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.     

科氏力对高速旋转汽轮机叶片动态特性的影响

采用解析的方法，建立了高速旋转汽轮机叶片中科氏力和科氏动应力的计算模型。该模型克服了以往在叶片动态特性分析时难以考虑科氏力影响的问题，导出了科氏动应力和非稳态气流动应力比值的计算公式以及科氏力和离心力比值的计算公式，并进行了实例分析．计算结果表明，科氏力对叶片轴向振动和扭转振动的固有频率没有影响，对切向振动的影响很小，可以忽略不计；科氏力所产生的动应力不到非稳态气流动应力的1%。     

One Dimensional Nanostructures for Lithium-ion Batteries, Gas Sensors and Optoelectronics Applications

1 Results One dimensional (1D) nanostructures such as nanowires,nanotubes,nanorods and nanoribbons have been extensively investigated for a wide range of applications[1].Here,we present the synthesis,characterization and technological applications of several 1D nanostructures including SnO2 nanowires,CuO nanoribbons,CdSe nanowires and In2O3 nanowires.SnO2 nanowires were synthesized by thermal evaporation combined with a self-catalyzed growth procedure.Scanning electron microscopy (SEM) observation shows...     

p53 mutant mice that display early ageing-associated phenotypes.

The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.     

An outlier robust GARCH model and forecasting volatility of exchange rate returns

Since volatility is perceived as an explicit measure of risk, financial economists have long been concerned with accurate measures and forecasts of future volatility and, undoubtedly, the Generalized Autoregressive Conditional Heteroscedasticity (GARCH) model has been widely used for doing so. It appears, however, from some empirical studies that the GARCH model tends to provide poor volatility forecasts in the presence of additive outliers. To overcome the forecasting limitation, this paper proposes a robust GARCH model (RGARCH) using least absolute deviation estimation and introduces a valuable estimation method from a practical point of view. Extensive Monte Carlo experiments substantiate our conjectures. As the magnitude of the outliers increases, the one‐step‐ahead forecasting performance of the RGARCH model has a more significant improvement in two forecast evaluation criteria over both the standard GARCH and random walk models. Strong evidence in favour of the RGARCH model over other competitive models is based on empirical application. By using a sample of two daily exchange rate series, we find that the out‐of‐sample volatility forecasts of the RGARCH model are apparently superior to those of other competitive models. Copyright © 2002 John Wiley & Sons, Ltd.     

Automated design of multiple-class piecewise linear classifiers

A new method and a supporting theorem for designing multiple-class piecewise linear classifiers are described. The method involves the cutting of straight line segments joining pairs of opposed points (i.e., points from distinct classes) ind-dimensional space. We refer to such straight line segments aslinks. We show how nearly to minimize the number of hyperplanes required to cut all of these links, thereby yielding a near-Bayes-optimal decision surface regardless of the number of classes, and we describe the underlying theory. This method does not require parameters to be specified by users — an improvement over earlier methods. Experiments on multiple-class data obtained from ship images show that classifiers designed by this method yield approximately the same error rate as the bestk-nearest neighbor rule, while providing faster decisions.This research was supported in part by the Army Research Office under grant DAAG29-84-K-0208 and in part by the University of California MICRO Program. We thank R. W. Doucette of the U.S. Naval Weapons Center and R. D. Holben of Ford Aerospace Corporation for providing the ship images in our experiments.     

The afterglow of GRB 050709 and the nature of the short-hard gamma-ray bursts

The final chapter in the long-standing mystery of the gamma-ray bursts (GRBs) centres on the origin of the short-hard class of bursts, which are suspected on theoretical grounds to result from the coalescence of neutron-star or black-hole binary systems. Numerous searches for the afterglows of short-hard bursts have been made, galvanized by the revolution in our understanding of long-duration GRBs that followed the discovery in 1997 of their broadband (X-ray, optical and radio) afterglow emission. Here we present the discovery of the X-ray afterglow of a short-hard burst, GRB 050709, whose accurate position allows us to associate it unambiguously with a star-forming galaxy at redshift z = 0.160, and whose optical lightcurve definitively excludes a supernova association. Together with results from three other recent short-hard bursts, this suggests that short-hard bursts release much less energy than the long-duration GRBs. Models requiring young stellar populations, such as magnetars and collapsars, are ruled out, while coalescing degenerate binaries remain the most promising progenitor candidates.     

Aspects of gene polymorphisms in cerebral infarction: inflammatory cytokines

During the last decade, a growing corpus of evidence has indicated an important role of inflammatory cytokines in the pathogenesis of cerebral lesion following stroke. Recent data suggest that genetics may in turn contribute to modulating the effects of inflammatory cytokines on cerebral infarction (CI). This paper reviews the physiologic characteristics of major inflammatory cytokines and recent research developments related to cell biology and pathobiology in CI. In particular, this review focuses on the genetic aspects of inflammatory cytokines and their implications in CI.Received 22 June 2004; received after revision 11 November 2004; accepted 16 December 2004