Characterization of E-cadherin endocytosis in isolated MCF-7 and Chinese hamster ovary cells - The initial fate of unbound E-cadherin

The endocytosis of E-cadherin has recently emerged as an important determinant of cadherin function with the potential to participate in remodeling adhesive contacts. In this study we focused on the initial fate of E-cadherin when it predominantly exists free on the cell surface prior to adhesive binding or incorporation into junctions. Surface-labeling techniques were used to define the endocytic itinerary of E-cadherin in MCF-7 cells and in Chinese hamster ovary cells stably expressing human E-cadherin. We found that in this experimental system E-cadherin entered a transferrin-negative compartment before transport to the early endosomal compartment, where it merged with classical clathrin-mediated uptake pathways. E-cadherin endocytosis was inhibited by mutant dynamin, but not by an Eps15 mutant that effectively blocked transferrin internalization. Furthermore, sustained signaling by the ARF6 GTPase appeared to trap endocytosed E-cadherin in large peripheral structures. We conclude that in isolated cells unbound E-cadherin on the cell surface is predominantly endocytosed by a clathrin-independent pathway resembling macropinocytotic internalization, which then fuses with the early endosomal system. Taken with earlier reports, this suggests the possibility that multiple pathways exist for E-cadherin entry into cells that are likely to reflect cell context and regulation.

The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine

NOR-1/NR4A3 is an orphan member of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hRORbeta, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.

Produtividade e sa??de financeira: a import??ncia da venda de servi??os pela Base Naval de Natal para clientes extra: Marinha

A Marinha, com sua vis??o para o futuro e preocupada com a dificuldade de mensura????o dos custos de suas organiza????es industriais e prestadoras de servi??os, instituiu, a partir de 1994, o sistema de Organiza????es Militares Prestadoras de Servi??os (OMPS). Nesse contexto, a base Naval de Natal (BNN) precisou encontrar propostas que a mantivesse superavit??ria. Para tal, tornou-se necess??rio o engajamento de todos os n??veis da OM para, dentro de uma vis??o sist??mica de mensura????o existente, atingir um desempenho global satisfat??rio. Ap??s a implanta????o da iniciativa, alcan??ou-se o aumento substancial do faturamento, com rela????o aos clientes extra-Marinha, a redu????o dos prazos de prontifica????o dos servi??os prestados, sem queda na qualidade e com a constante preocupa????o de se verificar o n??vel de satisfa????o do cliente; o incremento da terceiriza????o consciente; o surgimento de parcerias com a iniciativa privada que geraram a otimiza????o da capacidade instalada em algumas oficinas; maior agilidade no processo de obten????o, devido a uma melhor coordena????o entre as ??reas industrial e de log??stica; e a possibilidade de investimentos na ??rea industrial e nas condi????es de trabalho,em decorr??ncia do aumento da produtividade

Caf?? com debate: a gest??o de processos na administra????o p??blica federal: import??ncia, avan??os e desafios

A import??ncia, os avan??os e os desafios da gest??o de processos na administra????o p??blica federal foram abordados em mais uma edi????o do Caf?? com Debate, no ??ltimo dia 23 de outubro. O encontro, que reuniu cerca de 120 pessoas de diversos ??rg??os, permitiu a troca de experi??ncias sobre modelos que proporcionam a diminui????o dos tempos de ciclos internos, a melhoria da qualidade e da efici??ncia dos ??rg??os, bem como a redu????o de custos

M??dulo 1 - a import??ncia e a necessidade da lei de licita????es: curso legisla????o aplicada ?? log??stica de suprimentos lei 8.666/93, preg??o e registro de pre??os

Este documento trata de: aspectos conceituais da lei: finalidade, import??ncia e hierarquia da lei.; no????es gerais da lei de licita????es - Lei n?? 8.666/93; tipos de licita????o:menor pre??o, melhor t??cnica, t??cnica e pre??o e maior lance ou oferta; modalidades de licita????o: concorr??ncia, tomada de pre??os, convite, concurso e leil??o; exce????es ?? obrigatoriedade de licita????o: dispensa e inexigibilidade; regime de execu????o indireta; comiss??o de licita????o; etapas do processo licitat??rio: edital, procedimentos/documentos do certame, registro cadastral, habilita????o dos interessados, julgamento e encerramento; preg??o; registro de pre??os

Painel 3 - A Import??ncia da Integra????o das Estat??sticas Oficiais

Painel 3 - Monitoramento da A????o Governamental e a Import??ncia das Estat??sticas Oficiais; Palestra 1 - ???Monitoramento e Avalia????o do Desenvolvimento Humano: a insensibilidade do ??ndice de Desenvolvimento Humano ??s pol??ticas de desenvolvimento social???, apresentada por Paulo de Martino Jannuzzi; Palestra 2 - ???Comit?? de Estat??sticas Sociais contribui para o fortalecimento e integra????o das estat??sticas oficiais brasileiras???, apresentada por Jailson Mangueira Assis

A sociologia de Max Weber: sua import??ncia para a teoria e a pr??tica da administra????o

A tradu????o integral da obra de Max Weber ??? Wirtschaft und Gesellschaft ??? empreendida pela editora mexicana ??? Fondo de Cultura Econ??mica, sob a esclarecida dire????o de Jos?? Medina Echavarr??a, ?? um acontecimento a cuja magnitude esta Revista n??o pode permanecer indiferente. ?? esta a primeira vez que a referida obra aparece em l??ngua diferente da original, pois a anunciada tradu????o do seu primeiro volume, realizada por Parsons-Henderson, n??o foi editada at?? o presente e, ao que me consta, circula mimeografada, em restritos centros de estudo dos Estados Unidos. Apesar de inacabada e fragment??ria e de ser um livro p??stumo, publicado gra??as ?? dedica????o e compet??ncia de Marianna Weber, esposa do autor, Economia e Sociedade ?? a obra n??o s?? onde se re??nem os temas centrais de Max Weber, como tamb??m onde ele exp??e o seu sistema de sociologia.

Átomos na integração: a aproximação Brasil-Argentina no campo nuclear e a construção do Mercosul

Este trabalho tenciona ser uma reflexão sobre a importância da aproximação entre o Brasil e a Argentina no campo nuclear, na segunda metade da década de 80 e no início dos anos 90, como fundamento para a construção de um relacionamento novo que suplantou uma rivalidade histórica entre ambos. O processo de aproximação encetado com um propósito aparentemente econômico, tinha uma dimensão estratégica. As repercussões desse esforço iam além dos interesses bilaterais imediatos e se refletiram na busca de uma nova inserção internacional dos dois países, num momento de transformações profundas nos planos interno e internacional. Através do programa de integração Brasil-Argentina (que mais tarde também envolveu o Uruguai) e do MERCOSUL buscou-se estabelecer uma arquitetura político-jurídica, que criou uma realidade que extrapola o campo econômico e projeta-se no terreno político.

A integração bilateral Brasil-Argentina: tecnologia nuclear e Mercosul

O presente trabalho focaliza o complexo processo de integração bilateral Brasil-Argentina, iniciado formalmente na década de 80, desdobrado em sua dupla abrangência: a) cooperação pacífica da tecnologia nuclear; b) constituição de um mercado comum. A evolução desse processo conduziu-se através de ciclos fundamentais: primeira etapa, antecedentes de aproximação; segunda etapa, os decisivos instrumentos da ampla integração; terceira etapa, solidificação de duas bases, uma de nível tecnológico nuclear, pactuando um sistema sui generis de salvaguardas e a vigência do Tratado de Tlatelolco (emendado), e, outra, de nível econômico pelo Tratado de Assunção, instituindo o Mercosul.

Brazil and the nuclear issues in the years of the Luiz Inácio Lula da Silva government (2003-2010)

The present article is an analysis of Brazilian nuclear diplomacy and of the international relevance of the national nuclear program adopted during the two Presidential terms of Luiz Inácio Lula da Silva. Particular attention will be given to the Brazilian position in the agreement on nuclear non-proliferation, to the role of mediation between Iran and the nuclear powers, and finally to the national ambitions concerning the industrial and military uses of the nuclear technologies.

XRCC3 THR241MET polymorphism influence on nuclear buds frequency in exposed to formaldehyde

Formaldehyde (FA), also known as formalin, formal and methyl aldehydes, is a colorless, flammable, strong-smelling gas. It has an important application in embalming tissues and that result in exposures for workers in the pathology anatomy laboratories and mortuaries. Occupational exposure to FA has been shown to induce nasopharyngeal cancer and has been classified as carcinogenic to humans (group 1) on the basis of sufficient evidence in humans and sufficient evidence in experimental animals. Manifold in vitro studies clearly indicated that FA is genotoxic. FA induced various genotoxic effects in proliferating cultured mammalian cells. The cytokinesis-block micronucleus (CBMN) assay was originally developped as an ideal system form easuring micronucleus (MN), however it can also be used to measure nucleoplasmic bridges (NBP) and nuclear buds (NBUD). Over the past decade another unique mechanism of micronucleus formation, known as nuclear budding has emerged. NBUDS is considered as a marker of gene amplification and/or altered gene dosage because the nuclear budding process is the mechanism by which cells removed amplified and/excess DNA.

Solid-state Marx based two-switch voltage modulator for the On-Line Isotope Mass Separator accelerator at the European Organization for Nuclear Research

A new circuit topology is proposed to replace the actual pulse transformer and thyratron based resonant modulator that supplies the 60 kV target potential for the ion acceleration of the On-Line Isotope Mass Separator accelerator, the stability of which is critical for the mass resolution downstream separator, at the European Organization for Nuclear Research. The improved modulator uses two solid-state switches working together, each one based on the Marx generator concept, operating as series and parallel switches, reducing the stress on the series stacked semiconductors, and also as auxiliary pulse generator in order to fulfill the target requirements. Preliminary results of a 10 kV prototype, using 1200 V insulated gate bipolar transistors and capacitors in the solid-state Marx circuits, ten stages each, with an electrical equivalent circuit of the target, are presented, demonstrating both the improved voltage stability and pulse flexibility potential wanted for this new modulator.

Genotoxicity biomarkers micronucleus, nucleoplasmic bridges and nuclear buds

The increase of mortality from cancer brought urgency in identification and validation of predictive markers of risk and therefore early diagnosis. There is evidence that cytogenetic biomarkers are positively correlated with risk of cancer, and this is validated by studies of cohort and case-control. Cytokinesis-blocked micronucleus (CBMN) assay is used extensively in molecular epidemiology, and can be considered as a “cytome” assay covering cell proliferation, apoptosis, necrosis and chromosomal changes. The chromosomal alterations most reported and studied by the CBMN are: micronucleus (MN), nucleoplasmic bridges (NPB) and nuclear buds (NBUDS). The use of the MN assay in biomonitoring studies had a large increase in the last 15 years and international projects such as the HUMN have helped to increase the applicability and reliability of these tests.

A medicina nuclear no diagnóstico dos tumores gastroenteropancreáticos

Objectivo do estudo - Demonstrar o contributo, essencial, que a Medicina Nuclear apresenta no diagnóstico dos Tumores Gastroenteropancreáticos e demonstrar a importância da precocidade diagnóstica recorrendo, maioritariamente, aos exames de medicina nuclear.