全文获取类型
收费全文 | 21770篇 |
免费 | 1872篇 |
国内免费 | 1370篇 |
专业分类
25012篇 |
出版年
2024年 | 51篇 |
2023年 | 231篇 |
2022年 | 574篇 |
2021年 | 850篇 |
2020年 | 620篇 |
2019年 | 782篇 |
2018年 | 834篇 |
2017年 | 624篇 |
2016年 | 929篇 |
2015年 | 1400篇 |
2014年 | 1627篇 |
2013年 | 1702篇 |
2012年 | 2007篇 |
2011年 | 1924篇 |
2010年 | 1143篇 |
2009年 | 1091篇 |
2008年 | 1254篇 |
2007年 | 1147篇 |
2006年 | 1040篇 |
2005年 | 881篇 |
2004年 | 860篇 |
2003年 | 686篇 |
2002年 | 549篇 |
2001年 | 361篇 |
2000年 | 289篇 |
1999年 | 255篇 |
1998年 | 192篇 |
1997年 | 152篇 |
1996年 | 149篇 |
1995年 | 117篇 |
1994年 | 109篇 |
1993年 | 63篇 |
1992年 | 88篇 |
1991年 | 70篇 |
1990年 | 80篇 |
1989年 | 62篇 |
1988年 | 44篇 |
1987年 | 45篇 |
1986年 | 27篇 |
1985年 | 27篇 |
1984年 | 33篇 |
1983年 | 13篇 |
1982年 | 10篇 |
1981年 | 7篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1967年 | 2篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
961.
Jin Zhou Xiao‐Hui Dong Feng‐Zhi Zhang Hui‐Min Zhu Tong Hao Xiao‐Xia Jiang Wei‐Bo Zheng Tao Zhang Pei‐Zhe Wang Hong Li Jie Na Chang‐Yong Wang 《Cell proliferation》2019,52(3)
Induced pluripotent stem cells (iPSCs) are reprogrammed somatic cells that gained self‐renewal and differentiation capacity similar to embryonic stem cells. Taking the precious opportunity of the TianZhou‐1 spacecraft mission, we studied the effect of space microgravity (µg) on the self‐renewal capacity of iPSCs. Murine iPSCs carrying pluripotency reporter Oct4‐GFP were used. The Oct4‐EGFP‐iPSCs clones were loaded into the bioreactor and exposed to μg in outer space for 14 days. The control experiment was performed in identical device but on the ground in earth gravity (1 g). iPSCs clones were compact and highly expressed Oct4 before launch. In μg condition, cells in iPSC clones spread out more rapidly than those in ground 1 g condition during the first 3 days after launch. However, in 1 g condition, as the cell density increases, the Oct4‐GFP signal dropped significantly during the following 3 days. Interestingly, in μg condition, iPSCs originated from the spread‐out clones during the first 3 days appeared to cluster together and reform colonies that activated strong Oct4 expression. On the other hand, iPSC clones in 1 g condition were not able to recover Oct4 expression after overgrown. Our study for the first time performed real‐time imaging on the proliferation process of iPSCs in space and found that in μg condition, cell behaviour appeared to be more dynamic than on the ground. 相似文献
962.
Jia Jin Xiaoqing Ye Derrick Boateng Kaili Dai Fei Ye Pengfei Du Han Yu 《Bioorganic & medicinal chemistry letters》2019,29(16):2358-2363
Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin and leptin signaling. The development of small molecular inhibitors targeting PTP1B has been validated as a potential therapeutic strategy for Type 2 diabetes (T2D). In this work, we have identified a series of compounds containing dihydropyridine thione and particular chiral structure as novel PTP1B inhibitors. Among those, compound 4b showed moderate activity with IC50 value of 3.33 μM and meanwhile with good selectivity (>30-fold) against TCPTP. The further MOA study of PTP1B demonstrated that compounds 4b is a substrate-competitive inhibitor. The binding mode analysis suggested that compound 4b simultaneously occupies the active site and the second phosphotyrosine (pTyr) binding site of PTP1B. Furthermore, the cell viability assay of compound 4b showed tolerable cytotoxicity in L02 cells, thus 4b may be prospectively used to further in vivo study. 相似文献
963.
Ping Yu Wenjing Liu Jinghui Ren Yingying Wang Yao Ning Mingqi Huang Xinyi Hu Lili Wei Min Ji Jin Cai 《Bioorganic & medicinal chemistry letters》2019,29(16):2168-2172
Bromodomain-containing protein 4 (BRD4) is a new therapeutic target for the treatment of diseases including cardiovascular diseases, cancer, inflammation and central nervous system (CNS) disorders. In this study, we introduced the pharmacophore of fibrates to a BRD4 inhibitor, RVX-208, to design dual-active hypolipidemic compounds, and found that some of new analogues showed favorable hypolipidemic activities. Synthetic accessibility towards this class of compounds optimized RVX-208 as well as would supply more thoughts on hypolipidemic drugs. 相似文献
964.
965.
966.
967.
Jin Ding Hang Su Fan Wang Taiwei Chu 《Bioorganic & medicinal chemistry letters》2019,29(14):1791-1798
During the last four decades, nuclear medicine has undergone enormous growth, and positron emission tomography (PET) has been in the driving seat for most of the time. 18F-fluorodeoxyglucose (18F-FDG) is the most widely used agent for the detection of hibernating myocardium and metabolically active cancer tissue. But its cost and limited availability are the main limitations. For a long time different researchers and groups of pharmacists have tried to label glucose with a cheaper and long-acting radionuclide like 99mTc. However, they failed to achieve this goal owing to the chemical complexity of 99mTc and the lack of maintaining the physiological activity of diagnostic compounds. A pre-targeting strategy based on strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) reaction was applied to solve this problem. Functional click synthons were synthesized: 2-azido-2-deoxy-d-glucose (GlucN3) as a glucose analogue, and N- (2- (2- (2- (bis (pyridin-2-ylmethyl) amino) ethoxy) ethoxy) ethyl-2- (6H-11,12-didehydrodibenzo [a,e] cycloocten-5-ylideneaminooxy) acetamide (C7) as a 99mTc(CO)3 labeling and azido-binding group. The results of biodistribution experiments in mice bearing S180 tumor show the relatively high tumor/blood ratio (up to 2.95) and tumor/muscle ratio (up to 6.37), and both of them decreases significantly in the glucose blocking experiment. It indicates that GlucN3 behaves similarly to glucose and that in vivo SPAAC reactions can occur effectively. It is supposed that this pre-targeting strategy can indeed enhance target specificity and may be used for glucose metabolism imaging in tumor diagnosis. 相似文献
968.
Weiwei Li Jianjie Chu Tingting Fan Wei Zhang Minna Yao Zeqiong Ning Mingming Wang Jin Sun Xian Zhao Aidong Wen 《Bioorganic & medicinal chemistry letters》2019,29(14):1831-1835
In this investigation, a series of 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea receptor tyrosine kinase inhibitors were synthesized by a simple and efficient structure-based design. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against human chronic myeloid leukemia (CML) cell line K562, but very weak or no cellular toxicity through monitoring the growth kinetics of K562 cell during a period of 72 h using the real-time live-cell imaging. Among these compounds, 1-(5-((6-((3-morpholinopropyl) amino)pyrimidin-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (7) exhibited the least cellular toxicity and better biological activity in cellular assays (K562, IC50: 0.038 μM). Compound 7 also displayed very good induced-apoptosis effect for human CML cell line K562 and exerted its effect via a significantly reduced protein phosphorylation of PI3K/Akt signal pathway by Human phospho-kinase array analysis. In vitro results indicate that 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea derivatives are lead molecules for further development as treatment of chronic myeloid leukemia and cancer. 相似文献
969.
Dhimant Desai Matthew Lauver Alexandria Ostman Linda Cruz Kevin Ferguson Ge Jin Brianne Roper Daniel Brosius Aron Lukacher Shantu Amin Nick Buchkovich 《Bioorganic & medicinal chemistry》2019,27(9):1795-1803
Opportunistic viruses are a major problem for immunosuppressed individuals, particularly following organ or stem cell transplantation. Current treatments are non-existent or suffer from problems such as high toxicity or development of resistant strains. We previously published that a trafficking inhibitor that targets a host protein greatly reduces the replication of human cytomegalovirus. This inhibitor was also shown to be moderately effective against polyomaviruses, another family of opportunistic viruses. We have developed a panel of analogues for this inhibitor and have shown that these analogues maintain their high efficacy against HCMV, while substantially lowering the concentration required to inhibit polyomavirus replication. By targeting a host protein these compounds are able to inhibit the replication of two very different viruses. These observations open up the possibility of pan-viral inhibitors for immunosuppressed individuals that are effective against multiple, diverse opportunistic viruses. 相似文献