全文获取类型
收费全文 | 1171篇 |
免费 | 145篇 |
出版年
2021年 | 18篇 |
2019年 | 16篇 |
2018年 | 16篇 |
2017年 | 19篇 |
2016年 | 19篇 |
2015年 | 48篇 |
2014年 | 51篇 |
2013年 | 60篇 |
2012年 | 66篇 |
2011年 | 63篇 |
2010年 | 42篇 |
2009年 | 34篇 |
2008年 | 46篇 |
2007年 | 59篇 |
2006年 | 52篇 |
2005年 | 67篇 |
2004年 | 60篇 |
2003年 | 53篇 |
2002年 | 35篇 |
2001年 | 23篇 |
2000年 | 18篇 |
1999年 | 16篇 |
1998年 | 20篇 |
1997年 | 20篇 |
1996年 | 12篇 |
1995年 | 12篇 |
1993年 | 12篇 |
1992年 | 14篇 |
1991年 | 10篇 |
1990年 | 14篇 |
1989年 | 8篇 |
1988年 | 17篇 |
1987年 | 17篇 |
1986年 | 9篇 |
1985年 | 10篇 |
1984年 | 12篇 |
1983年 | 21篇 |
1982年 | 12篇 |
1981年 | 11篇 |
1980年 | 15篇 |
1979年 | 8篇 |
1978年 | 7篇 |
1977年 | 9篇 |
1976年 | 9篇 |
1975年 | 11篇 |
1973年 | 11篇 |
1972年 | 9篇 |
1971年 | 7篇 |
1969年 | 12篇 |
1964年 | 7篇 |
排序方式: 共有1316条查询结果,搜索用时 15 毫秒
991.
Prashanthi Menon Guoyong Yin Elaine M. Smolock Michael J. Zuscik Chen Yan Bradford C. Berk 《Journal of cellular physiology》2010,225(3):777-785
G‐protein‐coupled receptor (GPCR) kinase 2 interacting protein‐1 (GIT1) is a scaffold protein expressed in various cell types including neurons, endothelial, and vascular smooth muscle cells. The GIT1 knockout (KO) mouse has a pulmonary phenotype due to impaired endothelial function. Because GIT1 is tyrosine phosphorylated by Src kinase, we anticipated that GIT1 KO should have a bone phenotype similar to Src KO. Microcomputed tomography of the long bones revealed that GIT1 KO mice have a 2.3‐fold increase in bone mass compared to wild‐type controls. Histomorphometry showed increased trabecular number and connectivity suggesting impaired bone remodeling. Immunoblot analysis of GIT1 expression showed that it was expressed in both osteoclasts and osteoblasts. Osteoblast activity and function assayed by alkaline phosphatase, mineral nodule formation, and in vivo calcein labeling were normal in GIT1 KO mice suggesting that the observed increase in bone mass was due to an osteoclast defect. GIT1 KO bone marrow cells differentiated into multinucleated osteoclasts, but had defective bone resorbing function on dentin slices. This defect was likely caused by loss of podosome belt based on immunofluorescence analysis and previous studies showing that GIT1 is required for podosome formation. Furthermore, we found that GIT1 was a regulator of receptor activator of NFκB (RANK) signaling since it was tyrosine phosphorylated in a Src‐dependent manner and was required for phospholipase C‐γ2 phosphorylation. These data show that GIT1 is a key regulator of bone mass in vivo by regulating osteoclast function and suggest GIT1 as a potential target for osteoporosis therapy. J. Cell. Physiol. 225: 777–785, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
992.
Harlan N. Bradford Joseph A. Micucci Sriram Krishnaswamy 《The Journal of biological chemistry》2010,285(1):328-338
Prothrombinase converts prothrombin to thrombin via cleavage at Arg320
followed by cleavage at Arg271. Exosite-dependent binding of
prothrombin to prothrombinase facilitates active site docking by
Arg320 and initial cleavage at this site. Precise positioning of the
Arg320 site for cleavage is implied by essentially normal
cleavage at Arg320 in recombinant prothrombin variants bearing
additional Arg side chains either one or two residues away. However, mutation of
Arg320 to Gln reveals that prothrombinase can cleave prothrombin
following Arg side chains shifted by as many as two residues N-terminal to the
320 position at near normal rates. Further repositioning leads to a loss in
cleavage at this region with an abrupt shift toward slow cleavage at
Arg271. In contrast, the binding constant for the active site docking
step is strongly dependent on the sequence preceding the scissile bond as well
as position. Large effects on binding only yield minor changes in rate until the
binding constant passes a threshold value. This behavior is expected for a
substrate that can engage the enzyme through mutually exclusive active site
docking reactions followed by cleavage to yield different products. Cleavage
site specificity as well as the ordered action of prothrombinase on its compound
substrate is regulated by the thermodynamics of active site engagement of the
individual sites as well as competition between alternate cleavage sites for
active site docking. 相似文献
993.
Identification and sequence of a tet(M) tetracycline resistance determinant homologue in clinical isolates of Escherichia coli 总被引:3,自引:0,他引:3
下载免费PDF全文
![点击此处可从《Journal of bacteriology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The presence of the tetracycline resistance determinant tet(M) in human clinical isolates of Escherichia coli is described for the first time in this report. The homologue was >99% identical to the tet(M) genes reported to occur in Lactobacillus plantarum, Neisseria meningitidis, and Streptococcus agalactiae, and 3% of the residues in its deduced amino acid sequence diverge from tet(M) of Staphylococcus aureus. Sequence analysis of the regions immediately flanking the gene revealed that sequences upstream of tet(M) in E. coli have homology to Tn916; however, a complete IS26 insertion element was present immediately upstream of the promoter element. Downstream from the termination codon is an insertion sequence that was homologous to the ISVs1 element reported to occur in a plasmid from Vibrio salmonicida that has been associated with another tetracycline resistance determinant, tet(E). Results of mating experiments demonstrated that the E. coli tet(M) gene was on a mobile element so that resistance to tetracycline and minocycline could be transferred to a susceptible strain by conjugation. Expression of the cloned tet(M) gene, under the control of its own promoter, provided tetracycline and minocycline resistance to the E. coli host. 相似文献
994.
Nadauld LD Phelps R Moore BC Eisinger A Sandoval IT Chidester S Peterson PW Manos EJ Sklow B Burt RW Jones DA 《The Journal of biological chemistry》2006,281(49):37828-37835
995.
Identifying the interface between two interacting proteins provides important clues to the function of a protein, and is becoming increasing relevant to drug discovery. Here, surface patch analysis was combined with a Bayesian network to predict protein-protein binding sites with a success rate of 82% on a benchmark dataset of 180 proteins, improving by 6% on previous work and well above the 36% that would be achieved by a random method. A comparable success rate was achieved even when evolutionary information was missing, a further improvement on our previous method which was unable to handle incomplete data automatically. In a case study of the Mog1p family, we showed that our Bayesian network method can aid the prediction of previously uncharacterised binding sites and provide important clues to protein function. On Mog1p itself a putative binding site involved in the SLN1-SKN7 signal transduction pathway was detected, as was a Ran binding site, previously characterized solely by conservation studies, even though our automated method operated without using homologous proteins. On the remaining members of the family (two structural genomics targets, and a protein involved in the photosystem II complex in higher plants) we identified novel binding sites with little correspondence to those on Mog1p. These results suggest that members of the Mog1p family bind to different proteins and probably have different functions despite sharing the same overall fold. We also demonstrated the applicability of our method to drug discovery efforts by successfully locating a number of binding sites involved in the protein-protein interaction network of papilloma virus infection. In a separate study, we attempted to distinguish between the two types of binding site, obligate and non-obligate, within our dataset using a second Bayesian network. This proved difficult although some separation was achieved on the basis of patch size, electrostatic potential and conservation. Such was the similarity between the two interacting patch types, we were able to use obligate binding site properties to predict the location of non-obligate binding sites and vice versa. 相似文献
996.
Development and growth of parasites depend on resources provided by the host and the parasite's ability to use them. Identifying specific costs incurred by the host provides insight for assessment of parasite energy budgets, which differ among taxa and ontogenetic stages. Data from this study were analyzed using an accelerated failure-time model with intensity as a covariate. Results indicated significantly reduced survival of amphipods, Hyalella azteca, infected with the acanthocephalan Corynosoma constrictum compared with uninfected controls. Male and female amphipod survivorship and infection intensity did not differ; however, amphipods with high-intensity infections (> 16 larvae) died earlier compared with amphipods with low-intensity infections (< 3 larvae). The majority of infected amphipods died between 12 and 24 days postexposure, a period of rapid larval development. It is hypothesized that host death may be due either to an increase in overall larval nutritional demands or to parasite-mediated depletion of a specific host substance. Results from this study suggest that developing C. constrictum satisfies energy requirements by depriving amphipod hosts of resources normally used for somatic growth and maintenance. 相似文献
997.
998.
999.
Yibin Xiang Gary Asmussen Michael Booker Bradford Hirth John L. Kane Junkai Liao Kevin D. Noson Christopher Yee 《Bioorganic & medicinal chemistry letters》2009,19(21):6119-6121
Sphingosine kinase 1 (SK1) is an important enzyme that regulates the balance between ceramide and sphingosine-1-phosphate (S1P). Potent and novel SK1 inhibitors (6ag, 9ab and 12aa) have been discovered through a series of modifications of sphingosine (1), the substrate of this enzyme. 相似文献
1000.