全文获取类型
收费全文 | 320篇 |
免费 | 37篇 |
出版年
2022年 | 2篇 |
2021年 | 9篇 |
2020年 | 6篇 |
2019年 | 2篇 |
2018年 | 3篇 |
2017年 | 5篇 |
2016年 | 9篇 |
2015年 | 16篇 |
2014年 | 15篇 |
2013年 | 14篇 |
2012年 | 27篇 |
2011年 | 13篇 |
2010年 | 13篇 |
2009年 | 11篇 |
2008年 | 12篇 |
2007年 | 17篇 |
2006年 | 14篇 |
2005年 | 9篇 |
2004年 | 13篇 |
2003年 | 11篇 |
2002年 | 9篇 |
2001年 | 5篇 |
2000年 | 12篇 |
1999年 | 3篇 |
1998年 | 6篇 |
1997年 | 2篇 |
1996年 | 4篇 |
1995年 | 5篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 10篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 2篇 |
1981年 | 5篇 |
1980年 | 2篇 |
1979年 | 4篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1973年 | 2篇 |
1971年 | 3篇 |
1969年 | 2篇 |
1946年 | 2篇 |
1890年 | 1篇 |
排序方式: 共有357条查询结果,搜索用时 31 毫秒
61.
62.
Cytochemical localization of peroxidase activity in root cells 总被引:1,自引:0,他引:1
Summary The distribution of peroxidase in the apical 3 mm of pea roots has been investigated using the histochemical method employing 3,3-diaminobenzidine as a substrate. At the tissue level the enzyme is localized predominately in the root cap, epidermis, inner cortical cells, endodermis, phloem and maturing xylem. At the subcellular level peroxidase is found mainly in the intercellular regions of the cortex cell walls and in the cytoplasm and vacuoles of the steler cells. Root microbodies, unlike those of leaves, do not appear to be able to oxidize this substrate. The significance of these observations is discussed in relation to the validity of the technique and the proposed roles of the enzyme in cellular metabolism. 相似文献
63.
In this article, we consider nonparametric regression when covariates are measured with error. Estimation is performed using boosted regression trees, with the sum of the trees forming the estimate of the conditional expectation of the response. Both binary and continuous response regression are investigated. An approach to fitting regression trees when covariates are measured with error is described, and the boosting algorithms consist of its repeated application. The main feature of the approach is that it handles situations where multiple covariates are measured with error. Some simulation results are given as well as its application to data from the Framingham Heart Study. 相似文献
64.
65.
66.
67.
68.
Miller LJ Chen Q Lam PC Pinon DI Sexton PM Abagyan R Dong M 《The Journal of biological chemistry》2011,286(18):15895-15907
The glucagon-like peptide 1 (GLP1) receptor is an important drug target within the B family of G protein-coupled receptors. Its natural agonist ligand, GLP1, has incretin-like actions and the receptor is a recognized target for management of type 2 diabetes mellitus. Despite recent solution of the structure of the amino terminus of the GLP1 receptor and several close family members, the molecular basis for GLP1 binding to and activation of the intact receptor remains unclear. We previously demonstrated molecular approximations between amino- and carboxyl-terminal residues of GLP1 and its receptor. In this work, we study spatial approximations with the mid-region of this peptide to gain insights into the orientation of the intact receptor and the ligand-receptor complex. We have prepared two new photolabile probes incorporating a p-benzoyl-l-phenylalanine into positions 16 and 20 of GLP1(7-36). Both probes bound to the GLP1 receptor specifically and with high affinity. These were each fully efficacious agonists, stimulating cAMP accumulation in receptor-bearing CHO cells in a concentration-dependent manner. Each probe specifically labeled a single receptor site. Protease cleavage and radiochemical sequencing identified receptor residue Leu(141) above transmembrane segment one as its site of labeling for the position 16 probe, whereas the position 20 probe labeled receptor residue Trp(297) within the second extracellular loop. Establishing ligand residue approximation with this loop region is unique among family members and may help to orient the receptor amino-terminal domain relative to its helical bundle region. 相似文献
69.
Alaa Abdul-Ridha J. Robert Lane Shailesh N. Mistry Laura López Patrick M. Sexton Peter J. Scammells Arthur Christopoulos Meritxell Canals 《The Journal of biological chemistry》2014,289(48):33701-33711
Benzylquinolone carboxylic acid (BQCA) is the first highly selective positive allosteric modulator (PAM) for the M1 muscarinic acetylcholine receptor (mAChR), but it possesses low affinity for the allosteric site on the receptor. More recent drug discovery efforts identified 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one (referred to herein as benzoquinazolinone 12) as a more potent M1 mAChR PAM with a structural ancestry originating from BQCA and related compounds. In the current study, we optimized the synthesis of and fully characterized the pharmacology of benzoquinazolinone 12, finding that its improved potency derived from a 50-fold increase in allosteric site affinity as compared with BQCA, while retaining a similar level of positive cooperativity with acetylcholine. We then utilized site-directed mutagenesis and molecular modeling to validate the allosteric binding pocket we previously described for BQCA as a shared site for benzoquinazolinone 12 and provide a molecular basis for its improved activity at the M1 mAChR. This includes a key role for hydrophobic and polar interactions with residues Tyr-179, in the second extracellular loop (ECL2) and Trp-4007.35 in transmembrane domain (TM) 7. Collectively, this study highlights how the properties of affinity and cooperativity can be differentially modified on a common structural scaffold and identifies molecular features that can be exploited to tailor the development of M1 mAChR-targeting PAMs. 相似文献
70.
Alaa Abdul-Ridha Laura López Peter Keov David M. Thal Shailesh N. Mistry Patrick M. Sexton J. Robert Lane Meritxell Canals Arthur Christopoulos 《The Journal of biological chemistry》2014,289(9):6067-6079
Benzylquinolone carboxylic acid (BQCA) is an unprecedented example of a selective positive allosteric modulator of acetylcholine at the M1 muscarinic acetylcholine receptor (mAChR). To probe the structural basis underlying its selectivity, we utilized site-directed mutagenesis, analytical modeling, and molecular dynamics to delineate regions of the M1 mAChR that govern modulator binding and transmission of cooperativity. We identified Tyr-852.64 in transmembrane domain 2 (TMII), Tyr-179 and Phe-182 in the second extracellular loop (ECL2), and Glu-3977.32 and Trp-4007.35 in TMVII as residues that contribute to the BQCA binding pocket at the M1 mAChR, as well as to the transmission of cooperativity with the orthosteric agonist carbachol. As such, the BQCA binding pocket partially overlaps with the previously described “common” allosteric site in the extracellular vestibule of the M1 mAChR, suggesting that its high subtype selectivity derives from either additional contacts outside this region or through a subtype-specific cooperativity mechanism. Mutation of amino acid residues that form the orthosteric binding pocket caused a loss of carbachol response that could be rescued by BQCA. Two of these residues (Leu-1023.29 and Asp-1053.32) were also identified as indirect contributors to the binding affinity of the modulator. This new insight into the structural basis of binding and function of BQCA can guide the design of new allosteric ligands with tailored pharmacological properties. 相似文献