全文获取类型
收费全文 | 3793篇 |
免费 | 340篇 |
国内免费 | 325篇 |
专业分类
4458篇 |
出版年
2024年 | 7篇 |
2023年 | 45篇 |
2022年 | 110篇 |
2021年 | 201篇 |
2020年 | 131篇 |
2019年 | 165篇 |
2018年 | 155篇 |
2017年 | 123篇 |
2016年 | 184篇 |
2015年 | 224篇 |
2014年 | 248篇 |
2013年 | 280篇 |
2012年 | 319篇 |
2011年 | 289篇 |
2010年 | 185篇 |
2009年 | 165篇 |
2008年 | 205篇 |
2007年 | 154篇 |
2006年 | 167篇 |
2005年 | 145篇 |
2004年 | 136篇 |
2003年 | 107篇 |
2002年 | 115篇 |
2001年 | 97篇 |
2000年 | 85篇 |
1999年 | 79篇 |
1998年 | 46篇 |
1997年 | 44篇 |
1996年 | 38篇 |
1995年 | 34篇 |
1994年 | 28篇 |
1993年 | 21篇 |
1992年 | 19篇 |
1991年 | 23篇 |
1990年 | 11篇 |
1989年 | 6篇 |
1988年 | 10篇 |
1987年 | 14篇 |
1986年 | 8篇 |
1985年 | 8篇 |
1984年 | 8篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1974年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有4458条查询结果,搜索用时 0 毫秒
61.
62.
Steven W. Paugh David R. Coss Ju Bao Lucas T. Laudermilk Christy R. Grace Antonio M. Ferreira M. Brett Waddell Granger Ridout Deanna Naeve Michael Leuze Philip F. LoCascio John C. Panetta Mark R. Wilkinson Ching-Hon Pui Clayton W. Naeve Edward C. Uberbacher Erik J. Bonten William E. Evans 《PLoS computational biology》2016,12(2)
63.
Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers. To give a comprehensive understanding of molecular mechanism underlying inhibitor response to ALK tyrosine kinase mutations, we established an accurate assessment for the extensive profile of drug against ALK mutations by means of computational approaches. The molecular mechanics-generalized Born surface area (MM-GBSA) method based on molecular dynamics (MD) simulation was carried out to calculate relative binding free energies for receptor-drug systems. In addition, the structure-based virtual screening was utilized to screen effective inhibitors targeting wild-type ALK and the gatekeeper mutation L1196M from 3180 approved drugs. Finally, the mechanism of drug resistance was discussed, several novel potential wild-type and L1196M mutant ALK inhibitors were successfully identified. 相似文献
64.
Bao Cao Lars Christophersen Mette Kolpen Peter ?strup Jensen Kim Sneppen Niels H?iby Claus Moser Thomas Sams 《PloS one》2016,11(4)
Microbial cells embedded in a self-produced extracellular biofilm matrix cause chronic infections, e. g. by Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. The antibiotic killing of bacteria in biofilms is generally known to be reduced by 100–1000 times relative to planktonic bacteria. This makes such infections difficult to treat. We have therefore proposed that biofilms can be regarded as an independent compartment with distinct pharmacokinetics. To elucidate this pharmacokinetics we have measured the penetration of the tobramycin into seaweed alginate beads which serve as a model of the extracellular polysaccharide matrix in P. aeruginosa biofilm. We find that, rather than a normal first order saturation curve, the concentration of tobramycin in the alginate beads follows a power-law as a function of the external concentration. Further, the tobramycin is observed to be uniformly distributed throughout the volume of the alginate bead. The power-law appears to be a consequence of binding to a multitude of different binding sites. In a diffusion model these results are shown to produce pronounced retardation of the penetration of tobramycin into the biofilm. This filtering of the free tobramycin concentration inside biofilm beads is expected to aid in augmenting the survival probability of bacteria residing in the biofilm. 相似文献
65.
Chen Xu Nan Zhang Qianyu Huo Minghui Chen Rengfeng Wang Zhili Liu Xue Li Yunde Liu Huijing Bao 《Analytical biochemistry》2016
In this article, we discuss the polymerase chain reaction (PCR)–hybridization assay that we developed for high-throughput simultaneous detection and differentiation of Ureaplasma urealyticum and Ureaplasma parvum using one set of primers and two specific DNA probes based on urease gene nucleotide sequence differences. First, U. urealyticum and U. parvum DNA samples were specifically amplified using one set of biotin-labeled primers. Furthermore, amine-modified DNA probes, which can specifically react with U. urealyticum or U. parvum DNA, were covalently immobilized to a DNA–BIND plate surface. The plate was then incubated with the PCR products to facilitate sequence-specific DNA binding. Horseradish peroxidase–streptavidin conjugation and a colorimetric assay were used. Based on the results, the PCR–hybridization assay we developed can specifically differentiate U. urealyticum and U. parvum with high sensitivity (95%) compared with cultivation (72.5%). Hence, this study demonstrates a new method for high-throughput simultaneous differentiation and detection of U. urealyticum and U. parvum with high sensitivity. Based on these observations, the PCR–hybridization assay developed in this study is ideal for detecting and discriminating U. urealyticum and U. parvum in clinical applications. 相似文献
66.
67.
68.
Suppressive effect of epigallocatechin‐3‐O‐gallate on endoglin molecular regulation in myocardial fibrosis in vitro and in vivo 下载免费PDF全文
Chiu‐Mei Lin Hang Chang Bao‐Wei Wang Kou‐Gi Shyu 《Journal of cellular and molecular medicine》2016,20(11):2045-2055
Epigallocatechin‐3‐O‐gallate (EGCG), derived from green tea, has been studied extensively because of its diverse physiological and pharmacological properties. This study evaluates the protective effect of EGCG on angiotensin II (Ang II)‐induced endoglin expression in vitro and in vivo. Cardiac fibroblasts (CFs) from the thoracic aorta of adult Wistar rats were cultured and induced with Ang II. Western blotting, Northern blotting, real‐time PCR and promoter activity assay were performed. Ang II increased endoglin expression significantly as compared with control cells. The specific extracellular signal‐regulated kinase inhibitor SP600125 (JNK inhibitor), EGCG (100 μM) and c‐Jun N‐terminal kinase (JNK) siRNA attenuated endoglin proteins following Ang II induction. In addition, pre‐treated Ang II‐induced endoglin with EGCG diminished the binding activity of AP‐1 by electrophoretic mobility shift assay. Moreover, the luciferase assay results revealed that EGCG suppressed the endoglin promoter activity in Ang II‐induced CFs by AP‐1 binding. Finally, EGCG and the JNK inhibitor (SP600125) were found to have attenuated endoglin expression significantly in Ang II‐induced CFs, as determined through confocal microscopy. Following in vivo acute myocardial infarction (AMI)‐related myocardial fibrosis study, as well as immunohistochemical and confocal analyses, after treatment with endoglin siRNA and EGCG (50 mg/kg), the area of myocardial fibrosis reduced by 53.4% and 64.5% and attenuated the left ventricular end‐diastolic and systolic dimensions, and friction shortening in hemodynamic monitor. In conclusion, epigallocatechin‐3‐O‐gallate (EGCG) attenuated the endoglin expression and myocardial fibrosis by anti‐inflammatory effect in vitro and in vivo, the novel suppressive effect was mediated through JNK/AP‐1 pathway. 相似文献
69.
70.