Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation

Chemically induced skin carcinomas in mice are a paradigm for epithelial neoplasia, where oncogenic ras mutations precede p53 and INK4a/ARF mutations during the progression toward malignancy. To explore the biological basis for these genetic interactions, we studied cellular responses to oncogenic ras in primary murine keratinocytes. In wild-type keratinocytes, ras induced a cell-cycle arrest that displayed some features of terminal differentiation and was accompanied by increased expression of the p19ARF, p16INK4a, and p53 tumor suppressors. In ARF-null keratinocytes, ras was unable to promote cell-cycle arrest, induce differentiation markers, or properly activate p53. Although oncogenic ras produced a substantial increase in both nucleolar and nucleoplasmic p19ARF, Mdm2 did not relocalize to the nucleolus or to nuclear bodies but remained distributed throughout the nucleoplasm. This result suggests that p19ARF can activate p53 without overtly affecting Mdm2 subcellular localization. Nevertheless, like p53-null keratinocytes, ARF-null keratinocytes were transformed by oncogenic ras and rapidly formed carcinomas in vivo. Thus, oncogenic ras can activate the ARF-p53 program to suppress epithelial cell transformation. Disruption of this program may be important during skin carcinogenesis and the development of other carcinomas.

Telomere length and replicative aging in human vascular tissues.

Because repeated injury of the endothelium and subsequent turnover of intimal and medial cells have been implicated in atherosclerosis, we examined telomere length, a marker of somatic cell turnover, in cells from these tissues. Telomere lengths were assessed by Southern analysis of terminal restriction fragments (TRFs) generated by HinfI/Rsa I digestion of human genomic DNA. Mean TRF length decreased as a function of population doublings in human endothelial cell cultures from umbilical veins, iliac arteries, and iliac veins. When endothelial cells were examined for mean TRF length as a function of donor age, there was a significantly greater rate of decrease for cells from iliac arteries than from iliac veins (102 bp/yr vs. 47 bp/yr, respectively, P < 0.05), consistent with higher hemodynamic stress and increased cell turnover in arteries. Moreover, the rate of telomere loss as a function of donor age was greater in the intimal DNA of iliac arteries compared to that of the internal thoracic arteries (147 bp/yr vs. 87 bp/yr, respectively, P < 0.05), a region of the arterial tree subject to less hemodynamic stress. This indicates that the effect is not tissue specific. DNA from the medial tissue of the iliac and internal thoracic arteries showed no significant difference in the rates of decrease, suggesting that chronic stress leading to cellular senescence is more pronounced in the intima than in the media. These observations extend the use of telomere size as a marker for the replicative history of cells and are consistent with a role for focal replicative senescence in cardiovascular diseases.

Barley telomeres shorten during differentiation but grow in callus culture.

Eukaryotic chromosomes terminate with long stretches of short, guanine-rich repeats. These repeats are added de novo by a specialized enzyme, telomerase. In humans telomeres shorten during differentiation, presumably due to the absence of telomerase activity in somatic cells. This phenomenon forms the basis for several models of telomere role in cellular senescence. Barley (Hordeum vulgare L.) telomeres consist of thousands of TTTAGGG repeats, closely resembling other higher eukaryotes. In vivo differentiation and aging resulted in reduction of terminal restriction fragment length paralleled by a decrease of telomere repeat number. Dedifferentiation in callus culture resulted in an increase of the terminal restriction fragment length and in the number of telomere repeats. Long-term callus cultures had very long telomeres. Absolute telomere lengths were genotype dependent, but the relative changes due to differentiation, dedifferentiation, and long-term callus culture were consistent among genotypes. A model is presented to describe the potential role of the telomere length in regulation of a cell's mitotic activity and senescence.

Igualdades e diferenças nas políticas educacionais: a agenda das diversidades nos governos Lula e Dilma

Esta pesquisa aborda as chamadas políticas de diversidade na educação e sua contribuição para o reconhecimento e a promoção dos direitos humanos e a superação do racismo, do sexismo, da homofobia e das demais desigualdades e discriminações que marcam profundamente a sociedade e a educação brasileiras. Com base nas vozes de gestores/as públicos/as e ativistas da sociedade civil, na análise documental e da execução orçamentária e na experiência política da pesquisadora, é apresentado um balanço sobre os dez anos de existência da Secretaria de Educação Continuada, Alfabetização e Diversidade (Secad), órgão do Ministério da Educação criado no primeiro governo do Presidente Luiz Inácio Lula da Silva. Em especial, buscou-se identificar as provocações e os tensionamentos gerados pelas agendas das diversidades para o atual desenho, funcionamento e institucionalidade das políticas educacionais e sua influência nas concepções de qualidade educacional em disputa nas políticas federais. Essas disputas estiveram presentes nas Conferências Nacionais de Educação e no processo conflitivo de tramitação do novo Plano Nacional de Educação (Lei Federal n. 13.005/2014), analisados neste trabalho. Respaldado por convenções e pelas resoluções internacionais das Conferências da ONU e por normativas nacionais, o debate sobre diferenças ganhou espaço na agenda das políticas educacionais brasileiras. Essa discussão foi impulsionada por movimentos sociais negros, indígenas, LGBTs, feministas, de trabalhadores do campo, de pessoas com deficiências, de quilombolas, ambientalistas e por agendas de fronteira na efetividade do direito humano à educação, como a educação de jovens e adultos, a educação em territórios de alta vulnerabilidade social e a educação de pessoas privadas de liberdade, entre outras. Apresenta-se, neste trabalho, uma contribuição teórica ao debate sobre a relação entre qualidade educacional, diferenças e igualdades, com base nas teorias críticas de justiça social. Discutem-se as possibilidades de a noção da diversidade constituir uma resposta interseccional às múltiplas discriminações e desigualdades que atingem os sujeitos concretos no cotidiano da vida e, especificamente, nas instituições educacionais. Ao final da tese, embasadas na definição do contexto de estratégia política de Stephen Ball e nas contribuições para o aperfeiçoamento das políticas 14 previstas na metodologia de análise das políticas públicas, são apresentadas reflexões comprometidas com a ampliação da capacidade das políticas educacionais no sentido de dar respostas a essas agendas, em uma perspectiva de promoção da justiça na educação no marco dos direitos humanos.

Efeitos da imunossupressão sobre a depuração mucociliar de ratos: comparação entre dois esquemas de terapia tríplice

INTRODUÇÃO: O transplante de pulmão é parte fundamental no tratamento das doenças terminais do pulmão, constituindo uma modalidade terapêutica eficaz para pacientes com doença pulmonar incapacitante, progressiva e em estágio final. No entanto, as drogas imunossupressoras usadas para evitar a rejeição do enxerto podem causar efeitos colaterais em diversos tecidos. O sistema mucociliar, presente nas vias aéreas, é um dos principais mecanismos de defesa do trato respiratório e pode ser alterado por ação das drogas imunossupressoras. Desta forma, o objetivo deste estudo foi avaliar o sistema mucociliar traqueobrônquico de ratos submetidos a dois esquemas de terapia tríplice imunossupressora. MÉTODOS: Foram utilizados 90 ratos machos Wistar distribuídos em 3 grupos conforme o tratamento: controle (C) = solução salina; terapia 1 (TI) = tacrolimus + micofenolato de mofetil + prednisona; terapia 2 (TII) = ciclosporina + azatioprina + prednisona. Após o período de tratamento (7, 15 ou 30 dias), os animais foram sacrificados e realizadas as seguintes medidas: transportabilidade do muco (TM), frequência de batimento ciliar (FBC), quantificação de muco neutro e ácido, velocidade de transporte mucociliar (VTMC), e contagem total e diferencial de células no lavado broncoalveolar (LBA). RESULTADOS: A TM não foi afetada pelas terapias em nenhum dos tempos estudados. Ambas as terapias causaram significativa redução da FBC dos animais tratados por 7 e 15 dias. A produção de muco neutro foi menor nos animais tratados com a TI por 7, 15 e 30 dias. Porém, com a TII, essa redução ocorreu apenas aos 7 dias. Por outro lado, a quantidade de muco ácido foi significativamente maior em todos os animais tratados com as duas terapias. Todos os animais tratados com as terapias imunossupressoras apresentaram redução da VTMC nos três tempos. Houve aumento do número total de células e de macrófagos e neutrófilos no grupo TI em 7 dias. CONCLUSÕES: Ambas as terapias imunossupressoras foram prejudiciais ao transporte mucociliar das vias aéreas de ratos, tanto pela redução da FBC e da VTMC, quanto pela maior produção de muco ácido e menor produção de muco neutro. A TI foi mais prejudicial ao sistema mucociliar em comparação à TII

El debate de la ampliación europea y los medios de comunicación publicitaria: un enfoque interdisciplinar

El objetivo central del estudio es tratar de averiguar si existen diferencias significativas entre los países miembros de la Unión Europea y los candidatos desde una perspectiva novedosa: los medios de comunicación y la publicidad. De esta forma, mediante el análisis descriptivo y el de conglomerados jerárquicos se comprueba la coherencia entre los resultados que se obtienen de este análisis y los requisitos para formar parte de la Unión. Los primeros análisis corroboran las evaluaciones efectuadas a los países candidatos y resoluciones de la Comisión. Todo ello conduce a motivar un debate sobre las implicaciones sociales y económicas, que no creativas ni éticas, del mercado publicitario y de medios en el contexto de la Unión Europea.

Looking twice at the gender equity index for public health impact

Background: It has been shown that gender equity has a positive impact on the everyday activities of people (decision making, income allocation, application and observance of norms/rules) which affect their health. Gender equity is also a crucial determinant of health inequalities at national level; thus, monitoring is important for surveillance of women’s and men’s health as well as for future health policy initiatives. The Gender Equity Index (GEI) was designed to show inequity solely towards women. Given that the value under scrutiny is equity, in this paper a modified version of the GEI is proposed, the MGEI, which highlights the inequities affecting both sexes. Methods: Rather than calculating gender gaps by means of a quotient of proportions, gaps in the MGEI are expressed in absolute terms (differences in proportions). The Spearman’s rank coefficient, calculated from country rankings obtained according to both indexes, was used to evaluate the level of concordance between both classifications. To compare the degree of sensitivity and obtain the inequity by the two methods, the variation coefficient of the GEI and MGEI values was calculated. Results: Country rankings according to GEI and MGEI values showed a high correlation (rank coef. = 0.95). The MGEI presented greater dispersion (43.8%) than the GEI (19.27%). Inequity towards men was identified in the education gap (rank coef. = 0.36) when using the MGEI. According to this method, many countries shared the same absolute value for education but with opposite signs, for example Azerbaijan (−0.022) and Belgium (0.022), reflecting inequity towards women and men, respectively. This also occurred in the empowerment gap with the technical and professional job component (Brunei:-0.120 vs. Australia, Canada Iceland and the U.S.A.: 0.120). Conclusion: The MGEI identifies and highlights the different areas of inequities between gender groups. It thus overcomes the shortcomings of the GEI related to the aim for which this latter was created, namely measuring gender equity, and is therefore of great use to policy makers who wish to understand and monitor the results of specific equity policies and to determine the length of time for which these policies should be maintained in order to correct long-standing structural discrimination against women.

Multicomponent Azide-Alkyne Cycloaddition Catalyzed by Impregnated Bimetallic Nickel and Copper on Magnetite

A new bimetallic catalyst derived from nickel and copper has been used successfully for the first time in the multicomponent reaction of terminal alkynes, sodium azide, and benzyl bromide derivatives. The presence of both metallic species on the surface of magnetite seems to have a positive and synergetic effect. The catalyst loading is the lowest ever published for a catalyst of copper anchored on any type of iron support. The catalyst could be easily removed from the reaction media just by magnetic decantation and it could be reused up to ten times without any negative effect on the initial results.

EU Law, International Law and Economic Sanctions against Terrorism: The Judiciary in Distress? Research Papers in Law, 3/2008

From the Introduction. This article seeks to examine the relationship between European Union law, international law, and the protection of fundamental rights in the light of recent case law of the European Court of Justice (ECJ) and the Court of First Instance (CFI) relating to economic sanctions against individuals. On 3 September 2008, the ECJ delivered its long-awaited judgment in Kadi and Al Barakaat on appeal from the CFI.3 In its judgment under appeal,4 the CFI had held that the European Community (EC) is competent to adopt regulations imposing economic sanctions against private organisations in pursuance of UN Security Council (UNSC) Resolutions seeking to combat terrorism; that although the EC is not bound directly by the UN Charter, it is bound pursuant to the EC Treaty to respect international law and give effect to UNSC; and that the CFI has jurisdiction to examine the compatibility of EC regulations implementing UNSC resolutions with fundamental rights not as protected by the EC but as protected by jus cogens. On appeal, following the Opinion of Maduro AG, the ECJ rejected the CFI’s approach. It held that UNSC resolutions are binding only in international law. It subjected the contested regulations to full review under EC human rights standards and found them in breach of the right to a hearing, the right to judicial protection and the right to property. Kadi and Al Barakaat is the most important judgment ever delivered by the ECJ on the relationship between EC and international law and one of its most important judgments on fundamental rights. It is imbued by constitutional confidence, commitment to the rule of law but also some scepticism towards international law. In the meantime, the CFI has delivered a number of other judgments on anti-terrorist sanctions assessing the limits of the “emergency constitution” at European level. The purpose of this paper is to examine the above case law and explore the dilemmas and tensions facing the EU judiciary in seeking to define and protect the EU’s distinct constitutional space. It is divided as follows. It first looks at the judgment in Kadi. After a short presentation of the factual and legal background, it explores the question whether the EU has competence to adopt smart sanctions. It then examines whether the EU is bound by resolutions of the Security Council, whether the ECJ has jurisdiction to review Community measures implementing such resolutions and the applicable standard of judicial scrutiny. It analyses the contrasting views of the CFI, the Advocate General, and the ECJ taking account also of the case law of the European Court of Human Rights (ECtHR). Further, it explores the consequences of annulling the contested regulation. It then turns to discussing CFI case law in relation to sanctions lists drawn up not by the UN Security Council but by the EC. The paper concludes by welcoming the judgment of the ECJ. Whilst its reasoning on the issue of Community competence is questionable, once such competence is established, it is difficult to support the abrogation of Community standards for the protection of fundamental rights. Such standards should ensure procedural due process whilst recognising the importance of public security.

Stage-Specific Plasticity in Ovary Size Is Regulated by Insulin/Insulin-Like Growth Factor and Ecdysone Signaling in Drosophila

Animals from flies to humans adjust their development in response to environmental conditions through a series of developmental checkpoints, which alter the sensitivity of organs to environmental perturbation. Despite their importance, we know little about the molecular mechanisms through which this change in sensitivity occurs. Here we identify two phases of sensitivity to larval nutrition that contribute to plasticity in ovariole number, an important determinant of fecundity, in Drosophila melanogaster. These two phases of sensitivity are separated by the developmental checkpoint called "critical weight"; poor nutrition has greater effects on ovariole number in larvae before critical weight than after. We find that this switch in sensitivity results from distinct developmental processes. In precritical weight larvae, poor nutrition delays the onset of terminal filament cell differentiation, the starting point for ovariole development, and strongly suppresses the rate of terminal filament addition and the rate of increase in ovary volume. Conversely, in postcritical weight larvae, poor nutrition affects only the rate of increase in ovary volume. Our results further indicate that two hormonal pathways, the insulin/insulin-like growth factor and the ecdysone-signaling pathways, modulate the timing and rates of all three developmental processes. The change in sensitivity in the ovary results from changes in the relative contribution of each pathway to the rates of terminal filament addition and increase in ovary volume before and after critical weight. Our work deepens our understanding of how hormones act to modify the sensitivity of organs to environmental conditions, thereby affecting their plasticity.

Public laws enacted by the Philippine Legislature.

"Comprising Acts nos. 1 to including a numerical list of acts; a general list of repealed and amended acts; a list of codes, general orders, etc., amended; joint and concurrent resolutions of the Philippine Legislature

Mr. Whipple's report, and Mr. Otis's letter.

Also published, Providence? 1839, under title: Reports of the Select Committee to Whom Were Referred the Resolutions of Mr. Wells ... touching certain resolutions of the House of Representatives of the U. States ...

Virginia: a hand-book giving its history, climate, and mineral wealth; its educational, agricultural and industrial advantages.

Appended: p. 343, resolutions of the Board regarding William T. Sutherlin; p. 347-357, A paper prepared by Hon. P. W. McKinney for the convention of southern governors ... and Virginia and her wealth by P. W. McKinney.

Dutch-Friesian herd book.

"Containing a record of all the North Holland or Friesian cattle approved and admitted for registry previous to ... under the by-laws and resolutions of the American Association of Breeders of Thoroughbred Dutch or Friesian Cattle" (varies).

Koran : manuscript, [1892-1896].

marginal notes/ examined by M. Zacharia 8/24/89."