全文获取类型
收费全文 | 2871篇 |
免费 | 204篇 |
国内免费 | 2篇 |
出版年
2023年 | 18篇 |
2022年 | 50篇 |
2021年 | 85篇 |
2020年 | 50篇 |
2019年 | 51篇 |
2018年 | 69篇 |
2017年 | 76篇 |
2016年 | 93篇 |
2015年 | 114篇 |
2014年 | 158篇 |
2013年 | 219篇 |
2012年 | 247篇 |
2011年 | 210篇 |
2010年 | 148篇 |
2009年 | 117篇 |
2008年 | 125篇 |
2007年 | 128篇 |
2006年 | 119篇 |
2005年 | 126篇 |
2004年 | 97篇 |
2003年 | 79篇 |
2002年 | 76篇 |
2001年 | 48篇 |
2000年 | 40篇 |
1999年 | 33篇 |
1998年 | 23篇 |
1997年 | 12篇 |
1996年 | 18篇 |
1994年 | 13篇 |
1993年 | 11篇 |
1992年 | 26篇 |
1991年 | 20篇 |
1990年 | 24篇 |
1989年 | 20篇 |
1988年 | 26篇 |
1987年 | 16篇 |
1986年 | 23篇 |
1985年 | 15篇 |
1984年 | 16篇 |
1983年 | 16篇 |
1982年 | 16篇 |
1981年 | 11篇 |
1980年 | 15篇 |
1979年 | 20篇 |
1978年 | 18篇 |
1977年 | 14篇 |
1976年 | 14篇 |
1975年 | 14篇 |
1973年 | 13篇 |
1972年 | 13篇 |
排序方式: 共有3077条查询结果,搜索用时 421 毫秒
1.
2.
Miguel R. Lugo Ravikiran Ravulapalli Debajyoti Dutta 《Journal of biomolecular structure & dynamics》2016,34(12):2537-2560
C3larvin toxin is a new member of the C3 class of the mono-ADP-ribosyltransferase toxin family. The C3 toxins are known to covalently modify small G-proteins, e.g. RhoA, impairing their function, and serving as virulence factors for an offending pathogen. A full-length X-ray structure of C3larvin (2.3 Å) revealed that the characteristic mixed α/β fold consists of a central β-core flanked by two helical regions. Topologically, the protein can be separated into N and C lobes, each formed by a β-sheet and an α-motif, and connected by exposed loops involved in the recognition, binding, and catalysis of the toxin/enzyme, i.e. the ADP-ribosylation turn–turn and phosphate–nicotinamide PN loops. Herein, we provide two new C3larvin X-ray structures and present a systematic study of the toxin dynamics by first analyzing the experimental variability of the X-ray data-set followed by contrasting those results with theoretical predictions based on Elastic Network Models (GNM and ANM). We identify residues that participate in the stability of the N-lobe, putative hinges at loop residues, and energy-favored deformation vectors compatible with conformational changes of the key loops and 3D-subdomains (N/C-lobes), among the X-ray structures. We analyze a larger ensemble of known C3bot1 conformations and conclude that the characteristic ‘crab-claw’ movement may be driven by the main intrinsic modes of motion. Finally, via computational simulations, we identify harmonic and anharmonic fluctuations that might define the C3larvin ‘native state.’ Implications for docking protocols are derived. 相似文献
3.
The Cbl proteins (Cbl, Cbl-b, and Cbl-c) are a highly conserved family of RING finger ubiquitin ligases (E3s) that function as negative regulators of tyrosine kinases in a wide variety of signal transduction pathways. In this study, we identify a new Cbl-c interacting protein, Enigma (PDLIM7). This interaction is specific to Cbl-c as Enigma fails to bind either of its closely related homologues, Cbl and Cbl-b. The binding between Enigma and Cbl-c is mediated through the LIM domains of Enigma as removal of all three LIM domains abrogates this interaction, while only LIM1 is sufficient for binding. Here we show that Cbl-c binds wild-type and MEN2A isoforms of the receptor tyrosine kinase, RET, and that Cbl-c enhances ubiquitination and degradation of activated RET. Enigma blocks Cbl-c-mediated RETMEN2A ubiquitination and degradation. Cbl-c decreased downstream ERK activation by RETMEN2A and co-expression of Enigma blocked the Cbl-c-mediated decrease in ERK activation. Enigma showed no detectable effect on Cbl-c-mediated ubiquitination of activated EGFR suggesting that this effect is specific to RET. Through mapping studies, we show that Cbl-c and Enigma bind RETMEN2A at different residues. However, binding of Enigma to RETMENA prevents Cbl-c recruitment to RETMEN2A. Consistent with these biochemical data, exploratory analyses of breast cancer patients with high expression of RET suggest that high expression of Cbl-c correlates with a good outcome, and high expression of Enigma correlates with a poor outcome. Together, these data demonstrate that Cbl-c can ubiquitinate and downregulate RETMEN2A and implicate Enigma as a positive regulator of RETMEN2A through blocking of Cbl-mediated ubiquitination and degradation. 相似文献
4.
5.
6.
W N Hunter T Brown G Kneale N N Anand D Rabinovich O Kennard 《The Journal of biological chemistry》1987,262(21):9962-9970
The structure of the deoxyoligomer d(C-G-C-G-A-A-T-T-T-G-C-G) was determined at 2.5-A resolution by single crystal x-ray diffraction techniques. The final R factor is 18% with the location of 71 water molecules. The oligomer crystallizes in a B-DNA-type conformation, with two strands interacting to form a dodecamer duplex. The double helix consists of four A X T and six G X C Watson-Crick base pairs and two G X T mismatches. The G X T pairs adopt a "wobble" structure with the thymine projecting into the major groove and the guanine into the minor groove. The mispairs are accommodated in the normal double helix by small adjustments in the conformation of the sugar phosphate backbone. A comparison with the isomorphous parent compound containing only Watson-Crick base pairs shows that any changes in the structure induced by the presence of G X T mispairs are highly localized. The global conformation of the duplex is conserved. The G X T mismatch has already been studied by x-ray techniques in A and Z helices where similar results were found. The geometry of the mispair is essentially identical in all structures so far examined, irrespective of the DNA conformation. The hydration is also similar with solvent molecules bridging the functional groups of the bases via hydrogen bonds. Hydration may be an important factor in stabilizing G X T mismatches. A characteristic of Watson-Crick paired A X T and G X C bases is the pseudo 2-fold symmetry axis in the plane of the base pairs. The G X T wobble base pair is pronouncedly asymmetric. This asymmetry, coupled with the disposition of functional groups in the major and minor grooves, provides a number of features which may contribute to the recognition of the mismatch by repair enzymes. 相似文献
7.
The stability of oligodeoxyribonucleotide duplexes containing degenerate bases. 总被引:2,自引:2,他引:0
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Oligodeoxyribonucleotides containing N4-methoxycytosine (mo4C), N4-methoxy-5-methylcytosine (mo4m5C) and other base-analogues were synthesised and used to compare the stabilities of duplexes containing mo4C.A and mo4C.G base pairs with those containing normal and mismatch pairs. The Tm values and other thermodynamic parameters are recorded. The otherwise identical duplexes containing a mo4C.A and a mo4C.G base pair have closely similar stabilities to each other and to the corresponding duplexes containing normal base pairs, considerably greater than the stabilities of those containing mismatch pairs. Corresponding observations are recorded in dot-blot experiments using M13 cloned DNA carrying an insert complementary to the oligonucleotides; approximate Td values are given. 相似文献
8.
A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. 总被引:82,自引:19,他引:63
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
J Riley R Butler D Ogilvie R Finniear D Jenner S Powell R Anand J C Smith A F Markham 《Nucleic acids research》1990,18(10):2887-2890
The recent development of yeast artificial chromosome (YAC) vectors has provided a system for cloning fragments that are over ten times larger than those that can be cloned in more established systems. We have developed a method for the rapid isolation of terminal sequences from YAC clones. The YAC clone is digested with a range of restriction enzymes, a common linker is ligated to the DNA fragments and terminal sequences are amplified using a vector specific primer and a linker specific primer. Sequence data derived from these terminal specific products can be used to design primers for a further round of screening to isolate overlapping clones. The method also provides a convenient method of generating Sequence Tagged Sites for the mapping of complex genomes. 相似文献
9.
A 3.5 genome equivalent multi access YAC library: construction, characterisation, screening and storage. 总被引:27,自引:11,他引:16
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The construction of a yeast artificial chromosome (YAC) primary gridded library of 35,000 clones from human lymphoblastoid (48,XXXX) cell line DNA is described. The average YAC size is approximately 350kb representing a greater than 3.5 times coverage of the genome. The library is stored at -70 degrees C as gridded clones on nylon filters impregnated with 20% glycerol and as glycerol suspensions of individual clones in microtitre plates providing a prolonged multi-user potential. To date we have used 14 single copy probes to screen this library by colony hybridisation as well as PCR and have isolated between 1 and 5 YAC clones for every probe. 相似文献
10.
The WHI1+ gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog. 总被引:68,自引:16,他引:52
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)
WHI1-1 is a dominant mutation that reduces cell volume by allowing cells to commit to division at abnormally small sizes, shortening the G1 phase of the cell cycle. The gene was cloned, and dosage studies indicated that the normal gene activated commitment to division in a dose-dependent manner, and that the mutant gene had a hyperactive but qualitatively similar function. Mild over-expression of the mutant gene eliminated G1 phase, apparently entirely relaxing the normal G1 size control, but revealing hitherto cryptic controls. Sequence analysis showed that the hyperactivity of the mutant was caused by the loss of the C-terminal third of the wild-type protein. This portion of the protein contained PEST regions, which may be signals for protein degradation. The WHI1 protein had sequence similarity to clam cyclin A, to sea urchin cyclin and to Schizosaccharomyces pombe cdc13, a cyclin homolog. Since cyclins are inducers of mitosis, WHI1 may be a direct regulator of commitment to division. A probable accessory function of the WHI1 activator is to assist recovery from alpha factor arrest; WHI1-1 mutant cells could not be permanently arrested by pheromone, consistent with a hyperactivation of division. 相似文献