Trans allele methylation and paramutation-like effects in mice

In mammals, imprinted genes have parent-of-origin-specific patterns of DNA methylation that cause allele-specific expression. At Rasgrf1 (encoding RAS protein-specific guanine nucleotide-releasing factor 1), a repeated DNA element is needed to establish methylation and expression of the active paternal allele. At Igf2r (encoding insulin-like growth factor 2 receptor), a sequence called region 2 is needed for methylation of the active maternal allele. Here we show that replacing the Rasgrf1 repeats on the paternal allele with region 2 allows both methylation and expression of the paternal copy of Rasgrf1, indicating that sequences that control methylation can function ectopically. Paternal transmission of the mutated allele also induced methylation and expression in trans of the normally unmethylated and silent wild-type maternal allele. Once activated, the wild-type maternal Rasgrf1 allele maintained its activated state in the next generation independently of the paternal allele. These results recapitulate in mice several features in common with paramutation described in plants.     

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.     

Achromatic Fresnel optics for wideband extreme-ultraviolet and X-ray imaging

Advances in extreme-ultraviolet (EUV) and X-ray optics are providing powerful new capabilities in high-resolution imaging and trace-element analysis of microscopic specimens, and the potential for fabricating devices of smaller critical dimensions in next-generation integrated circuit lithography. However, achieving the highest resolution with such optics usually requires the illuminating EUV or X-ray beam to be highly monochromatic. It would therefore be highly desirable to have large-field-of-view, sub-100-nm resolution optics that are achromatic to a significant degree, allowing more light to be utilized from broader bandwidth sources such as laser-produced plasmas. Here we report an achromatic Fresnel optical system for EUV or X-ray radiation that combines a Fresnel zone plate with a refractive lens with opposite chromatic aberration. We use the large anomalous dispersion property of the refractive lens material near an absorption edge to make its fabrication practical. The resulting structure can deliver a resolution comparable to that of the Fresnel zone plates that have achieved the highest resolution (25 nm; ref. 3) in the entire electromagnetic spectrum, but with an improvement of two or more orders of magnitude in spectral bandwidth.     

Enhanced Model-Based Clustering,Density Estimation,and Discriminant Analysis Software: MCLUST

MCLUST is a software package for model-based clustering, density estimation and discriminant analysis interfaced to the S-PLUS commercial software and the R language. It implements parameterized Gaussian hierarchical clustering algorithms and the EM algorithm for parameterized Gaussian mixture models with the possible addition of a Poisson noise term. Also included are functions that combine hierarchical clustering, EM and the Bayesian Information Criterion (BIC) in comprehensive strategies for clustering, density estimation, and discriminant analysis. MCLUST provides functionality for displaying and visualizing clustering and classification results. A web page with related links can be found at .     

Optimization of a High Speed Spinning Disk Spindle System for Minimum RRO , NRRO, and Lightweight by Using G.A.

Law level of RRO(Repeatable Run Out), NRRO(Non Repe at able Run Out), and lightweight construction are a major trend in the high-speed HDD(Hard Disk Drive) sytem to reduce track misregestration and to achieve high track density, which lead to succeed in the market. However, it is not easy to r educe RRO, NRRO, and the weight of the spinning disk spindle system efficiently because lightweight construction and or bearing stiffness changes often yields a decrease in the static and dynamic stiffness of the ...     

Predicting stock index volatility: can market volume help?

This paper explores a number of statistical models for predicting the daily stock return volatility of an aggregate of all stocks traded on the NYSE. An application of linear and non-linear Granger causality tests highlights evidence of bidirectional causality, although the relationship is stronger from volatility to volume than the other way around. The out-of-sample forecasting performance of various linear, GARCH, EGARCH, GJR and neural network models of volatility are evaluated and compared. The models are also augmented by the addition of a measure of lagged volume to form more general ex-ante forecasting models. The results indicate that augmenting models of volatility with measures of lagged volume leads only to very modest improvements, if any, in forecasting performance. © 1998 John Wiley & Sons, Ltd.     

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献