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.

Low-temperature single-crystal Raman and neutron-diffraction study of the hydrogenous ammonium copper(II) tutton salt and the deuterated analogue in the metastable state

Low-temperature (15 K) single-crystal neutron-diffraction structures and Raman spectra of the salts (NX4)(2)[CU(OX2)(6)](SO4)(2), where X = H or D, are reported. This study is concerned with the origin of the structural phase change that is known to occur upon deuteration. Data for the deuterated salt were measured in the metastable state, achieved by application of 500 bar of hydrostatic pressure at similar to303 K followed by cooling to 281 K and the subsequent release of pressure. This allows for the direct comparison between the hydrogenous and deuterated salts, in the same modification, at ambient pressure and low temperature. The Raman spectra provide no intimation of any significant change in the intermolecular bonding. Furthermore, structural differences are few, the largest being for the long Cu-O bond, which is 2.2834(5) and 2.2802(4) Angstrom for the hydrogenous and the deuterated salts, respectively. Calorimetric data for the deuterated salt are also presented, providing an estimate of 0.17(2) kJ/mol for the enthalpy difference between the two structural forms at 295.8(5) K. The structural data suggest that substitution of hydrogen for deuterium gives rise to changes in the hydrogen-bonding interactions that result in a slightly reduced force field about the copper(II) center. The small structural differences suggest different relative stabilities for the hydrogenous and deuterated salts, which may be sufficient to stabilize the hydrogenous salt in the anomalous structural form.

Structural variations and formation constants of first-row transition metal complexes of biologically active aroylhydrazones

Iron chelators of the 2-pyridinecarbaldehyde isonicotinoylhydrazone (HPCIH) class show high potential for the treatment of iron overload diseases. In the present study, selected first-row transition metal (from Mn to Zn) complexes with HPCIH and 2-pyridinecarbaldehyde (4'-aminobenzoyl)hydrazone (HPCAH) were synthesised and characterised. Crystallography reveals that HPCAH exclusively forms bis complexes with divalent transition metals, with each ligand coordinating meridionally through its pyridine-N, imine-N and carbonyl-O atoms, forming distorted octahedral cis-MN4O2 complexes. Complexes of HPCIH were more varied and unpredictable, with metal/ligand ratios of 1:1, 1:2, 2:2 and 3:2 obtained with different metal ions. The isonicotinoyl ring N-atom in HPCIH was found to be an effective ligand, and this resulted in the varied metal/ligand ratios observed. The formation constants of divalent metal complexes with HPCIH were determined by potentiometric titrations and the values obtained were consistent with similar tridentate ligands and with the Irving-Williams order. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Papel do teste de detecção rápida do antígeno do estreptococcus beta-hemolítico do grupo a em pacientes com faringoamigdalites

O Streptococcus beta-hemolítico do grupo A (SGA) é o agente etiológico mais comum das faringoamigdalites (FA). O diagnóstico etiológico correto e tratamento adequado evitam complicações supurativas e não-supurativas da faringoamigdalite estreptocócica, entretanto, métodos clínicos de diagnóstico não são confiáveis. Os métodos rápidos de detecção do antígeno do SGA podem ser utilizados no diagnóstico deste agente e evitar uso indevido de antibióticos. OBJETIVOS: Os autores objetivaram avaliar a sensibilidade e especificidade dos testes rápidos para detecção do antígeno do SGA em nosso meio. FORMA DE ESTUDO: Clínico prospectivo. METODOLOGIA: Oitenta e um pacientes com faringoamigdalite aguda, atendidos no PS-ORL do Hospital das Clínicas da FMUSP, no período de maio de 2001 a abril de 2002, foram submetidos a duas coletas simultâneas de material de orofaringe com swabs. O teste rápido de detecção do SGA foi confrontado com a cultura em placa agar-sangue ("gold standard" para o diagnóstico etiológico). RESULTADOS: De 81 pacientes, 56% tiveram teste rápido positivo e 44% negativo; 40.7% apresentaram crescimento de SGA na cultura; a sensibilidade e especificidade do teste rápido foram, respectivamente, 93,9% e 68,7%. O valor preditivo negativo e positivo foram, respectivamente, 94,2% e 67,4%. CONCLUSÕES: A alta sensibilidade do exame permite utilizá-lo com intuito de identificar pacientes com SGA. Os testes de detecção rápida do antígeno estreptocócico se mostraram uma importante arma coadjuvante no diagnóstico etiológico das faringoamigdalites.

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.

Dynamical behaviour on the parameter space: new populational growth models proportional to beta densities

We present new populational growth models, generalized logistic models which are proportional to beta densities with shape parameters p and 2, where p > 1, with Malthusian parameter r. The complex dynamical behaviour of these models is investigated in the parameter space (r, p), in terms of topological entropy, using explicit methods, when the Malthusian parameter r increases. This parameter space is split into different regions, according to the chaotic behaviour of the models.

Leptonic CP violation

Several topics on CP violation in the lepton sector are reviewed. A few theoretical aspects concerning neutrino masses, leptonic mixing, and CP violation will be covered, with special emphasis on seesaw models. A discussion is provided on observable effects which are manifest in the presence of CP violation, particularly, in neutrino oscillations and neutrinoless double beta decay processes, and their possible implications in collider experiments such as the LHC. The role that leptonic CP violation may have played in the generation of the baryon asymmetry of the Universe through the mechanism of leptogenesis is also discussed.

Viabilidade económica da implementação de um reactor nuclear para a produção de energia eléctrica em Portugal

O presente trabalho tem como objectivo avaliar economicamente e determinar a viabilidade da implementação de um reactor nuclear para produção de energia eléctrica. Faz-se uma abordagem a aspectos da energia nuclear no mundo e em particular a energia nuclear na união europeia, faz-se uma análise sobre a estrutura do sector nuclear em Espanha e o futuro da energia no mundo. É realizada uma análise sobre a energia nuclear em Portugal, são abordados aspectos como o planeamento energético, a localização da central nuclear, os recursos nacionais e internacionais, a inspecção e regulação nuclear e o impacto industrial. Por fim, faz-se uma análise sobre o mix energético português. Faz-se uma descrição do ciclo de combustível, isto é, um estudo a todas as fases pela qual o combustível nuclear passa desde a sua extracção, passando pela produção de energia e processamento dos resíduos. São descritos os principais componentes de uma central nuclear e o seu princípio de funcionamento. São analisados em detalhe os principais componentes de um reactor PWR (Objecto de estudo deste trabalho) e faz-se uma breve descrição de alguns modelos de reactores nucleares. É feita uma breve abordagem aos principais acidentes nucleares que ocorreram, e descrita a escala de ocorrências nucleares e as várias fases de desmantelamento de uma central. São apresentados os principais custos da central nuclear. Também é apresentado um estudo de viabilidade económica analisando três cenários diferentes e é apresentada uma análise de sensibilidade do VAL em função de algumas variáveis que têm grande influência na avaliação económica. São apresentadas as principais conclusões.