全文获取类型
收费全文 | 647篇 |
免费 | 38篇 |
国内免费 | 2篇 |
出版年
2022年 | 2篇 |
2021年 | 14篇 |
2019年 | 3篇 |
2018年 | 14篇 |
2017年 | 6篇 |
2016年 | 11篇 |
2015年 | 21篇 |
2014年 | 21篇 |
2013年 | 39篇 |
2012年 | 59篇 |
2011年 | 46篇 |
2010年 | 27篇 |
2009年 | 29篇 |
2008年 | 51篇 |
2007年 | 39篇 |
2006年 | 43篇 |
2005年 | 36篇 |
2004年 | 27篇 |
2003年 | 31篇 |
2002年 | 33篇 |
2001年 | 11篇 |
2000年 | 7篇 |
1999年 | 4篇 |
1998年 | 8篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 2篇 |
1992年 | 7篇 |
1991年 | 10篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 7篇 |
1987年 | 7篇 |
1986年 | 5篇 |
1984年 | 5篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 5篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 5篇 |
1974年 | 1篇 |
1973年 | 5篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 3篇 |
1967年 | 5篇 |
1964年 | 1篇 |
排序方式: 共有687条查询结果,搜索用时 171 毫秒
51.
52.
Varkondi E Schäfer E Bökönyi G Gyökeres T Orfi L Petak I Pap A Szokoloczi O Keri G Schwab R 《Journal of receptor and signal transduction research》2005,25(1):45-56
Receptor tyrosine kinases (PTKs) play key roles in the pathogenesis of numerous human diseases, including cancer, and therefore PTK inhibitors are currently under intense investigation as potential drug candidates. PTK inhibitor screening data are, however, poorly comparable because of the different assay technologies used. Here we report a comparison of ELISA-based assays for screening epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitory compound libraries to study interassay variations. All assays were based on the same protocol, except for the source of EGFR-TK enzymes. In the first protocol, the enzyme was isolated from A431 cells without affinity purification. In the second protocol, commercial EGFR-TK (Sigma) isolated from A431 cells by affinity-purification was employed. In the third protocol, an enzyme preparation obtained from a recombinant (Baculovirus transfected Sf9 cells) expression system was used. All assays employed the synthetic peptide substrate poly-(Glu,Tyr)l:4 and an ELISA-based system to detect phosphorylated tyrosine residues by a monoclonal antibody. We observed significant differences in both the activity of the enzymes and in the EGFR-TK inhibitory effect of our reference compound PD153035. The differences were significant in case of A431 cell lysate compared to affinity purified EGFR-TKs derived from either A431 cells or Baculovirus transfected Sf9 cells, whereas the latter two showed comparable results. Our data suggest that differences in terms of interassay variation are not related to the source of the enzyme but to its purity; changes in the mode of detection can markedly influence the reproducibility of results. In conclusion, normalization of the EGFR activity used for inhibitor screening and standardization of detection methods enable safe comparison of data. 相似文献
53.
Verma S Nagarathnam D Shao J Zhang L Zhao J Wang Y Li T Mull E Enyedy I Wang C Zhu Q Altieri M Jordan J Dang TT Reddy S 《Bioorganic & medicinal chemistry letters》2005,15(8):1973-1977
A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities. 相似文献
54.
Gu X Li C Wei W Lo V Gong S Li SH Iwasato T Itohara S Li XJ Mody I Heintz N Yang XW 《Neuron》2005,46(3):433-444
Expanded polyglutamine (polyQ) proteins in Huntington's disease (HD) as well as other polyQ disorders are known to elicit a variety of intracellular toxicities, but it remains unclear whether polyQ proteins can elicit pathological cell-cell interactions which are critical to disease pathogenesis. To test this possibility, we have created conditional HD mice expressing a neuropathogenic form of mutant huntingtin (mhtt-exon1) in discrete neuronal populations. We show that mhtt aggregation is a cell-autonomous process. However, progressive motor deficits and cortical neuropathology are only observed when mhtt expression is in multiple neuronal types, including cortical interneurons, but not when mhtt expression is restricted to cortical pyramidal neurons. We further demonstrate an early deficit in cortical inhibition, suggesting that pathological interactions between interneurons and pyramidal neurons may contribute to the cortical manifestation of HD. Our study provides genetic evidence that pathological cell-cell interactions elicited by neuropathogenic forms of mhtt can critically contribute to cortical pathogenesis in a HD mouse model. 相似文献
55.
Role of CDK/cyclin complexes in transcription and RNA splicing 总被引:10,自引:0,他引:10
56.
New 1,20-substituted eicosanes carrying phosphate headgroups and readily derivatizable thiol, maleimido, and activated carboxylic ester moieties were prepared. The C20-backbone of these molecules was assembled by a halopolycarbon homologation from 1,8-dichlorooctane and 1,6-dibromohexane. 20-Mercapto- and 20-maleimido-icosylphosphates were synthesized via omega-bromo di-t-butyl protected icosylphosphate while 20-phosphonooxy-icosanoic acid N-hydroxysuccinimidoyl ester was prepared via omega-bromo dibenzyl protected icosylphosphate in multistep syntheses. These molecules can serve as model compounds for studying binding and structural organization on different surfaces with potential applications in the fields of biosensors. 相似文献
57.
Caged-Ca(2+) compounds such as nitrophenyl-EGTA (NP-EGTA) and DM-nitrophen (DMn) are extremely useful in biological research, but their use in live cells is hampered by cytoplasmic [Mg(2+)]. We determined the properties of Ca(2+) release from NP-EGTA and DMn by using Oregon green BAPTA-5N to measure changes in [Ca(2+)] after ultraviolet flash photolysis in vitro, with or without Mg(2+) present. A large fraction (65%) of NP-EGTA, which has a negligible Mg(2+) affinity, uncages with a time constant of 10.3 ms, resulting in relatively slow increases in [Ca(2+)]. Uncaging of DMn is considerably faster, but DMn has a significant affinity for Mg(2+) to complicate the uncaging process. With experimentally determined values for the Ca(2+) and Mg(2+) binding/unbinding rates of DMn and NP-EGTA, we built a mathematical model to assess the utility of NP-EGTA and DMn in rapid Ca(2+)-uncaging experiments in the presence of Mg(2+). We discuss the advantages and disadvantages of using each compound under different conditions. To determine the kinetics of Ca(2+) binding to biologically relevant Ca(2+) buffers, such as Ca(2+)-binding proteins, the use of DMn is preferable even in the presence of Mg(2+). 相似文献
58.
59.
Nathanson KL Kanetsky PA Hawes R Vaughn DJ Letrero R Tucker K Friedlander M Phillips KA Hogg D Jewett MA Lohynska R Daugaard G Richard S Chompret A Bonaïti-Pellié C Heidenreich A Olah E Geczi L Bodrogi I Ormiston WJ Daly PA Oosterhuis JW Gillis AJ Looijenga LH Guilford P Fosså SD Heimdal K Tjulandin SA Liubchenko L Stoll H Weber W Rudd M Huddart R Crockford GP Forman D Oliver DT Einhorn L Weber BL Kramer J McMaster M Greene MH Pike M Cortessis V Chen C Schwartz SM Bishop DT Easton DF 《American journal of human genetics》2005,77(6):1034-1043
Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region—known as the “gr/gr” deletion—has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3–3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5–6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6–5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72–3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT. 相似文献
60.
Botos I Melnikov EE Cherry S Tropea JE Khalatova AG Rasulova F Dauter Z Maurizi MR Rotanova TV Wlodawer A Gustchina A 《The Journal of biological chemistry》2004,279(9):8140-8148
ATP-dependent Lon protease degrades specific short-lived regulatory proteins as well as defective and abnormal proteins in the cell. The crystal structure of the proteolytic domain (P domain) of the Escherichia coli Lon has been solved by single-wavelength anomalous dispersion and refined at 1.75-A resolution. The P domain was obtained by chymotrypsin digestion of the full-length, proteolytically inactive Lon mutant (S679A) or by expression of a recombinant construct encoding only this domain. The P domain has a unique fold and assembles into hexameric rings that likely mimic the oligomerization state of the holoenzyme. The hexamer is dome-shaped, with the six N termini oriented toward the narrower ring surface, which is thus identified as the interface with the ATPase domain in full-length Lon. The catalytic sites lie in a shallow concavity on the wider distal surface of the hexameric ring and are connected to the proximal surface by a narrow axial channel with a diameter of approximately 18 A. Within the active site, the proximity of Lys(722) to the side chain of the mutated Ala(679) and the absence of other potential catalytic side chains establish that Lon employs a Ser(679)-Lys(722) dyad for catalysis. Alignment of the P domain catalytic pocket with those of several Ser-Lys dyad peptide hydrolases provides a model of substrate binding, suggesting that polypeptides are oriented in the Lon active site to allow nucleophilic attack by the serine hydroxyl on the si-face of the peptide bond. 相似文献