluation of isopropylparaben, isobutylparaben, phenylparaben, benzylparaben and pentylparaben. As a result, for these compounds, the human risk cannot be evaluated. Therefore, those substances should no longer be listed in Annex V and, given that they might be used as antimicrobial agents, they should be listed in Annex II to make clear that they are prohibited in cosmetic products.(1)OJ L 342, 22.12.2009, p. 59.(2)Commission Decision 2008/721/EC of 5 August 2008 setting up an advisory structure of Scientific Committees and experts in the fieldof consumer safety, public health and the environment and repealing Decision 2004/210/EC (OJ L 241, 10.9.2008, p. 21).(3)SCCP/1192/08, http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_166.pdf(4)SCCS/1414/11, http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_054.pdf(5)SCCS/1348/10 Revision 22 March 2011.(6)SCCS/1446/11.(7)OJ L 262, 27.9.1976, p. 169.(8) The conclusions the SCCS drew in the same opinions on propylparaben and butylparaben were challenged by astudy carried out by the French authorities (1), therefore a further risk assessment of those two substances was adopted by the SCCS in May 2013 (2). Measures on propylparaben and butylparaben are under preparation, as a second step in the risk management of parabens.(9) No concerns were raised on the safety of 4-Hydroxybenzoic acid and its salts (calcium paraben, sodium paraben,potassium paraben).(10) The relevant annexes to Regulation (EC) No 1223/2009 should therefore be amended accordingly.(11)The application of the above-mentioned restrictions should be deferred to allow the industry to make the necessary adjustments to product formulations. In particular, undertakings should be granted six months to place on the market compliant products, and 15 months to stop making available on the market non-compliant products after the entry into force of this Regulation, in order to allow existing stocks to be exhausted.(12) The measures provided for in this Regulation are in accordance with the opinion of the Standing Committee onCosmetic Products,HAS ADOPTED THIS REGULATION:Article 1Annexes II and V to Regulation (EC) No 1223/2009 are amended in accordance with the Annex to this Regulation.Article 2From 30 October 2014 only cosmetic products which comply with this Regulation shall be placed on the Union market.From 30 July 2015 only cosmetic products which comply with this Regulation shall be made available on the Union market.Article 3This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.This Regulation shall be binding in its entirety and directly applicable in all Member States.Done at Brussels, 9 April 2014.For the CommissionThe PresidentJosé Manuel BARROSO(1)Gazin V., Marsden E., Briffaux J-P (2012), Propylparaben: 8-week postweaning juvenile toxicity study with 26-week treatment free periodin male Wistar rat by the oral route (gavage) Poster SOT Annual Meeting San Francisco USA — Abstract ID 2359*327.(2)SCCS/1514/13.ANNEXThe annexes to Regulation (EC) No 1223/2009 are amended as follows: (1) in Annex II the following entries 1374 to 1378 are added:(2) Annex V is amended as follows:(a) entry 12 is replaced by the following:10.4.2014L 107/8Official Journal ofthe European Union(b) entry 25 is replaced by the following:10.4.2014L 107/9Official Journal ofthe European Union。
CTEK COMFORT CONNECT电池充电器说明书
E SCÓMO CARGAR1. Conecte el cargador a la batería. Los pilotos 4, 5 y 6 ahora empiezan a parpadear para indicar el programa COMPROBAR TENSIÓN. No lo tenga en cuenta y prosiga con la siguiente etapa.2. Enchufe el cargador al enchufe de pared. El piloto de encendido indicará si el cable de alimentación está enchufado al enchufe de pared. El piloto de error indica si las pinzas de la batería están mal conectadas. La protección contra polaridad inversa garantiza que ni la batería ni el cargador sufrirán daños.3. Pulse el botón MODE para seleccionar el programa de carga.PROGRAMA PARA BATERíAS PEqUEñASPROGRAMA PARA BATERíAS ORDINARIASSiga pulsando el botón MODE para combinar el programa de carga con las opciones de carga.OPCIÓN PARA TIEMPO FRíOOPCIÓN REC O ND (REGENERACIÓN)Pulse el botón MODE varias veces hasta que se iluminen la combinación de pro -grama de carga y opciones que desee.4. Siga el proceso de carga a través del indicador de 8 etapas.La batería estará lista para arrancar el motor cuando se encienda la ETAPA 4. La batería estará totalmente cargada cuando se encienda la ETAPA 7.5. Para interrumpir la carga en cualquier instante, desenchufe el cable de alimentación del enchufe de pared.Nota: si en el cargador se encienden el piloto (10) START POWER (Energía de arranque) y el piloto (4) MAL, pulse el botón MODE durante dos segundos para salir de VOLTAGE TEST PROGRAM (Programa comprobar tensión).COMPRUEBE LOS PILOTOS DE RESULTADOSCÓMO COMPROBARPROGRAMAS DE COMPROBACIÓN DISPONIBLES• B ATTERY (Batería) – Muestra el nivel de carga actual de la batería.• START POWER (Energía de arranque) – Para evaluar su estado global, monitoriza la salida de la batería mientras arranca el motor.• ALTERNATOR (Alternador) – Determina si el sistema de carga de un vehículo carga correctamente la batería o no.ANTES DE COMPROBAR1. Lea la sección de SEGuRIDAD del manual para asegurarse de que conecta/desconecta la unidad a la batería de forma segura.2. Antes de hacer las comprobaciones START POWER o ALTERNATOR , asegúrese de que la batería está totalmente cargada. En caso contrario, los resultados podrían ser erróneos. Antes de hacer una comprobación BATTERY , asegúrese de que la temperatura ambiente es de al menos 5 °C y que la batería no ha sido cargada (con el vehículo o con un cargador desde la red eléctrica) al menos una hora antes de la comprobación.3. Los pilotos 4, 5 y 6, muestran los resultados. 4 (rojo) indica MAL , 5 (naranja) ACEPTABLE , 6 (verde) BIEN .COMPROBACIÓN(NO SE REquIERE CONEXIÓN A LA RED ELÉCTRICA)1. Enchufe el cargador a la batería. Los pilotos 4, 5 y 6 se iluminan secuencialmente para indicar que el cargador está en Modo comprobación y preparado.2. Presione el botón MODE (3) para cambiar entre los programas de comprobación: BATTERY (9), START POWER (10), ALTERNATOR (11).BATTERY (Batería)1. Seleccione BATTERY (9) con el botón MODE (3).Después de unos segundos la unidad mostrará los resultados.MAL (4) recargue la batería cuanto antes.ACEPTABLE (5) se recomienda cargar para maximizar la duración de la batería.BIEN (6) el estado de carga de la batería es elevado. START POWER (Energía de arranque)1. Seleccione START POWER (10) con el botón MODE (3).2. Arranque el motor cuanto antes. Mantenga el arranque unos segundos, o hasta que arranque el motor.MAL (4) recargue la batería cuanto antes.ACEPTABLE (5) se recomienda cargar para maximizar la duración de la batería.BIEN (6) el estado de carga de la batería es elevado.ALTERNATOR (Alternador)1. Seleccione ALTERNATOR (11) con el botón MODE (3)2. Arranque el motor, manténgalo a 2000 rpm y monitorice los resultados.MAL (4) Falla el sistema de carga.ACEPTABLE (5) Falla el sistema de carga.BIEN (6) El sistema de carga del vehículo funciona bien.SUGERENCIAS1. Si el piloto de error (2) se enciende inmediatamente, la batería está mal conectada. Desenchufe el cargador, corrija las conexiones a la batería y vuelva al paso 1.2. Si el piloto no se enciende puede ser porque la batería está tan descargada que no puede ni alimentar el cargador. En ese caso, cargue completamente la batería.3. Si se detecta la tensión de la red eléctrica, el MXS 5.0 TEST&CHARGE pasaráautomáticamente al modo de carga. Presione dos segundos el botón MODE (3) para regresar al modo de comprobación, que se indicará con el encendido secuencial de los pilotos 4–6.4. Comprobación de Energía de arranqueBIEN (6) se iluminará al empezar la comprobación, pero podría caer a MAL (4). Antes de descartar una batería, es recomendable cargarla con el modo Recond(Regeneración) del cargador y luego volver a hacer la comprobación START POWER . Las baterías que no superen esta comprobación con tiempo cálido es casi seguro que fallarán por completo cuando caigan las temperaturasETAPA 1 DESULPHATION (DESULFATACIÓN)las placas de plomo de la batería y restablecen su capacidad. ETAPA 2 SOFT START (INICIO SUAVE) defectuosas.ETAPA 3 BULK (CARGA DE VOLUMEN)capacidad de la batería.ETAPA 4 ABSORPTION (ABSORCIÓN)batería.ETAPA 5 ANALYSE (ANáLISIS)carga quizás deberán ser reemplazadas.ETAPA 6 REGENERACIÓN (RECOND)Seleccionedevuelve energía a la misma.ETAPA 7 FLOAT (FLOTANTE)ETAPA 8 PULSE (PULSOS)cargada.SEGURIDAD• Este cargador está diseñado para cargar baterías únicamente conforme a lasespecificaciones técnicas indicadas. no lo utilice para ningún otro fin. Siga siempre las recomendaciones del fabricante de su batería.• nunca intente recargar baterías no recargables.• Compruebe los cables del cargador antes de usarlos. Cerciórese de que no haya grietas ni en los cables ni en la protección contra codos. Si el cargador tiene el cable dañado debe devolverlo a su distribuidor. Si el cable de suministro eléctrico está dete -riorado, contacte con un representante de CTEK para que lo reemplace.• Nunca cargue una batería dañada.• nunca cargue una batería congelada.• Nunca coloque el cargador sobre la batería al realizar la carga.• Durante la carga, compruebe siempre que la ventilación sea adecuada.• Evite recubrir el cargador.• una batería que está siendo cargada puede emitir gases explosivos. Evite las chispas cerca de la batería. Cuando la vida de servicio de una batería empieza a llegar a su fin, podrían producirse chispas internas.• Más tarde o temprano, todas las baterías quedan inutilizadas. Si una batería falladurante la carga, normalmente el sistema de control avanzado del cargador se encarga de procesar error, no obstante, en la batería podrían aparecer algunos otros fallos poco corrientes. Durante la carga, no deje la batería desatendida durante periodos de tiempo prolongados.• Asegúrese de que los cables no queden enmarañados ni entren en contacto con superfi -cies calientes ni bordes afilados.• El ácido de las baterías es corrosivo. Si el ácido entra en contacto con la piel o los ojos, enjuague con agua inmediatamente y solicite asistencia médica.• Compruebe siempre que el cargador haya conmutado a la ETAPA 7 antes de dejarlo desatendido y conectado durante periodos prolongados. Si el cargador no ha conmu -tado a la ETAPA 7 en un plazo de 50 horas, ello indica que hay un fallo. Desconecte el cargador manualmente.• Las baterías consumen agua durante su uso y la carga. En las baterías en las que se puede añadir agua, el nivel del agua se deberá controlar regularmente. Si el nivel fuera bajo, añada agua destilada.• Este equipo no está diseñado para ser utilizado por niños ni por personas que no puedan leer o comprender el manual, a menos que estén bajo la supervisión de una persona responsable que garantice que puedan usar el cargador de baterías conseguridad. Almacene y use el cargador de baterías alejado del alcance de los niños, y asegúrese de que ningún niño pueda jugar con el cargador.• La conexión a la red eléctrica debe realizarse siguiendo la normativa para instalaciones eléctricas vigente en el país.ESPECIFICACIONES TÉCNICASNúmero de modelo 1066Tensiónnominal de CA 220–240 Vca, 50–60 HzTensión de carga 14,4 V, 14,7 V,15,8 VTensiónde batería mín.2,0 V Corriente de carga 5 A máx.Corriente, red eléctrica 0,65 A rms (a plena corriente de carga)Pérdidas decontracorriente*<1 Ah/mes en modos de carga y comprobación Rizado**<4%Temperatura ambiente -20°C a +50°C, la potencia de salida se reduce automática -mente a altas temperaturasTipo de cargador De 8 etapas, ciclo de carga completamente automático Tipos de baterías Todos los tipos de baterías de plomo de 12 V (húmedas, MF, Ca/Ca, AGM y GEL)Capacidad de la batería 1,2–110 Ah, hasta 160 Ah para mantenimiento Dimensiones 168 x 65 x 38 mm (Long. x Anch. x Alt.) Clase de aislamiento IP65Peso0,6 kg *) La pérdida de contracorriente es la corriente consumida mientras el cargador no está conectado a la red eléctrica. Los cargadores CTEK tienen una contracorriente muy baja.**) La calidad de la tensión de carga y de la corriente de carga es muy importante. una corriente de ondulación (rizado) alta calienta la batería, lo cual acelera el enve -jecimiento del electrodo positivo. una tensión de ondulación alta puede dañar otros equipos conectados a la batería. Los cargadores de baterías CTEK producen tensión y corriente muy limpia, con baja ondulación.E SGARANTíA LIMITADACTEK SWEDEN AB, expide la presente garantía limitada al comprador original de este producto. Esta garantía limitada no es transferible. La garantía rige para defectos de fabri-cación y material durante cinco años a partir de la fecha de compra. El cliente deberá devolver el producto al punto de compra junto con el recibo de compra. Esta garantía no es válida si el cargador de baterías ha sido abierto, manejado descuidadamente o reparado por personal no perteneciente a CTEK SWEDEN AB o a sus representantes auto -rizados. uno de los orificios de los tornillos de la parte inferior del cargador está sellado. Si se retira o deteriora el sello, se anulará la garantía. CTEK SWEDEN AB no concede otra garantía distinta a esta garantía limitada y no se hace responsable de otros costes distintos a los arriba mencionados, es decir, no se hace responsable de daños consecuentes. Además, CTEK SWEDEN AB no está obligada a otra garantía que la presente.ASISTENCIA TÉCNICACTEK ofrece asesoramiento profesional a los clientes: .Para consultar la revisión más reciente del manual del usuario, visite . Correo electrónico: ************Teléfono: +46(0) 225 351 80. Fax +46(0) 225 351 95.LOS PRODUCTOS DE CTEK ESTáNPROTEGIDOS POR:2012–05–3020017986A。
Maquiladora Tax Regime 2014 Tax Reforms
IMMEX companies currently operate under a preferential tax and customs regime.
They are allowed to import raw materials, parts, components and other assets on a temporary basis, a transaction that is exempt for VAT purposes.
Tax Reform 2014 Maquiladora Regime
Background
The reform seems to deliver a message of increasing tax collections through:
Increase of tax rates
Elimination of many tax benefits
October 31
Congress approval by the senate.
4
© 2013 Galaz, Yamazaki, Ruiz Urquiza, S.C.
Tax Reform 2014 Maquiladora Regime
2014 economic package
Strategies, objectives and targets of income, expenses, debt and public rates
Partial exemption of income tax, equal to 3% of base that is higher between:
- 6.5% over expenses or - 6.9% over assets
西语缩写集锦
AG: Asamblea General 联合国大会APEC: Cooperación Económica del Asia-Pacífico 亚太经合组织ASEAN: Asociación de Naciones del Sureste Asiático 东南亚国家联盟AVE: Trenes de Alta Velocidad Española 高速火车BM: Banco Mundial 世界银行CEPAL: Comisión Económica para América Latina y el Caribe 拉美和加勒比经济委员会CCI: Cámara de Comercio Internacional 国际商会CIJ: Corte Internacional de Justicia 国际法庭CNUAH: Centro de las Naciones Unidas para los Asentamientos Humanos 联合国人类住区规划署CP: Consejo Permanente 常任理事会（联合国）CP: Código Postal 邮政编码CV: Currículum Vitae 履历表DELE: Diplomas del Español como Lengua Extranjera 西班牙语水平测试证书DNI: Documento Nacional de IdentidadEEUU: Estados Unidos 美国FAO: Organización para la Agricultura y la Alimentación 联合国粮农组织FARC: Fuerzas Armadas Revolucionarias de Colombia 哥伦比亚革命武装力量FIDA: Fondo Internacional de Desarrolo Agrícola 联合国农业发展基金会FMI: Fondo Monetario Internacional 国际货币基金组织FMI: Foro Militar Internacional国际军事法庭GATT:Acuerdo General sobre Aranceles, Aduaneros y Comercio 关贸总协定ISBN: International Standard Book Number 国际标准书号ISO: Organización Mundial para la Estandarización 国际标准化组织IVA: Impuesto al Valor Agregado 增值税JJ.OO.: Juegos Olímpicos 奥林匹克运动会MERCOSUR: Mercado Común del Sur 南方共同体市场NOAL: Movimeinto de Países No Alineados 不结盟运动OIEA: Organismo Internacional de Energía Atómica 国际原子能机构OMC: Organización Mundial de Comercio 国际贸易组织OMPI: Organización Mundial de la Propiedad Intelectual 世界知识产权组织OMS: Organización Mundial de la Salud 世界卫生组织ONG: Organizaciones No Gubernamentales 非政府组织ONUDI: Organizacion de Naciones Unidas para el Desarrollo Industrial 联合国工业发展组织OPEP: Organización de Países Exportadores de Petróleo 石油输出国组织OTAN: Organización del Tratado del Atlántico Norte 北大西洋公约组织OVNI: Objeto Volador No Identificado 不明飞行物PAU: Prueba de Acceso a la Universidad, Selectividad 大学入学考PCC: Partido Comunista de China 中国共产党PCE: Partido Comunista de España 西班牙共产党PIB: Producto Interior Bruto 国内生产总值PNB: Producto Nacional Bruto 国民生产总值PP: Partido Popular 西班牙人民党PSOE: Partido Socialista Obrero Español 西班牙社会劳工党PYME: Pequeña y Mediana Empresa 中小企业RAE: Real Academia Española 西班牙皇家语言学院RENFE: Red Nacional de Ferrocarriles Españolas 西班牙国家铁路局RNE: Radio Nacional de Esapña 西班牙国家广播电台RPC: Renta Per Capita 按人口计算的国民平均收入SA: Sociedad Anónima 股份公司SIDA: Síndrome de Inmunodeficiencia Adquirida 艾滋病SMI: Sistema Monetario Internacional 国际货币体系SONIMAG: Sonido e Imagen 视听SOS: Save Our Souls 救命SP: Servicio Público 公共服务TNP: Tratado de No Proliferación Nuclear 不扩散核武器条约TVE: Televisión Española 西班牙国家电视台UCD: Unión de Centro Democrático 西班牙中间民主联盟UCD: Unión de Cobranza de Deudas 催讨债务联盟UE: Unión Europea 欧盟UNESCO: Organización de las Naciones Unidas para la Educación, Ciencia y Cultura 联合国教科文组织UNICEF: Fondo de las Naciones Unidas para la Infancia 联合国儿童基金会UPU: Unión Postal Universal 万国邮政联盟UVA: Ultravioleta 紫外线VNU: Voluntarios de Naciones Unidas 联合国志愿者VO: Versión Original 原版。
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修正0,(EC) No 108 2008,修订关于食品中维生素,矿物质和其它特定物质的添加的条例No 1925 2006
REGULATION(EC)No108/2008OF THE EUROPEAN PARLIAMENT AND OF THE COUNCILof15January2008amending Regulation(EC)No1925/2006on the addition of vitamins and minerals and of certainother substances to foodsTHE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,Having regard to the Treaty establishing the European Commu-nity,and in particular Article95thereof,Having regard to the proposal from the Commission,Having regard to the opinion of the European Economic and Social Committee(1),Acting in accordance with the procedure laid down in Article251 of the Treaty(2),Whereas:(1)Regulation(EC)No1925/2006of the European Parliamentand of the Council(3)provides that the regulatory procedure established by Council Decision1999/468/EC of28June1999laying down the procedures for the exercise of implementing powers conferred on the Commission(4)is to be applied for the adoption of implementing measures concerning that Regulation.(2)Decision1999/468/EC has been amended by Decision2006/512/EC,which introduced the regulatory procedure with scrutiny for the adoption of measures of general scope and designed to amend non-essential elements of a basic instrument adopted in accordance with the procedure referred to in Article251of the Treaty,inter alia,by deleting some of those elements or by supplementing the instru-ment with new non-essential elements.(3)The Commission should be empowered to adopt modifica-tions to Annexes I and II to Regulation(EC)No1925/2006;to establish additional foods to which particular vitamins or minerals may not be added;to take decisions to establish and/or amend the lists of authorised,prohibited or restricted other substances;to define the conditions under which vitamins and minerals may be used,such as purity criteria,maximum amounts,minimum amounts and other restrictions or prohibitions on the addition of vitamins and minerals to food;and to establish derogations from certain provisions of that Regulation.Since those measures are of general scope and are designed to amend non-essential elements of that Regulation,inter alia,by supplementing it with new non-essential elements,they must be adopted inaccordance with the regulatory procedure with scrutiny provided for in Article5a of Decision1999/468/EC.(4)When,on imperative grounds of urgency,the normal time-limits for the regulatory procedure with scrutiny cannot be complied with,the Commission should be able to use the urgency procedure provided for in Article5a(6)of Decision 1999/468/EC for the deletion of certain vitamins or minerals listed in the annexes and for the inclusion and amendment of certain other substances in Annex III to Regulation(EC)No1925/2006.(5)Regulation(EC)No1925/2006should therefore beamended accordingly,HAVE ADOPTED THIS REGULATION:Article1Regulation(EC)No1925/2006is hereby amended as follows: 1.Article3(3)shall be replaced by the following:‘3.Modifications to the lists referred to in paragraph1of this Article shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Arti-cle14(3),taking account of the opinion of the Authority.On imperative grounds of urgency,the Commission may use the urgency procedure referred to in Article14(4)in order to remove a vitamin or a mineral from the lists referred to in paragraph1of this Article.Prior to making these modifications,the Commission shall carry out consultations with interested parties,in particular food business operators and consumer groups.’;2.in Article4,the second paragraph shall be replaced by thefollowing:‘Measures determining the additional foods or categories of foods to which particular vitamins and minerals may not be added and designed to amend non-essential elements of this Regulation may be adopted in accordance with the regulatory procedure with scrutiny referred to in Arti-cle14(3)in the light of scientific evidence and taking into account their nutritional value.’;13.2.2008EN Official Journal of the European Union L39/11(1)OJ C325,30.12.2006,p.40.(2)Opinion of the European Parliament of7June2007(not yetpublished in the Official Journal)and Council Decision of17December2007.(3)OJ L404,30.12.2006,p.26.(4)OJ L184,17.7.1999,p.23.Decision as amended by Decision2006/512/EC(OJ L200,22.7.2006,p.11).3.Article5(1)shall be replaced by the following:‘1.Measures determining the purity criteria for vitamin formulations and mineral substances listed in Annex II and designed to amend non-essential elements of this Regula-tion by supplementing it shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article14(3),except where they apply pursuant to paragraph2of this Article.’;4.Article6shall be amended as follows:(a)paragraph1shall be replaced by the following:‘1.When a vitamin or a mineral is added to foods,the total amount of the vitamin or mineral present,forwhatever purpose,in the food as sold shall not exceedmaximum amounts.Measures setting that amountand designed to amend non-essential elements of thisRegulation by supplementing it shall be adopted inaccordance with the regulatory procedure withscrutiny referred to in Article14(3).The Commissionmay,to this end,submit a draft of measures for themaximum amounts by19January2009.Forconcentrated and dehydrated products,the maximumamounts set shall be those present in the foods whenprepared for consumption according to the manufac-turer's instructions.’;(b)paragraph2shall be replaced by the following:‘2.Any conditions restricting or prohibiting theaddition of a specific vitamin or mineral to a food or acategory of foods and designed to amend non-essential elements of this Regulation,inter alia,bysupplementing it,shall be adopted in accordance withthe regulatory procedure with scrutiny referred to inArticle14(3).’;(c)paragraph6shall be replaced by the following:‘6.The addition of a vitamin or a mineral to a foodshall result in the presence of that vitamin or mineralin the food in at least a significant amount where thisis defined according to the Annex to Directive90/496/EEC.Measures determining the minimumamounts,including any lower amounts,by derogationfrom the significant amounts mentioned above,forspecific foods or categories of foods and designed toamend non-essential elements of this Regulation bysupplementing it shall be adopted in accordance withthe regulatory procedure with scrutiny referred to inArticle14(3)of this Regulation.’;5.Article7(1)shall be replaced by the following:‘1.The labelling,presentation and advertising of foods to which vitamins and minerals have been added shall not include any mention stating or implying that a balanced and varied diet cannot provide appropriate quantities of nutrients.Where appropriate,a derogation concerning a specific nutrient and designed to amend non-essential elements of this Regulation by supplementing it may be adopted in accordance with the regulatory procedure with scrutiny referred to in Article14(3).’;6.Article8shall be amended as follows:(a)paragraph2shall be replaced by the following:‘2.On its own initiative or on the basis ofinformation provided by Member States,the Commis-sion may take a decision designed to amend non-essential elements of this Regulation,following ineach case an assessment of available information bythe Authority,in accordance with the regulatoryprocedure with scrutiny referred to in Article14(3),toinclude,if necessary,the substance or ingredient inAnnex III.In particular:(a)if a harmful effect on health has been identified,the substance and/or the ingredient containingthe substance shall:(i)be placed in Annex III,Part A,and itsaddition to foods or its use in themanufacture of foods shall be prohibited;or(ii)be placed in Annex III,Part B,and itsaddition to foods or its use in themanufacture of foods shall only be allowedunder the conditions specified therein;(b)if the possibility of harmful effects on health isidentified but scientific uncertainty persists,thesubstance shall be placed in Annex III,Part C.On imperative grounds of urgency,the Commissionmay use the urgency procedure referred to inArticle14(4)in order to include the substance orthe ingredient in Annex III,Part A or B.’;L39/12EN Official Journal of the European Union13.2.2008(b)paragraph5shall be replaced by the following:‘5.Within four years from the date a substance hasbeen listed in Annex III,Part C,a decision designed toamend non-essential elements of this Regulation shallbe taken in accordance with the regulatory procedurewith scrutiny referred to in Article14(3)and takinginto account the opinion of the Authority on any filessubmitted for evaluation as mentioned in paragraph4of this Article,to generally allow the use of asubstance listed in Annex III,Part C,or to list it inAnnex III,Part A or B,as appropriate.On imperative grounds of urgency,the Commissionmay use the urgency procedure referred to inArticle14(4)in order to include the substance orthe ingredient in Annex III,Part A or B.’;7.Article14shall be replaced by the following:‘A rticle14Committee procedure1.The Commission shall be assisted by the StandingCommittee on the Food Chain and Animal Healthestablished by Article58(1)of Regulation(EC)No178/ 2002.2.Where reference is made to this paragraph,Articles5and7of Decision1999/468/EC shall apply,having regard to the provisions of Article8thereof.The period laid down in Article5(6)of Decision1999/468/ EC shall be set at three months.3.Where reference is made to this paragraph,Article5a(1)to(4),and Article7of Decision1999/468/EC shallapply,having regard to the provisions of Article8thereof.4.Where reference is made to this paragraph,Article5a(1),(2)and(6),and Article7of Decision1999/468/ECshall apply,having regard to the provisions of Article8 thereof.’Article2This Regulation shall enter into force on the20th day following its publication in the Official Journal of the European Union.This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Strasbourg,15January2008.For the European ParliamentThe PresidentH.-G.PÖTTERING For the Council The President J.LENARČIČ13.2.2008EN Official Journal of the European Union L39/13。
有机朗肯循环的研究进展_邓立生
第2卷 第3期 新 能 源 迚 展Vol. 2 No. 32014年6月ADVANCES IN NEW AND RENEWABLE ENERGYJun. 2014* 收稿日期：2013-12-26 修订日期：2014-05-18基金项目：中国科学院外籍青年科学家计划（2013Y1GA0008） † 通信作者：黄宏宇，E-mail ：huanghy@文章编号：2095-560X （2014）03-0180-10有机朗肯循环的研究进展*邓立生1，黄宏宇1†，何兆红1，窪田光宏1,2，袁浩然1，呼和涛力1，小林敬幸1,2（1. 中国科学院广州能源研究所，中国科学院可再生能源重点实验室，广州 510640；2. 日本名古屋大学，名古屋 4648603）摘 要：有机朗肯循环是一种被认为能有效利用低温热能的技术。
科研工作者在不同斱面（包括工质、膨胀机、换热器的影响、系统的优化）对有机朗肯循环系统效率的影响迚行了大量的研究。
本文针对不同热源的工质筛选、膨胀机的特点、系统循环优化以及换热器的影响斱面迚行了讨论和总结，为有机朗肯循环系统的实际应用提供参考。
关键词：有机朗肯循环；工质；膨胀机；换热器；效率中图分类号：TK11+5 文献标志码：A doi ：10.3969/j.issn.2095-560X.2014.03.003Research Progress on Organic Rankine CycleDENG Li-sheng 1, HUANG Hong-yu 1, HE Zhao-hong 1, KUBOTA Mitsuhiro 1,2,YUAN Hao-ran 1, HUHE Tao-li 1, KOBAYASHI Noriyuki 1,2(1. CAS Key Laboratory of Renewable Energy, Guangzhou Institute of Energy Conversion, Chinese Academy of Sciences,Guangzhou 510640, China; 2. Nagoya University, Nagoya 4648603, Japan)Abstract: Organic Rankine Cycle (ORC) is considered as a promising technology for effective utilization of low-temperature energy. Large number of studies on the ORC system (including the working fluid, the expander, the heat exchanger, and optimization of system) have been carried out by the researchers. In this study, the working fluids selection for different type heat sources, characteristics of expanders, heat exchanger influences and system design optimization are discussed and summarized to provide some references for the utilization of the ORC system. Key words: Organic Rankine Cycle (ORC); working fluid; expander; heat exchanger; efficiency0 前 言随着经济的持续发展，能源需求不断增长，世界各国的能源消耗急剧增加，而能源消耗的来源主要是依靠石油、煤炭等不可再生资源。
Estimating Remaining Useful Life With Three-Source Variability in Degradation Modeling
Estimating Remaining Useful Life With Three-Source Variability in Degradation ModelingXiao-Sheng Si,Wenbin Wang,Chang-Hua Hu,and Dong-Hua Zhou,Senior Member,IEEEAbstract—The use of the observed degradation data of a system can help to estimate its remaining useful life(RUL).However, the degradation progression of the system is typically stochastic, and thus the RUL is also a random variable,resulting in the difficulty to estimate the RUL with certainty.In general,there are three sources of variability contributing to the uncertainty of the estimated RUL:1)temporal variability,2)unit-to-unit variability, and3)measurement variability.In this paper,we present a rela-tively general degradation model based on a Wiener process.In the presented model,the above three-source variability is simul-taneously characterized to incorporate the effect of three-source variability into RUL estimation.By constructing a state-space model,the posterior distributions of the underlying degradation state and random effect parameter,which are correlated,are estimated by employing the Kalmanfiltering technique.Further, the analytical forms of not only the probability distribution but also the mean and variance of the estimated RUL are derived,and can be real-time updated in line with the arrivals of new degra-dation observations.We also investigate the issues regarding the identifiability problem in parameter estimation of the presented model,and establish the according results.For verifying the presented approach,a case study for gyros in an inertial platform is provided,and the results indicate that considering three-source variability can improve the modelingfitting and the accuracy of the estimated RUL.Index Terms—Remaining useful life,degradation model,three-source variability,Wiener process,prognostics.A CRONYMSAIC Akaike information criterionCDF cumulative distribution functionCM condition monitoringFHTfirst hitting timeINS inertial navigation systemsManuscript received April01,2013;revised July15,2013;accepted September29,2013.Date of publication January17,2014;date of current version February27,2014.The work was supported in part by the National973 Project under Grant2010CB731800,and the NSFC under Grants61210012, 61290324,71231001,61174030,61104223,61374126,and61025014.Asso-ciate Editor:Y.Guangbin.Xiao-Sheng Si is with the Department of Automation,Xi’an Institute of High-Tech,Xi’an,Shaanxi710025,China,and also with the Depart-ment of Automation,Tsinghua University,Beijing100084,China(e-mail: sxs09@;sixiaosheng@).Wenbin Wang is with Dongling School of Economics and Management, University of Science and Technology Beijing,Beijing100083,China(e-mail: wangwb@).Chang-Hua Hu is with the Department of Automation,Xi’an Institute of High-Tech,Xi’an,Shaanxi710025,China(e-mail:hch6603@). Dong-Hua Zhou is with the Department of Automation,TNList,Tsinghua University,Beijing100084,China(e-mail:zdh@).MLE maximum likelihood estimationMSE mean-squared errorPDF probability density functionPHM prognostics and health managementRE relative errorRUL remaining useful lifeTMSE total MSEN OTATIONnumber of tested systemsnumber of the degradation measurements foreach systemdiscrete degradation observation timethreshold levellifetimenormally distributed with mean and variancestandard Brownian motionunderlying degradation processmeasurement processrandom effect parameter,diffusion coefficient,withmeasurement error with realizationRUL at with realizationunderlying degradation state,and observedmeasurement atset of the degradation states up to,withset of the degradation measurements up to,withestimated mean,and variance of atestimated mean,and variance ofPDF,and CDF ofconditional PDF of the RUL atconditional CDF of the RUL atCDF of standard normal distributionexpectation operatorvariance operatorDawson integral for realvector transpositionunknown parameter vector,withset of degradation measurements for the thsystem,.set of degradation measurements for systemswithlog-likelihood functionI.I NTRODUCTIONP ROGNOSTICS AND HEALTH MANAGEMENT (PHM)can make full use of condition monitoring(CM) data from a functioning system to assess the reliability of the system in its actual life cycle conditions,to determine the advent of failure,and to mitigate system risk through manage-rial activities[16],[29],[33],[54].A requirement of a PHM enabled system is the ability to estimate the remaining useful life(RUL),which can provide the decision-maker with enough lead-time to perform the necessary maintenance actions prior to failure.This RUL estimation is a fundamental prerequisite for proactive maintenance because utilizing information about the system’s RUL in maintenance decisions can improve the system’s availability,extend the system’s life,and further reduce life-cycle costs.So far,the estimated RUL,conditional on the CM data,has been considered as one of the most central components in PHM and has been attached great importance in practice.Therefore,the purpose of this paper is to investigate how to estimate the RUL from the CM data,and emphasis is placed on handling various sources of variability in stochastic degradation modeling.A.MotivationWith advances in information and sensing technologies, degradation signals of the system can be obtained relatively easily through CM techniques,and the past decade has wit-nessed an increasingly growing research interest on various aspects of PHM of systems based on measured degradation sig-nals(see[12],[17],[21],[35],[53],and the references therein). However,it is quite common in practice that the degradation occurs in a stochastic way for a number of engineering systems such as bearings,gyros,and battery systems.As a result,the RUL is also a random variable,resulting in the difficulty to estimate the RUL with certainty;see[35]for an overview of this topic.To characterize the uncertainty of the RUL,attention is affected by numerous sources of variability contributing to the uncertainty of the estimated RUL:1)temporal variability, 2)unit-to-unit variability,3)measurement variability,and4) model error;see[9],[17],[25],[27],[30],[45],[47],[48]for some examples.Recent advances in managing uncertainties associated with prognostics can be found in[4],[22],[32]. Particularly,Baraldi et al.in[4]investigated the capabilities of different prognostic approaches to deal with various sources of uncertainty in RUL estimation,and formulated the effect of model error(e.g.,resulted from model assumptions and sim-plifications made on the form and structure of the degradation model)on RUL estimation.In this paper,we mainly focus on thefirst three sources of variability.First,temporal variability is referred to as the inherent uncertainty associated with the progression of the degradation over time[1],[15],[27],[34].Due to the stochastic nature of a degradation process,it is appropriate to model such degrada-tion by a stochastic process.Second,the unit-to-unit variability determines heterogeneity among the degradation paths of dif-ferent units.Taking gyros in an inertial navigation system for example,as a gyro degrades,the drift tends to increase.When the drift reaches a threshold(which is typically determined by an associated industrial standard),the gyro is considered to have failed.In this case,the degradation rate of gyros differs from each other.Such difference in degradation rates can usu-ally be modelled by introducing unit-specific random effects through some model parameters[14],[25],[51].Last,perfect measurements for degradation are practically impossible to achieve,and the measured data are inevitably contaminated by measurement error resulting from disturbance,non-ideal measurement instruments,and other noise[11],[17],[19],[26], [30],[48].In this case,the observed degradation signals can only partially reflect the underlying degradation state.From the above introduction,it has been recognized that tem-poral variability,unit-to-unit variability,and measurement vari-ability are three important factors having to be taken into ac-count simultaneously when investigating the RUL estimation in the framework of stochastic modeling.Most published works on RUL estimation using stochastic models focused on models that only considered one source or two sources of variability[7], [9],[14],[18],[23],[24],[30],[36],[37],[41],[43],[46],[52]. In contrast,the research on RUL estimation using degradation models with three-source variability is very limited.On the other hand,even for the few models that considered three-source variability,the research is limited to the case of modeling the degradation process only or estimating the life-time for a population of statistically identical systems,ignoring the impact of imperfect measurements on the lifetime distribu-tion[18],[30],[45],[48].In addition,updating the estimated RUL for a particular system in service using real-time data is increasingly important and desirable so that the most recently calculated RUL value can accurately reflect the current reality of the system.This updating mechanism has been considered by others(see for example[13],[14],[36],[43]),but not in the context with three-source variability in degradation modeling.SI et al.:ESTIMATING REMAINING USEFUL LIFE WITH THREE-SOURCE V ARIABILITY IN DEGRADATION MODELING169Throughout this paper,the term three-source variability means considering temporal variability,unit-to-unit variability, and measurement variability simultaneously.B.Related WorksThere is a great need to develop stochastic models to model the degradation process for RUL estimation,and a significant volume of research has been published,such as random co-efficient regression models[7],[24],[28],Gamma processes [23],[27],[52],inverse Gaussian processes[44],[49],[50],and Wiener processes[9],[18],[23],[30],[36],[41]–[43],[46].A recent review on these models can be found in[35].In these research works,degradation processes described by Wiener processes are particularly attractive because they not only have some favorable mathematical properties but also can model non-monotonic degradation signals frequently encoun-tered in practice.Therefore,this type of stochastic process has been widely used to characterize the path of the degradation process where successivefluctuations in degradation are ob-served,such as in the examples in[9],[14],[36],[37],[41],[42]. It is noted however that the above works considered mostly the temporal variability or unit to unit variability,or both.For ex-ample,in[43],the authors considered a Wiener process for RUL estimation using a deterministic drift parameter,and adaptively updated this parameter by a state-space model and Kalmanfil-tering technique.However,in the estimated RUL distribution, only the point estimation of the drift parameter is considered, and the issue regarding the presence of the unit-to unit vari-ability and measurement variability is missing.Recently,an ex-tension in[36]considered the effect of the estimation uncer-tainty of the drift parameter on the estimated RUL,but omitted the measurement variability as well.There are reported works considering measurement vari-ability using state space models in[13],[40],[43],[46],[52]. However,the other two sources of variability were not con-sidered simultaneously together in these works.For example, in[13],a state-space based prognostic model was proposed to characterize the nonlinearity and measurement variability by applying the extended Kalmanfilter.However,only the approximate probability density function(PDF)of the RUL is obtained,and the cumulative distribution function(CDF), mean,and variance of the estimated RUL cannot be derived analytically because of the involved nonlinearity.In addition, all the model parameters in the work of[13]are deterministic. Therefore,the method in[13]ignores the unit-to-unit vari-ability.There are some exceptions such as the works by[18], [30],[45],[48],where three-source variability was taken into account at the same time.However,all these works only con-sider the measurement variability in parameter estimation,and ignore the effect of the uncertainty in the estimated degradation state on the RUL distribution due to measurement errors.They also did not consider the updating mechanism for the RUL in line with the newly measured degradation signals unique to an parameters in the degradation model.However,all the existing works do not address this problem.C.Contributions of This PaperIn this paper,we present a Wiener process based degrada-tion modeling framework for RUL estimation with three-source variability.The main novelty of the presented model lies in the concerned problem of how to enable us to consider three-source variability simultaneously to estimate and update the RUL dis-tribution using the degradation data across the population,and the real-time observed measurements of an individual system in service.This novelty in considering three-source variability dis-tinguishes our model from the existing results such as[9],[13], [14],[18],[30],[36],[37],[43],[45],[46],[48]in several major aspects.1)Three sources of variability are simultaneously considered;and by constructing a state-space model,the correlated posterior distributions of the underlying degradation state and random effect parameter are estimated by employing the Kalmanfiltering technique.This approach differs from the cases that the parameters of the degradation model are deterministic.2)On the basis of the posterior distributions of the underlyingdegradation State,and the random effect parameter,the an-alytical forms of the PDF,CDF,mean,and variance of the estimated RUL are derived.It is found that three kinds of variability can propagate into the estimated Results;thus, we account for the effect of three-source variability on the estimated RUL simultaneously.3)The results with three-source variability can be updatedwith the newly measured degradation data unique to the system in service,and the RUL estimation results only con-sidering one-or two-source variability are obviously spe-cial cases of our results.4)The identifiability of the parameters in the presented modelis investigated.Then,a MLE method is given to specify the initial parameters of the state-space model based on the historical degradation observations of multiple units.Thus the linkage between the past and real-time data is established.Finally,we provide a practical case study for gyros in an in-ertial navigation platform to illustrate the application of the de-veloped approach.With realistic data,we compare the estimated RUL results considering three-source variability with the results only considering one-or two-source variability based on several measures:Akaike information criterion(AIC),mean squared error(MSE),and relative error(RE).The results verify that con-sidering three-source variability can improve the modelfit,and the accuracy of the RUL estimation.Section II gives the description of the degradation modeling framework with three-source variability.In Section III,we estimate the RUL under three sources of variability.Section IV investigates the issues regarding the identifiability and param-eter estimation of the presented model.Section V provides170IEEE TRANSACTIONS ON RELIABILITY,VOL.63,NO.1,MARCH2014II.D ESCRIPTION OF D EGRADATION M ODELING W ITHT HREE-S OURCE V ARIABILITY FOR RUL E STIMATIONLet denote the stochastic process describing the underlying degradation progression over operating time, which is modeled by a Wiener process.In general,a Wiener-process-based degradation model can be represented as(1) where for,representing the stochastic dynamics of the degradation process,and is a known initial degradation state.Without loss of generality,we assumein the following.Equation(1)can characterize the temporal variability due to the dynamics of.However,each system possibly experiences different operating conditions,and thus the degra-dation paths of different systems exhibit different degradation rates to increase.Therefore,for a degradation model to be real-istic,it is more appropriate to incorporate unit-to-unit variability in the degradation process.As such,we treat the parameter to be a random effect representing between-unit variation,and to be afixed parameter representing the degradation feature common to all systems in the population.For simplicity,we as-sume that follows,and is statistically indepen-dent of.The ideas of random effects and Gaussian assumptions are widely used in degradation modeling literature [25],[35].Additionally,perfect measurement of the underlying degra-dation state is often impossible or costly.Instead,the obtained measurements are inevitably subject to measurement variability, resulting from noise,disturbance,non-ideal instruments,etc. In this case,the observed measurements are imperfect,and can partially reflect the underlying degradation state.To characterize the effect of the measurement variability,the measurement process,which describes the rela-tionship between the observable but uncertain measurements and the underlying degradation state at time,is formulated as(2) where is the random measurement error,assumed to be statis-tically independent and identically distributed(i.i.d.)with at any time point.It is further assumed that,and are mutually statistically independent.All these assump-tions are widely adopted in the practice of degradation model-ling and RUL estimation.Before addressing the RUL estimation issues based on the above model setting,we have the following remark regarding the linkage of the above model,which we refer to as our model, with the existing results.Remark1:The choice of the parameters is made to obtain a model that includes,as special cases,other models that have already found practical applications in literature.In fact,it is easy to verify the following points.1)When,our model with three-source variability re-2)when,our model with three-source variability re-duces to the linear Wiener process model with random drift in[9],[12],[21],[36],and[37],where only the temporal uncertainty and unit-to-unit variability are considered. 3)When,our model with three-source variability re-duces to the linear but hidden degradation model in[46], and[40],where only the temporal uncertainty and mea-surement uncertainty are considered.4)When,our model with three-sourcevariability reduces to the traditional linear Wiener process model in[41],[43],and[47],where only the temporal un-certainty is considered.Remark2:From the above work,see that the underlying as-sumptions of the proposed model include:1)the system oper-ates in time-invariant environments,and thus the rate of degra-dation can be approximated as a constant for simplicity,i.e.,the degradation process is linear or can be treated as locally linear; and2)the measurement noise is Gaussian.These assumptions have been widely used in degradation modeling.As a result of Remark1and Remark2,our model can include many existing models as special cases,and thus is more gen-eral andflexible.As in other degradation modelling works[20], [35],we adopt the concept of thefirst hitting time(FHT)to de-fine the lifetime,and then proceed to deducing the RUL.In other words,once the degradation process is equal to or beyond a pre-defined threshold level,the system will be consid-ered to be failed,and therefore,the lifetime can be interpreted as the FHT of the degradation process to the threshold level. According to the concept of FHT,the lifetime of a system is defined as(3) where is the pre-defined threshold level.The above formulation is mainly focused on a population of the system.The main objective here is to estimate and update the RUL distribution of an individual system in service based on the real-time observations of the degradation process.Sup-pose the degradation process is discretely monitored at time,and let denote the degra-dation observation at time.The set of the degradation mea-surements up to is represented by, and the corresponding set of the degradation states up to is represented by,where. As a result,we further express discrete measurement at time as,where the measurement errors are assumed to be i.i.d.realizations of.Therefore,using the concept of the FHT,we define the RUL of a system at time as(4) with conditional PDF,and conditional CDF as(5)shown at the bottom of the next page,where is the observed measurements available up to.SI et al.:ESTIMATING REMAINING USEFUL LIFE WITH THREE-SOURCE V ARIABILITY IN DEGRADATION MODELING171III.RUL E STIMATION W ITH T HREE-S OURCE V ARIABILITY To investigate RUL estimation with three-source variability, we consider three cases in this section:1)temporal variability and unit-to-unit variability together,2)temporal variability and measurement variability together,and3)three-source variability simultaneously.A.Case1:RUL Estimation With Temporal Variability and Unit-to-Unit VariabilityInitially,we only consider the temporal variability in the degradation process by making be determin-istic.It is well-known that the FHT of the Wiener process crossing afixed threshold follows an inverse Gaussian distribu-tion[8].In the following,we summarize the main results and properties of the lifetime in this case only considering the temporal variability.Lemma1:For the Wiener process as in(1)and(3),given, the following equations hold,see(6)–(9)at the bottom of the page.is the CDF of standard normal distribution.When we consider the random effect of representing unit-to-unit variability,the PDF and CDF of the lifetime can be respectively computed by the law of total probability as(10) and(11) where is the PDF of,and is the expectation operator with respect to.To facilitate the derivation and explicitly calculate the inte-grals such as those in(10)and(11),wefirst give the following lemmas,which can be proved directly through some lengthy al-gebraic manipulations;thus the proofs are omitted here,and the interested readers can refer to[39].Lemma2:If,and,then,see(12)at the of the page.Lemma3:If,and,then,see(13)at the bottom of the page.Based on Lemmas1–3,we can calculate(10)and(11)explic-itly.The main results are summarized in the following theorem. Theorem1:For the Wiener process in(1)and(3),taking into account the random effect of with,the following results hold,see(14)–(17)at the bottom of next page.where is the Dawson integral for real.The above formulations in(14)and(15)are consistent with the results in[30],which are mainly focused on a population of the ly,in(14),the estimated PDF of the FHT does not consider the real-time degradation state of the monitored system.If the degradation state at current time can be observed directly,and there is,we assume that the system has been functioning before.In this paper,we use this assumption to update the knowledge of the degradation process. Note that this assumption is often adopted in the literature in-cluding in[14],[21],[36],[37].This approach differs from that of[13],where the made assumption is used to approximate the PDF of the lifetime.Thus,the time in the assumption of [13]corresponds to a future time because the current time there is.As a result,using the assumption in[13]to estimate the RUL at time,the time in the assumption is trans-formed to,which is still a future time.However,for our used assumption,if at current time,the system has been functioning before.Unlike[13],our treatment does not impose additional constraints and ignore the probability of the event occurring for calculating the PDF of the RUL.(5)(6)(7)(8)(9)(12)172IEEE TRANSACTIONS ON RELIABILITY,VOL.63,NO.1,MARCH2014As a result,for,given and,we revise the degradation process over time since according to the Markov property of the Wiener process as(18) In such a case,the residual corresponds to the real-ization of the RUL at time if is the FHT of, according to the definition of the RUL in(4).Therefore,wefirst take the transformation for(16),where.Then the process can be represented with the residual time as(19) As a result,the RUL at time is equal to the FHT of the process crossing threshold,where,and.That is to say,given ,(20) To derive,it is necessary to prove that the stochastic process,with,is still a BM.This result is guaranteed by the following lemma([37]).Lemma4:Given,the stochastic processwith for any is still a standard BM,where is a standard BM.Therefore,the estimated PDF of the RUL,,conditional on the current degradation stateand,can be obtained by the following theorem.Theorem2:For the Wiener process defined in(1),and the definition of the RUL in(4),given and the current degradation state,the following equations for RUL estimation at time hold,see(21)-(24)at the bottom of the page.In general,as the age of the system grows,the system’s degradation gradually increases.Therefore,prognostics is more commonly applied to aged systems(corresponding to large)rather than new systems(corresponding to small). Actually,this interest can be reflected by the above obtained results.Take(21)and(22)for example.If,then the estimated PDF of the RUL,and the CDF.This result re ects the aging character increasing.When the random effect of is considered,according to Theorem1and Theorem2,we have the following results for ,and.Theorem3:For the in(1),and the definition of the RUL in(4),given the current degradation state and(13)(14)(15)(16)(17)(21)(22)(23)SI et al.:ESTIMATING REMAINING USEFUL LIFE WITH THREE-SOURCE V ARIABILITY IN DEGRADATION MODELING173,the following equations for RUL estimation at time hold,see(25)–(28)at the bottom of the page,where ,and is the Dawson integral for real.The above results are based on the condition that the current degradation state can be observed directly and exactly.How-ever,due to the measurement variability,the true degradation state at time is unobservable,and its accurate value is im-possible to be known as discussed previously.In this case,it is better to let the true degradation process be a latent process, which is continuouslyfluctuating but not directly observable. Thus the degradation state is needed to be estimated from the measurements.This approach is the focus in the next part. B.Case2:RUL Estimation With Temporal Variability and Uncertain MeasurementsHere,given,we derive the RUL estimation results taking into account the temporal variability and measurement vari-ability.In this case,only uncertain measurements up to the current time are available,and the degradation state cannot be directly used,so we have to estimate the distribution of at time to account for the effect of the measurement variability on the RUL estimation.To identify the degradation state,the state and measurement equations should be converted into the discrete time equations to facilitate the state estimation once the new observations are available at the CM point.Then,we can obtain the transformed dynamic system equations at the discrete time point:(29) where,and is the realization of at.and are.noise sequences. According to the model setting in Section II,we further have,and.According the established we utilize a Kalmanfilter to estimate the underlying degradation state.First,we define,andas the expectation,and variance of that are conditional on the measurement history, respectively.We also define,andas the one-step-ahead predicted expectation,and variance,respectively.Therefore,at time, the Kalmanfilter for state estimation can be summarized as follows.State estimation:Variance update:The initial values of the degradation state are specified as and because of the model setting in Section II.Applying the above Kalmanfiltering algorithm,the poste-rior of conditional on the measurement sequence up to is Gaussian and analytically tractable,i.e.,.In this case,due to measurement variability,the degradation state is estimated from the measurements,and thus estimation uncertainty is involved.To account for estimation uncertainty,the RUL estimation in this case is derived by(30) and(31)at the bottom of the next page,where is the conditional PDF of,with mean,and vari-ance.In we present the following lemma to help evaluate the integrals in(30)and(31).Lemma5:Given the current degradation state,andat time,we have(32)(33)Proof:According to the definition in(5),utilizing the Markov property of the Wiener process,we have(34)at the bottom of the page.This completes the proof.Based on Lemma2,Lemma3,and Lemma5,we have the following results for RUL estimation in the case of taking tem-poral variability and measurement variability into account.(25)(26)(27)(28)。
阿尔法拉瓦尔Pharma-line S双层管道穿插式热交换器说明书
Hojas del tuboFig.1.Los tubos de doble hoja evitan la contaminación entre elproducto y los medios de calentamiento/refrigeración.DATOS FÍSICOSPiezas de acero bañadas por producto:..............316L(tubos enteros) Juntas:................PTFE(cumplimiento con normativaFDA y certificación USP clase VI) Conexiones:............Placa NAC para conectar a Tri-clampen el extremo del tubo y bridas en elextremo de mantenimientoGama estándarEl Alfa Laval Pharma-line es un intercambiador de calor tubular de doble hoja con carcasa de gran calidad diseñado para satisfacer las exigentes necesidades de la industria farmacéutica y biotecnológica. Estádisponible en diversos tamaños estándar y cumple con lasmás exigentes normas de higiene,tanto de la industria como de organismos gubernamentales y de control.Pharma-line S estádisponible en21modelos,todos con diseños de tubos en U aptos para la mayoría de aplicaciones.Dentro de la gama de productos Pharma-line,encontraráa su disposición2series:Pharma-line S(diseño estándar)Pharma-line P(diseño estándar y diseño personalizado disponiblea petición)InstalaciónLas patas móviles facilitan el posicionamiento flexible.Pharma-line S puede instalarse tanto en horizontal como en vertical,en función de las necesidades concretas.Para facilitar la instalación,los ganchos de elevación están sujetos a las unidades.DATOS TÉCNICOSÁrea de transferencia decalor:............0.1m2–4m2Temperatura de diseño:-10°C-150°CPresión de diseño:...FV/10bargCódigos de depósitos depresión:..........PED.TSG chino y licencia de fabricacióndisponibles Soldadura:........conforme con SS-EN-IOS15614-1,EN287-1,EN-1418ASME IXAcabado superficial,piezas bañadas porproducto:.........Pulido mecánico a Ra<0,5µm.Opciones:Documentación•Lana mineral (ASTM C795)de aislamiento con revestimiento de acero inoxidable304Diseño higiénicoPharma-line S no tiene zonas muertas y se puede drenar por completo en el lado del producto.Todas las piezas bañadas del producto de Pharma-line S se han pulido electrónicamente a Ra<0.5µm.Los tubos de Pharma-line S no tienen soldaduras y los tubos en U tienen un radio de curva mayor que el exigido por ASME BPE.Pharma-line S se limpia fácilmente y se puede esterilizar con s juntas cuentan con un certificado USP Clase VI y tienen conformidad con FDA.Pharma-line se suministra con el manual de calidad de Alfa Laval que contiene:•Planos y cálculos aprobados y firmados por el organismo notificado •Lista de soldadores,procedimientos de soldadura y habilitación de los soldadores• 3.1Certificados de material,presión y partes de acero bañadas por producto•Certificados de conformidad con FDA y USP Clase VI,juntas •Procedimiento e informe de pruebas de líquidos penetrantes •Certificado de rugosidad de la superficie •Informe de control de dimensiones•Certificado de pruebas de presión,firmado por el organismo notificado•Identificación (firma técnica)•Certificado de sistema de calidad •Documentación de CEUnidades estándar,mediciones (aproximadas)[mm]TipoCarcasa OD(mm)Tamaño de lasboquillas tubo Tamaño de las boquillas brida A B C Pharma-line S 1[mm]Pharma-line S 1-0.1761"DN501150225195Pharma-line S 1-0.3891"DN501150225195Pharma-line S 1-0.41011"DN501150225195Pharma-line S 1-0.611411/2"DN501150230195Pharma-line S 1-0.71412"DN801150260245Pharma-line S 1-1.11412"DN801150260245Pharma-line S 1-1.21682"DN801150260245Pharma-line S 2[mm]Pharma-line S 2-0.3761"DN502150225195Pharma-line S 2-0.6891"DN502150225195Pharma-line S 2-1.01011"DN502150225195Pharma-line S 2-1.311411/2"DN502150230195Pharma-line S 2-1.41412"DN802150260245Pharma-line S 2-2.41412"DN802150260245Pharma-line S 2-2.61682"DN802150260245Pharma-line S 3[mm]Pharma-line S 3-0.4761"DN503150225195Pharma-line S 3-1.0891"DN503150225195Pharma-line S 3-1.61011"DN503150225195Pharma-line S 3-2.011411/2"DN503150230195Pharma-line S 3-2.21412"DN803150260245Pharma-line S 3-3.71412"DN803150260245Pharma-line S 3-4.01682"DN803150260245T2T1Programa de boquillaComponenteServicio DirecciónEstándar y dimensiones T1Entrada del tubo Placa NAC para Tri-clamp Adecuado para ASME BPE T2Salida del tubo Placa NAC para Tri-clamp Adecuado para ASME BPEM1Entrada de la carcasa Brida tipo cuello soldable DIN2635/EN1092-1M2Salida de la carcasaBridatipo cuello soldableDIN2635/EN1092-1ESE00376ES1507La información incluida en el presente documento es correcta en el momentode su publicación,no obstante puede estar sujeta a modificaciones sinprevio aviso.ALFA LAVAL es una marca registrada de Alfa Laval CorporateAB(Suecia).©Alfa LavalCómo ponerse en contacto con Alfa Laval Cómo ponerse en contacto con Alfa Laval nosotros en cada país,se actualiza constan-temente en nuestra página web.Visite para acceder a esta. información.。
联合国机构简称表
简称表AEO Africa Environment Outlook 非洲环境展望非洲环境展望AGEDI Abu Dhabi Global Environmental Data Initiative 阿布扎比倡议阿布扎比全球环境数据倡议AISD Arab Initiative for Sustainable Development 阿拉伯举措关于可持续发展的阿拉伯举措ALLO League of Arab States 阿盟阿拉伯国家联盟AMCEN African Ministerial Conference on the Environment 非洲环境会议非洲部长级环境会议AMCOW flAfrican Ministers Council on Water 非洲水事理事会非洲部长级水事理事会AMU Arab Maghreb Union 阿马联阿拉伯马格里布联盟APELL A wareness and Preparedness for Emergencies at a Local Level 当地一级警惕并预防紧急事件方案当地一级警惕并预防紧急事件方案AREED African Rural Energy Enterprise Development 非洲农村能源企业发展非洲农村能源企业发展ASEAN Association of South-east Asian Nations 东盟东南亚国家联盟BPOA Barbados Programme of Action 巴巴多斯行动纲领巴巴多斯行动纲领BPOA/SIDS Barbados Programme of Action for Sustainable Development of SIDS巴巴多斯小岛屿发展中国家行动纲领巴巴多斯小岛屿发展中国家可持续发展行动纲领CA Cities Alliance 城市联盟城市联盟CARICOM Caribbean Community 加共体加勒比共同体CAST Caribbean Alliance for Sustainable Tourism 加勒比旅游联盟加勒比可持续旅游联盟CBD Convention on Biological Diversity 生物公约生物多样性公约CDM Clean Development Mechanism 清洁发展机制清洁发展机制CEB Chief Executive Board Members 执行首长理事会成员执行首长理事会成员CEDA Central Dredging Association 中央疏浚协会中部疏浚协会CGIAR Consultative Group on International Agricultural Research 农研组国际农业研究协商小组CITES Convention on International Trade in Endangered Species ofWild Fauna and Flora濒危物种公约濒危野生动植物种国际贸易公约COP Conference of the Parties 缔约方会议缔约方会议CPPS Permanent Commission for the South Pacific 南太平洋常设委员会南太平洋常设委员会CSC Capability & Sustainable Centre 能力和可持续中心能力和可持续中心CSD Commission on Sustainable Development 可持续发展委员会可持续发展委员会CSOs Civil Society Organization 民间社会组织民间社会组织CTO Caribbean Tourism Organization 加勒比旅游组织加勒比旅游组织UNEP/GC.23/85Division of Communications and Public Information 交流和新闻司交流和新闻司DEC Division of Environmental Conventions 环境公约司环境公约司DEPI Division of Environmental Policy Implementation 环境政策执行司环境政策执行司DEWA Division of Early Warning and Assessment 预警和评估司预警和评估司DPDL Division of Policy Development and Law 政策制订和法律司政策制订和法律司DRC Division of Regional Cooperation 区域合作司区域合作司DTIE Division of Technology, Industry and Economics 技术工业和经济司技术工业和经济司EAS East Asian Seas 东亚海洋东亚海洋ECCAS Economic Community of Central African States 中非经共体中非国家经济共同体ECOWAS Economic Community of West African States 西非经共体西非国家经济共同体EECCA Eastern Europe, Caucuses and Central Asia 东欧高加索和中亚东欧高加索和中亚EEHC European Environment and Health Committee 欧洲环境和健康委员会欧洲环境和健康委员会EIs Economic Instruments 经济文书经济文书EMG Environmental Management Group 环境管理组环境管理组ERWDA Environmental Research and Wildlife Development Agency 环境研究和野生动植物发展局环境研究和野生动植物发展局EST Environmentally Sound Technology 无害环境技术无害环境技术ETN Environmental Training Network 环境培训网环境培训网EUCC The Coastal Union 欧盟海岸保护组织欧盟海岸保护组织FAO Food and Agriculture Organization of the United Nations 粮农组织联合国粮食和农业组织FI Finance Initiative 财务举措财务举措GA General Assembly 大会联合国大会GC/GMEF Governing Council/Global Ministerial Environment Forum 理事会/全球环境论坛理事会/全球部长级环境论坛GC.OS Global Climate Observing System 气候观测系统全球气候观测系统GCSS Governing Council Special Session 理事会特别会议理事会特别会议GEF Global Environment Facility 全环基金全球环境基金GEF/IW Global International Facility/International Waters 全环基金/国际水域全球环境基金/国际水域GEMS Global Environment Monitoring Systems 监测系统全球环境监测系统GEO Global Environment Outlook 全球环境展望全球环境展望GIWA Global International Waters Assessment 水域评估全球国际水域评估GLCN Global Land Cover Network 土地覆盖网络全球土地覆盖网络GLOBE Global Legislators Organization for a Balanced Environment 平衡环境组织全球立法者促进平衡环境组织GMA Global Marine Assessment 全球海洋评估全球海洋评估GMA Global Marine Assessment 全球海洋评估全球海洋评估GMEF Global Ministerial Environment Forum 全球环境论坛全球部长级环境论坛UNEP/GC.23/86GOOS Global Ocean Observing System 海观系统全球海洋观测系统GPA Global Programme of Action for the Protection of the Marine Environment from Land-based Activities保护海洋环境行动纲领保护海洋环境免受陆地活动影响全球行动纲领GRID Global Resource Information Database 资源信息库全球资源信息数据库GTOS Global Terrestrial Observing System 陆观系统全球陆地观测系统GWP Global Water Partnership 水事伙伴关系全球水事伙伴关系HELCOM Helsinki Commission for the Protection of the Marine Environment of the Baltic Sea Area赫尔辛基委员会保护波罗的海区域海洋环境赫尔辛基委员会HELI Health and Environmental Linkages Initiative 健康与环境联系倡议健康与环境联系倡议IADC International Association of Dredging Companies 钻井承包商协会国际钻井承包商协会IAPH International Association of Ports and Harbors 港埠协会国际港埠协会ICARM Integrated Coastal Area and River-basin Management 综合沿海地区和河川流域管理综合沿海地区和河川流域管理ICFTU International Confederation of Free Trade Unions 自由工联国际自由工会联合会ICLEI International Council for Local Environmental Initiatives 环境倡议理事会国际地方环境倡议理事会IETC International Environmental Technology Centre 环境技术中心国际环境技术中心IFRCS International Federation of Red Cross and Red Crescent Societies红十字会与红新月会联合会红十字会与红新月会国际联合会IGOs Intergovernmental Organizations 政府间组织政府间组织IGOS Integrated Global Observing Strategy 综合观测战略全球综合观测战略IGR Inter-Governmental Review 政府间审查政府间审查IISD International Institute for Sustainable Development 可持续发展所国际可持续发展研究所ILO International Labour Organization 劳工组织国际劳工组织IMF International Monetary Fund 货币基金组织国际货币基金组织IMO International Maritime Organization 海事组织国际海事组织IOI International Ocean Institute 海洋学会国际海洋学会IPCC Intergovernmental Panel on Climate Change 气候小组政府间气候变化问题小组IPPC Intergovernmental Plant Protection Convention 植保公约国际植物保护公约IPU Inter-Parliamentary Union 议会联盟各国议会联盟IRBM Integrated River Basin Management 综合河川流域管理综合河川流域管理IUCN World Conservation Union 自然保护联盟世界自然保护联盟IWRM Integrated Water Resources Management 综合水资源管理综合水资源管理JMP Joint Monitoring Programme on Water & Sanitation coverage 水事和卫生监测方案水事和卫生联合监测方案JPOI Johannesburg Plan of Implementation 约堡执行计划约翰内斯堡执行计划LADA Lands Degradation Assessment 土地退化评估土地退化评估UNEP/GC.23/87LDC Least-Developed Countries 最不发达国家最不发达国家MA Millennium Assessment 千年评估千年评估MARPOL International Convention for the Prevention of Pollution from Ships船污公约国际防止船舶造成污染公约MDGs Millennium Development Goals 千年发展目标千年发展目标MEAs Multilateral Environment Agreements 多边环境协定多边环境协定NACA Network of Aquaculture Centres in Asia and Pacific 亚太水产养殖中心网络亚洲和太平洋水产养殖中心网络NAP National Action Plan 国家行动计划国家行动计划NEP North East Pacific 东北太平洋东北太平洋NEPAD flNew Partnership for Africa s Development 非洲发展新伙伴关系非洲发展新伙伴关系NGOs Non-governmental Organizations 非政府组织非政府组织NOWPAP North-West Pacific Action Plan 西北太平洋行动计划西北太平洋行动计划OCTA Organization of the Amazonian Cooperation Treaty 亚马逊条约组织亚马逊合作条约组织OECD Organization for Economic Cooperation and Development 经合组织经济合作与发展组织OSPAR Oslo-Paris Convention for the Protection of the Marine Environment of the North-East Atlantic奥斯陆巴黎公约奥斯陆巴黎保护东北大西洋海洋环境公约PADELIA Partnership for the Development of Environmental Law and Institutions in Africa非洲环境法和体制发展伙伴关系非洲环境法和体制发展伙伴关系PADH Physical Alteration and Destruction of Habitats 具体的生境改变和破坏具体的生境改变和破坏PARLA TINO Parlamento Latino/Americano 拉美议会拉丁美洲议会PCFV Partnership for Clean Fuels & V ehicles 清洁燃料与清洁车辆伙伴关系清洁燃料与清洁车辆全球伙伴关系PERSGA Regional Organization for the Conservation of the Environment of the Red Sea and the Gulf of Aden保护红海和亚丁湾组织保护红海和亚丁湾环境区域组织PFII Permanent Forum for Indigenous Issues 土著问题常设论坛土著问题常设论坛POPs Persistent Organic Pollutants 持久性有机污染物持久性有机污染物PRTR Pollutant Release and Transfer Register 污染物排放与转移登记制度污染物排放与转移登记制度ROPME Regional Organization for the Protection of the Marine Environment区域护洋组织保护海洋环境区域组织RS Regional Seas 区域海洋区域海洋SAARC South Asian Association for Regional Cooperation 南盟南亚区域合作联盟SACEP South Asian Cooperative Environment Programme 南亚环境方案南亚合作环境方案SADC Southern Africa Development Community 南部非洲共同体南部非洲发展共同体SAS/SACEP South Asian Seas-South Asian Cooperative Environment Programme南亚海洋南亚环境方案南亚海洋南亚合作环境方案UNEP/GC.23/88SIDA Swedish International Development Agency 瑞典开发署瑞典国际开发署SIDS Small Island Developing States 小岛屿发展中国家小岛屿发展中国家SMEs Small and Medium Sized Enterprises 中小型企业中小型企业SRAP Sub-Regional Action Plan 分区域行动计划分区域行动计划THE PEP Transport, Health and Environment Pan-European Programme 泛欧运输健康和环境方案泛欧运输健康和环境方案UCC-Water UNEP Collaborating Centre on Water and Environment / DHI 环境署合作中心丹麦水文所环境署水事和环境合作中心/丹麦水文所UNCCD United Nations Convention to Combat Desertification 防治荒漠化公约联合国防治荒漠化公约UNCTAD United Nations Conference on Trade and Development 贸发会议联合国贸易和发展会议UNDOALOS United Nations Division for Ocean Affairs and the law of the Sea海洋事务和海洋法司联合国海洋事务和海洋法司UNDP United Nations Development Programme 开发署联合国开发计划署UNECA United Nations Economic Commission for Africa 非洲经委会联合国非洲经济委员会UNECE United Nations Economic Commission for Europe 欧洲经委会联合国欧洲经济委员会UNEP-WCMC UNEP World Conservation Monitoring Centre 养护监测中心环境规划署世界养护监测中心UNESCAP United Nations Economic and social Commission for Asia and Pacific亚太经社会联合国亚洲及太平洋经济社会委员会UNESCO United Nations Educational, Scientific and Cultural Organization教科文组织联合国教育科学及文化组织UNESCO-IHE UNESCO Institute for Water Education / IHE 教科文组织水事教育研究所/基础设施水利和环境研究所联合国教科文组织水事教育研究所/基础设施水利和环境研究所UNFCCC United Nations Framework Convention on Climate Change 气候公约联合国气候变化框架公约UNFF United Nations Forum on Forests 森林论坛联合国森林问题论坛UN-Habitat United Nations Human Settlements Programme 人居署联合国人类住区规划署UNICEF flUnited Nations Children s Fund 儿童基金会联合国儿童基金会UNICP United Nations Informal Consultative Process 非正式协商程序联合国非正式协商程序UNICPOLOS United Nations Open-ended Informal Consultative Process onOceans and the Law of the Sea海洋非正式磋商程序联合国海洋事务不限成员名额非正式磋商程序UNIDO United Nations Industrial Development Organization 工发组织联合国工业发展组织UNIFIP United Nations Fund for International Partnerships 合作基金联合国国际合作基金UNITAR United Nations Institute for Training and Research 训研所联合国训练研究所UNOLA UN Office of Legal Affairs 法律事务厅联合国法律事务厅UNSD United Nations Statistical Division 统计司联合国统计司UNU United Nations University 联合国大学联合国大学UNEP/GC.23/89US NIEHS US National Institute of Environmental Health Sciences 美国国家环境卫生学会美国国家环境卫生学会WB World Bank 世行世界银行WBCSD World Business Council for Sustainable Development 促发世商会促进可持续发展世界商业理事会WED World Environment Day 世界环境日世界环境日WHO World Health Organization 卫生组织世界卫生组织WIOMSA West Indian Ocean Marine Science Association 西印度洋海洋科学协会西印度洋海洋科学协会WOCA T World Overview of Conservation Approaches and Technologies水土保持方法和技术概览世界水土保持方法和技术概览WSSCC Water Supply and Sanitation Collaborative Council 供水和卫生合作理事会供水和卫生合作理事会WSSD World Summit on Sustainable Development 可持续发展首脑会议可持续发展问题世界首脑会议WTO World Trade Organization 世贸组织世界贸易组织WTO/OMT World Tourism Organization 旅游组织世界旅游组织WWAP World Water Assessment Programme 水资源评估方案世界水资源评估方案WWDR World Water Development Report 水发展报告世界水发展报告WWF World Wide Fund for Nature 大自然基金世界大自然基金UNEP/GC.23/8。
西班牙语日常词汇生活整理篇
1. Hola(奥拉)：你好(大家好)2.Gracias(格拉西亚斯)：谢谢3. Muchas gracias (木恰斯格拉西亚斯)：非常感谢4.Adios (阿迪奥斯)：再见5. Hasta luego (阿斯达鲁艾戈)：回见(再见)6.Perdon(贝东)：对不起7.De nada(得纳达)：没关系8.Donde esta el lavabo?(懂得爱斯达呃拉瓦波?)：厕所在哪儿?9.Que guapo(盖瓜波!)：你太帅了(男)。
10.Que guapa (盖瓜巴!)：你太美了(女)。
11.Mucho gusto(木臭古斯多)：很高兴(认识你/您)12.Paella (巴埃亚/爸哎呀)：西班牙海鲜饭13.Amigo (阿米哥)：朋友(男性)14.Amiga(阿米嘎)：朋友(女性)15. Muy bien (木一变/摸一遍)：很好(副词)16. Buenos dias (布埃诺斯迪亚斯)：早上好17. Buenas tardes(布埃那斯达而德斯):下午好18. Buenas noches (布埃那斯诺切斯)：晚上好/晚安19. Habla usted ingles? (阿布拉乌斯得因格列斯)：您讲英语吗?20. No hablo espanol. (喏阿布罗埃斯巴鸟)：我不会将西班牙语。
21. Jamon (哈!梦!)：火腿22. Te quiero (得盖也楼)：我喜欢你(我爱你)23. Chico (奇狗)：男孩24. Chica (奇嘎)：女孩一般用语* 基本表达* 计量单位* 时间* 数字* 星期* 月份* 季节* 天气* 颜色常用词西语常用词汇：西班牙语生活常用口语中华考试网() 【大中小】 [ 2010年7月5日 ] ¡Buen fin de semana! - Igualmente周末愉快 - 你也一样Mañana tengo un examen - ¡Suerte!明天我有个考试–祝你好运！Me he dejado el libro en casa – Noimpo rta我把书落在家里了–没关系Tengo un trabajo nuevo - ¡Felicidades!我找到了一个新工作–恭喜!Hoy es mi cumpleaños - ¡Feliz cumpleaño s!今天我生日–生日快乐!¿Quieres un poco más de tarta? – Si gr acias – No gracias, estoy lleno还要吃一些蛋糕吗?¿Puedo tomar otra taza de café? –Sírv ete tu mismo还能给我来一杯咖啡吗? –请自便Tengo que irme –Nos vemos mañana我得走了-明天见Usted es muy amable你真好Gracias - De nada谢谢–不客气¿Habla usted inglés? - Lo siento, no ha blo inglés你会说英语吗? –抱歉，我不会英语Hable en inglés, por favor请说英语No hablo español我不说英语Hablo un poco de español我会讲一点西班牙语¿Hay alguien por aquí que hable inglés?附近有人说英语吗？¿Quién habla inglés?谁会说英语？¿Qué significa esto?这是什么意思?¿Cómo sedice esto en español?西班牙语这是什么意思?Por favor, hable despacio请慢慢说Por favor, hable más despacio请说慢点Comprendo我懂了。
网易路由器 Wi-Fi USB 适配器 A6200 安装指南说明书
®Guía de instalación Adaptador Wi-Fi USB A6200Adaptador Wi-Fi 802.11acContenido de la cajaCD de recursosAdaptador Wi-Fi 802.11acDual Bandy base para escritorio Instalación1. Introduzca el CD de recursos en la unidad de CD del equipo. Si no se abre lapantalla principal del CD, acceda a los archivos del CD y haga doble clic enautorun.exe.2. Haga clic en Setup (Configurar).Aparecerá la ventana de búsqueda de actualizaciones de software.3. Si está conectado a Internet, haga clic en Check for Updates (Buscaractualizaciones). Si no lo está, haga clic en Install from CD (Instalar desde elCD).4. Haga clic en la opción I Agree (Aceptar) del acuerdo de licencia y, acontinuación, en Next (Siguiente).Aparecerá un mensaje en el que sele pedirá que espere mientras seinstala el software. Tras unosminutos, NETGEAR Genie le solicitaque introduzca el adaptador.5. Puede utilizar el adaptador con o sinla base para escritorio:• Para usar el adaptador con unabase para escritorio, coloque eladaptador inalámbrico en la basey conecte el cable USB al puertoUSB del equipo.• Para utilizarlo sin la base paraescritorio, inserte el adaptador enun puerto USB del equipo, comose muestra en la imagen de laderecha.6. Haga clic en Siguiente.NETGEAR Genie muestra una lista de las redes inalámbricas disponibles ensu área.Instalación del controlador independiente1.Introduzca el CD de recursos en la unidad de CD del equipo. Si no se abre lapantalla principal del CD, acceda a los archivos del CD y haga doble clic enautorun.exe.2. Haga clic en Install WindowsStandalone Driver (Instalar controladorindependiente para Windows).El controlador se instala en el equipo.3. Introduzca el adaptador en un puerto USBdel equipo cuando se le solicite, o bien,conéctelo con el cable USB incluido en lacaja del producto.Septiembre de 2012Este símbolo aparece conforme a la directiva 2002/96 de la UE sobre residuos de aparatoseléctricos y electrónicos (directiva RAEE). Si tuviera que desechar este producto dentro de la Unión Europea, deberá tratarlo y reciclarlo de conformidad con lo dispuesto en las leyes locales pertinentes, en aplicación de la directiva RAEE.NETGEAR, el logotipo de NETGEAR y Connect with Innovation son marcas comerciales o marcas comerciales registradas de NETGEAR, Inc. o sus filiales en Estados Unidos y otros países. La información contenida en el documento puede sufrir modificaciones sin previo aviso. El resto de marcas y nombres de productos son marcas comerciales o marcas comerciales registradas por sus respectivos titulares. ©NETGEAR, Inc. Todos los derechos reservados.Para uso exclusivo en interiores en todos los países de la UE y Suiza.Para consultar la declaración de conformidad de la UE completa, visite /app/answers/detail/a_id/11621/.Condiciones : con el fin de mejorar el diseño interno, el funcionamiento y la fiabilidad, NETGEAR se reserva el derecho de realizar modificaciones del producto descrito en el presente documento sin previo aviso. NETGEAR no asume responsabilidad alguna derivada del uso o la aplicación del producto o del circuito descritos en el presente documento.Conexión a una red inalámbricaPuede conectarse a una red inalámbrica desde NETGEAR Genie o bien, usar el botón WPS (Wi-Fi Protected Setup) si el router inalámbrico lo admite.• Opción 1: NETGEAR Genie . Haga clic en su red inalámbrica (SSID) paraseleccionarla y, a continuación, haga clic en Connect (Conectar). Si la red está protegida, introduzca la contraseña o clave de red. • Opción 2: WPS . Mantenga pulsado el botón WPS del lateral del adaptadordurante 2 segundos.Antes de que transcurran 2 minutos, pulse el botón WPS del router o la puerta de enlace inalámbricos.El adaptador se conectará a la red. Este proceso puede tardar varios minutos.La configuración se guarda en un perfil.Botón WPSComprobación del estado de la conexiónTras instalar el adaptador, el icono de NETGEAR Genie aparece en la barra de sistema de Windows y en el escritorio. Haga doble clic en él para abrir NETGEAR Genie y realizar cambios o conectarse a una red inalámbrica diferente. El color del icono indica la intensidad de la conexión inalámbrica:Blanco: 3-5 barras (intensidad alta)Amarillo: 1-2 barras (intensidad baja)Rojo: 0 (cero) barras (sin conexión)Si extrae el adaptador, NETGEAR Genie no estará disponible, por lo que el icono tampoco se mostrará. Cuando vuelva a conectar el adaptador, el icono apareceráde nuevo.Ampliación del alcance y del rendimientoPara aumentar el alcance y el rendimiento, puede gira la parte superior del adaptador de modo que quede perpendicular al mismo:En esta posición, las antenas internas se extienden desde el adaptador y aumenta el rendimiento Wi-Fi.Servicio técnicoUna vez instalado el dispositivo, busque el número de serie en la etiqueta del producto y regístrelo en https:// .De lo contrario, no podrá hacer uso del servicio telefónico de asistencia deNETGEAR. NETGEAR recomienda registrar el producto a través del sitio web de NETGEAR. Podrá encontrar actualizaciones del producto y asistencia técnica en .Encontrará el manual del usuario en línea en o a través de un vínculo en la interfaz de usuario.。
内源性大麻素系统用于骨质疏松症预防与治疗的研究进展
Tianjin Med J,September 2023,Vol.51No.9内源性大麻素系统用于骨质疏松症预防与治疗的研究进展王蕾1，杨涛1，耿立成1，孙天威2△摘要：骨质疏松症（OP ）是一种以骨量减少和骨组织微结构改变为特征的全身性骨骼疾病，其发病率呈逐年上升趋势，已经成为严重的公共健康隐患。
成骨细胞和破骨细胞介导的骨代谢失衡是OP 的重要发病机制。
内源性大麻素系统（ECS ）广泛分布于骨组织中，参与调节成骨细胞及破骨细胞的多种生物学功能，可能是OP 的潜在治疗靶点，靶向ECS 进行深入研究能够为OP 的临床治疗提供新的理论依据。
就ECS 在调控OP 发病过程中的具体作用进行了综述。
关键词：骨质疏松；受体，大麻酚；大麻素受体调节剂；成骨细胞；骨代谢中图分类号：R681.4，R614，R285文献标志码：A DOI ：10.11958/20230510Research progress of endocannabinoid system for prevention and treatment of osteoporosisWANG Lei 1,YANG Tao 1,GENG Licheng 1,SUN Tianwei 2△1Department of Anesthesiology,2Department of Spine Surgery,Tianjin Union Medical Center,Tianjin 300121,China△Corresponding Author E-mail:Abstract:Osteoporosis (OP)is a kind of systemic bone disease characterized by reduced bone mass and changes of bone microstructure.The incidence rate of OP has been increasing gradually year by year,which has become a severe public health issue.The imbalance of bone metabolism mediated by osteoblasts and osteoclast is an important pathogenesis of OP.The endocannabinoid system (ECS)is widely distributed in bone tissue and participates in regulating multiple biological effects of osteoblasts and osteoclasts,suggesting that ECS may be a potential treatment target of OP.Further study on targeting ESC can provide a new theoretical basis for the clinical treatment of OP.This article reviews the specific role of ECS in regulating the pathogenesis of OP.Key words:osteoporosis;receptors,cannabinoid;cannabinoid receptor modulators;osteoblasts;bone metabolism基金项目：天津市科技计划项目（22JCZDJC00250）作者单位：1天津市人民医院麻醉科（邮编300121），2脊柱外科作者简介：王蕾（1972），男，主治医师，主要从事麻醉药理与骨质疏松症疼痛机制研究。
2014年日历gravotech
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LG 液氮蒸汽冰箱：使用指南和操作方法说明书
Guida alla refrigerazione: la temperatura giustaAlimenti - Refrigerazione e congelamento Refrigerazione e congelamentoContenuto ---Corretta refrigerazione – per un sano piacere La giusta temperatura per ogni alimento Le opzioni BioFresh in un colpo d’occhio Carne e latticini Frutta e verdura PesceCongelamento corretto con una tecnologia innovativa FrostSafe: mantiene il freddo nel vano congelatore SuperFrost: per congelare in modo semplice DuoCooling: la combinazione perfettaCome congelare correttamente il pranzo della domenica Confezionare gli alimenti secondo le norme vigenti.Lista di controllo del congelatore: una panoramica delle pietanzeCome sbrinare in modo sempliceCon quale frequenza si deve sbrinare il congelatore?Dove si mettono gli alimenti congelati durante lo sbrinamento? In questo modo si accelera il processo di sbrinamento.NoFrost: mai più sbrinamentoLe classi climatiche: cosa significano?Frigorifero – GuidaCorretta refrigerazione –per un sano piacere.---“Nessun piacere è fugacepoiché l’impressione che lascia è permanente”, affermava Johann Wolfgang von Goethe. Le nuove tecnologie garantiscono un piacere più duraturo perché mantengono più a lungo l’aroma e le vitamine degli alimenti, e con essi anche la freschezza. Refrigerazione, congelamento o conservazione: il fattore decisivo è l’interazione tra temperature costanti e un’umidità adeguata agli alimenti conservati.Frigorifero – GuidaLe opzioni BioFresh in un colpo d’occhio.---Con i suoi cassetti regolabili in modo flessibile, BioFresh offre condizioni di conservazione ottimali perogni categoria di alimenti. Qui potete apprendere quale temperatura e quale opzione BioFresh sono più adatte per i diversi alimenti.La giusta temperatura per ogni alimento.---La corretta interazione tratemperatura e umidità è il fattore deciso per una lunga conservazione che preservi le sostanze nutritive. Ciascun prodotto alimentare tuttavia ha esigenze di conservazione diverse. Il prosciutto di elevata qualità viene stagionato all’aria secca di montagna, i manghi crescono in luoghi molto umidi, il formaggio sviluppa il proprio aroma in grotte fresche.Carne e latticiniAnche i prodotti a base di carne sono molto esigenti in termini di temperatura e umidità. Nel cassetto BioFresh Meat & Dairy trovano l’ambiente ideale. La bassa umidità e una temperatura di poco superiore al punto di congelamento riducono significativamente l’attività dei microrganismi ,assicurando così una durata di conservazione particolarmente lunga. Condizioni climatiche ottimali anche per latte, formaggio e yogurt.Frutta e verduraL’elevato contenuto di acqua della frutta e verdura richiede una conservazione in un ambiente con umidità elevata. Il BioFresh con cassetto Safe per frutta e verdura crea il clima ideale e il suo sistema elettronico preciso assicura una temperatura costante di poco superiore a 0 °C. Le condizioni di conservazione ottimali non solo impediscono il congelamento indesiderato dei prodotti, ma li proteggono anche dalla perdita di freschezza conservando il più possibile le preziose sostanze nutritive.PesceIl pesce e i frutti di mare in negozio sono conservati nel ghiaccio perché la loro temperatura di conservazione ideale si aggira attorno al punto di congelamento. Impostato a 0 °C, il cassetto Safe BioFresh è adatto alla conservazione del pesce. Anguilla, salmone e luccioperca durano ancora di più con BioFresh Professional con cassetto Fish & Seafood. Grazie al comando individuale, la temperatura in questa zona climatica può essere abbassata esattamente a -2 °C. In combinazione con l’impostazione Meat & Dairy-Safe, il pesce rimane fresco molto più a lungo.comma before the word correct?FrostSafe: mantiene il freddo nel vano congelatore.Quando si apre il congelatore, fuoriesce aria fredda. Questo non solo comporta un maggiore consumo di energia, ma provoca anche variazioni di temperatura che pregiudicano la qualità dei prodotti conservati. I cassetti possono essere una soluzione a questo problema. Grazie ai cassetti particolarmente alti e completamente chiusi , con FrostSafe fuoriesce molto meno aria fredda rispetto ai cassetti di un congelatore convenzionale.SuperFrost: per congelare in modo semplice.La funzione automatica SuperFrost facilita il congelamento e fa risparmiare energia. Riduce rapidamente la temperatura a -32 °C per creare la riserva di freddo che serve a preservare le vitamine. Non appena il processo di congelamento è completato, la modalità automatica SuperFrost torna al funzionamento normale, facendo così risparmiare corrente elettrica.DuoCooling: la combinazione perfetta.Con la tecnologia DuoCooling, la temperatura dei frigo- congelatori combinati può essere impostata e controllata in modo preciso e indipendente nel vano frigorifero e nel vano congelatore. Questa funzione è disponibile nelle apparecchiature in cui il vano frigorifero e il vano congelatore hanno ciascuno il proprio sistema di controllo per la regolazione della temperatura. Il DuoCooling impedisce che gli odori degli alimenti conservati si trasferiscano dal vano del congelatore a quello del frigorifero e viceversa. Questo impedisce anche l’essiccazione degli alimenti.Congelamentocorretto – tecnologia innovativa.---Il congelamento degli alimenti non solo prolunga la durata diconservazione: prima viene congelato il prodotto fresco, maggiore sarà la percentuale di vitamine e minerali preservati. Ecco perché il pesce viene congelato appena pescato, direttamente in alto mare. Grazie al “congelamento d’urto”, il prodotto anche dopo lo scongelamento risulta più fresco rispetto a quello venduto al banco del supermercato dopo un lungo trasporto. A proposito: a differenza del congelamento, lo scongelamento deve avvenire in modo lento e delicato, preferibilmente in frigorifero. Eccovi ulterioriinformazioni sulle innovative opzioni di congelamento.Come congelare correttamente il pranzo della domenica.Nei giorni di festa è bello pranzare insieme alla propria famiglia. Ma che fine fanno gli avanzi delle giornata di festa? Una possibilità è quella di congelarli! Scoprite come congelarecorrettamente stufati, carne, salse e zuppe e cosa dovete tenere a mente quando li scongelate. Come preparare gli alimenti con cura.– Carne: lasciarla raffreddare e riposare, suddividerla in pratiche porzioni.– Verdure: pulirle, lavarle, tagliarle e scottarle, lasciarle raffreddare rapidamente.– Frutta: lavarla, togliere i noccioli o i semi,staccare il gambo oppure sbucciarla o congelarla con o senza soluzione zuccherina.Confezionare le giuste quantità.– Verdura e frutta fino a max 1 kg per confezione– Carne fino a max 3 kg per confezione – Pietanze fino a max 1 kg per confezioneLista di controllo del congelatore: una panoramica delle pietanzePietanze SformatiArrostiStufatiOca/anatraSpezzatino di carneLepreCostata di maiale affumicata, pezzo interoGnocchiInvoltini di manzoCavolo rossoCarne di maialeZuppe PreparazionePrecongelare il prodotto crudo o cotto nella teglia, toglierlodalla teglia e avvolgerlo nella pellicolaCongelare il prodotto intero o a fette, inserire una pellicolatra una fetta e l’altraFar cuocere brevemente, confezionare in porzioni in contenitoririgidi o in sacchetti a prova di ebollizioneEviscerare, preparare per la cottura e confezionareConfezionare in porzioni non superiori a 3 kgEviscerare, confezionare il prodotto intero o a pezziSuddividere e confezionare in porzioni non superiori a 3 kgUna volta cotti, metterli in contenitori rigidi o in sacchettida cotturaConfezionare massimo 6-8 pezzi in orizzontale, l’inserimentodi una pellicola tra un pezzo e l’altro èideale per il congelamentoLa carne magra può essere conservata più a lungo di quellagrassa. Non confezionare pezzi superiori ai 3 kgPrecongelare le zuppe possibilmente senza grassi in contenitori,poi confezionarle nella pellicolaDurata di conservazionenel congelatore2-3 mesi3 mesi3 mesi2-4 mesi3-6 mesi8 mesi2-3 mesi3 mesi9-12 mesi8-10 mesi4-7 mesi4-6 mesiConfezionaregli alimenti secondo le norme vigenti.---I cibi solidi, come carne, verdura, pane o prodotti da forno, destinati allo scongelamento e alla cottura in un forno a microonde, devono essere conservati soloin contenitori adatti. Gli alimenti liquidi e morbidi come succhi, zuppe o frutta morbida, devono essere contenuti in recipienti forati o rigidi, all’occorrenza adatti al microonde.Perché è necessario sbrinare?---Vi chiederete prima di tutto perché è necessario sbrinare il congelatore. L’umidità proviene dagli alimenti conservati, ma penetra all’interno dell’apparecchio ogni volta chesi apre la porta. Questa umidità si deposita sotto forma di ghiaccio all’interno del congelatore, rendendo difficile l’estrazione dei cassetti. Inoltre, per poter mantenere la temperatura desiderata semprea un livello costante, la formazione di ghiaccio comporta un dispendio maggiore di energia. Questo causa un maggiore consumo di corrente.Dove si mettono gli alimenti congelati durante lo sbrinamento?Prima di iniziare a sbrinare il congelatore, si devono rimuovere i prodotti congelati. Potete avvolgere gli alimenti in carta da giornale e poi conservarli in un luogo refrigerato. Oppure i prodotti congelati possono essere conservati insieme ad accumulatori di freddo nei cassetti del congelatore. E se si possiede un’apparecchio con la funzione SuperFrost, attivarla circa 24 ore prima del processo di sbrinamento. Questo abbassa la temperatura dai normali -18 °C alla massima capacità di refrigerazione. In questo modo si ritarda un po’ il processo di scongelamento degli alimenti.In questo modo si accelera il processodi sbrinamento.Prima di sbrinare, consigliamo di spegnere l’apparecchio e scollegarla dalla rete elettrica. Per avviare lo sbrinamento, aprire la porta del congelatore per consentire al ghiaccio di sciogliersi lentamente. È possibile accelerare questo processo mettendo una ciotola di acqua calda all’interno dell’apparecchio tenendo la porta chiusa. In questo modo il calore scioglie più rapidamente il ghiaccio depositato ed è possibile rimuovere più facilmente le parti di ghiaccio che si sono formate anche sulle pareti laterali. Rimuovere l’acqua del ghiaccio scongelato e il ghiaccio ancora presente con una spugna o un panno. Questo eviteràche troppa acqua finisca sul pavimento.NoFrost: mai più sbrinamentoSe non avete voglia di perdere tempo a sbrinare periodicamente l’apparecchio, vi consigliamo i congelatori con tecnologia NoFrost. Grazie a questa innovazione, il fastidioso sbrinamento non è più necessario. La tecnologia NoFrost fa congelare gli alimenti con aria di ricircolo refrigerata, convogliando l’umidità all’esterno. In questo modo, il vano congelatore rimane sempre privo di ghiaccio e non si forma più brina sugli alimenti.Ma per risparmiare a voi lo sbrinamento periodico, la funzione NoFrost lo esegue automaticamente. Non appena sull’evaporatore si accumula uno strato di ghiaccio, un sensore avvia il processo di sbrinamento. In questo caso, la ventola si spegne, i tubi dell’evaporatore si riscaldano e lo strato di ghiaccio si scioglie senza che la temperatura nel vano congelatore stesso aumenti. L’apparecchio rimane priva di ghiaccio e il consumo energetico rimane costante.E voi non dovete più sbrinare.Come sbrinarein modo semplice.---In linea di massima, l’umiditàsi condensa nel punto più freddo. Conoscete di sicuro il fenomeno della condensazione del vapore acqueo sui vetri delle finestredi casa. Il motivo è che le finestre sono di solito il punto più freddo della casa. Allo stesso modo,l’umidità nel congelatoresi condensa sul cosiddetto evaporatore, un sistema di tubi attraverso il quale scorreil refrigerante. Nei congelatoripiù datati, i tubi dell’evaporatore passano attraverso i ripianisu cui poggiano i cassetti del congelatore. Si forma così ghiaccio intorno ai ripianidi alluminio con i tubidell’evaporatore, rendendo necessario uno sbrinamento.Frigorifero – Guida Con quale frequenza si deve sbrinareil congelatore?Per evitare la formazione di ghiaccio e quindi mantenereil consumo energetico il più basso possibile, consigliamodi sbrinare il congelatore 1-2 volte all’anno. A secondadella percentuale di umidità presente nel luogo diinstallazione del congelatore, potrebbe essere necessariouno sbrinamento dell’apparecchio più frequente. Inoltre,lo sbrinamento a intervalli regolari favorisce il correttofunzionamento dell’apparecchio nel lungo periodo.Le classi climatiche: cosa significano?---Affinché un frigorifero o un congelatore funzioni sempre in modo ottimale, viene indicata la classe climatica. Questa si trova sulla targhetta dati e fornisce informazioni sulle temperature ambiente ideali per un impiego ottimale dell’apparecchio. A seconda della marcatura delle apparecchiature, queste ultime sono adatte per diversi range di temperatura ambiente. In base alla classificazione/marcatura i clienti possono vedere in quale range di temperatura ambiente si mantengono le temperature di conservazione richieste. Qualcuno di voi tiene eventualmente un secondo frigorifero o congelatore sul terrazzo o in garage. Qui, in invernola temperatura può scendere anche sotto i +10 °C. Ecco perché l’indicazione della classe climatica è molto importante: in determinate circostanze questo può avere un impatto sul funzionamento e sulla durata della vita utile dell’apparecchio, nonché sul suo consumo energetico. Se si possiede un’apparecchio di questo tipo, progettata per il range SN-T, non si deve metterla in funzionea temperature ambiente inferiori a +10 °C. Il motivo:le proprietà di scorrimento (viscosità) dell’olio nel compressore diminuiscono. Se l’olio diventa viscoso,la “lubrificazione” ottimale non è più garantita e il compressore potrebbe danneggiarsi.Ai sensi della norma DIN EN ISO 15502, sono state stabilite in modo vincolante le seguenti classi climatiche per tutti i frigoriferi e congelatori:SN Subnormale Per temperature ambiente da 10 °C a 32 °CN Normale Per temperature da 16 °C a 32 °CST Subtropicale Per temperature ambiente da 16 °C a 38 °CT Tropicale Per temperature ambiente da 16 °C a 43 °C Frigorifero – GuidaChi siamo.---Frigoriferi e congelatori di elevata qualità e soluzioni digitali perun maggiore comfort nella vita quotidiana.Dal 1954 Liebherr-Hausgeräte sviluppa e produce frigoriferi e congelatori per le esigenze più svariate dei clienti.La gamma di prodotti spazia da frigo-congelatori combinati a congelatori classici, fino a includere le più moderne apparecchiature da incasso. Liebherr-Hausgeräte offre anche le apparecchiature giuste per gli intenditori di vino e sigari. Oltre a un’ampia gamma di frigoriferi e congelatori per uso domestico, Liebherr-Hausgeräte offre anche frigoriferi e congelatori di elevata qualità per uso professionale. Che si tratti di panifici o pasticcerie, laboratori, negozi di alimentari, industria delle bevandee dei prodotti surgelati, del settore alberghiero e della ristorazione, i frigoriferi e i congelatori Liebherr offrono la soluzione giusta per qualsiasi esigenza di conservazione. Quasi tutte le apparecchiature a posizionamento liberoo da incasso possono essere collegate in rete e integrate nelle soluzioni SmartHome già esistenti.。
Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation
Cytokinesis Failure Triggers HippoTumor Suppressor Pathway ActivationNeil J.Ganem,1,5,6,*Hauke Cornils,1,5Shang-Yi Chiu,1Kevin P.O’Rourke,1Jonathan Arnaud,2Dean Yimlamai,3 Manuel The´ry,2,4Fernando D.Camargo,3and David Pellman1,*1Howard Hughes Medical Institute,Department of Pediatric Oncology,Dana-Farber Cancer Institute,Children’s Hospital and Department of Cell Biology,Harvard Medical School,Boston,MA02115,USA2CEA,Institut de Recherche en Technologie et Science pour le Vivant,UMR5168,CEA/UJF/INRA/CNRS,17rue des martyrs,38054Genoble, France3Stem Cell Program,Children’s Hospital Boston,Boston,MA02115,USA4Physics of Cytoskeleton and Morphogenesis,Hopital Saint Louis,Institut Universitaire d’Hematologie,U1160,INSERM/AP-HP/Universite´Paris Diderot,Paris75010,France5Co-first author6Present address:The Cancer Center,Departments of Pharmacology and Experimental Therapeutics and Medicine,Division of Hematology and Oncology,Boston University School of Medicine,Boston,MA02118,USA*Correspondence:nganem@(N.J.G.),david_pellman@(D.P.)/10.1016/j.cell.2014.06.029SUMMARYGenetically unstable tetraploid cells can promotetumorigenesis.Recent estimates suggest that $37%of human tumors have undergone a genome-doubling event during their development.This poten-tially oncogenic effect of tetraploidy is counteredby a p53-dependent barrier to proliferation.However,the cellular defects and corresponding signalingpathways that trigger growth suppression in tetra-ploid cells are not known.Here,we combine RNAiscreening and in vitro evolution approaches todemonstrate that cytokinesis failure activates theHippo tumor suppressor pathway in cultured cells,as well as in naturally occurring tetraploid cells in vivo.Induction of the Hippo pathway is triggered in partby extra centrosomes,which alter small G proteinsignaling and activate TS2in turnstabilizes p53and inhibits the transcriptional regula-tors YAP and TAZ.Thesefindings define an importanttumor suppression mechanism and uncover adaptivemechanisms potentially available to nascent tumorcells that bypass this inhibitory regulation. INTRODUCTIONProliferating tetraploid cells are genetically unstable and can promote tumorigenesis(Davoli and de Lange,2011,2012;Fuji-wara et al.,2005;Ganem et al.,2007).Accumulating evidence points to a significant contribution of tetraploid intermediates in shaping the composition of cancer genomes:$20%of all solid tumors exhibit tetraploid or near-tetraploid karyotypes, and computational analysis of human exome sequences from $4,000human cancers reveals that$37%of all tumors,even those with a near-diploid karyotype,have undergone at least one whole-genome-doubling event at some point in their evolu-tion(Dewhurst et al.,2014;Zack et al.,2013).Potentially oncogenic tetraploid cells arise spontaneously through a variety of different cell division errors.Defects in mitosis and cytokinesis are thought to be the most common routes;however,tetraploid cells also develop as a consequence of viral-induced cell fusion,chromosome endoreduplication, oncogene activation,chronic inflammation,entosis,and telo-mere erosion(Davoli and de Lange,2011;Ganem et al.,2007). Importantly,tetraploid cells are capable of promoting trans-formed growth irrespective of the mechanism by which they were initially generated(Davoli and de Lange,2012;Fujiwara et al.,2005).Given the potentially oncogenic consequences of tetraploidy, it is not surprising that tumor suppression mechanisms have evolved that limit the proliferation of these cells.Indeed,the restrained growth of tetraploid cells has long been recognized; it wasfirst demonstrated in1967that inhibition of cytokinesis in nontransformed cells severely impairs the proliferation of the resulting binucleated tetraploids(Carter,1967).Subsequently, it became clear that p53is the key mediator of this arrest(An-dreassen et al.,2001;Ganem and Pellman,2007;Kuffer et al., 2013;Wright and Hayflick,1972).However,the defect(s)that triggers this stress response and the downstream signaling path-ways that activate p53remain key unresolved questions in can-cer biology.Consequently,the mechanisms by which tetraploid cells might bypass this response to drive tumor development are not known.We took two approaches to understand the mechanism of p53 activation in tetraploid cells.First,we performed RNAi screens to identify genes that are required to activate or maintain cell-cycle arrest in tetraploid cells,but not cells with DNA damage.Second, we carried out in vitro evolution experiments to identify sponta-neous adaptations that enable sustained proliferation of tetra-ploid cells.Our experiments demonstrate that the impaired proliferation of tetraploid cells is due to activation of the Hippo tumor suppressor pathway both in vitro and in vivo.Cell158,833–848,August14,2014ª2014Elsevier Inc.833The conserved Hippo tumor suppressor pathway regulates cell proliferation by negatively regulating the oncogenic tran-scriptional coactivators YAP and TAZ(Pan,2010;Yu and Guan,2013).This is primarily accomplished through activation of the kinases LATS1and LATS2,which phosphorylate and inac-tivate YAP/TAZ.Active LATS2also binds to and inhibits the E3 ubiquitin ligase MDM2,which normally targets p53for destruc-tion(Aylon et al.,2006).Thus,activation of the Hippo pathway can limit cellular proliferation in at least two ways:inactivating YAP/TAZ and stabilizing p53.Defining the inputs that initiate Hippo signaling is central to un-derstanding how the Hippo pathway restrains tumorigenesis. Recent studies have demonstrated that the Hippo pathway is regulated by complex inputs that monitor cell-cell adhesion, cell-matrix adhesion,and contractile tension from the actin cyto-skeleton.The molecular details of these upstream signals,espe-cially those from the actin cytoskeleton,are poorly understood (Halder et al.,2012).Here,we demonstrate that cytokinesis fail-ure,generating tetraploid cells,is another physiological activator of the Hippo pathway,and we provide mechanistic insight into this important tumor suppression mechanism.RESULTSTetraploid Cells Activate the p53PathwayWe developed a method to purify tetraploid cells as a prerequi-site for an RNAi screen to identify the genes required for the p53-dependent G1cell-cycle arrest following cytokinesis failure.We used RPE-1cells,which are diploid nontransformed human epithelial cells that maintain a normal p53-response.To generate tetraploid cells,RPE-1cells were treated with dihydrocytochala-sin B(DCB),an inhibitor of actin polymerization that prevents cytokinesis.However,separating the resulting binucleated tetra-ploids from the remaining diploids poses a technical challenge because the two populations cannot be distinguished by DNA content alone:diploid cells in G2/M have the same DNA con-tent(4C)as tetraploid cells arrested G1.We overcame this diffi-culty by combining DNA content analysis with thefluorescent ubiquitin-based cell cycle indicator(FUCCI)reporter system. FUCCI consists of twofluorescent proteins whose expression alternates based on cell-cycle position:hCdt1-mCherry is ex-pressed in G1,whereas hGem-Azami Green is expressed in S/G2/M(Sakaue-Sawano et al.,2008).Using this approach,we could efficiently separate G2/M diploids(green)from G1tetra-ploids(red)and were able to isolate$95%pure G1tetraploid cells.Using the RPE-FUCCI cell line,we assessed p53levels in tetraploid cells relative to diploids.Levels of p53(and its target p21)gradually increased in tetraploids to$2.5-fold over diploid levels by48hr after cytokinesis failure(Figures1A,1B,S1A, and S1B available online).To examine the consequences of this p53accumulation on cell-cycle progression,live-cell imag-ing of diploid and tetraploid FUCCI cells was performed.Imaging revealed that97.3%of G1diploids entered S phase and divided, usually within24–36hr of replating(Figure1C and Movie S1).By contrast,only14.3%of tetraploid cells entered S phase within 4days;the majority remained arrested in G1until they became senescent(Figures1C and S1C and Movie S2).The rare tetra-ploid cells that did progress through the cell cycle and complete mitosis predominantly arrested in the following G1phase,as pre-viously documented(Krzywicka-Racka and Sluder,2011;Kuffer et al.,2013).Depletion of p53enabled95.1%of tetraploid cells to enter S phase(Figure1C and Movie S3),confirming that the tetraploid arrest is p53dependent.Similar results were observed when cells were made tetraploid through cytokinesis failure induced by either small interfering RNA(siRNA)-mediated depletion of ECT2or by treatment with the Aurora B inhibitor Hesperidin(Figure S1E).These data suggest that tetraploidiza-tion caused by cytokinesis failure imposes a stress on cells that leads to the stabilization of p53and eventual G1arrest. Consistent with previous studies(Fujiwara et al.,2005;Krzy-wicka-Racka and Sluder,2011),ourfindings exclude subtle DNA damage as the underlying cause for G1arrest in tetraploid cells:(1)Diploid cells exposed to the same cell culture condi-tions,drug treatments,and FACS sorting procedures as tetra-ploid cells did not trigger G1arrest(Figure1C).(2)No increase in DNA damage or reactive oxygen species was observed in tetraploid cells(Figure S1F),and the antioxidant N-acetylcys-teine was unable to overcome tetraploid-induced arrest(Fig-ure S1D).(3)Tetraploid cells failed to enter S phase even after 14days in culture,which is ample time for DNA repair(Fig-ure S1C).(4)Tetraploid cells depleted of p53not only progressed through G1/S but also through G2/M,strongly arguing against the presence of persistent DNA damage,which would activate p53-independent G2arrest(as is seen in p53-depleted cells after doxorubicin treatment;Figure2C).(5)Inhibition of ATM kinase was insufficient to overcome tetraploid-induced arrest,despite the fact that it was sufficient to overcome DNA damage-induced arrest caused by low-dose doxorubicin treatment(which ele-vates p53/p21protein levels to a similar extent as tetraploidiza-tion)(Figures1D and1E).(6)Finally,below we describe genetic conditions permissive for tetraploid cells,but not cells with DNA damage,to continue proliferating(and vice versa),demon-strating that these arrest mechanisms are fundamentally distinct.A Genome-wide RNAi Screen to Identify Regulators of Tetraploid-Induced Cell-Cycle ArrestWe performed an RNAi screen to identify the genes required for tetraploid-induced G1cell-cycle arrest using pooled siRNAs targeting the druggable portion of the human genome($7,300 genes).Automated image analysis measured the total number of tetraploid cells per well and the percentage that emitted green fluorescence(indicative of S/G2/M and proliferation)at96hr posttransfection(Figure1F).The screen identified98proteins for which depletion with at least two individual siRNAs allowed tetraploid cells to escape G1arrest(Table S1):two of the strongest hits identified from this screen were p53and p21,validating the overall approach. Genome-wide enrichment of seed sequence matches(GESS) analysis of all siRNA sequences that released tetraploid cells from arrest revealed no common30UTR region,reducing the possibility of a common off-target gene(Sigoillot et al.,2012). Although the primary objective of the tetraploid screen was to uncover genes that are necessary to activate or maintain tetra-ploid-induced cell-cycle arrest,we anticipated that many of the candidates we identified would also have roles in the general834Cell158,833–848,August14,2014ª2014Elsevier Inc.A CD F EBFigure1.Genes that Mediate Cell-Cycle Arrest of Tetraploid Cells(A)Western blot of p53levels in diploid(2N)and tetraploid(4N)cells48hr after sorting(n=6;*p<0.001,unpaired t test).(B)Diploid(arrowhead)and binucleated tetraploid(arrow)cells stained for p53(green),p21(yellow),actin(red),and DNA(blue).Scale bar,25m m.(C)Still images of sorted diploid and tetraploid RPE-FUCCI cells that were transfected with the indicated siRNAs(from a live-cell imaging experiment). The percentage of cells that progress into S phase fromfive independent imaging experiments is shown on right(2N,n=119;4N,n=326;4N p53siRNA,n=211; *p<0.00001,unpaired t test).Time,hr:min.Scale bar,100m m.(D)The fraction of S/G2cells from2N and tetraploid4N cells following treatment with±25ng/ml doxorubicin and±10m M ATM inhibitor for24hr(n=3;*p<0.05, unpaired t test,n.s.,not significant).(E)Representative images of FUCCI cells from the experiment in(D).Scale bar,100m m.(F)Protocol for genome-wide RNAi screen to identify genes necessary to activate or maintain G1cell-cycle arrest in tetraploid cells after cytokinesis failure. All error bars represent mean±SEM.Cell158,833–848,August14,2014ª2014Elsevier Inc.835A BC E F DG(legend on next page)836Cell158,833–848,August14,2014ª2014Elsevier Inc.maintenance of p53-induced cell-cycle arrest,independent of tetraploidy.To distinguish between these two broad classes of genes,we performed a second genome-wide screen to identify genes that,when suppressed,enable cells to bypass G1arrest in response to low-level DNA damage.This screen was similar in design to the tetraploid screen detailed above,except that, instead of cells being treated with DCB to create tetraploids, they were continuously treated with40ng/ml of the DNA-damaging drug doxorubicin,which elevates p53and p21levels to a similar extent as cytokinesis failure(Figures S2A and4C).A comparison of the results from the tetraploid screen with the DNA damage screen identified three classes of gene knock-downs(Figures2A–2C):(1)those that allow cells with DNA dam-age(but not tetraploid cells)to progress into S phase,suggesting a specific role for the encoded proteins in the DNA damage response(e.g.,ataxia telangiectasia mutated,ATM)(Table S2). These factors were not further characterized in this study.(2) Knockdowns that enable both tetraploid cells,as well as cells with DNA damage,to progress into S phase,implying a role for the encoded proteins in the general maintenance of cell-cycle ar-rest upon p53activation(e.g.,p21).(3)Knockdowns that allow tetraploid cells(but not cells with DNA damage)to progress into S phase,implying a role for the encoded proteins in acti-vating or maintaining G1arrest specifically in the context of tetra-ploidy(e.g.,LATS2).Hyperactivation of Growth Factor Signaling Is a General Mechanism to Bypass Tetraploid-Induced ArrestWe expected that our screens might identify genes that are generally required to activate p53.To test this,we assessed p53/p21levels following siRNA knockdown of several strong screen hits.Surprisingly,depletion of most genes did not reduce p53/p21levels,demonstrating that cell proliferation can occur via mechanisms that bypass p53activation rather than sup-pressing it(Figure2D).Interestingly,many strong hits from the screen(e.g.,SPINT2) are putative negative regulators of growth factor signaling(Naka-mura et al.,2011),suggesting that sustained growth factor signaling may be one route to overcome p53cell-cycle arrest. We measured the kinetics of ERK1/2and AKT activation after serum addition to serum-starved cells and confirmed that deple-tion of our strongest hit,SPINT2,causes a sustained increase in growth factor signaling(Figures2E and S2B).We also found that increasing the concentration of serum or adding recombinant IGF-1alone was sufficient to overcome G1arrest in tetraploid cells(Figures2F and2G).Thus,one general mechanism for bypassing p53-dependent cell-cycle arrest of tetraploid cells is to activate growth factor signaling;this suggests that other hits identified from the screen might therefore represent uncharac-terized negative regulators of growth factor signaling.In fact, we found that depletion of the RNA-binding protein PTBP1, one of the strongest hits from the screen,similarly increased growth factor signaling(Figures2E and S2B).Tetraploid Cells Activate the Hippo PathwayWe next focused on genes that activated or maintained G1arrest specifically in the context of tetraploidy.The strongest ploidy-specific hit was the kinase LATS2,a core component of the Hip-po tumor suppressor pathway(Pan,2010;Yu and Guan,2013). We confirmed that depletion of LATS2withfive independent siRNAs,targeting both the coding and UTR regions of LATS2 mRNA,enabled the proliferation of tetraploid cells,but not cells with DNA damage(Figures3A,3B,and S3A–S3C).Depletion of LATS2similarly promoted the proliferation of tetraploid cells generated by siRNA depletion of the cytokinesis regulators ECT2and PRC1(Figure S3D).Importantly,expression of siRNA-resistant wild-type LATS2in proliferating tetraploid cells that were depleted of endogenous LATS2was sufficient to rescue cell-cycle arrest,confirming that the effect of LATS2 depletion is not due to off-target RNAi effects(Figure3C).By contrast,expression of kinase-dead LATS2failed to rescue,indi-cating that the arrest mechanism requires the kinase activity of LATS2(Figure3C).Depletion of LATS1kinase,which is highly homologous to LATS2and has many overlapping functions, was not sufficient to enable the proliferation of tetraploids(Fig-ure3A);however,codepletion of both LATS1and LATS2pro-duced a small increase in the rate of proliferation of tetraploid cells relative to LATS2depletion alone(Figure S3C).These data suggested that G1arrest in tetraploids requires LATS2activation.Indeed,LATS2was phosphorylated to a signif-icantly greater extent in tetraploid cells(Figure3D),which led to a corresponding increase in the level of phosphorylated YAP in tetraploid cells relative to diploids(Figures3E,S3E,and S3H). We also found that YAP was biased to be cytoplasmic(inactive) in tetraploid cells,in contrast to its primarily nuclear(active)local-ization in diploid cells(Figure3F).Thisfinding was independently verified in tetraploid cells that were generated by use of ECT2 siRNA(Figure S3F).In addition,levels of the YAP-related tran-scriptional coactivator TAZ,which is proteasomally degraded upon phosphorylation by active LATS,were significantlyFigure2.Enhanced Growth Factor Signaling Overcomes p53-Induced G1Arrest(A)Venn diagram depicting genes necessary to maintain G1arrest in response to low-level DNA damage(gray),tetraploidization(red),or both.(B)Representative images of G1-arrested diploid RPE-FUCCI cells treated±40ng/ml doxorubicin(top row)and untreated tetraploid RPE-FUCCI cells(bottom row)transfected with the indicated siRNAs.Scale bar,50m m.(C)Quantification of the percentage of S/G2from(B)(n=3;*p<0.002,unpaired t test).(D)Western blot of p53and p21protein levels in2N and4N cells transfected with the indicated siRNAs for48hr.(E)A representative western blot(and quantitation)of phosphorylated AKT(p-AKT)relative to total AKT at various time points following serum addition to starved cells that were transfected with the indicated siRNAs.(F)The percentage of S/G2tetraploid RPE-FUCCI cells in growth medium containing increasing concentrations of serum from one representative experiment (n=48for each condition).Right:representative images from a live-cell experiment.Scale bar,50m m.(G)The percentage of S/G2tetraploid RPE-FUCCI cells in growth medium supplemented with50ng/ml IGF-1or IGF-1and the MEK inhibitor U0126(10nM)(n=3; *p<0.0005,unpaired t test).All error bars represent mean±SEM.Cell158,833–848,August14,2014ª2014Elsevier Inc.837AB CD FG EHFigure 3.Tetraploid Cells Activate the Hippo Pathway(A)The percentage of S/G 2tetraploid RPE-FUCCI cells following transfection with the indicated siRNAs (n =4;*p <0.0001,unpaired t test).Representative images from (A)are on the right.Scale bar,100m m.(B)As in (A),except cells are treated with 40ng/ml doxorubicin (n =3;*p <0.0001,unpaired t test).(C)The percentage of S/G 2tetraploid RPE-FUCCI cells stably expressing wild-type LATS2(LATS2-WT),kinase-dead LATS2(LATS2-KD),or empty vector control (control)and transfected with the indicated siRNAs (n =3;*p <0.007,unpaired t test).(D)Western blot analysis and quantitation of LATS phosphorylation in 2N and 4N cells (n =3;*p <0.009,unpaired t test).Note:cells stably overexpressing LATS2were used in this experiment to better assess LATS2phosphorylation.(E)Western blot analysis and quantitation of YAP phosphorylation (S127)in 2N and 4N cells (n =3;*p <0.008,unpaired t test).(legend continued on next page)838Cell 158,833–848,August 14,2014ª2014Elsevier Inc.decreased in tetraploid cells(Figure3G).Furthermore,canonical YAP/TAZ target genes had reduced expression in tetraploid cells (Figure3H).This differential activation of Hippo signaling be-tween diploids and tetraploids is not due to subtle differences in cell-cycle position because diploid and tetraploid cells syn-chronized in G1by release from serum starvation displayed the same changes(Figures S3G and S3H).Hippo activation in tetra-ploids is also not a secondary consequence of p53activation (Aylon et al.,2006),as depletion of p53did not prevent Hippo activation in tetraploid cells(Figure S3I).Thus,LATS2-mediated Hippo signaling is selectively activated in tetraploid cells. Next,we characterized the mechanisms through which deple-tion of LATS2overcomes tetraploid-induced arrest.As ex-pected,depletion of LATS2activated YAP,as demonstrated by a decrease in YAP phosphorylation and an accumulation of nuclear YAP(Figures4A and S4A).Moreover,overexpression of a constitutively active mutant version of YAP(with all of the LATS phosphorylation sites mutated to alanines:YAP-S5A) released tetraploid cells into the cell cycle,irrespective of whether they were generated by DCB treatment or siRNA-medi-ated knockdown of ECT2or PRC1.Importantly,expression of constitutively active YAP-S5A restored proliferation to tetraploid cells without affecting the steady-state levels of p53(Figures4B and S4B–S4D).By contrast,overexpression of WT-YAP alone was insufficient to drive tetraploid cells into the cell cycle,pre-sumably because of the ability of endogenous LATS kinases to phosphorylate and inactivate WT-YAP.Next,we examined whether active LATS2contributes to the observed increase in p53levels in tetraploid cells.We found that depletion of LATS2from tetraploid cells restored p53to the basal levels observed in diploid cells(Figure4C).By contrast, depletion of LATS1had no effect(Figure S4E),explaining why depletion of LATS1alone was insufficient to promote tetra-ploid proliferation(Figures3A and S3A).Although depletion of LATS2reduced p53levels in tetraploid cells,the kinase had no effect on the accumulation of p53in cells with DNA damage(Fig-ure4C).These data establish that the mechanism underlying p53 stabilization and cell-cycle arrest in tetraploid cells is LATS2 dependent but is functionally distinct from that used to activate p53in cells with DNA damage.Active LATS2binds and inhibits the E3ubiquitin ligase MDM2, which targets p53for destruction,thereby indirectly leading to the stabilization of p53(Aylon et al.,2006).We found that LATS2interacted with MDM2in tetraploid,but not diploid,cells (Figure4D),similar to what had been previously observed in tetraploid cells generated from mitotic slippage(Aylon et al., 2006).Collectively,thesefindings demonstrate that activation of LATS2in tetraploid cells inactivates YAP and stabilizes p53. Tetraploid Cells Have Reduced RhoA ActivityWe sought to understand the mechanisms leading to LATS2 activation in tetraploid cells.Canonically,the kinases MST1and MST2act directly upstream of LATS2in Hippo pathway signaling;however,we found that codepletion of MST1/2did not trigger the proliferation of tetraploids,demonstrating that the tetraploid-induced activation of LATS2is MST1/2indepen-dent(Figure S4F).Recent work shows that reduced assembly or contractility of the actin cytoskeleton or reduced RhoA activity can activate LATS1/2independent of MST1/2(Mo et al.,2012; Wada et al.,2011;Yu et al.,2012;Zhao et al.,2012).The cyto-skeleton of tetraploid cells is qualitatively different from that of diploid cells:tetraploid cells are bigger,possess longer stress fibers,and have extra centrosomes that cluster together and nucleate a greater number of microtubules(Figure S4G).How-ever,they do not exhibit obvious defects in cell attachment, migration,or cell spreading(Movie S2).Nevertheless,we found that active RhoA was reduced by$50%in tetraploid cells compared to diploids(Figure4E),which correlates well with a comparable decrease in downstream phosphorylation of myosin light chain(Figure S4H).The biological impact of this reduction of RhoA activity was as-sessed using two independent approaches.First,we compared the contractility of diploid and tetraploid cells using traction force microscopy.A mix of diploid and tetraploid RPE-1cells was plated on deformable polyacrylamide hydrogels coated with fibronectin.Gel deformation induced by the contraction of cells was then monitored to measure the forces produced.This anal-ysis demonstrated that,relative to their size,tetraploid cells ex-erted significantly reduced contractile force on the underlying substrate than diploids(Figures4F,S5A,and S5B).We also employed a commonly used indirect assay for the tensile state of cells,the differentiation of human mesenchymal stem cells (hMSCs)(McBeath et al.,2004).When hMSCs have high RhoA activity and are more contractile,which occurs when these cells are plated at low density on stiff substrates,hMSCs activate YAP and primarily differentiate into osteoblasts.By contrast,when RhoA activity is low,which occurs when cells are contact in-hibited,hMSCs exhibit less YAP activation and more frequently differentiate into adipocytes.Supporting ourfinding that tetra-ploids have less active Rho,we found that,when isogenic diploid and tetraploid hMSCs were plated in mixed differentiation medium at low densities,tetraploid cells significantly more frequently differentiated into adipocytes(Figure4G).Finally,reactivation of RhoA was sufficient to inactivate the Hippo pathway,reduce p53levels,and restore proliferative ca-pacity to tetraploid cells(Figure4H).Treatment of G1-arrested tetraploid cells with LPA or S1P(glycophospholipids known to activate RhoA)(Miller et al.,2012;Yu et al.,2012)significantly increased the fraction of tetraploid cells that entered the cell cycle(Figure S5C),as did induced expression of RhoA-WT or constitutively active RhoA-Q61L(Figure4H).Importantly,neither of these conditions had any effect on the G1arrest imposed by low-level DNA damage(Figures4H and S5D).These data demonstrate that tetraploid cells have reduced RhoA activity,(F)Diploid(arrowhead)and binucleated tetraploid(arrow)RPE-1cells stained for YAP(green)and DNA(blue).YAP localization was quantified(n=2;N=C,YAP is evenly distributed;N<C,YAP is enriched in the cytoplasm;N>C,YAP is enriched in nucleus).Scale bar,25m m.(G)Western blot analysis and quantitation of TAZ levels in2N and4N RPE-FUCCI cells(n=4;*p<0.005,one sample t test).(H)qPCR analysis of YAP target gene expression in2N and4N cells(n=3;*p<0.02and**p<0.005,one sample t test).All error bars represent mean±SEM.Cell158,833–848,August14,2014ª2014Elsevier Inc.839A BC D FG HETS2Inhibits the Proliferation of Tetraploid Cells by Stabilizing p53and Inactivating YAP and Is Triggered by Reduced RhoA Activity(A)Western blot of p53,LATS2,and active YAP(p-S127)levels in2N and4N cells transfected with the indicated siRNAs.(B)Representative images of2N and4N RPE-FUCCI cells overexpressing either empty vector control(control),YAP-WT,or YAP-S5A,with quantitation of the percentage of S/G2cells for each condition shown on the right(from one representative experiment).Scale bar,100m m.(C)Western blot analysis of p53and LATS2levels in2N,4N,and40ng/ml doxorubicin-treated2N(2N+Dox)RPE-FUCCI cells transfected with the indicated siRNAs.(D)Coimmunoprecipitation of HA-tagged LATS2-WT and endogenous MDM2from2N and4N RPE-1cells using anti-HA antibodies(one of two independent experiments).(legend continued on next page) 840Cell158,833–848,August14,2014ª2014Elsevier Inc.。
GlideScope视频喉咙镜操作指南说明书
SUGERENCIAS Y TÉCNICASCuando guíe el tubo endotraqueal (TET) a la punta distal del videolaringoscopio,asegúrese de ver la boca del paciente, no la pantalla del monitor de vídeo. Si nolo hace puede provocar lesiones en las amígdalas o el paladar suave.TÉCNICA DE CUATRO PASOS1. Mire a la boca: Con la pala del videolaringoscopio en su mano izquierda,introdúzcala en la línea central de la orofaringe.2. Mire a la pantalla: Identifique la epiglotis y luego manipule la pala paraobtener la mejor vista de la glotis.3. Mire a la boca: Guíe con cuidado la punta distal del tubo a su posición cercade la punta de la pala.4. Mire a la pantalla: Complete la intubación, girando suavemente o colocandoen ángulo el tubo según sea necesario para redirigirlo.SUGERENCIAS PARA LA INSERCIÓN DE LA PALA• Inserte la pala abajo de la línea central de la lengua hacia la epiglotis.• Las intubaciones utilizando videolaringoscopios GlideScope requieren aproximadamente 0.5 a 1.5 kg (1.1 a 3.3 lb) de fuerza de elevación.• Se recomienda el uso de un estilete de tubo endotraqueal. El Estilete rígido GlideRite® está diseñado para complementar el ángulo de las palas para adulto.Se puede utilizar un estilete flexible con un ángulo de60 a 90°.• Para ayudar a que pase el TET, retire el estileteaproximadamente 5 cm, (2 in) mientras lo hace avanzarsuavemente. Retirar la pala 1 cm (0.4 in) también puedeser beneficioso para reducir el ángulo de visualización ypermitir que la glotis baje.INICIO RÁPIDOCONECTE EL BASTÓN DE VÍDEO Y LA STAT1. Seleccione la Stat (pala de un solo uso) y bastón devídeo apropiados.2. Inserte el bastón de vídeo en la Stat y luego presione labase del bastón de vídeo hasta que bloquee en su sitio.3. Al lado derecho del monitor, detrás de la base, alinee laflecha del cable y la flecha del puerto y luego inserte elconector del cable hasta escuchar un clic.PREPARE EL SISTEMA4. En el monitor de vídeo, mueva el interruptor de encendidoa la izquierda.5. Asegúrese de que la batería tenga suficiente carga.La luz verde de encendido no debe titilar.6. Verifique que el monitor muestre una imagen del bastón de vídeo. Unapequeña parte de la Stat puede ser visible en la parte superior o en la esquina superior.Debe desinfectar algunos componentes antes de usarlos. Para obtener instrucciones detalladas consulte el Manual de funcionamiento ymantenimiento .GlideRite, GlideScope, el símbolo de GlideScope, Verathon yel símbolo de antorcha de Verathon son marcas comercialesde Verathon Inc.© 2018 Verathon Inc. 0900‑4696‑ESMX‑02‑60Verathon Medical (Canada) ULC 2227 Douglas Road Burnaby, BC V5C 5A9CanadáTel: 604.439.3009Fax: 604.439.3039Verathon Medical (Europe) B.V .Willem Fenengastraat 131096 BL Amsterdam,Países Bajos Tel: +31 (0) 20 210 30 91Fax: +31 (0) 20 210 30 92Verathon Inc.20001 North Creek Parkway Bothell, WA 98011, EE. UU.Tel: 800.331.2313 (solo EE. UU. y Canadá)Tel: +1.425.867.1348 Fax: +。
Sugar——精选推荐
SugarDepartment ofAgricultureSugar: World Markets and Trade ForeignAgriculturalServiceNovember 2014Global Sugar Consumption ExpandsWhile Production DeceleratesGlobal sugar production for 2014/15 is estimated down 2.6 million metric tons (raw value) at 172.5 million on reductions in Brazil, Thailand, and China. Global imports are expected to remain flat while consumption is projected to reach a record 171.0 million tons as ending stocks shrink slightly.To receive the circular via email, register at._________________________________________________________________________________________________________ 2014/15 Sugar OverviewUnited States production is estimated unchanged from last year at 7.7 million tons. Stocks are expected to fall over 20 percent as consumption holds steady and imports decline to 3.1 million tons. On October 27, 2014, the Department of Commerce announced its affirmative determination in the anti-dumping investigation of sugar imported from Mexico. Commerce set dumping margins on sugar from Mexican sugar processors ranging from 39.54 percent to 47.26 percent. These preliminary duties come after the agency imposed preliminary countervailing duties in August ranging from 2.99 to 17.01 percent on sugar derived from sugarbeets and sugarcane. As a result of the determination, U.S. Customs and Border Control will require cash deposits on sugar products covered under the investigation.Also on October 27, the department announced a draft agreement with the Government of Mexico to suspend the anti-dumping and countervailing duty investigations. The terms of the agreement include:Required export licenses for sugar to enter the United States from Mexico.Minimum reference prices of 23.57 cents per pound for refined sugar and 20.75 cents per pound for all other sugar.Export limits, based on a formula to determine expected U.S. needs for imported sugar.The estimates provided in specific WASDE reports would provide the data to calculate the quantities to determine Mexican market access.Limits on the amount of refined sugar that can enter the United States under the suspension agreement.Limits on the timing of shipments—specifically, the amount of sugar that could be shipped prior to December 31 and March 31 of the marketing year.Interested parties were asked to provide comments on the draft agreement until November 18, 2014. The investigations would be suspended upon a final agreement. If an agreement is not reached, the anti-dumping and countervailing duty investigations would continue and the preliminary duties would remain in place. The Mexican supply and use forecasts provided in the November WASDE do not reflect market conditions that would take place under the draft agreement, as those terms were not finalized and signed at the report’s release.Brazil’s production is estimated to ease 2.0 million tons to 35.8 million as drought conditions lower yield and a lower percentage of the sugarcane (estimated 45 percent) is diverted to sugar, compared to last year on better profitability for ethanol production. Consumption is expected to increase slightly reflecting population growth and expansion in the food processing sector. Exports are projected down 2.2 million tons to 24.0 million on lower exportable supplies. Thailand’s production is forecast to decline 1.1 million tons to 10.2 million as drought conditions lower yield. Exports are forecast to jump to a record 8.5 million tons as stocks are drawndown to meet high Asian demand, particularly from Indonesia and Cambodia. Consumption continues to trend higher, driven by rising industrial use.India’s production is estimated tomillion due to increased yields.With high demand, imports areexpected to expand asconsumption rises to a record 27million tons. India is the largestconsumer and second largestproducer of sugar and imports varygreatly from year to year. Exportsare estimated to fall to 1.5 milliontons.Production in the EuropeanUnion is estimated at 16.3 milliontons, up nearly 300,000 on bothincreased sugar beet area andyield. As consumption continues to trend higher, imports are projected to grow 200,000 tons to 3.5 million tons. Exports remain at 1.5 million tons, limited by the sugar export ceiling in the World Trade Organization.China’s production is projected at 13.3 million tons, down nearly 1.0 million on lower yield. Rising consumption, which outpaces production, and lower imports are expected to draw down stocks.Mexico’s production is estimated slightly higher at 6.5 million tons. Exports are projected down nearly 50 percent to 1.8 million tons on consumption and stock growth of 5 and 10 percent, respectively.Australia’s sugar production is estimated to increase 200,000 tons to 4.6 million based on a combination of higher sugar yields and an increase in area. Australian sugar exports are estimated over 5 percent higher at 3.5 million tons on higher exportable supplies as consumption remains relatively flat.Russia’s production is expected down 200,000 tons to 4.2 million as an increase in area is offset by reduced yield. Consumption is estimated to increase as imports swell to fill the gap of lowerproduction.Selected 2013/14 Revisions from May Forecast:-Global production is down slightly (694,000 tons) to 175.0 million.o India is revised down 440,000 tons to 26.6 million as more cane was used for non-centrifugal sugar.o Mexico is lowered 349,000 tons to 6.4 million due to adverse wet weather.-Global imports are raised 1.4 million tons to 51.8 million.o India expanded 750,000 tons to 850,000 tons as imports rose to meet domestic demand.o China is revised up 430,000 tons to 4.3 million on growing demand.FAS Reports from Overseas OfficesThe Sugar: World Markets and Trade circular is based on post reports submitted since September 2014 and on available secondary information. The individual country reports can be obtained on FAS Online at:/doc/abdff57159eef8c75ebfb32f.html /Pages/Default.aspx.PSD OnlineThe entire USDA PSD database is available online at /doc/abdff57159eef8c75ebfb32f.html /psdonline. Additional ResourcesPlease refer to the USDA-FAS Citrus website at: /doc/abdff57159eef8c75ebfb32f.html /commodities/fruits-and-vegetables/citrus-fruit for additional data and analysis.Situation and outlook information on U.S. sugar and sweeteners can be obtained from the USDA-Economic Research Service at: /doc/abdff57159eef8c75ebfb32f.html /topics/crops/sugar-sweeteners.aspx.Future Releases and Contact InformationPlease visit /doc/abdff57159eef8c75ebfb32f.html /data/citrus-world-markets-and-trade to view archived and future releases. The next release of this circular will be in May 2015.To receive the circular via email, go to:https:///doc/abdff57159eef8c75ebfb32f.html /accounts/USDAFAS/subscriber/new.World Centrifugal SugarWorld Centrifugal Sugar: Imports and Exports。
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AIS VS ARIAS-STELLA CHANGE Features Favoring Arias-Stella
ENDOCERVICAL GLANDULAR DYSPLASIA
A glandular lesion characterized by significant nuclear abnormalities that are more striking than those encountered in glandular atypia but do not fulfill the criteria for adenocarcinoma in situ (WHO, 2003)
HPVandular epithelium does not support productive HPV infection. • LSIL – episomal HPV, productive infection. • HSIL – integrated HPV, expression of viral oncogenes E6 and E7
AIS VS MICROGLANDULAR HYPERPLASIA (MGH)
*MGH predominantly a pattern alteration (clustered small tubules) predominantly a cytologic alteration
AIS
* Applies to other endocervical hyperplasias
• Concept: An adenocarcinoma with stromal invasion but negligible risk of metastases.
• Definition: WHO (2003) recommends using FIGO staging criteria (we use stage IA1 but vascular invasion precludes dx) • Problematic issues: Recognition and measurement (thickness preferred)
• Endocervical glandular dysplasia • Superficially invasive adenocarcinoma
MICROGLANDULAR HYPERPLASIA
Hormonally induced OCs – 67% of cases Pregnancy – 7% of cases Young patients (mean age = 34 yrs) 6% of patients post menopausal Usually asymptomatic Can form polypoid mass Can cause vaginal bleeding/discharge
Jaworski et al. Cancer 61:1171,1988 (Definitive diagnosis requires complete excision)
% of cases 100% 100% 56% 39% 14% 14%
APOPTOTIC BODIES (ABs) AND MITOSES (MFs) IN ENDOCERVICAL AIS VS NON-NEOPLASTIC ENDOCERVIX
*PCR for HPV DNA Quint et al. Gynecol Oncol 114:390,2009
NON-HPV ENDOCERVICAL ADENOCARCINOMAS
• • • • Adenoma Malignum Mesonephric adenocarcinoma Clear cell adenocarcinoma Gastrointestinal type – variable intestinal (goblet cells) and gastric (foveolar and pyloric epithelium). Only a minority are non-HPV.
ENDOCERVICAL AIS
• • • • • • • Precursor of invasive adenocarcinoma Asymptomatic, clinically occult Linked to HPV, relatively more HPV 18 No diagnostic colposcopic findings 65% involve the transformation zone At least 10%-15% multifocal 67% of cases have CIN
Single epithelial layer Absence of architectural change Absence of mitoses Cytoplasmic and nuclear vacuolization
EARLY INVASIVE (MICROINVASIVE) ENDOCERVICAL ADENOCARCINOMA
*HPV in Endocervical AIS and Invasive Adenocarcinoma
HPV genotype HPV 16 HPV 18 HPC 16+18 HPV 16 + other HPV 18 + other Other HPV types Total AIS 15 7 1 6 0 2 31 (100%) Inv. Adeno 8 5 0 1 1 1 16 (100%)
Variable ABs present ABs/10 hpfs range mean MFs present MFs/10 hpfs range mean AIS cases 95% Controls 46%
1-36 16 100%
1-53 18
1-6 2.3 14%
1-3 1.8
Biscotti and Hart, AJSP 4:434,1998
Scattered atypical cells
Absence of mitoses Vacuolated cytoplasm
Degenerative chromatin
Low N/C ratio
AIS VS RADIATION EFFECT Features Favoring Radiation
AIS VS TUBAL METAPLASIA Features Favoring Tubal Metaplasia
Ciliated cells
Mixture of cell types
Absence of mitoses Absence of apoptosis
ARIAS-STELLA CHANGE
3-d groups Increased N/C ratio Altered nuclear polarity Marked hyperchromasia Columnar shape Feathering Apoptosis Mitoses
(Biscotti et al Diagn Cytopathol 17:326, 1997)
GLANDULAR LESIONS OF THE UTERINE CERVIX
ENDOCERVICAL ADENOCARCINOMA IN SITU (AIS) Definition
Normally situated glands lined by cytologically malignant glandular epithelium (WHO, 2003).
Hybrid Capture 2 in Patients with Atypical Glandular (AGL) Pap Tests
Cytologic Interpretations and Hybrid Capture Results
Cytology HSIL + AGL AIS AGL alone HPV pos. 93% (14 of 15) 71% (5 of 7) 29% (36 of 124)
AIS VS SUPERFICIALLY INVASIVE ADENOCARCINOMA Features Favoring Invasion
ENDOCERVICAL AIS Immunostains
• P16 (diffuse and strong) • Ki67 (high labeling index) • CEA (67% of cases positive, must be cytoplasmic) • Vimentin (AIS is negative, tubal metaplasia/endometriosis are positive)
Endocervical AIS and p16
ENDOCERVICAL AIS Histologic Differential Diagnosis
• Benign
Reactive endocervix Microglandular hyperplasia Tubal metaplasia Endometriosis Arias-Stella change Radiation effect
Percent of cases
79% 100% 88% 91% 100% 88% 73% 64%
HISTOLOGIC FEATURES OF AIS
Feature Mitoses Apoptosis Exophytic buds Cribriform pattern Papillae Normal architecture