全文获取类型
收费全文 | 264篇 |
免费 | 30篇 |
出版年
2023年 | 1篇 |
2021年 | 4篇 |
2020年 | 2篇 |
2019年 | 4篇 |
2018年 | 5篇 |
2017年 | 7篇 |
2016年 | 6篇 |
2015年 | 10篇 |
2014年 | 9篇 |
2013年 | 17篇 |
2012年 | 23篇 |
2011年 | 26篇 |
2010年 | 12篇 |
2009年 | 17篇 |
2008年 | 20篇 |
2007年 | 9篇 |
2006年 | 21篇 |
2005年 | 21篇 |
2004年 | 17篇 |
2003年 | 14篇 |
2002年 | 10篇 |
2001年 | 3篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1998年 | 5篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1990年 | 1篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1969年 | 4篇 |
1968年 | 1篇 |
1966年 | 2篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1963年 | 1篇 |
1961年 | 2篇 |
1955年 | 1篇 |
排序方式: 共有294条查询结果,搜索用时 46 毫秒
1.
Dual Cyclin-Binding Domains Are Required for p107 To Function as a Kinase Inhibitor 总被引:11,自引:6,他引:5 下载免费PDF全文
Enrique Castao Yelena Kleyner Brian David Dynlacht 《Molecular and cellular biology》1998,18(9):5380-5391
The retinoblastoma (pRB) family of proteins includes three proteins known to suppress growth of mammalian cells. Previously we had found that growth suppression by two of these proteins, p107 and p130, could result from the inhibition of associated cyclin-dependent kinases (cdks). One important unresolved issue, however, is the mechanism through which inhibition occurs. Here we present in vivo and in vitro evidence to suggest that p107 is a bona fide inhibitor of both cyclin A-cdk2 and cyclin E-cdk2 that exhibits an inhibitory constant (Ki) comparable to that of the cdk inhibitor p21/WAF1. In contrast, pRB is unable to inhibit cdks. Further reminiscent of p21, a second cyclin-binding site was mapped to the amino-terminal portions of p107 and p130. This amino-terminal domain is capable of inhibiting cyclin-cdk2 complexes, although it is not a potent substrate for these kinases. In contrast, a carboxy-terminal fragment of p107 that contains the previously identified cyclin-binding domain serves as an excellent kinase substrate although it is unable to inhibit either kinase. Clustered point mutations suggest that the amino-terminal domain is functionally important for cyclin binding and growth suppression. Moreover, peptides spanning the cyclin-binding region are capable of interfering with p107 binding to cyclin-cdk2 complexes and kinase inhibition. Our ability to distinguish between p107 and p130 as inhibitors rather than simple substrates suggests that these proteins may represent true inhibitors of cdks. 相似文献
2.
3.
F A Beemer J M van Doorne R J Gorlin J M Klep-de Pater 《Journal of craniofacial genetics and developmental biology》1984,4(3):233-241
Roentgencephalometric anomalies in three cases of Warkany syndrome (trisomy 8 mosaicism) are described. These include asymmetry of the mandible with a wide gonial angle and a high and narrow symphysis; SNA (anteroposterior position of maxilla) and SNB (anteroposterior position of mandible) values indicate a backward position of the mandible. Other findings point to a disturbance in the vertical growth of the facial skeleton. These measurements may explain at least part of the facial phenotype and may aid in diagnosis, especially in those cases with an uncertain clinical diagnosis and "normal" karyotype in peripheral blood lymphocytes. 相似文献
4.
Yelena Katsenovich Denny Carvajal Rakesh Guduru Leonel Lagos Chen-Zhong Li 《Geomicrobiology journal》2013,30(2):120-130
Production of nuclear fuel has resulted in hazardous waste streams that have contaminated the soil and groundwater. Arthrobacter strains, G975, G968, and G954 were used in the prescreening tests to evaluate their tolerance to UO2 2+ and investigate bacteria-U(VI) interactions under oxidizing pH-neutral conditions. Experiments have shown G975 is the fastest growing and the most uranium tolerant strain that removed about 90% of uranium from growth media. Atomic Force Microscopy images exhibited an irregular surface structure, which perhaps provided a larger surface area for uranium precipitation. The data indicate that aerobic heterotrophic bacteria may offer a solution to sequestering uranium in oxic conditions, which prevail in the vadose zone. 相似文献
5.
Polyanionic candidate microbicides, including cellulose sulfate, carrageenan, PRO 2000, were proven ineffective in preventing HIV-1 transmission and even cellulose sulfate showed increased risk of HIV acquisition in the Phase III efficacy trials. Semen plays critical roles in HIV-1 sexual transmission. Specifically, amyloid fibrils formed by fragments of prostatic acidic phosphatase (PAP) in semen termed semen-derived enhancer of virus infection (SEVI) could drastically enhance HIV-1 infection. Here we investigated the interaction between polyanions and PAP248-286, a prototype peptide of SEVI, to understand the possible cause of polyanionic candidate microbicides to fail in clinical trials. We found anionic polymers could efficiently promote SEVI fibril formation, most likely mediated by the natural electrostatic interaction between polyanions and PAP248-286, as revealed by acid native PAGE and Western blot. The overall anti-HIV-1 activity of polyanions in the presence or absence of PAP248-286 or semen was evaluated. In the viral infection assay, the supernatants of polyanions/PAP248-286 or polyanions/semen mixtures containing the free, unbound polyanionic molecules showed a general reduction in antiviral efficacy, while the pellets containing amyloid fibrils formed by the polyanion-bound PAP248-286 showed aggravated enhancement of viral infection. Collectively, from the point of drug-host protein interaction, our study revealed that polyanions facilitate SEVI fibril formation to promote HIV-1 infection, thus highlighting a molecular mechanism underlying the failure of polyanions in clinical trials and the importance of drug-semen interaction in evaluating the anti-HIV-1 efficacy of candidate microbicides. 相似文献
6.
7.
Saranna Fanning Aftabul Haque Thibaut Imberdis Valeriya Baru M. Inmaculada Barrasa Silke Nuber Daniel Termine Nagendran Ramalingam Gary P.H. Ho Tallie Noble Jackson Sandoe Yali Lou Dirk Landgraf Yelena Freyzon Gregory Newby Frank Soldner Elizabeth Terry-Kantor Tae-Eun Kim Dennis Selkoe 《Molecular cell》2019,73(5):1001-1014.e8
8.
The Escherichia coli chaperonin GroEL is a complex of identical subunit proteins (57 kDa each) arranged in a back-to-back stacking of two heptameric rings. Its hallmarks include nested positive intra-ring and negative inter-ring cooperativity in adenosine trisphosphate (ATP) binding and the ability to mediate the folding of newly transcribed and/or denatured substrate proteins. We performed unbiased molecular dynamics simulations of the GroEL subunit protein in explicit water both with and without the nucleotide KMgATP to understand better the details of the structural transitions that enable these behaviors. Placing KMgATP in the equatorial domain binding pocket of a t state subunit, which corresponds to a low ATP-affinity state, produced a short-lived (6 ns) state that spontaneously transitioned to the high ATP-affinity r state. The important feature of this transition is a large-scale rotation of the intermediate domain's helix M to close the ATP binding pocket. Pivoting of helix M is accompanied by counterclockwise rotation and slight deformation of the apical domain, important for lowering the affinity for substrate protein. Aligning simulation conformations into model heptamer rings demonstrates that the t-->r transition in one subunit is not sterically hindered by t state neighbors, but requires breakage of Arg(197)-Glu(386) intersubunit salt bridges, which are important for inter-ring positive cooperativity. Lowest-frequency quasi-harmonic modes of vibration computed pre- and post-transition clearly show that natural vibrations facilitate the transition. Finally, we propose a novel mechanism for inter-ring cooperativity in ATP binding inspired by the observation of spontaneous insertion of the side chain of Ala(480) into the empty nucleotide pocket. 相似文献
9.
Kung Ban Sandra Duffy Yelena Khakham Vicky M. Avery Andrew Hughes Oliver Montagnat Kasiram Katneni Eileen Ryan Jonathan B. Baell 《Bioorganic & medicinal chemistry letters》2010,20(20):6024-6029
We report on the discovery of 3-alkylthio-1,2,4-triazine dimers that are potently toxic to Plasmodium falciparum, with single digit nanomolar activity, and up to several thousand-fold lower toxicity to mammalian cells. They are equipotent against chloroquine-resistant strains of P. falciparum. 相似文献
10.
Chromosomal study in patients with cysts of the jaw,multiple nevoid basal cell carcinomata and bifid rib syndrome 总被引:7,自引:0,他引:7
Summary A chromosomal abnormality in a patient with cysts of the jaw, recurrent nevoid basal cell carcinomata and bifid ribs is described. The patient presented a normal female complement, except for the unusual length of one arm of one of the chromosomes No. 1. Her mother, two sisters, and a male child of one of these two sisters presented a similar chromosomal anomaly with no expression of the syndrome. Several possible explanations are discussed.Supported (in part) by a Public Health Service training grant (number 2G-628 PATC) from the Division of General Medical Sciences, and (in part) by a research grant (number E 798) from the National Institute of Allergy and Infectious Diseases. 相似文献