全文获取类型
收费全文 | 10630篇 |
免费 | 851篇 |
国内免费 | 731篇 |
专业分类
12212篇 |
出版年
2024年 | 27篇 |
2023年 | 156篇 |
2022年 | 366篇 |
2021年 | 577篇 |
2020年 | 380篇 |
2019年 | 450篇 |
2018年 | 488篇 |
2017年 | 377篇 |
2016年 | 444篇 |
2015年 | 649篇 |
2014年 | 710篇 |
2013年 | 811篇 |
2012年 | 1000篇 |
2011年 | 878篇 |
2010年 | 500篇 |
2009年 | 426篇 |
2008年 | 584篇 |
2007年 | 485篇 |
2006年 | 435篇 |
2005年 | 357篇 |
2004年 | 279篇 |
2003年 | 258篇 |
2002年 | 194篇 |
2001年 | 175篇 |
2000年 | 150篇 |
1999年 | 157篇 |
1998年 | 92篇 |
1997年 | 97篇 |
1996年 | 95篇 |
1995年 | 78篇 |
1994年 | 86篇 |
1993年 | 64篇 |
1992年 | 58篇 |
1991年 | 74篇 |
1990年 | 58篇 |
1989年 | 42篇 |
1988年 | 32篇 |
1987年 | 18篇 |
1986年 | 22篇 |
1985年 | 18篇 |
1984年 | 17篇 |
1983年 | 20篇 |
1982年 | 8篇 |
1980年 | 3篇 |
1978年 | 2篇 |
1975年 | 2篇 |
1973年 | 2篇 |
1971年 | 3篇 |
1968年 | 2篇 |
1966年 | 2篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
992.
Zhong‐Ze Fang Haina Wang Yun‐Feng Cao Dong‐Xue Sun Li‐Xuan Wang Mo Hong Ting Huang Jian‐Xing Chen Jia Zeng 《Chirality》2015,27(3):189-193
UDP‐glucuronosyltransferases (UGTs)‐catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms‐catalyzed 4‐methylumbelliferone (4‐MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)‐carprofen and (S)‐carprofen towards multiple UGT isoforms. The results showed that (S)‐carprofen exhibited stronger inhibition potential than (R)‐carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)‐carprofen and (S)‐carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)‐carprofen and (R)‐carprofen towards UGT2B7. A Lineweaver–Burk plot showed that both (S)‐carprofen and (R)‐carprofen exhibited competitive inhibition towards UGT2B7‐catalyzed 4‐MU glucuronidation. The inhibition kinetic parameter (Ki) was calculated to be 7.0 μM and 31.1 μM for (S)‐carprofen and (R)‐carprofen, respectively. Based on the standard for drug–drug interaction, the threshold for (S)‐carprofen and (R)‐carprofen to induce a drug–drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP‐glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)‐carprofen and (R)‐carprofen to possibly induce the drug–drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)‐carprofen is more important than (R)‐carprofen to avoid a possible drug–drug interaction between carprofen and the drugs mainly undergoing UGT2B7‐catalyzed metabolism. Chirality 27:189–193, 2015. © 2014 Wiley Periodicals, Inc. 相似文献
993.
A novel reductive graphene oxide‐based magnetic molecularly imprinted poly(ethylene‐co‐vinyl alcohol) polymers for the enrichment and determination of polychlorinated biphenyls in fish samples 下载免费PDF全文
Saichai Lin Ning Gan Jiabin Zhang Xidong Chen Yuting Cao Tianhua Li 《Journal of molecular recognition : JMR》2015,28(6):359-368
The novel reductive graphene oxide‐based magnetic molecularly imprinted poly(ethylene‐co‐vinyl alcohol) polymers (rGO@m‐MIPs) were successfully synthesized as adsorbents for six kinds of polychlorinated biphenyls (PCBs) in fish samples. rGO@m‐MIPs was prepared by surface molecular imprinting technique. Besides, Fe3O4 nanoparticles (NPs) were employed as magnetic supporters, and rGO@Fe3O4 was in situ synthesis. Different from functional monomer and cross‐linker in traditional molecularly imprinted polymer, here, 3,4‐dichlorobenzidine was employed as dummy molecular and poly(ethylene‐co‐vinyl alcohol) was adopted as the imprinted polymers. After morphology and inner structure of the magnetic adsorbent were characterized, the adsorbent was employed for disperse solid phase extraction toward PCBs and exhibited great selectivity and high adsorption efficiency. This material was verified by determination of PCBs in fish samples combined with gas chromatography‐mass spectrometry (GC‐MS) method. According to the detection, the low detection limits (LODs) of PCBs were 0.0035–0.0070 µg l−1 and spiked recoveries ranged between 79.90 and 94.23%. The prepared adsorbent can be renewable for at least 16 times and expected to be a new material for the enrichment and determination of PCBs from contaminated fish samples. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
994.
Yugang Zhang Huaiqing Cao Zhirong Liu 《Protein science : a publication of the Protein Society》2015,24(5):688-705
To assess the potential of intrinsically disordered proteins (IDPs) as drug design targets, we have analyzed the ligand-binding cavities of two datasets of IDPs (containing 37 and 16 entries, respectively) and compared their properties with those of conventional ordered (folded) proteins. IDPs were predicted to possess more binding cavity than ordered proteins at similar length, supporting the proposed advantage of IDPs economizing genome and protein resources. The cavity number has a wide distribution within each conformation ensemble for IDPs. The geometries of the cavities of IDPs differ from the cavities of ordered proteins, for example, the cavities of IDPs have larger surface areas and volumes, and are more likely to be composed of a single segment. The druggability of the cavities was examined, and the average druggable probability is estimated to be 9% for IDPs, which is almost twice that for ordered proteins (5%). Some IDPs with druggable cavities that are associated with diseases are listed. The optimism versus obstacles for drug design for IDPs is also briefly discussed. 相似文献
995.
Chaoyi Li Lijuan Kan Yan Chen Xiudeng Zheng Weini Li Wenxin Zhang Lei Cao Xiaohui Lin Shanming Ji Shoujun Huang Guoqiang Zhang Xiaohui Liu Yi Tao Shian Wu Dahua Chen 《Cell research》2015,25(10):1152-1170
Many stem cell populations are tightly regulated by their local microenvironment (niche), which comprises distinct types of stromal cells. However, little is known about mechanisms by which niche subgroups coordinately determine the stem cell fate. Here we identify that Yki, the key Hippo pathway component, is essential for escort cell (EC) function in promoting germline differentiation in Drosophila ovary. We found that Hedgehog (Hh) signals emanating primarily from cap cells support the function of ECs, where Cubitus interruptus (Ci), the Hh signaling effector, acts to inhibit Hippo kinase cascade activity. Mechanistically, we found that Ci competitively interacts with Hpo and impairs the Hpo-Wts signaling complex formation, thereby promoting Yki nuclear localization. The actions of Ci ensure effective Yki signaling to antagonize Sd/Tgi/Vg-mediated default repression in ECs. This study uncovers a mechanism explaining how subgroups of niche cells coordinate to determine the stem cell fate via Hh-Hippo signaling crosstalk, and enhances our understanding of mechanistic regulations of the oncogenic Yki/YAP signaling. 相似文献
996.
Weiyang Chen Wei Qian Gang Wu Weizhong Chen Bo Xian Xingwei Chen Yaqiang Cao Christopher D Green Fanghong Zhao Kun Tang Jing-Dong J Han 《Cell research》2015,25(5):574-587
Aging is associated with many complex diseases. Reliable prediction of the aging process is important for assessing the risks of aging-associated diseases. However, despite intense research, so far there is no reliable aging marker. Here we addressed this problem by examining whether human 3D facial imaging features could be used as reliable aging markers. We collected > 300 3D human facial images and blood profiles well-distributed across ages of 17 to 77 years. By analyzing the morphological profiles, we generated the first comprehensive map of the aging human facial phenome. We identified quantitative facial features, such as eye slopes, highly associated with age. We constructed a robust age predictor and found that on average people of the same chronological age differ by ± 6 years in facial age, with the deviations increasing after age 40. Using this predictor, we identified slow and fast agers that are significantly supported by levels of health indicators. Despite a close relationship between facial morphological features and health indicators in the blood, facial features are more reliable aging biomarkers than blood profiles and can better reflect the general health status than chronological age. 相似文献
997.
998.
999.
Lipoate-protein ligases are used to scavenge lipoic acid from the environment and attach the coenzyme to its cognate proteins, which are generally the E2 components of the 2-oxoacid dehydrogenases. The enzymes use ATP to activate lipoate to its adenylate, lipoyl-AMP, which remains tightly bound in the active site. This mixed anhydride is attacked by the ϵ-amino group of a specific lysine present on a highly conserved acceptor protein domain, resulting in the amide-linked coenzyme. The Streptomyces coelicolor genome encodes only a single putative lipoate ligase. However, this protein had only low sequence identity (<25%) to the lipoate ligases of demonstrated activity and appears to be a circularly permuted version of the known lipoate ligase proteins in that the canonical C-terminal domain seems to have been transposed to the N terminus. We tested the activity of this protein both by in vivo complementation of an Escherichia coli ligase-deficient strain and by in vitro assays. Moreover, when the domains were rearranged into a protein that mimicked the arrangement found in the canonical lipoate ligases, the enzyme retained complementation activity. Finally, when the two domains were separated into two proteins, both domain-containing proteins were required for complementation and catalysis of the overall ligase reaction in vitro. However, only the large domain-containing protein was required for transfer of lipoate from the lipoyl-AMP intermediate to the acceptor proteins, whereas both domain-containing proteins were required to form lipoyl-AMP. 相似文献
1000.
Qi Cao Xi Zo? Zhong Yuanjie Zou Ruth Murrell-Lagnado Michael X. Zhu Xian-Ping Dong 《The Journal of cell biology》2015,209(6):879-894
Intra-endolysosomal Ca2+ release is required for endolysosomal membrane fusion with intracellular organelles. However, the molecular mechanisms for intra-endolysosomal Ca2+ release and the downstream Ca2+ targets involved in the fusion remain elusive. Previously, we demonstrated that endolysosomal P2X4 forms channels activated by luminal adenosine triphosphate in a pH-dependent manner. In this paper, we show that overexpression of P2X4, as well as increasing endolysosomal P2X4 activity by alkalinization of endolysosome lumen, promoted vacuole enlargement in cells and endolysosome fusion in a cell-free assay. These effects were prevented by inhibiting P2X4, expressing a dominant-negative P2X4 mutant, and disrupting the P2X4 gene. We further show that P2X4 and calmodulin (CaM) form a complex at endolysosomal membrane where P2X4 activation recruits CaM to promote fusion and vacuolation in a Ca2+-dependent fashion. Moreover, P2X4 activation-triggered fusion and vacuolation were suppressed by inhibiting CaM. Our data thus suggest a new molecular mechanism for endolysosomal membrane fusion involving P2X4-mediated endolysosomal Ca2+ release and subsequent CaM activation. 相似文献