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991.
Synthesis and antibacterial activity of C6-carbazate ketolides 总被引:1,自引:0,他引:1
Tennakoon MA Henninger TC Abbanat D Foleno BD Hilliard JJ Bush K Macielag MJ 《Bioorganic & medicinal chemistry letters》2006,16(24):6231-6235
A novel series of ketolides containing heteroaryl groups that are linked to the erythronolide ring via a C6-carbazate functionality has been successfully synthesized. Careful modulation of the heteroaryl groups, the length and degree of saturation of the C6-carbazate linker, and the substituents present on each of the carbazate nitrogens led to compounds with potent activity against key bacterial respiratory pathogens. The best analogs of this series had in vitro and in vivo (sc dosing) profiles that were comparable to telithromycin. 相似文献
992.
Sabat M VanRens JC Laufersweiler MJ Brugel TA Maier J Golebiowski A De B Easwaran V Hsieh LC Walter RL Mekel MJ Evdokimov A Janusz MJ 《Bioorganic & medicinal chemistry letters》2006,16(23):5973-5977
This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases). 相似文献
993.
Maier JA Brugel TA Clark MP Sabat M Golebiowski A Bookland RG Laufersweiler MJ Laughlin SK Vanrens JC De B Hsieh LC Brown KK Juergens K Walter RL Janusz MJ 《Bioorganic & medicinal chemistry letters》2006,16(13):3514-3518
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction. 相似文献
994.
Maier JA Brugel TA Sabat M Golebiowski A Laufersweiler MJ VanRens JC Hopkins CR De B Hsieh LC Brown KK Easwaran V Janusz MJ 《Bioorganic & medicinal chemistry letters》2006,16(14):3646-3650
A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study. 相似文献
995.
996.
997.
The products of the herpes simplex virus type 1 immediate-early US1/US1.5 genes downregulate levels of S-phase-specific cyclins and facilitate virus replication in S-phase Vero cells
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Herpes simplex virus type 1 ICP22-/U(S)1.5- mutants initiate viral gene expression in all cells; however, in most cell types, the replication process stalls due to an inability to express gamma2 late proteins. Although the function of ICP22/U(S)1.5 has not been established, it has been suggested that these proteins activate, induce, or repress the activity of cellular proteins during infection. In this study, we hypothesized that cell cycle-associated proteins are targets of ICP22/U(S)1.5. For this purpose, we first isolated and characterized an ICP22-/U(S)1.5- mutant virus, 22/n199. Like other ICP22-/U(S)1.5- mutants, 22/n199 replicates in a cell-type-specific manner and fails to induce efficient gamma2 late gene expression in restrictive cells. Although synchronization of restrictive human embryonic lung cells in each phase of the cell cycle did not overcome the growth restrictions of 22/n199, synchronization of permissive Vero cells in S phase rendered them less able to support 22/n199 plaque formation and replication. Consistent with this finding, expression of cellular S-phase cyclins was altered in an ICP22/U(S)1.5-dependent manner specifically when S-phase Vero cells were infected. Collectively, these observations support the notion that ICP22/U(S)1.5 deregulates the cell cycle upon infection of S-phase permissive cells by altering expression of key cell cycle regulatory proteins either directly or indirectly. 相似文献
998.
Disease modifying therapy for AD?1 总被引:10,自引:0,他引:10
Golde TE 《Journal of neurochemistry》2006,99(3):689-707
Alzheimer's disease (AD) is the most common form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Only two types of drugs are currently approved for the treatment of AD: inhibitors of acetyl cholinesterase, which symptomatically enhance cognitive state to some degree but are not disease modifying; and the adamantane derivative, memantine. Memantine preferentially blocks excessive NMDA receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that blocks excitotoxicty. Memantine therefore may have a potentially disease modifying effect in multiple neurodegenerative conditions. An improved understanding of the pathogeneses of AD has now led to the identification of numerous therapeutic targets designed to alter amyloid beta protein (Abeta) or tau accumulation. Therapies that alter Abeta and tau through these various targets are likely to have significant disease modifying effects. Many of these targets have been validated in proof of concept studies in preclinical animal models, and some potentially disease modifying therapies targeting Abeta or tau are being tested in the clinic. This review will highlight both the promise of and the obstacles to developing such disease modifying AD therapies. 相似文献
999.
The Alzheimer's disease-associated beta-amyloid peptide is produced through cleavage of amyloid precursor protein by beta-secretase and gamma-secretase. gamma-Secretase is a complex containing presenilin (PS) as the catalytic component and three essential cofactors: Nicastrin, anterior pharynx defective (APH-1) and presenilin enhancer-2 (PEN-2). PS and signal peptide peptidase (SPP) define a novel family of aspartyl proteases that cleave substrates within the transmembrane domain presumptively using two membrane-embedded aspartic acid residues for catalysis. Apart from the two aspartate-containing active site motifs, the only other region that is conserved between PS and SPP is a PAL sequence at the C-terminus. Although it has been well documented that this motif is essential for gamma-secretase activity, the mechanism underlying such a critical role is not understood. Here we show that mutations in this motif affect the conformation of the active site of gamma-secretase resulting in a complete loss of PS binding to a gamma-secretase transition state analog inhibitor, Merck C. Analogous mutations in SPP significantly inhibit its enzymatic activity. Furthermore, these mutations also abolish SPP binding to Merck C, indicating that SPP and gamma-secretase share a similar active site conformation, which is dependent on the PAL motif. Exploring the amino acid requirements within this motif reveals a very small side chain requirement, which is conserved during evolution. Together, these observations strongly support the hypothesis that the PAL motif contributes to the active site conformation of gamma-secretase and of SPP. 相似文献
1000.
David B. Rosen Santosh Putta Todd Covey Ying-Wen Huang Garry P. Nolan Alessandra Cesano Mark D. Minden Wendy J. Fantl 《PloS one》2010,5(8)