全文获取类型
收费全文 | 4523篇 |
免费 | 400篇 |
国内免费 | 450篇 |
出版年
2023年 | 116篇 |
2022年 | 86篇 |
2021年 | 135篇 |
2020年 | 170篇 |
2019年 | 259篇 |
2018年 | 240篇 |
2017年 | 203篇 |
2016年 | 190篇 |
2015年 | 167篇 |
2014年 | 240篇 |
2013年 | 347篇 |
2012年 | 174篇 |
2011年 | 236篇 |
2010年 | 191篇 |
2009年 | 221篇 |
2008年 | 205篇 |
2007年 | 232篇 |
2006年 | 187篇 |
2005年 | 151篇 |
2004年 | 174篇 |
2003年 | 158篇 |
2002年 | 145篇 |
2001年 | 94篇 |
2000年 | 91篇 |
1999年 | 93篇 |
1998年 | 69篇 |
1997年 | 56篇 |
1996年 | 54篇 |
1995年 | 48篇 |
1994年 | 52篇 |
1993年 | 53篇 |
1992年 | 54篇 |
1991年 | 49篇 |
1990年 | 40篇 |
1989年 | 36篇 |
1988年 | 33篇 |
1987年 | 29篇 |
1986年 | 30篇 |
1985年 | 27篇 |
1984年 | 39篇 |
1983年 | 27篇 |
1982年 | 25篇 |
1981年 | 16篇 |
1980年 | 22篇 |
1979年 | 18篇 |
1978年 | 18篇 |
1976年 | 14篇 |
1975年 | 9篇 |
1973年 | 17篇 |
1971年 | 11篇 |
排序方式: 共有5373条查询结果,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2020,28(11):115492
Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition. 相似文献
2.
《Bioorganic & medicinal chemistry》2020,28(24):115819
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models. 相似文献
3.
4.
L. P. Lefkovitch 《Biometrical journal. Biometrische Zeitschrift》1991,33(8):899-912
By using deviance standardized residuals, the seemingly unrelated regression estimation procedure is extended to generalized linear models, and fitted by an iterative procedure. The matrix of cross products of standardized residuals is asymptotically multivariate normal, and can be used for further multivariate analyses and for hypothesis testing. 相似文献
5.
We compare the performances of local and global rules for smoothingparameter choice, in terms of asymptotic mean squared errorsof the resulting estimators. In some instances there is surprisinglylittle to choose between local and global approaches; our analysisidentifies contexts where the differences are small or large.This work motivates development of smoothing rules that forma half-way house between local and global smoothing.There, interpolation provides a basis for partial local smoothing.A key result shows that interpolation on even a coarse gridcan produce a very good approximation to full local smoothing.Our theoretical and numerical results lead us to suggest linearinterpolation of a bandwidth obtained by integral approximationson discrete intervals. 相似文献
6.
Three series of bitobic arylpiperazine-phenyl-hexahydropyrazinoquino- lines analogues were designed, synthesizedand evaluated as a novel class of selective ligands for the dopamine D3 receptor. Compounds 15a (Ki of 11.7 ± 1.8 and 373 nM at D3 and D2, respectively), 15c (Ki of 5.49 and 264 nM at D3 and D2, respectively), 15e (Ki of 14.9 and 325 nM at D3 and D2, respectively), 15i (Ki of 13.8 and 401 nM at D3 and D2, respectively) and 15l (Ki of 13.6 and 870 nM at D3 and D2, respectively) were found to demonstrate good binding affinity and selectivity, and especially compound 15c showeda similar binding affinity and selectivity compared with the contrast drug BP897. 相似文献
7.
8.
9.
The frequency of recirprocal translocations, inducedm by X-irradiation of mouse spermatogonial cells and observed at diakinesis-metaphase I in primary spermatocytes, was measured over a dose range of 0–1200 R. The resulting dose-response curve gave a best fit to the model Y = bD+CD2 over the range of 0–500 R. Above 600 R, howeverm, the yeild of translocations decreased with increasing dose, leadiong to a “humped” dose-response curve over the whole dose range studied, as has been observed by several worker previously.The significance of the nonlinear dose-response curve over the lower dose range is discussed in terms of the known fractionation and dose-rate effects for reciprocal translocations induced in spermatogonia.A dose of 800 R was split into two 400-R fractions separated by 8 weeks, or one of 1200 R into three equal parts, each separated by an 8-week interval. The resulting yield of translocations was the same as the sum of two, or three, separate 400-dose doses, but was much higher than a single dose of 800 R or 1200 R.It is suggested that these results, namely the shape of the dose-response curve and the “reverse” fractionation effect, can be explained in terms of resistant and sensitive stem-cell populations, but that any one cell can be in either population, depending upon the stage of the cell cycle in which it is at the time of irradiation. 相似文献
10.
F. -W. Bentrup 《European biophysics journal : EBJ》1980,6(3):175-189
This review treats some examples of electrogenic transport across the outer plasmamembrane (plasmalemma) of plant cells. The selection includes primary active uniport by membrane ATPases (e.g., the proton pump), secondary active transport of hexoses by proton-dependent cotransport, and passive uniport of amines. Primacy is given to the presentation of electrophysiological data and to the discussion of voltage-dependence of the transport mechanisms.Lecture from the Annual Meeting of the Deutsche Gesellschaft für Biophysik at Konstanz 相似文献