NO-independent regulatory site on soluble guanylate cyclase

Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.     

Signal sequence directs localized secretion of bacterial surface proteins

All living cells require specific mechanisms that target proteins to the cell surface. In eukaryotes, the first part of this process involves recognition in the endoplasmic reticulum of amino-terminal signal sequences and translocation through Sec translocons, whereas subsequent targeting to different surface locations is promoted by internal sorting signals. In bacteria, N-terminal signal sequences promote translocation across the cytoplasmic membrane, which surrounds the entire cell, but some proteins are nevertheless secreted in one part of the cell by poorly understood mechanisms. Here we analyse localized secretion in the Gram-positive pathogen Streptococcus pyogenes, and show that the signal sequences of two surface proteins, M protein and protein F (PrtF), direct secretion to different subcellular regions. The signal sequence of M protein promotes secretion at the division septum, whereas that of PrtF preferentially promotes secretion at the old pole. Our work therefore shows that a signal sequence may contain information that directs the secretion of a protein to one subcellular region, in addition to its classical role in promoting secretion. This finding identifies a new level of complexity in protein translocation and emphasizes the potential of bacterial systems for the analysis of fundamental cell-biological problems.     

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.     

穿过时间：宇宙的起源

这不是科学幻想小说.它是我们关于宇宙如何始于"热大爆炸"的最佳理论,而且有可靠的证据支持它.天文学家能够测量到随宇宙不断膨胀而迅速后退的遥远星系.他们能够探测余辉,而在这次膨胀前它     

第四种中微子的发现冲击现有的理论

英国和美国的物理学家们最近获得一些惊人的证据,表明可能存在着又大又重的第四种中微子,它不时地在原子核的β衰变中出驯.当一个中子衰变为一个质子时,同时释放一个电子和一个中微子,一般情况下放出的电子和中微子质量很小或几乎完全没有质量.1985年,一位加拿大物理学家在实验室中观测到     

黄海周边河流的稀土元素地球化学及沉积物物源示踪

黄海周边的中韩主要河流悬浮沉积物中稀土元素组成不同, 韩国河流的稀土元素分异强于中国长江、黄河和鸭绿江, 表现为上陆壳标准化模式上明显的轻稀土相对富集. 不同级别的流域内源岩组成差异是形成这些河流稀土元素组成差异的主要因素. 稀土元素分异参数(La/Yb)_UCC和(Gd/Yb)_UCC, 以及稳定的La/Sc和Th/Sc元素比是识别进入黄海的中韩河流沉积物的可靠指标, 可以用于中国边缘海沉积物物源研究和古环境分析.