全文获取类型
收费全文 | 331篇 |
免费 | 31篇 |
出版年
2022年 | 2篇 |
2021年 | 10篇 |
2020年 | 6篇 |
2019年 | 6篇 |
2018年 | 5篇 |
2017年 | 8篇 |
2016年 | 2篇 |
2015年 | 16篇 |
2014年 | 12篇 |
2013年 | 20篇 |
2012年 | 17篇 |
2011年 | 22篇 |
2010年 | 11篇 |
2009年 | 5篇 |
2008年 | 17篇 |
2007年 | 13篇 |
2006年 | 15篇 |
2005年 | 10篇 |
2004年 | 13篇 |
2003年 | 17篇 |
2002年 | 4篇 |
2001年 | 10篇 |
2000年 | 8篇 |
1999年 | 5篇 |
1997年 | 2篇 |
1994年 | 6篇 |
1993年 | 6篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 9篇 |
1987年 | 10篇 |
1986年 | 6篇 |
1985年 | 4篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 4篇 |
1972年 | 2篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1968年 | 3篇 |
1967年 | 3篇 |
1964年 | 1篇 |
1963年 | 1篇 |
排序方式: 共有362条查询结果,搜索用时 187 毫秒
101.
102.
DNA methylation precedes chromatin modifications under the influence of the strain-specific modifier Ssm1 下载免费PDF全文
Ssm1 is responsible for the mouse strain-specific DNA methylation of the transgene HRD. In adult mice of the C57BL/6 (B6) strain, the transgene is methylated at essentially all CpGs. However, when the transgene is bred into the DBA/2 (D2) strain, it is almost completely unmethylated. Strain-specific methylation arises during differentiation of embryonic stem (ES) cells. Here we show that Ssm1 causes striking chromatin changes during the development of the early embryo in both strains. In undifferentiated ES cells of both strains, the transgene is in a chromatin state between active and inactive. These states are still observed 1 week after beginning ES cell differentiation. However, 4 weeks after initiating differentiation, in B6, the transgene has become heterochromatic, and in D2, the transgene has become euchromatic. HRD is always expressed in D2, but in B6, it is expressed only in early embryos. The transgene is already more methylated in B6 ES cells than in D2 ES cells and becomes increasingly methylated during development in B6, until essentially all CpGs in the critical guanosine phosphoribosyl transferase core are methylated. Clearly, DNA methylation of HRD precedes chromatin compaction and loss of expression, suggesting that the B6 form of Ssm1 interacts with DNA to cause strain-specific methylation that ultimately results in inactive chromatin. 相似文献
103.
104.
105.
Large conductance, voltage- and Ca2+-activated K+ (BK(Ca)) channels regulate blood vessel tone, synaptic transmission, and hearing owing to dual activation by membrane depolarization and intracellular Ca2+. Similar to an archeon Ca2+-activated K+ channel, MthK, each of four alpha subunits of BK(Ca) may contain two cytosolic RCK domains and eight of which may form a gating ring. The structure of the MthK channel suggests that the RCK domains reorient with one another upon Ca2+ binding to change the gating ring conformation and open the activation gate. Here we report that the conformational changes of the NH2 terminus of RCK1 (AC region) modulate BK(Ca) gating. Such modulation depends on Ca2+ occupancy and activation states, but is not directly related to the Ca2+ binding sites. These results demonstrate that AC region is important in the allosteric coupling between Ca2+ binding and channel opening. Thus, the conformational changes of the AC region within each RCK domain is likely to be an important step in addition to the reorientation of RCK domains leading to the opening of the BK(Ca) activation gate. Our observations are consistent with a mechanism for Ca2+-dependent activation of BK(Ca) channels such that the AC region inhibits channel activation when the channel is at the closed state in the absence of Ca2+; Ca2+ binding and depolarization relieve this inhibition. 相似文献
106.
In silico proteomics complements computational genomics in characterizing genome evolution. Here we examine cluster patterns in archaeal and bacterial proteomes using compositional properties of protein sequences in contrast to the traditionally used sequence alignment procedures. Application of standard Principal Component Analysis to the multi-dimensional data identified cluster patterns. Two types of cluster patterns exist in bacterial proteomes. Proteomes of type I have one major cluster with few isolated points in space revealing an underlying largely homogeneous compositional structure. In type II proteomes two clusters of protein distribution were discernible. The two clusters differ in size and were separated from each other although the boundary was somewhat fuzzy. Proteins falling in the major cluster were labeled as 'typical' and proteins of the minor cluster were called 'atypical'. The atypical proteins were mapped to Cluster of Orthologous Groups. Species distribution in COGs maps with respect to atypical proteins illuminated the biological relationships of extreme diversity among the archaeal members and of diversity among bacteria in relation to their niche. Amino acids that were over-represented in the atypical proteins had higher biosynthetic cost compared to 'typical' ribosomal proteins. However, archaea and bacteria economize by preferring the less costly amino acid to others closely related in chemical structure. Further, over-representation of serine in atypical proteins of archaeal members suggests re-examining these proteomes for the presence of Serine/Threonine phosphatases and kinases in Archaea. Our computational procedure can serve as a useful addition to the existing tools for carrying out in silico proteomics. 相似文献
107.
A novel approach to study of the structural basis of enzyme polymorphism. Analysis of carboxylesterase B of Escherichia coli as model. 下载免费PDF全文
In order to understand the structural basis of charge differences among enzyme variants without undertaking purification and sequencing of the protein, an original approach was developed. The approach is applicable to any enzyme or protein provided that there is a specific staining procedure. This consists, as a first step, in the projection of electrophoretically obtained mobility values versus pI of all variants into a two-dimensional profile. In a second step, starting from the most common variant, various theoretical possibilities of substitutions are envisaged, taking into consideration the pH of the electrophoretic conditions, pI of the variants and range of variations of the pK values of several amino acid side chains. In a third step, verification of the theoretical data is obtained through comparative protein titration curves by combined isoelectrofocusing-electrophoresis of several pairs of relevant variants. The validity of this approach is tested on the highly polymorphic carboxylesterase B enzyme of Escherichia coli and is found to provide valuable information. 相似文献
108.
Cochlear blood flow regulation is important to prevent hearing loss caused by ischemia and oxidative stress. Cochlear blood supply is provided by the spiral modiolar artery (SMA). The myogenic tone of the SMA is enhanced by the nitric oxide synthase (NOS) blocker L-NG-Nitro-Arginine (LNNA) in males, but not in females. Here, we investigated whether this gender difference is based on differences in the cytosolic Ca2+ concentration and/or the Ca2+ sensitivity of the myofilaments. Vascular diameter, myogenic tone, cytosolic Ca2+, and Ca2+ sensitivity were evaluated in pressurized SMA segments isolated from male and female gerbils using laser-scanning microscopy and microfluorometry. The gender difference of the LNNA-induced tone was compared, in the same vessel segments, to tone induced by 150 mM K+ and endothelin-1, neither of which showed an apparent gender-difference. Interestingly, LNNA-induced tone in male SMAs was observed in protocols that included changes in intramural pressure, but not when the intramural pressure was held constant. LNNA in male SMAs did not increase the global Ca2+ concentration in smooth muscle cells but increased the Ca2+ sensitivity. This increase in the Ca2+ sensitivity was abolished in the presence of the guanylyl cyclase inhibitor ODQ or by extrinsic application of either the nitric oxide (NO)-donor DEA-NONOate or the cGMP analog 8-pCPT-cGMP. The rho-kinase blocker Y27632 decreased the basal Ca2+ sensitivity and abolished the LNNA-induced increase in Ca2+ sensitivity in male SMAs. Neither LNNA nor Y27632 changed the Ca2+ sensitivity in female SMAs. The data suggest that the gender difference in LNNA-induced tone is based on a gender difference in the regulation of rho-kinase mediated Ca2+ sensitivity. Rho-kinase and NO thus emerge as critical factors in the regulation of cochlear blood flow. The larger role of NO-dependent mechanisms in male SMAs predicts greater restrictions on cochlear blood flow under conditions of impaired endothelial cell function. 相似文献
109.
110.