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111.
Anavi-Goffer S Baillie G Irving AJ Gertsch J Greig IR Pertwee RG Ross RA 《The Journal of biological chemistry》2012,287(1):91-104
GPR55 is activated by l-α-lysophosphatidylinositol (LPI) but also by certain cannabinoids. In this study, we investigated the GPR55 pharmacology of various cannabinoids, including analogues of the CB1 receptor antagonist Rimonabant®, CB2 receptor agonists, and Cannabis sativa constituents. To test ERK1/2 phosphorylation, a primary downstream signaling pathway that conveys LPI-induced activation of GPR55, a high throughput system, was established using the AlphaScreen® SureFire® assay. Here, we show that CB1 receptor antagonists can act both as agonists alone and as inhibitors of LPI signaling under the same assay conditions. This study clarifies the controversy surrounding the GPR55-mediated actions of SR141716A; some reports indicate the compound to be an agonist and some report antagonism. In contrast, we report that the CB2 ligand behaves as a partial agonist of GPR55 alone and enhances LPI signaling. GPR55 has been implicated in pain transmission, and thus our results suggest that this receptor may be responsible for some of the antinociceptive actions of certain CB2 receptor ligands. The phytocannabinoids Δ9-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55. GW405833相似文献
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113.
Allosteric rescuing of loss-of-function FFAR2 mutations 总被引:1,自引:0,他引:1
Gayathri Swaminath Peter Jaeckel Qi Guo Jennifer Weiszmann Yingcai Wang Yang Li 《FEBS letters》2010,584(19):4208-4214
FFAR2 (GPR43) is a receptor for short-chain fatty acids (SCFAs), acetate and propionate. In the current study, we investigate the molecular determinants contributing to receptor activation by endogenous ligands. Mutational analysis revealed several important residues located in transmembrane domains (TM) 3, 4, 5, 6, and 7 for acetate binding. Interestingly, mutations that abolished acetate activity, including the mutation in the well-conserved D(E)RY motif, could be rescued by a recently identified synthetic allosteric agonist. These findings provide additional insight into agonist binding and activation which may aid in designing allosteric ligands for targeting receptor function in various diseases. 相似文献
114.
CD84 is a member of the immunoglobulin gene superfamily (IgSF) with two Ig-like domains expressed primarily on B lymphocytes
and macrophages. Here we describe the cloning of the mouse homologue of human CD84. Mouse CD84 cDNA clones were isolated from
a macrophage library. The nucleotide sequence of mouse CD84 was shown to include an open reading frame encoding a putative
329 amino acid protein composed of a 21 amino acid leader peptide, two extracellular immunoglobulin (Ig)-like domains, a hydrophobic
transmembrane region, and an 87 amino acid cytoplasmic domain. Mouse CD84 shares 57.3% amino acid sequence identity (88.7%,
considering conservative amino acid substitutions) with the human homologue. Chromosome localization studies mapped the mouse
CD84 gene to distal chromosome 1 adjacent to the gene for Ly-9, placing it close to the region where other members of the CD2 IgSF (CD48 and 2B4) have been mapped. Northern blot analysis revealed that the expression of mouse CD84 was predominantly restricted to hematopoietic
tissues. Two species of mRNA of 3.6 kilobases (kb) and 1.5 kb were observed. The finding that the pattern of expression was
restricted to the hematopoietic system and the conserved sequence of the mouse CD84 homologue suggests that the function of
the CD84 glycoprotein may be similar in humans and mice.
Received: 1 July 1998 / Revised: 31 August 1998 相似文献
115.
Glycoproteins commercially available in multi-gram quantities, were used to prepare milligram amounts of neoglycoproteins. The glycoproteins bromelain and bovine -globulin were proteolyzed to obtain glycopeptides or converted to a mixture of glycans through hydrazinolysis. The glycan mixture was structurally simplified by carbohydrate remodeling using exoglycosidases. Glycopeptides were biotinylated using N-hydroxysuccinimide activated-long chain biotin while glycoprotein-derived glycans were first reductively aminated with ammonium bicarbonate and then biotinylated. The resulting biotinylated carbohydrates were structurally characterized and then bound to streptavidin to afford neoglycoproteins. The peptidoglycan component of raw, unbleached heparin (an intermediate in the manufacture of heparin) was similarly biotinylated and bound to streptavidin to obtain milligram amounts of a heparin neoproteoglycan. The neoglycoconjugates prepared contain well defined glycan chains at specific locations on the streptavidin core and should be useful for the study of protein-carbohydrate interactions and affinity separations. 相似文献
116.
Perryman AL Lin JH McCammon JA 《Protein science : a publication of the Protein Society》2004,13(4):1108-1123
The protease from type 1 human immunodeficiency virus (HIV-1) is a critical drug target against which many therapeutically useful inhibitors have been developed; however, the set of viral strains in the population has been shifting to become more drug-resistant. Because indirect effects are contributing to drug resistance, an examination of the dynamic structures of a wild-type and a mutant could be insightful. Consequently, this study examined structural properties sampled during 22 nsec, all atom molecular dynamics (MD) simulations (in explicit water) of both a wild-type and the drug-resistant V82F/I84V mutant of HIV-1 protease. The V82F/I84V mutation significantly decreases the binding affinity of all HIV-1 protease inhibitors currently used clinically. Simulations have shown that the curling of the tips of the active site flaps immediately results in flap opening. In the 22-nsec MD simulations presented here, more frequent and more rapid curling of the mutant's active site flap tips was observed. The mutant protease's flaps also opened farther than the wild-type's flaps did and displayed more flexibility. This suggests that the effect of the mutations on the equilibrium between the semiopen and closed conformations could be one aspect of the mechanism of drug resistance for this mutant. In addition, correlated fluctuations in the active site and periphery were noted that point to a possible binding site for allosteric inhibitors. 相似文献
117.
Sugo T Murakami Y Shimomura Y Harada M Abe M Ishibashi Y Kitada C Miyajima N Suzuki N Mori M Fujino M 《Biochemical and biophysical research communications》2003,310(3):860-868
Urotensin II (UII) has been reported as the most potent known vasoconstrictor. While rat and mouse orthologs of UII precursor protein have been reported, only the tentative structures of UII peptides of these animals have been demonstrated, since prepro-UII proteins lack typical processing sites for their mature peptides. In the present study, we isolated a novel peptide, UII-related peptide (URP), from the extract of the rat brain as the sole immunoreactive substance to anti-UII antibody; the amino acid sequence of the peptide was determined as ACFWKYCV. cDNAs encoding rat, mouse, and human precursor proteins for URP were cloned and revealed that the sequences of mouse and human URP peptides are the same as that for rat URP. Prepro-URP gene is expressed in several rat tissues such as those of the thymus, spleen, testis, and spinal cord, although with lower levels than the prepro-UII gene. In the human, the prepro-URP gene is expressed comparably to prepro-UII in several tissues except the spinal cord. URP was found to bind and activate the human or rat UII receptors (GPR14) and showed a hypotensive effect when administered to anesthetized rats. These results suggest that URP is the endogenous and functional ligand for UII receptor in the rat and mouse, and possibly in the human. We also describe the preparation of specific monoclonal antibodies raised against UII peptide and the establishment of a highly sensitive enzyme immunoassay system for UII peptides. 相似文献
118.
Phosphate Transporter Gene Family of Arabidopsis thaliana 总被引:6,自引:0,他引:6
119.
120.