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.

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.

Electrospun silk-elastin-like fiber mats for tissue engineering applications

Protein-based polymers are present in a wide variety of organisms fulfilling structural and mechanical roles. Advances in protein engineering and recombinant DNA technology allow the design and production of recombinant protein-based polymers (rPBPs) with an absolute control of its composition. Although the application of recombinant proteins as biomaterials is still an emerging technology, the possibilities are limitless and far superior to natural or synthetic materials, as the complexity of the structural design can be fully customized. In this work, we report the electrospinning of two new genetically engineered silk-elastin-like proteins (SELPs) consisting of alternate silk- and elastin-like blocks. Electrospinning was performed with formic acid and aqueous solutions at different concentrations without addition of further agents. The size and morphology of the electrospun structures was characterized by scanning electron microscopy showing to be dependent of concentration and solvent used. Treatment with air saturated with methanol was employed to stabilize the structure and promote water insolubility through a time-dependent conversion of random coils into β-sheets (FTIR). The resultant methanol-treated electrospun mats were characterized for swelling degree (570-720%), water vapour transmission rate (1083 g/m2/day) and mechanical properties (modulus of elasticity of ~126 MPa). Furthermore, the methanol-treated SELP fiber mats showed no cytotoxicity and were able to support adhesion and proliferation of normal human skin fibroblasts. Adhesion was characterized by a filopodia-mediated mechanism. These results demonstrate that SELP fiber mats can provide promising solutions for the development of novel biomaterials suitable for tissue engineering applications.

Effect of poling state and morphology of piezoelectric poly(vinylidene fluoride) membranes for skeletal muscle tissue engineering

This work reports on the influence of polarization and morphology of electroactive poly(vinylidene fluoride), PVDF, on the biological response of myoblast cells. Non-poled, ‘‘poled +’’ and “poled-“ -PVDF were prepared in the form of films. Further, random and aligned electrospun -PVDF fiber mats were also prepared. It is demonstrated that negatively charged surfaces improve cell adhesion and proliferation and that the directional growth of the myoblast cells can be achieved by the cell culture on oriented fibers. Therefore, the potential application of electroative materials for muscle regeneration is demonstrated.

GUIsurfer: A Reverse Engineering Framework for User Interface Software

GUIsurfer: A Reverse Engineering Framework for User Interface Software

The GUISurfer tool: towards a language independent approach to reverse engineering GUI code

Graphical user interfaces (GUIs) are critical components of today's software. Developers are dedicating a larger portion of code to implementing them. Given their increased importance, correctness of GUIs code is becoming essential. This paper describes the latest results in the development of GUISurfer, a tool to reverse engineer the GUI layer of interactive computing systems. The ultimate goal of the tool is to enable analysis of interactive system from source code.

Combining Formal Methods and Functional Strategies Regarding the Reverse Engineering of Interactive Applications

Abstract. Graphical user interfaces (GUIs) make software easy to use by providing the user with visual controls. Therefore, correctness of GUI’s code is essential to the correct execution of the overall software. Models can help in the evaluation of interactive applications by allowing designers to concentrate on its more important aspects. This paper describes our approach to reverse engineer an abstract model of a user interface directly from the GUI’s legacy code. We also present results from a case study. These results are encouraging and give evidence that the goal of reverse engineering user interfaces can be met with more work on this technique.

Models for the Reverse Engineering of Java/Swing Applications

Abstract. Interest in design and development of graphical user interface (GUIs) is growing in the last few years. However, correctness of GUI's code is essential to the correct execution of the overall software. Models can help in the evaluation of interactive applications by allowing designers to concentrate on its more important aspects. This paper describes our approach to reverse engineering abstract GUI models directly from the Java/Swing code.

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.