全文获取类型
收费全文 | 3112篇 |
免费 | 210篇 |
出版年
2023年 | 9篇 |
2022年 | 15篇 |
2021年 | 43篇 |
2020年 | 24篇 |
2019年 | 29篇 |
2018年 | 47篇 |
2017年 | 57篇 |
2016年 | 78篇 |
2015年 | 119篇 |
2014年 | 131篇 |
2013年 | 203篇 |
2012年 | 184篇 |
2011年 | 173篇 |
2010年 | 121篇 |
2009年 | 123篇 |
2008年 | 193篇 |
2007年 | 196篇 |
2006年 | 165篇 |
2005年 | 141篇 |
2004年 | 149篇 |
2003年 | 138篇 |
2002年 | 143篇 |
2001年 | 89篇 |
2000年 | 66篇 |
1999年 | 67篇 |
1998年 | 29篇 |
1997年 | 26篇 |
1996年 | 21篇 |
1995年 | 23篇 |
1994年 | 26篇 |
1993年 | 23篇 |
1992年 | 44篇 |
1991年 | 41篇 |
1990年 | 40篇 |
1989年 | 33篇 |
1988年 | 34篇 |
1987年 | 27篇 |
1986年 | 27篇 |
1985年 | 30篇 |
1984年 | 26篇 |
1983年 | 20篇 |
1982年 | 10篇 |
1981年 | 10篇 |
1980年 | 11篇 |
1979年 | 24篇 |
1977年 | 14篇 |
1976年 | 11篇 |
1975年 | 9篇 |
1973年 | 10篇 |
1966年 | 6篇 |
排序方式: 共有3322条查询结果,搜索用时 125 毫秒
981.
The polarity-inducing kinase Par-1 controls Xenopus gastrulation in cooperation with 14-3-3 and aPKC
Par (partitioning-defective) genes were originally identified in Caenorhabditis elegans as determinants of anterior/posterior polarity. However, neither their function in vertebrate development nor their action mechanism has been fully addressed. Here we show that two members of Par proteins, 14-3-3 (Par-5) and atypical PKC (aPKC), regulate the serine/threonine kinase Par-1 to control Xenopus gastrulation. We find first that Xenopus Par-1 (xPar-1) is essential for gastrulation but not for cell fate specification during early embryonic development. We then find that xPar-1 binds to 14-3-3 in an aPKC-dependent manner. Our analyses identify two aPKC phosphorylation sites in xPar-1, which are essential for 14-3-3 binding and for proper gastrulation movements. The aPKC phosphorylation-dependent binding of xPar-1 to 14-3-3 does not markedly affect the kinase activity of xPar-1, but induces relocation of xPar-1 from the plasma membranes to the cytoplasm. Finally, we show that Xenopus aPKC and its binding partner Xenopus Par-6 are also essential for gastrulation. Thus, our results identify a requirement of Par proteins for Xenopus gastrulation and reveal a novel interrelationship within Par proteins that may provide a general mechanism for spatial control of Par-1. 相似文献
982.
Negative feedback loop in T-cell activation through MAPK-catalyzed threonine phosphorylation of LAT 总被引:5,自引:0,他引:5
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Matsuda S Miwa Y Hirata Y Minowa A Tanaka J Nishida E Koyasu S 《The EMBO journal》2004,23(13):2577-2585
Mitogen-activated protein kinase (MAPK) cascades are involved in a variety of cellular responses including proliferation, differentiation, and apoptosis. We have developed an expression screening method to detect in vivo substrates of MAPKs in mammalian cells, and identified a membrane protein, linker for activation of T cells (LAT), as an MAPK target. LAT, an adapter protein essential for T-cell signaling, is phosphorylated at its Thr 155 by ERK in response to T-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of LAT to recruit PLCgamma1 and SLP76, leading to attenuation of subsequent downstream events such as [Ca2+]i mobilization and activation of the ERK pathway. Our data reveal a new role for MAPKs in a negative feedback loop in T-cell activation via threonine phosphorylation of LAT. 相似文献
983.
Asano T Yoshioka Y Kurei S Sakamoto W Machida Y;Sodmergen 《The Plant journal : for cell and molecular biology》2004,38(3):448-459
We identified a novel mutation of a nuclear-encoded gene, designated as CRUMPLED LEAF (CRL), of Arabidopsis thaliana that affects the morphogenesis of all plant organs and division of plastids. Histological analysis revealed that planes of cell division were distorted in shoot apical meristems (SAMs), root tips, and embryos in plants that possess the crl mutation. Furthermore, we observed that differentiation patterns of cortex and endodermis cells in inflorescence stems and root endodermis cells were disturbed in the crl mutant. These results suggest that morphological abnormalities observed in the crl mutant were because of aberrant cell division and differentiation. In addition, cells of the crl mutant contained a reduced number of enlarged plastids, indicating that the division of plastids was inhibited in the crl. The CRL gene encodes a novel protein with a molecular mass of 30 kDa that is localized in the plastid envelope. The CRL protein is conserved in various plant species, including a fern, and in cyanobacteria, but not in other organisms. These data suggest that the CRL protein is required for plastid division, and it also plays an important role in cell differentiation and the regulation of the cell division plane in plants. A possible function of the CRL protein is discussed. 相似文献
984.
985.
CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Cdc37 is a kinase-associated molecular chaperone whose function in concert with Hsp90 is essential for many signaling protein kinases. Here, we report that mammalian Cdc37 is a pivotal substrate of CK2 (casein kinase II). Purified Cdc37 was phosphorylated in vitro on a conserved serine residue, Ser13, by CK2. Moreover, Ser13 was the unique phosphorylation site of Cdc37 in vivo. Crucially, the CK2 phosphorylation of Cdc37 on Ser13 was essential for the optimal binding activity of Cdc37 toward various kinases examined, including Raf1, Akt, Aurora-B, Cdk4, Src, MOK, MAK, and MRK. In addition, nonphosphorylatable mutants of Cdc37 significantly suppressed the association of Hsp90 with protein kinases, while the Hsp90-binding activity of the mutants was unchanged. The treatment of cells with a specific CK2 inhibitor suppressed the phosphorylation of Cdc37 in vivo and reduced the levels of Cdc37 target kinases. These results unveil a regulatory mechanism of Cdc37, identify a novel molecular link between CK2 and many crucial protein kinases via Cdc37, and reveal the molecular basis for the ability of CK2 to regulate pleiotropic cellular functions. 相似文献
986.
987.
Saito S Takahashi-Sasaki N Araki W 《Biochemical and biophysical research communications》2005,330(4):1068-1072
APH-1 is one of the four essential components of the presenilin-gamma-secretase complex and has two human homologs, APH-1a, and APH-1b, both of which are seven-pass membrane proteins. Here, we identified a novel splice variant of human APH-1b. This variant lacks exon 4, which encodes the entire fourth transmembrane domain. The mRNA expression of this variant was detected in most tissues at low levels. In transiently transfected cells, protein expression of the APH-1b variant was much lower than that of the wild-type. Furthermore, exogenous expression of the APH-1-interacting protein, nicastrin, significantly increased the variant protein levels. These data suggest that the APH-1b variant protein is destabilized, and implies that the fourth transmembrane domain plays an important role in the protein stability and function of APH-1. 相似文献
988.
989.
Mori S Yamasaki M Maruyama Y Momma K Kawai S Hashimoto W Mikami B Murata K 《Biochemical and biophysical research communications》2005,327(2):500-508
NAD kinase is a key enzyme in NADP biosynthesis. We solved the crystal structure of polyphosphate/ATP-NAD kinase from Mycobacterium tuberculosis (Ppnk) complexed with NAD (Ppnk-NAD) at 2.6A resolution using apo-Ppnk structure solved in this work, and revealed the details of the structure and NAD-binding site. Superimposition of tertiary structures of apo-Ppnk and Ppnk-NAD demonstrated a substantial conformational difference in a loop (Ppnk-flexible loop). As a quaternary structure, these Ppnk structures exhibited tetramer as in solution condition. Notably, the Ppnk-flexible loop was involved in the intersubunit contact and probably related to the NAD-binding of the other subunit. Furthermore, the two residues (Asp189, His226) substantially contributed to creating NAD-binding site on the other subunit. The two residues and the residues involved in NAD-binding were conserved. However, residues corresponding to the Ppnk-flexible loop were not conserved, making us to speculate that the Ppnk-flexible loop may be Ppnk-specific. 相似文献
990.
Control of MAP kinase signaling to the nucleus 总被引:11,自引:0,他引:11
MAP kinase (MAPK) signaling is among central signaling pathways that regulate cell proliferation, cell differentiation and apoptosis. As MAPK should transmit extracellular signals to proper regions or compartments in cells, controlling subcellular localization of MAPK is important for regulating fidelity and specificity of MAPK signaling. The ERK1/2-type of MAPK is the best characterized member of the MAPK family. In response to extracellular stimulus, ERK1/2 translocates from the cytoplasm to the nucleus by passing through the nuclear pore by several independent mechanisms. Sef (similar expression to fgf genes), a transmembrane protein, has been shown to be a regulator of subcellular distribution of ERK1/2. Sef binds to activated MEK1/2, the specific activator of ERK1/2, and tethers the activated MEK1/2/activated ERK1/2 complex to the Golgi apparatus and the plasma membrane. Thus, Sef blocks ERK1/2 signaling to the nucleus and allows signaling to the cytoplasm. Here we review recent findings on spatial regulation of MAPK, especially on nucleocytoplasmic trafficking of ERK1/2. 相似文献