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61.
The membrane-bound form of mammalian aminopeptidase P (AP-P; EC 3.4. 11.9) is a mono-zinc-containing enzyme that lacks any of the typical metal binding motifs found in other zinc metalloproteases. To identify residues involved in metal binding and catalysis, sequence and structural information was used to align the sequence of porcine membrane-bound AP-P with other members of the peptidase clan MG, including Escherichia coli AP-P and methionyl aminopeptidases. Residues predicted to be critical for activity were mutated and the resultant proteins were expressed in COS-1 cells. Immunoelectrophoretic blot analysis was used to compare the levels of expression of the mutant proteins, and their ability to hydrolyze bradykinin and Gly-Pro-hydroxyPro was assessed. Asp449, Asp460, His523, Glu554, and Glu568 are predicted to serve as metal ion ligands in the active site, and mutagenesis of these residues resulted in fully glycosylated proteins that were catalytically inactive. Mutation of His429 and His532 also resulted in catalytically inactive proteins, and these residues, by analogy with E. coli AP-P, are likely to play a role in shuttling protons during catalysis. These studies indicate that mammalian membrane-bound AP-P has an active-site configuration similar to that of other members of the peptidase clan MG, which is compatible with either a dual metal ion model or a single metal ion in the active site. The latter model is consistent, however, with the known metal stoichiometry of both the membrane-bound and cytosolic forms of AP-P and with a recently proposed model for methionyl aminopeptidase. 相似文献
62.
63.
T.K. Sasikumar Duane A. Burnett Theodros Asberom Wen-Lian Wu Chad Bennett David Cole Ruo Xu William J. Greenlee John Clader Lili Zhang Lynn Hyde 《Bioorganic & medicinal chemistry letters》2010,20(12):3645-3648
Complex tetracyclic sulfones were designed as γ-secretase inhibitors and a stereoselective synthesis was achieved. γ-Secretase activity was seen predominately in the (?) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency. 相似文献
64.
Timothy D. Rohrbach Nishi Shah William P. Jackson Erin V. Feeney Samantha Scanlon Robert Gish Ryan Khodadadi Stephen O. Hyde Patricia H. Hicks Joshua C. Anderson John S. Jarboe Christopher D. Willey 《PloS one》2015,10(10)
Translocation to the nucleus of diacylglycerol kinase (DGK)– ζ is dependent on a sequence homologous to the effector domain of Myristoylated Alanine Rich C-Kinase Substrate (MARCKS). These data would suggest that MARCKS could also localize to the nucleus. A single report demonstrated immunofluorescence staining of MARCKS in the nucleus; however, further experimental evidence confirming the specific domain responsible for this localization has not been reported. Here, we report that MARCKS is present in the nucleus in GBM cell lines. We then over-expressed wild-type MARCKS (WT) and MARCKS with the effector domain deleted (ΔED), both tagged with V5-epitope in a GBM cell line with low endogenous MARCKS expression (U87). We found that MARCKS-WT localized to the nucleus, while the MARCKS construct without the effector domain remained in the cytoplasm. We also found that over-expression of MARCKS-WT resulted in a significant increase in total cellular phosphatidyl-inositol (4,5) bisphosphate (PIP2) levels, consistent with prior evidence that MARCKS can regulate PIP2 levels. We also found increased staining for PIP2 in the nucleus with MARCKS-WT over-expression compared to MARCKS ΔED by immunofluorescence. Interestingly, we observed MARCKS and PIP2 co-localization in the nucleus. Lastly, we found changes in gene expression when MARCKS was not present in the nucleus (MARCKS ΔED). These data indicate that the MARCKS effector domain can function as a nuclear localization signal and that this sequence is critical for the ability of MARCKS to regulate PIP2 levels, nuclear localization, and gene expression. These data suggests a novel role for MARCKS in regulating nuclear functions such as gene expression. 相似文献
65.
Emma Holder Barbara Stevenson Raymond Farley Tom Hilliard Theresa Wodehouse Lucinda Somerton Mia Larsen Jean O'Donoghue Rebecca L. Coles Ronald K. Scheule Seng H. Cheng Deborah R. Gill Stephen C. Hyde Uta Griesenbach Eric W. F. W. Alton David J. Porteous A. Christopher Boyd 《The journal of gene medicine》2010,12(1):55-63
66.
Min Zhong Wang Shen Kenneth J. Barr Jennifer P. Arbitrario Michelle R. Arkin Minna Bui Teresa Chen Brian C. Cunningham Marc J. Evanchik Emily J. Hanan Ute Hoch Karen Huen Jennifer Hyde Jeffery L. Kumer Teresa Lac Chris E. Lawrence Jose R. Martell Johan D. Oslob Kumar Paulvannan Saileta Prabhu W. Mike Flanagan 《Bioorganic & medicinal chemistry letters》2010,20(17):5269-5273
This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model. 相似文献
67.
Mariannaea aquaticola sp. nov. is described, illustrated, and compared with closely related taxa. Phylogenetic analysis of rDNA ITS and 28S sequences
show that Mariannaea aquaticola has affinity with Nectriaceae, which is in agreement with other Mariannaea species. Other morphologically similar genera such as Verticillium and Clonostachys are shown to be phylogenetically distant to Mariannaea. The generic concept of Mariannaea is discussed, and the affinity to Nectriaceous teleomorphs is suggested as additional generic character. A key to Mariannaea species is provided. 相似文献
68.
Josien H Bara T Rajagopalan M Asberom T Clader JW Favreau L Greenlee WJ Hyde LA Nomeir AA Parker EM Pissarnitski DA Song L Wong GT Zhang L Zhang Q Zhao Z 《Bioorganic & medicinal chemistry letters》2007,17(19):5330-5335
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease. 相似文献
69.
Wu-Yang Huang Yi-Zhong Cai Kevin D. Hyde Harold Corke Mei Sun 《World journal of microbiology & biotechnology》2007,23(9):1253-1263
Diverse endophytic fungi exist within plant aerial tissues, with a global estimate of up to a million undescribed species.
These endophytes constitute a rich bio-resource for exploration to discover new natural products. Here we investigate fungal
endophytes associated with a medicinal plant, Nerium oleander L. (Apocynaceae). A total of 42 endophytic fungal strains were isolated from the host plant. Total antioxidant capacity,
xanthine oxidase inhibitory activity, antimicrobial activity, and total phenolic content (TPC) were evaluated for 16 representative
fungal cultures grown in improved Czapek’s broth and for the host plant. The total antioxidant capacities and phenolic contents
of the fungal cultures ranged from 9.59 to 150.79 μmol trolox/100 mL culture, and from 0.52 to 13.95 mg gallic acid/100 mL
culture, respectively. The fungal culture of an endophytic strain Chaetomium sp. showed the strongest antioxidant capacity, contained the highest level of phenolics, and to some extent inhibited xanthine
oxidase activity with an IC50 value of 109.8 μg/mL. A significant positive correlation was found between antioxidant capacity and TPC in the tested samples.
Most of the endophytic fungal cultures tested have a wide range of antimicrobial activities, which were not very strong, but
much better than those of the host plant. The major bioactive constituents of the fungal cultures were investigated using
LC-ESI-MS and GC-MS, and preliminary identification detected phenolics (e.g. phenolic acids and their derivatives, flavonoids)
and volatile and aliphatic compounds. This study shows that the endophytic fungi isolated from N. oleander can be a potential antioxidant resource. 相似文献
70.