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991.
Klöck C Jin X Choi K Khosla C Madrid PB Spencer A Raimundo BC Boardman P Lanza G Griffin JH 《Bioorganic & medicinal chemistry letters》2011,21(9):2692-2696
Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had Ki values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals. 相似文献
992.
993.
We are witnessing the growing menace of both increasing cases of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains and the challenge to produce the first new tuberculosis (TB) drug in well over 40 years. The TB community, having invested in extensive high-throughput screening efforts, is faced with the question of how to optimally leverage these data to move from a hit to a lead to a clinical candidate and potentially, a new drug. Complementing this approach, yet conducted on a much smaller scale, cheminformatic techniques have been leveraged and are examined in this review. We suggest that these computational approaches should be optimally integrated within a workflow with experimental approaches to accelerate TB drug discovery. 相似文献
994.
995.
The FDA-approved drug suberoylanilide hydroxamic acid (SAHA, Vorinostat) was modified to improve its selectivity for a single histone deaetylase (HDAC) isoform. We show that attaching an ethyl group at the C3 position transforms SAHA from nonselective to an HDAC6-selective inhibitor. Theses results indicate that small structural changes in SAHA can significantly influence selectivity, which will lead future anti-cancer design efforts targeting HDAC proteins. 相似文献
996.
997.
While natural antimicrobial peptides are potential therapeutic agents, their physicochemical properties and bioactivity generally
need to be enhanced for clinical and commercial development. We have previously developed a cationic, amphipathic α-helical,
11-residue peptide (named herein GA-W2: FLGWLFKWASK-NH2) with potent antimicrobial and hemolytic activity, which was derived from a 24-residue, natural antimicrobial peptide isolated
from frog skin. Here, we attempted to optimize peptide bioactivity by a rational approach to sequence modification. Seven
analogues were generated from GA-W2, and their activities were compared with that of a 12-residue peptide, omiganan, which
is being developed for clinical and commercial applications. Most of the modifications reported here improved antimicrobial
activity. Among them, the GA-K4AL (FAKWAFKWLKK-NH2) peptide displayed the most potent antimicrobial activity with negligible hemolytic activity, superior to that of omiganan.
The therapeutic index of GA-K4AL was improved more than 53- and more than 31-fold against Gram-negative and Gram-positive
bacteria, respectively, compared to that of the starting peptide, GA-W2. Given its relatively shorter length and simpler amino
acid composition, our sequence-optimized GA-K4AL peptide may thus be a potentially useful antimicrobial peptide agent. 相似文献
998.
Choi JM Chu SJ Ahn KH Kim SK Ji JE Won JH Kim HC Back MJ Kim DK 《Molecules and cells》2011,32(4):325-331
Ceramide has been suggested to be not only a tumorsuppressive lipid but also a regulator of phagocytosis. We examined whether
exogenous cell-permeable C6-ceramide enhances the phagocytic activity of Kupffer cells (KCs) and affects the level of cellular ceramides. Rat KCs were
isolated by collagenase digestion and differential centrifugation, using Percoll system. Phagocytic activity was measured
by FACS analysis after incubating KCs with fluorescence-conjugated latex beads, and the level of cellular ceramide was analyzed
by liquid chromatography tandem-mass spectrometry (LC-MS/MS). In this study we found that permeable C6-ceramide increases the cellular levels of endogenous ceramides via a sphingosine-recycling pathway leading to enhanced phagocytosis
by KCs. 相似文献
999.
Interleukin 10 (IL-10) is a multifunctional cytokine that regulates diverse functions of immune cells. Natural killer (NK)
cells express the IL-10 and IL-10 receptor, but little is known about the function of IL-10 on NK cell activation. In this
study, we show the expression and role of IL-10 in human NK cells. Among the cytokines tested, IL-15 was the most potent inducer
of IL-10, with a maximal peak expression at 5 h after treatment. Furthermore, IL-10 receptor was shown to be expressed in
NK cells. IL-10 alone had a significant effect on NK cytotoxicity which additively increased NK cell cytotoxicity in the presence
of IL-15. Neutralizing IL-10 with anti-IL-10 antibody suppressed the inductive effect of IL-10 on NK cell cytotoxicity; however,
IL-10 had no effect on IFN-γ or TNF-α production or NK cell activatory receptor expression. STAT signals are implicated as
a key mediator of IL-10/IL-15 cytotoxicity response. Thus, the effect of IL-10 on NK cells is particularly interesting with
regard to the STAT3 signal that was enhanced by IL-10 or IL-15. 相似文献
1000.
Kim SN Shim HP Jeon BN Choi WI Hur MW Girton JR Kim SH Jeon SH 《Molecules and cells》2011,32(6):549-554
Polycomb group (PcG) proteins maintain the spatial expression patterns of genes that are involved in cell-fate specification
along the anterior-posterior (A/P) axis. This repression requires cis-acting silencers, which are called PcG response elements (PREs). One of the PcG proteins, Pleiohomeotic (Pho), which has
a zinc finger DNA binding protein, plays a critical role in recruiting other PcG proteins to bind to PREs. In this study,
we characterized the effects of a pho mutation on embryonic segmentation. pho maternal mutant embryos showed various segmental defects including pair-rule gene mutant patterns. Our results indicated
that engrailed and even-skipped genes were misexpressed in pho mutant embryos, which caused embryonic segment defects. 相似文献