全文获取类型
收费全文 | 187篇 |
免费 | 24篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2020年 | 2篇 |
2019年 | 5篇 |
2018年 | 5篇 |
2017年 | 10篇 |
2016年 | 3篇 |
2015年 | 3篇 |
2014年 | 3篇 |
2013年 | 21篇 |
2012年 | 17篇 |
2011年 | 14篇 |
2010年 | 13篇 |
2009年 | 12篇 |
2008年 | 14篇 |
2007年 | 3篇 |
2006年 | 7篇 |
2005年 | 8篇 |
2004年 | 6篇 |
2003年 | 4篇 |
2002年 | 3篇 |
2001年 | 4篇 |
2000年 | 1篇 |
1999年 | 4篇 |
1998年 | 1篇 |
1994年 | 2篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1984年 | 1篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1977年 | 3篇 |
1974年 | 3篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1965年 | 1篇 |
1963年 | 1篇 |
1961年 | 3篇 |
1960年 | 3篇 |
1959年 | 2篇 |
1958年 | 4篇 |
1956年 | 1篇 |
1955年 | 1篇 |
1939年 | 1篇 |
排序方式: 共有211条查询结果,搜索用时 46 毫秒
51.
Assembly and disassembly of RecA protein filaments occur at opposite filament ends. Relationship to DNA strand exchange 总被引:3,自引:0,他引:3
RecA protein primarily associates with and dissociates from opposite ends of nucleoprotein filaments formed on linear duplex DNA. RecA nucleoprotein filaments that are hydrolyzing ATP therefore engage in a dynamic process under some conditions that has some of the properties of treadmilling. We have also investigated whether the net polymerization of recA protein at one end of the filament and/or a net depolymerization at the other end drives unidirectional strand exchange. There is no demonstrable correlation between recA protein association/dissociation and the strand exchange reaction. RecA protein-mediated DNA strand exchange is affected minimally by changes in reaction conditions (dilution, pH shift, or addition of small amounts of adenosine-5'-O-(3-thiotriphosphate) that have large and demonstrable effects on recA protein association, dissociation, or both. Rather than driving strand exchange, these assembly and disassembly processes may simply represent the mechanism by which recA nucleoprotein filaments are recycled in the cell. 相似文献
52.
HLA-DR-restricted cytotoxicity of cytomegalovirus-infected monocytes mediated by Leu-3-positive T cells 总被引:6,自引:0,他引:6
M D Lindsley D J Torpey C R Rinaldo 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(8):3045-3051
Mononuclear leukocytes from 14 cytomegalovirus (CMV)-seropositive and six CMV-seronegative normal healthy donors were treated with soluble CMV antigen for 5 days to generate cytotoxic T lymphocyte (CTL) activity. CMV-antigen-stimulated lymphocytes from CMV-seropositive but not CMV-seronegative donors lysed autologous peripheral blood monocyte targets infected with CMV in 13 of 14 donors (mean percentage of virus-specific lysis = 19.0 +/- 4.5%, effector to target ratio of 50:1). Freshly donated, unstimulated lymphocytes displayed little or no lysis of CMV-infected monocytes. Lysis was virus specific in that CMV-stimulated CTL did not kill herpes simplex virus-infected monocytes. The mean level of lysis of CMV-infected autologous targets was equivalent to that of HLA-DR-matched targets (20.0 +/- 8.0%), and was significantly greater than that of HLA-A/B-matched targets (6.3 +/- 2.5%, p less than 0.035) and HLA-mismatched targets (3.3 +/- 2.5%, p less than 0.01). Enrichment for T cell subsets with the use of selective depletion methods with monoclonal antibodies showed that CTL activity against autologous and HLA-DR-matched allogeneic targets was present predominantly in Leu-3-positive T lymphocytes. These results show for the first time that short term stimulation of heterogeneous lymphocytes from CMV-seropositive donors with CMV antigen can generate CMV-specific, Leu-3-positive CTL that are primarily restricted in their activity to autologous and class II, HLA-DR-matched targets. Our findings suggest a role for Leu-3-phenotypic CTL in immunity to CMV, and provide a model for analysis of this antiviral effector function during immunodeficient states. 相似文献
53.
54.
Darren W. Engers Audrey Y. Frist Craig W. Lindsley Charles C. Hong Corey R. Hopkins 《Bioorganic & medicinal chemistry letters》2013,23(11):3248-3252
A structure–activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation. 相似文献
55.
J. Phillip Kennedy P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2009,19(12):3204-3208
This Letter describes the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin, and the resulting SAR of H3 antagonism. Multiple rounds of iterative parallel synthesis improved human H3 IC50 ~33-fold, and afforded a new class of H3 antagonists based on the novel bromotyramine core of dispyrin. 相似文献
56.
Michael S. Poslusney Christian Sevel Thomas J. Utley Thomas M. Bridges Ryan D. Morrison Nathan R. Kett Douglas J. Sheffler Colleen M. Niswender J.S. Daniels P.J. Conn Craig W. Lindsley Michael R. Wood 《Bioorganic & medicinal chemistry letters》2012,22(22):6923-6928
Utilizing a combination of high-throughput and multi-step synthesis, SAR in a novel series of M1 acetylcholine receptor antagonists was rapidly established. The efforts led to the discovery the highly potent M1 antagonists 6 (VU0431263), and 8f (VU0433670). Functional Schild analysis and radioligand displacement experiments demonstrated the competitive, orthosteric binding of these compounds; human selectivity data are presented. 相似文献
57.
58.
Darren W. Engers Bruce J. Melancon Allison R. Gregro Jeanette L. Bertron Sean R. Bollinger Andrew S. Felts Leah C. Konkol Michael R. Wood Katrina A. Bollinger Vincent B. Luscombe Alice L. Rodriguez Carrie K. Jones Michael Bubser Samantha E. Yohn Michael W. Wood Nicholas J. Brandon Mark E. Dugan Colleen M. Niswender Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2019,29(14):1714-1718
This letter describes progress towards an M4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe. 相似文献
59.
60.
Franck Potet Amanda N. Lorinc Sebastien Chaigne Corey R. Hopkins Raghav Venkataraman Svetlana Z. Stepanovic L. Michelle Lewis Emily Days Veniamin Y. Sidorov Darren W. Engers Beiyan Zou David Afshartous Alfred L. George Jr. Courtney M. Campbell Jeffrey R. Balser Min Li Franz J. Baudenbacher Craig W. Lindsley C. David Weaver Sabina Kupershmidt 《The Journal of biological chemistry》2012,287(47):39613-39625
The human Ether-à-go-go-related gene (hERG)-encoded K+ current, IKr is essential for cardiac repolarization but is also a source of cardiotoxicity because unintended hERG inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes IKr block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC70 of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC50 of dofetilide from 38.7 to 76.3 nm. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors. 相似文献