64 research outputs found

    Mapeamento genético e dignidade humana: um panorama da legislação brasileira atual frente à prospecção axiológica

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    O objetivo deste trabalho é verificar o status da legislação sobre dados genéticos vigente no Brasil, em comparação com as legislações internacionais de vanguarda que contemplam os dados genéticos humanos: a americana, a alemã e a francesa, tendo como foco a área laboral para dimensionar a realidade normativa do país ante as tendências sociais de reconhecimento das diferenças e a abertura jurídica prospectiva. Método: Trata-se de uma revisão da literatura e pesquisa documental, cujo escopo é o diálogo da Bioética na interface com a Medicina do Trabalho e a Genética, em vista do referente comum: a dignidade humana. Resultados: Há tendência a um consenso legalístico mundial quanto à admissão do mapeamento genético de trabalhadores em áreas como pesquisa e tratamento médico. No Brasil, apenas o Código Civil brasileiro a contempla dentro da perspectiva culturalista que o envolve. Conclusão: Faz-se necessária uma estrutura legal consistente e segura que atenda a demanda moderna e que acompanhe o desenvolvimento biotecnológico e, que sobretudo, promova o acatamento à dignidade humana. As legislações internacionais podem ser um excelente campo de pesquisa e servir de referência para construção das leis brasileiras

    Mapeo genético laboral : prospección axiológica, bioética y legislación brasileña

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    Objetiva-se comparar o estado da legislação brasileira sobre mapeamento genético com o de legislações internacionais visando dimensionar a realidade normativa do país quanto às tendências sociais de reconhecimento das diferenças e a abertura jurídica prospectiva, com foco na área laboral. Trata-se de revisão de literatura e pesquisa documental sobre o diálogo entre bioética, medicina do trabalho e genética, que têm a dignidade humana como ponto em comum. Concluiu-se que se tende a admitir o mapeamento genético de trabalhadores para pesquisa e prevenção do adoecimento, inferindo-se, dado seu referencial comum e de acordo com a perspectiva culturalista do Código Civil, que essa possibilidade se estende à identificação genética de habilidades do trabalhador para o exercício de atividades.This work aims to verify the status of Brazilian legislation on genetic mapping, focusing on the occupational sphere, in comparison to international legislation, to assess the country’s normative reality regarding social trends related to the recognition of differences and prospective legal opening. This is a review of literature and documents regarding the dialogue between bioethics, occupational medicine and genetics, taking into account that they have human dignity as a common ground. It was concluded that there is a tendency to accept the genetic mapping of workers for research and prevention of illness. Given their common reference and in accordance with the culturalist perspective of the Civil Code, it is inferred that this possibility extends to the genetic identification of workers’ skills for the exercise of their duties.El objetivo de este trabajo es comparar el estado de la legislación brasileña sobre mapeo genético en relación con el de las legislaciones internacionales, buscando dimensionar la realidad normativa del país ante las tendencias sociales de reconocimiento de las diferencias y la apertura jurídica prospectiva, con foco en el área laboral. Se trata de una revisión de la literatura y de una investigación documental sobre el diálogo entre bioética, medicina del trabajo y genética, considerando que tienen a la dignidad humana como punto en común. Se concluyó que se tiende a admitir el mapeo genético de los trabajadores para la investigación y prevención de enfermedades, infiriéndose, dada su referencia común y de acuerdo con la perspectiva culturalista del Código Civil, que esta posibilidad se extiende a la identificación genética de habilidades del trabajador para para el ejercicio de actividades

    Rearrangements in thyroid hormone receptor charge clusters that stabilize bound 3,5',5-triiodo-l-thyronine and inhibit homodimer formation

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    In this study, we investigated how thyroid hormone (3,5′,5-triiodo-l-thyronine, T3) inhibits binding of thyroid hormone receptor (TR) homodimers, but not TR-retinoid X receptor heterodimers, to thyroid hormone response elements. Specifically we asked why a small subset of TRβ mutations that arise in resistance to thyroid hormone syndrome inhibit both T3 binding and formation of TRβ homodimers on thyroid hormone response elements. We reasoned that these mutations may affect structural elements involved in the coupling of T3 binding to inhibition of TR DNA binding activity. Analysis of TR x-ray structures revealed that each of these resistance to thyroid hormone syndrome mutations affects a cluster of charged amino acids with potential for ionic bond formation between oppositely charged partners. Two clusters (1 and 2) are adjacent to the dimer surface at the junction of helices 10 and 11. Targeted mutagenesis of residues in Cluster 1 (Arg338, Lys342, Asp351, and Asp355) and Cluster 2 (Arg429, Arg383, and Glu311) confirmed that the clusters are required for stable T3 binding and for optimal TR homodimer formation on DNA but also revealed that different arrangements of charged residues are needed for these effects. We propose that the charge clusters are homodimer-specific extensions of the dimer surface and further that T3 binding promotes specific rearrangements of these surfaces that simultaneously block homodimer formation on DNA and stabilize the bound hormone. Our data yield insight into the way that T3 regulates TR DNA binding activity and also highlight hitherto unsuspected T3-dependent conformational changes in the receptor ligand binding domain

    Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

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    The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription

    Mitochondrial Reactive Oxygen Species Are Obligatory Signals for Glucose-Induced Insulin Secretion

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    OBJECTIVE—Insulin secretion involves complex events in which the mitochondria play a pivotal role in the generation of signals that couple glucose detection to insulin secretion. Studies on the mitochondrial generation of reactive oxygen species (ROS) generally focus on chronic nutrient exposure. Here, we investigate whether transient mitochondrial ROS production linked to glucose-induced increased respiration might act as a signal for monitoring insulin secretion

    Thyroid hormone response element organization dictates the composition of active receptor

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    Thyroid hormone (triiodothyronine, T3) is known to activate transcription by binding heterodimers of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs). RXR-TRs bind to T3 response elements (TREs) composed of direct repeats of the sequence AGGTCA spaced by four nucleotides (DR-4). In other TREs, however, the half-sites can be arranged as inverted palindromes and palindromes (Pal). Here we show that TR homodimers and monomers activate transcription from representative TREs with alternate half-site placements. TRβ activates transcription more efficiently than TRα at an inverted palindrome (F2), and this correlates with preferential TRβ homodimer formation at F2 in vitro. Furthermore, reconstruction of TR transcription complexes in yeast indicates that TRβ homodimers are active at F2, whereas RXR-TRs are active at DR-4 and Pal. Finally, analysis of TRβ mutations that block homodimer and/or heterodimer formation reveal TRE-selective requirements for these surfaces in mammalian cells, which suggest that TRβ homodimers are active at F2, RXR-TRs at DR-4, and TR monomers at Pal. TRβ requires higher levels of hormone for activation at F2 than other TREs, and this differential effect is abolished by a dimer surface mutation suggesting that it is related to composition of the TR·TRE complex. We propose that interactions of particular TR oligomers with different elements play unappreciated roles in TRE-selective actions of liganded TRs in vivo

    Disentangling the Evolution of Electrons and Holes in photoexcited ZnO nanoparticles

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    The evolution of charge carriers in photoexcited room temperature ZnO nanoparticles in solution is investigated using ultrafast ultraviolet photoluminescence spectroscopy, ultrafast Zn K-edge absorption spectroscopy and ab-initio molecular dynamics (MD) simulations. The photoluminescence is excited at 4.66 eV, well above the band edge, and shows that electron cooling in the conduction band and exciton formation occur in <500 fs, in excellent agreement with theoretical predictions. The X-ray absorption measurements, obtained upon excitation close to the band edge at 3.49 eV, are sensitive to the migration and trapping of holes. They reveal that the 2 ps transient largely reproduces the previously reported transient obtained at 100 ps time delay in synchrotron studies. In addition, the X-ray absorption signal is found to rise in ~1.4 ps, which we attribute to the diffusion of holes through the lattice prior to their trapping at singly-charged oxygen vacancies. Indeed, the MD simulations show that impulsive trapping of holes induces an ultrafast expansion of the cage of Zn atoms in <200 fs, followed by an oscillatory response at a frequency of ~100 cm-1, which corresponds to a phonon mode of the system involving the Zn sub-lattice

    Helix 12 dynamics and thyroid hormone receptor activity: experimental and molecular dynamics studies of Ile280 mutants

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    Nuclear hormone receptors (NRs) form a family of transcription factors that mediate cellular responses initiated by hormone binding. It is generally recognized that the structure and dynamics of the C-terminal helix 12 (H12) of NRs' ligand binding domain (LBD) are fundamental to the recognition of coactivators and corepressors that modulate receptor function. Here we study the role of three mutations in the I280 residue of H12 of thyroid hormone receptors using site-directed mutagenesis, functional assays, and molecular dynamics simulations. Although residues at position 280 do not interact with coactivators or with the ligand, we show that its mutations can selectively block coactivator and corepressor binding, and affect hormone binding affinity differently. Molecular dynamics simulations suggest that ligand affinity is reduced by indirectly displacing the ligand in the binding pocket, facilitating water penetration and ligand destabilization. Mutations I280R and I280K link H12 to the LBD by forming salt bridges with E457 in H12, stabilizing H12 in a conformation that blocks both corepressor and coactivator recruitment. The I280M mutation, in turn, blocks corepressor binding, but appears to enhance coactivator affinity, suggesting stabilization of H12 in agonist conformation.FAPESPCNPq (476895/2008-1; 620195/2008)CAPE
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