全文获取类型
收费全文 | 137788篇 |
免费 | 7991篇 |
国内免费 | 8107篇 |
出版年
2023年 | 1420篇 |
2022年 | 1777篇 |
2021年 | 3619篇 |
2020年 | 2820篇 |
2019年 | 3688篇 |
2018年 | 3293篇 |
2017年 | 2612篇 |
2016年 | 3481篇 |
2015年 | 5782篇 |
2014年 | 9351篇 |
2013年 | 10621篇 |
2012年 | 7111篇 |
2011年 | 8499篇 |
2010年 | 6426篇 |
2009年 | 6894篇 |
2008年 | 7334篇 |
2007年 | 7615篇 |
2006年 | 6231篇 |
2005年 | 5847篇 |
2004年 | 4831篇 |
2003年 | 4356篇 |
2002年 | 3945篇 |
2001年 | 2771篇 |
2000年 | 2357篇 |
1999年 | 2431篇 |
1998年 | 2230篇 |
1997年 | 1837篇 |
1996年 | 1706篇 |
1995年 | 2098篇 |
1994年 | 1952篇 |
1993年 | 1786篇 |
1992年 | 1618篇 |
1991年 | 1346篇 |
1990年 | 1100篇 |
1989年 | 1065篇 |
1988年 | 1084篇 |
1987年 | 913篇 |
1986年 | 765篇 |
1985年 | 1018篇 |
1984年 | 1439篇 |
1983年 | 936篇 |
1982年 | 1094篇 |
1981年 | 936篇 |
1980年 | 732篇 |
1979年 | 679篇 |
1978年 | 442篇 |
1977年 | 399篇 |
1976年 | 383篇 |
1974年 | 251篇 |
1973年 | 258篇 |
排序方式: 共有10000条查询结果,搜索用时 62 毫秒
21.
Purification and partial characterization of an iron regulated outer membrane protein of B. fragilis under non-denaturing conditions 总被引:2,自引:0,他引:2
The CHAPS-PAGE gelsystem we applied gave a good separation of the proteins of Bacteroides fragilis under non-denaturing conditions. We succeeded with preparative CHAPS-PAGE in purifying an iron regulated outer membrane protein (a 44 kDa polypeptide on SDS-PAGE) of B. fragilis. This integral membrane protein proved to be a lipopolysaccharide binding protein with an isoelectric point of approximately pH 5.5. This method of purifying membrane proteins could be an important step in research into the function of membrane proteins. 相似文献
22.
23.
24.
Four series of para or meta - substituted thiazolylbenzenesulfonamides bearing Cl substituents were designed, synthesized, and evaluated as inhibitors of all 12 catalytically active recombinant human carbonic anhydrase (CA) isoforms. Observed affinities were determined by the fluorescent thermal shift assay and the intrinsic affinities were calculated based on the fractions of binding-ready deprotonated sulfonamide and CA bearing protonated hydroxide bound to the catalytic Zn(II) in the active site. Several compounds exhibited selectivity towards CA IX, an anticancer target. Intrinsic affinities reached 30 pM, while the observed affinities - 70 nM. The structure-intrinsic affinity relationship map of the compounds showed the energetic contributions of the thiazole ring and its substituents. 相似文献
25.
The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549. 相似文献
26.
建立一种靶点蛋白质快速定量检测方法。在原有侧向流动免疫层析技术的基础上,通过优化层析材料和纳米微球的均一性、改进检测区的检测方法,经逐点扫描技术,建立标准浓度曲线,以达到对临床靶点蛋白质的定量检测。以乳腺癌组织中的Her2表达为例,通过对已知浓度样品的检测,验证本技术方法的准确度大于96%。另外,以蛋白质免疫印迹作为组织中特定蛋白质检测金标准,分析临床肿瘤组织中Her2蛋白的含量,其准确率也达到95.5%,而免疫组织化学方法检测准确率仅为69.58%。新型免疫层析法检测结果与靶向治疗患者的愈后密切相关(P<0.01)。改进后的新型免疫层析方法能够准确地对临床靶点蛋白质进行定量检测,而且结合侧向流动技术的简单、快速和易用性,这种新型检测方法可以广泛应用于临床组织标本、血液标本和体液标本中靶点蛋白质的临场定量检测,在一定程度上可以替代免疫组化技术。 相似文献
27.
《Bioorganic & medicinal chemistry》2020,28(22):115739
N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC50 = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest. 相似文献
28.
Hisao Tsukamoto Yoshihiro Kubo David L. Farrens Mitsumasa Koyanagi Akihisa Terakita Yuji Furutani 《The Journal of biological chemistry》2015,290(45):27176-27187
Melanopsins play a key role in non-visual photoreception in mammals. Their close phylogenetic relationship to the photopigments in invertebrate visual cells suggests they have evolved to acquire molecular characteristics that are more suited for their non-visual functions. Here we set out to identify such characteristics by comparing the molecular properties of mammalian melanopsin to those of invertebrate melanopsin and visual pigment. Our data show that the Schiff base linking the chromophore retinal to the protein is more susceptive to spontaneous cleavage in mammalian melanopsins. We also find this stability is highly diversified between mammalian species, being particularly unstable for human melanopsin. Through mutagenesis analyses, we find that this diversified stability is mainly due to parallel amino acid substitutions in extracellular regions. We propose that the different stability of the retinal attachment in melanopsins may contribute to functional tuning of non-visual photoreception in mammals. 相似文献
29.
30.