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Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9*2,*3 and *8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9*1/*1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.
Asunto(s)
Anticoagulantes , Pueblo Asiatico/genética , Negro o Afroamericano/genética , Citocromo P-450 CYP2C9/genética , Vitamina K Epóxido Reductasas/genética , Warfarina , Población Blanca/genética , Algoritmos , Anticoagulantes/administración & dosificación , Anticoagulantes/sangre , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Masculino , Tasa de Depuración Metabólica/genética , Persona de Mediana Edad , Modelos Biológicos , Pruebas de Farmacogenómica , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Warfarina/administración & dosificación , Warfarina/sangreRESUMEN
Gear-shaped amphiphile molecules (1) recently synthesized by Hiraoka et al. self-assemble into a hexameric structure, nanocubes (16), in 25% aqueous methanol due to a solvophobic effect. Here we have carried out molecular dynamic simulations to elucidate the stability of these hexameric capsules (16 and 26) in water, 25% aqueous methanol, and methanol. In all solvents, the 16 nanocubes are maintained for all trajectories. On the other hand, 26 was found to collapse for one trajectory in water and seven trajectories in 25% aqueous methanol. In a pure methanol solvent, 26 was found to collapse for all trajectories. The number of collapsed trajectories of 26 increased with the amount of methanol in the solvent. We therefore focused on the structure of the π-π stacking between pyridyl groups and the CH-π interactions between the methyl and pyridyl groups within the nanocube. Our study clearly shows the role played by the methanol solvent molecules in the assembly of the nanocube in terms of the substituent and solvent effects at the molecular level, and that these substituent and solvent effects are important for the self-assembly of the nanocubes.
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Apraxias/congénito , Síndrome de Cogan/genética , Enzimas Reparadoras del ADN/genética , Microcefalia/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Convulsiones/genética , Adulto , Edad de Inicio , Apraxias/diagnóstico por imagen , Apraxias/genética , Apraxias/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Niño , Síndrome de Cogan/diagnóstico por imagen , Síndrome de Cogan/fisiopatología , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico por imagen , Microcefalia/fisiopatología , Mutación , Linaje , Convulsiones/diagnóstico por imagen , Convulsiones/fisiopatologíaRESUMEN
Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. We identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein O-linked mannose beta1, 2-N-acetylglucosaminyltransferase (POMGnT1), respectively. Recent studies have revealed that posttranslational modification of alpha-dystroglycan is associated with these congenital muscular dystrophies with brain malformations. All are characterized by hypoglycosylated alpha-dystroglycan. Fukutin's function and the relation with other alpha-dystroglycanopathies are discussed.
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Distrofias Musculares/genética , Proteínas/genética , Animales , Quimerismo , Distroglicanos , Glicosilación , Humanos , Proteínas de la Membrana , N-Acetilglucosaminiltransferasas/genéticaRESUMEN
A 260-kDa protein, termed cgABP260, which localized in the dense plaques and dense bodies of smooth muscle cells, was found in a low-salt alkaline extract of chicken gizzard smooth muscle. An antibody against cgABP260 was used to screen a chicken gizzard cDNA library, and the nucleotide sequence of the partial cDNA encoding this protein was determined. Comparison of predicted amino acid sequences revealed that the protein had significant homology with human ABP-280 and chicken retina filamin [Barry, C.P. et al. (1993) J. Biol. Chem. 268, 25577-25586], but despite the high homology, cgABP260 was immunologically distinguishable from filamin. Immunoblot analysis showed that an anti-cgABP260 antibody reacted exclusively with the cgABP260 band of smooth, skeletal, and cardiac muscle tissues. By indirect immunofluorescence, the membrane-affinity-purified antibody against cgABP260 intensely stained the dense plaques of the isolated smooth muscle cells. Immunoelectron microscopy showed that immunogold particles representing cgABP260 were found abundantly on the dense plaques and less abundantly on the dense bodies. Its amino acid sequence, molecular size, immunological reactivity, and localization in smooth muscle thus indicated that cgABP260 is a new component of the dense plaques and dense bodies of smooth muscle cells.
Asunto(s)
Molleja de las Aves/química , Proteínas Musculares/análisis , Proteínas Musculares/genética , Músculo Liso/química , Homología de Secuencia de Aminoácido , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Pollos , Clonación Molecular , Proteínas Contráctiles/análisis , Proteínas Contráctiles/genética , Filaminas , Proteínas de Microfilamentos/análisis , Proteínas de Microfilamentos/genética , Datos de Secuencia Molecular , Peso Molecular , Proteínas Musculares/química , Proteínas Musculares/aislamiento & purificación , Proteínas Recombinantes de Fusión , Análisis de Secuencia de ADN , Vinculina/análisisRESUMEN
To elucidate if the metabolic methylation participates in the induction of inorganic arsenic-responsible genetic damage, arsenite (ARS) and its methylated metabolites, methanearsonic acid (MMAA) and dimethylarsinic acid (DMAA), were comparatively assayed for the induction of DNA damage by determining DNA repair synthesis using polymerization inhibitors such as aphidicolin (aph) and hydroxyurea (HU). When human alveolar epithelial type II (L-132) cells in culture were exposed to either one of these three arsenic compounds, DNA single-strand breaks resulting from the inhibition of repair polymerization were remarkably produced by exposure to DMAA at 5 to 100 microM, while not by that to ARS and MMAA even at 100 microM. Furthermore, a bromodeoxyuridine (BrdrU)-photolysis assay indicated that the induction of DNA repair synthesis was observed only in the case of exposure to DMAA. When L-132 cells were exposed to 100 microM MMAA in the presence of 10 mM S-adenosyl-L-methionine (SAM), which is a well-known methyl-group donor in metabolic methylation of arsenics, DNA repair synthesis was induced along with an increase in the amount of dimethylarsenic in the cells. These results indicate that metabolic methylation of inorganic arsenics to dimethylarsenics is predominantly involved in the induction of DNA damage.
Asunto(s)
Intoxicación por Arsénico , Arsenicales , Ácido Cacodílico/toxicidad , Mutágenos/toxicidad , Línea Celular , Cromatografía de Gases , Reparación del ADN , Humanos , MetilaciónRESUMEN
A convenient formalism is developed for the evaluation of atomic integrals composed of a hybrid Gaussian type function and plane-wave (GTF-PW) basis set, based upon the recursion scheme proposed by McMurchie and Davidson [L. E. McMurchie and E. R. Davidson, J. Comput. Phys. 26, 218 (1978)] which was originally for Gaussian type basis functions. We show that revisions of recursion relations in the original article are necessary in order to allow systematic production of overlap, kinetic energy, nuclear attraction, and electron repulsion integrals in compact forms. Involving easy calculation of complex incomplete gamma functions, the recursion relations enable the use of hybrid GTF-PW basis functions with arbitrarily large angular momentum. This basis function can be applied to the first-principle calculation for solids involving localized electron orbitals.
RESUMEN
We propose a novel method of stabilizing laser oscillation frequency that uses a sub-Doppler spectrum of atoms in a thin vapor cell. An extended-cavity diode laser is frequency-locked to a hyperfine component of the Cs-D(2) line. In the Allan-variance measurements on the beat note between two lasers thus stabilized, a frequency stability of 6.6x10(-11) is achieved at an averaging time of 5.8 s. The frequency can be controlled even when the laser beam intensity is as small as 70 nW/cm(2).
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Distrofias Musculares/congénito , Distrofias Musculares/genética , Animales , Pueblo Asiatico , Marcadores Genéticos , Humanos , Japón , Desequilibrio de Ligamiento , Proteínas de la Membrana , Ratones , Ratones Noqueados , Mutación , Mapeo Físico de Cromosoma , Proteínas/genética , Retroelementos/genética , TransferasasRESUMEN
Two approaches for the determination of the primary and secondary geometric isotope effect are compared for the exemplary porphyrinoid system porphycene, which has two intramolecular hydrogen bonds. A three-dimensional Born-Oppenheimer potential energy surface is calculated in terms of the symmetric and antisymmetric N-H stretching as well as a low-frequency hydrogen bond vibrational normal mode coordinate. From the respective ground-state nuclear wavefunction the quantum correction to the classical equilibrium geometry is determined. Further, geometry optimization within a full-dimensional multi-component molecular orbital (MC_MO) type calculation, which treats both the electrons and the hydrogen-bonded protons quantum mechanically, is performed. Both approaches yield geometric isotope effects, that is, upon H/D double substitution the hydrogen bonds are weakened and the respective N-N distances increase. In addition the MC_MO calculation gives a H/D isotope effect on the electronic structure, that is, the electronic wavefunction becomes more localized at the deuterium nucleus as compared with the proton case.
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Simulación por Computador , Deuterio/química , Hidrógeno/química , Modelos Químicos , Porfirinas/química , Teoría Cuántica , Enlace de Hidrógeno , Propiedades de Superficie , VibraciónRESUMEN
Two DNA binding proteins, Cro and the amino-terminal domain of the repressor of bacteriophage 434 (434 Cro and 434 repressor) that regulate gene expression and contain a helix-turn-helix (HTH) motif responsible for their site-specific DNA recognition adopt very similar three-dimensional structures when compared to each other. To reveal structural differences between these two similar proteins, their dynamic structures, as examined by normal mode analysis, are compared in this paper. Two kinds of structural data, one for the monomer and the other for a complex with DNA, for each protein, are used in the analyses. From a comparison between the monomers it is found that the interactions of Ala-24 in 434 Cro or Val-24 in 434 repressor, both located in the HTH motif, with residues 44, 47, 48, and 51 located in the domain facing the motif, and the interactions between residues 17, 18, 28, and 32, located in the HTH motif, cause significant differences in the correlative motions of these residues. From the comparison between the monomer and the complex with DNA for each protein, it was found that the first helix in the HTH motif is distorted in the complex form. While the residues in the HTH motif in 434 Cro have relatively larger positive correlation coefficients of motions with other residues within the HTH motif, such correlations are not large in the HTH motif of 434 repressor. It is suggestive to their specificity because the 434 repressor is less specific than 434 Cro. Although a structural comparison of proteins has been performed mainly from a static or geometrical point of view, this study demonstrates that the comparison from a dynamic point of view, using the normal mode analysis, is useful and convenient to explore a difference that is difficult to find only from a geometrical point of view, especially for proteins very similar in structure.
Asunto(s)
Bacteriófago lambda/química , Proteínas Represoras/química , Secuencia de Aminoácidos , ADN/química , ADN/metabolismo , Proteínas de Unión al ADN/química , Secuencias Hélice-Giro-Hélice , Enlace de Hidrógeno , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Alineación de Secuencia , Proteínas Virales , Proteínas Reguladoras y Accesorias ViralesRESUMEN
We present a novel technique for resonantly pumping a continuous-wave far-infrared NH(3) laser with a linetunable mid-infrared NH(3) laser that is optically pumped by a CO(2) laser. In this two-step process we first convert 10-microm CO(2) laser photons into 11-13-microm NH(3) laser photons, which are then converted into 60-400-microm photons in a far-infrared NH(3) laser. Continuous-wave laser action on 10 far-infrared lines of (15)NH(3), including four new ones, has been obtained with a single CO(2) laser pump line.
RESUMEN
Freshwater and seawater acclimated (FWA and SWA) killifish (Oryzias latipes) were exposed to pentachlorophenol (PCP) for 3-10 days. Uptake and clearance rates of FWA and SWA killifish were determined. The estimated bioaccumulation factors (BCF) of PCP for FWA and SWA killifish were 1680 and 370, respectively. The smaller uptake rate and faster clearance rate resulted in the lower BCF for SWA killifish. Fresh- and seawater killifish excreted the PCP metabolites, the glucuronide and sulfate conjugates of PCP; the major metabolite of freshwater killifish was PCP sulfate; for seawater acclimated fish, it was PCP glucuronide. The greater excretion of PCP glucuronide by seawater killifish may be responsible for the rapid elimination of PCP. PCP accumulation in killifish decreased with higher pH levels in both freshwater and seawater environments, but these differences were less than the effect of salinity. The results indicate that salinity can affect the accumulation and elimination of environmental pollutants in killifish.
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Peces Killi/metabolismo , Pentaclorofenol/farmacocinética , Contaminantes Químicos del Agua/farmacocinética , Animales , Agua Dulce , Vesícula Biliar/metabolismo , Concentración de Iones de Hidrógeno , Pentaclorofenol/metabolismo , Agua de Mar , Distribución TisularRESUMEN
A commercially available spin-on-glass material, hydrogen silsesquioxane, has been rendered photopatternable to micrometer dimensions by the introduction of a photobase generator at concentrations of <5 wt %. The cure process proceeds via hydrolysis of the silyl hydride linkage by residual water in the film, as activated by a photogenerated base catalyst. Subsequent reaction of the generated silanol with neighboring silyl hydride groups yields a thermally stable siloxane cross-link. The photochemical cross-linking of hydrogen silsesquioxane shows high sensitivity (<40 mJ/cm2) and is not inhibited by molecular oxygen. The resultant oxide films can be further cured at elevated temperature either under an inert atmosphere to minimize the dielectric constant or heated in an air atmosphere to complete the conversion to silica glass. The oxidative nature of both the photo and thermal cure processes and the release of only traces of hydrogen as byproduct results in minimal weight loss in the film during processing.
RESUMEN
We generated tunable far-infrared radiation by mixing CO(2) -laser,(15)NH(3) -laser, and microwave radiations in a W-Co metal-insulator-metal diode. We used this far-infrared radiation to measure accurately the torsion-rotation transitions of CH(3)OH in the 6-8-THz region.
RESUMEN
Using primary cultured mouse hepatocytes, in vitro study was performed to discuss the effect of Cr(III) and several other trace metals, Cr(VI), Mn(II), Zn(II), Co(II), Cu(II), Ni(II), and Ga(III) on acute liver damage induced by CCl4 exposure. 1) The LDH activity 60 min after CCl4 exposure increased dose-dependently with CCl4 concentrations in all of the trace metal pretreatment groups, except for the Cr(VI) pretreatment group, which showed a significant protective effect even after 30 min of CCl4 exposure. 2) LDH leakage was not observed 10 min after CCl4 exposure at 3 or 5 mM, while lipid peroxidation was increased dose-dependently with CCl4 concentrations in all groups except the Cr(VI) pretreatment group, in which the production of peroxidated lipid was significantly inhibited. 3) Similarly to the pretreatment with Cr(VI), LDH leakage 30 min after exposure to 5 mM CCl4 was inhibited by pretreatment with such antioxidants as N,N'-diphenyl-p-phenylenediamine or DL-alpha-tocopherol. 4) The Cr(VI) uptake was about 50% of the added amount, whereas the Cr(III) uptake was only 5% of the added amount. 5) 90% or more of the intracellular chromium was reduced to Cr(III) 10 min after Cr(VI) treatment. The results suggested that the in vitro protective effect of pretreatment with Cr(VI) was due to a rapid reduction of Cr(VI) to Cr(III), and the radical scavenger-like effect of the produced Cr(III) was the same effect as in vivo Cr(III); it therefore suggests that Cr(III) contributes to protective effect on CCl4-induced hepatotoxicity.
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Tetracloruro de Carbono/toxicidad , Cromo/toxicidad , Hígado/efectos de los fármacos , Oligoelementos/toxicidad , Animales , Antioxidantes/farmacología , Tetracloruro de Carbono/antagonistas & inhibidores , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cromo/metabolismo , Peroxidación de Lípido , Hígado/citología , Hígado/metabolismo , Masculino , RatonesRESUMEN
Copyright
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Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disorder with a high prevalence in the Japanese population, is characterised by severe muscular dystrophy associated with brain malformation (cortical dysgenesis) and mental retardation. In Japan, 87% of FCMD-bearing chromosomes carry a 3-kb retrotransposal insertion of tandemly repeated sequences within the disease gene recently identified on chromosome 9q31, and most of them share a common founder haplotype. FCMD is the first human disease known to be caused primarily by an ancient retrotransposal integration. By applying two methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, the age of the insertion mutation causing FCMD in Japanese patients is calculated to be approximately 102 generations (95% confidence interval: 86-117 g), or slightly less. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or a few centuries before) the Yayoi people started migrating to Japan from the Korean peninsula. This finding makes the molecular population genetics of FCMD understandable in the context of Japan's history and the founder effect consistent with the prevalent theory on the origins of the modern Japanese population.