全文获取类型
收费全文 | 481篇 |
免费 | 40篇 |
出版年
2023年 | 5篇 |
2022年 | 7篇 |
2021年 | 20篇 |
2020年 | 4篇 |
2019年 | 3篇 |
2018年 | 17篇 |
2017年 | 19篇 |
2016年 | 16篇 |
2015年 | 27篇 |
2014年 | 20篇 |
2013年 | 29篇 |
2012年 | 47篇 |
2011年 | 36篇 |
2010年 | 26篇 |
2009年 | 21篇 |
2008年 | 27篇 |
2007年 | 31篇 |
2006年 | 8篇 |
2005年 | 14篇 |
2004年 | 11篇 |
2003年 | 9篇 |
2002年 | 11篇 |
2001年 | 5篇 |
2000年 | 7篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1993年 | 4篇 |
1991年 | 9篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 3篇 |
1978年 | 2篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1971年 | 3篇 |
1970年 | 2篇 |
1969年 | 3篇 |
1967年 | 2篇 |
1965年 | 3篇 |
1964年 | 3篇 |
排序方式: 共有521条查询结果,搜索用时 15 毫秒
71.
Maya Deshmukh Margery L. Evans Matthew R. Chapman 《Journal of molecular biology》2018,430(20):3631-3641
The term amyloid has historically been used to describe fibrillar aggregates formed as the result of protein misfolding and that are associated with a range of diseases broadly termed amyloidoses. The discovery of “functional amyloids” expanded the amyloid umbrella to encompass aggregates structurally similar to disease-associated amyloids but that engage in a variety of biologically useful tasks without incurring toxicity. The mechanisms by which functional amyloid systems ensure nontoxic assembly has provided insights into potential therapeutic strategies for treating amyloidoses. Some of the most-studied functional amyloids are ones produced by bacteria. Curli amyloids are extracellular fibers made by enteric bacteria that function to encase and protect bacterial communities during biofilm formation. Here we review recent studies highlighting microbial functional amyloid assembly systems that are tailored to enable the assembly of non-toxic amyloid aggregates. 相似文献
72.
N-terminal Proline-rich Domain Is Required for Scrambling Activity of Human Phospholipid Scramblases
Sarika Rayala Vincent G. Francis Ulaganathan Sivagnanam Sathyanarayana N. Gummadi 《The Journal of biological chemistry》2014,289(19):13206-13218
Human phospholipid scramblase 1 (hPLSCR1), a type II integral class membrane protein, is known to mediate bidirectional scrambling of phospholipids in a Ca2+-dependent manner. hPLSCR2, a homolog of hPLSCR1 that lacks N-terminal proline-rich domain (PRD), did not show scramblase activity. We attribute this absence of scramblase activity of hPLSCR2 to the lack of N-terminal PRD. Hence to investigate the above hypothesis, we added the PRD of hPLSCR1 to hPLSCR2 (PRD-hPLSCR2) and checked whether scramblase activity was restored. Functional assays showed that the addition of PRD to hPLSCR2 restored scrambling activity, and deletion of PRD in hPLSCR1 (ΔPRD-hPLSCR1) resulted in a lack of activity. These results suggest that PRD is crucial for the function of the protein. The effects of the PRD deletion in hPLSCR1 and the addition of PRD to hPLSCR2 were characterized using various spectroscopic techniques. Our results clearly showed that hPLSCR1 and PRD-hPLSCR2 showed Ca2+-dependent aggregation and scrambling activity, whereas hPLSCR2 and ΔPRD-hPLSCR1 did not show aggregation and activity. Thus we conclude that scramblases exhibit Ca2+-dependent scrambling activity by aggregation of protein. Our results provide a possible mechanism for phospholipid scrambling mediated by PLSCRs and the importance of PRD in its function and cellular localization. 相似文献
73.
Comparative performance of different scale‐down simulators of substrate gradients in Penicillium chrysogenum cultures: the need of a biological systems response analysis 下载免费PDF全文
74.
75.
Sarika Gunjan Sunil Kumar Singh Tanuj Sharma Hemlata Dwivedi Bhavana Singh Chauhan Mohammad Imran Siddiqi Renu Tripathi 《Apoptosis : an international journal on programmed cell death》2016,21(9):955-964
Recent studies pioneer the existence of a novel programmed cell death pathway in malaria parasite plasmodium and suggest that it could be helpful in developing new targeted anti-malarial therapies. Considering this fact, we evaluated the underlying action mechanism of this pathway in mefloquine (MQ) treated parasite. Since cysteine proteases play a key role in apoptosis hence we performed preliminary computational simulations to determine binding affinity of MQ with metacaspase protein model. Binding pocket identified using computational studies, was docked with MQ to identify it’s potential to bind with the predicted protein model. We further determined apoptotic markers such as mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in MQ treated/untreated parasites by cell based assay. Our results showed low mitochondrial membrane potential, enhanced activity of cysteine protease and increased number of fragmented DNA in treated parasites compared to untreated ones. We next tested the involvement of oxidative stress in MQ mediated cell death and found significant increase in reactive oxygen species generation after 24 h of treatment. Therefore we conclude that apart from hemozoin inhibition, MQ is competent to induce apoptosis in plasmodium by activating metacaspase and ROS production. 相似文献
76.
Jurre Y. Siegers Vijaykrishna Dhanasekaran Ruopeng Xie Yi-Mo Deng Sarika Patel Vanra Ieng Jean Moselen Heidi Peck Ammar Aziz Borann Sarr Savuth Chin Seng Heng Asheena Khalakdina Michael Kinzer Darapheak Chau Philomena Raftery Veasna Duong Ly Sovann Ian G. Barr Erik A. Karlsson 《Journal of virology》2021,95(24)
77.
78.
Nagarajan Muthukaman Macchindra Tambe Mahamadhanif Shaikh Dnyandeo Pisal Sanjay Deshmukh Shital Tondlekar Neelam Sarode Lakshminarayana Narayana Jitendra M. Gajera Vidya G. Kattige Srinivasa Honnegowda Vikas Karande Abhay Kulkarni Dayanidhi Behera Satyawan B. Jadhav Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2017,27(11):2594-2601
A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F = 33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model. 相似文献
79.
80.