全文获取类型
收费全文 | 7453篇 |
免费 | 354篇 |
国内免费 | 304篇 |
出版年
2024年 | 11篇 |
2023年 | 82篇 |
2022年 | 157篇 |
2021年 | 168篇 |
2020年 | 230篇 |
2019年 | 344篇 |
2018年 | 349篇 |
2017年 | 239篇 |
2016年 | 248篇 |
2015年 | 211篇 |
2014年 | 483篇 |
2013年 | 745篇 |
2012年 | 234篇 |
2011年 | 433篇 |
2010年 | 261篇 |
2009年 | 331篇 |
2008年 | 332篇 |
2007年 | 346篇 |
2006年 | 284篇 |
2005年 | 288篇 |
2004年 | 263篇 |
2003年 | 235篇 |
2002年 | 205篇 |
2001年 | 126篇 |
2000年 | 91篇 |
1999年 | 96篇 |
1998年 | 96篇 |
1997年 | 112篇 |
1996年 | 115篇 |
1995年 | 89篇 |
1994年 | 70篇 |
1993年 | 73篇 |
1992年 | 71篇 |
1991年 | 64篇 |
1990年 | 35篇 |
1989年 | 46篇 |
1988年 | 35篇 |
1987年 | 40篇 |
1986年 | 40篇 |
1985年 | 47篇 |
1984年 | 80篇 |
1983年 | 45篇 |
1982年 | 63篇 |
1981年 | 40篇 |
1980年 | 37篇 |
1979年 | 37篇 |
1978年 | 19篇 |
1977年 | 18篇 |
1976年 | 19篇 |
1974年 | 15篇 |
排序方式: 共有8111条查询结果,搜索用时 296 毫秒
991.
《Bioorganic & medicinal chemistry letters》2014,24(8):1923-1927
Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery. 相似文献
992.
《Bioorganic & medicinal chemistry letters》2014,24(18):4402-4406
The oral pathogenic bacterium Porphyromonas gingivalis, encodes for two carbonic anhydrase (CA, EC 4.2.1.1) one belonging to the β-class (PgiCAb) and another one to the γ-class (PgiCA). This last enzyme has been characterized earlier for its inhibition profile with various classes of CA inhibitors, such as the sulfonamides and anions, whereas for PgiCAb such data were not yet reported. Here we show that PgiCAb has a good catalytic activity for the CO2 hydration reaction, with kcat 2.8 × 105 s−1 and kcat/Km of 1.5 × 107 M−1 × s−1, being inhibited by cyanate and diethyldithiocarbamate in the submillimolar range (KIs of 0.23–0.76 mM) and more efficiently by sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid (KIs of 60–78 μM). The anion inhibition profile of the two P. gingivalis enzymes is very different. Identification of selective inhibitors of PgiCAb/PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of these enzymes, since this bacterium is the main causative agent of periodontitis and few treatment options are presently available. 相似文献
993.
Inhibition of cell-substratum attachment of cultured rat heart cells by protein synthesis inhibitors
David W. Speicher Richard L. McCarl 《Biochimica et Biophysica Acta (BBA)/General Subjects》1979,583(3):394-402
Addition of cycloheximide to growth medium of neonatal rat heart cell cultures prevented cell-substratum attachment. Even concentrations of cycloheximide which inhibited only 50% of normal protein synthesis prevented some cells from attaching. Cells which required the longest time to attach were most dependent on protein synthesis. The kinetics of cell-substratum adhesion in the presence of various concentrations of cycloheximide supported the hypothesis that repair of damaged cell membranes was required prior to attachment. An alternate hypothesis that protein synthesis was required for substratum attachment either to synthesize new unique proteins or higher concentrations of existing proteins not damaged by enzymes was not supported by experimentally obtained data. If the second hypothesis were true, no cells would have attached when protein synthesis was completely inhibited (greater than 95%) and all cells should have been equally affected by protein synthesis inhibition; such was not the case. Inhibition of mRNA formation by actinomycin D also should have inhibited attachement completely and this was not observed. Since attachment was minimally affected by actinomycin D, protein synthesis on long-lived mRNA was apparently sufficient for cell-substratum adhesion. 相似文献
994.
The Oxidative Inactivation of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) by Hypochlorous Acid (HOCl) is Suppressed by Anti-Rheumatic Drugs 总被引:2,自引:0,他引:2
Tissue inhibitors of metalloproteinases (TIMPs) prevent uncontrolled connective tissue destruction by limiting the activity of matrix metalloproteinases (MMPs). That TIMPs should be susceptible to oxidative inactivation is suggested by their complex tertiary structure which is dependent upon 6 disulphide bonds. We examined the oxidative inactivation of human recombinant TIMP-1 (hr TIMP-1) by HOCl and the inhibition of this process by anti-rheumatic agents.
TIMP-1 was exposed to HOCl in the presence of a variety of disease modifying anti-rheumatic drugs. TIMP-1 activity was measured by its ability to inhibit BC1 collagenase activity as measured by a fluorimetric assay using the synthetic pEptide substrate (DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg), best cleaved by MMP-1.
The neutrophil derived oxidant HOCl, but not the derived oxidant N-chlorotaurine, can inactivate TIMP-1 at concentrations achieved at sites of inflammation. Anti-rheumatic drugs have the ability to protect hrTIMP-1 from inactivation by HOCl. For D-penicil-lamine, this effect occurs at plasma levels achieved with patients taking the drug but for other anti-rheumatic drugs tested this occurs at relatively high concentrations that are unlikely to be achieved in vivo, except possibly in a microenvironment. These results are in keeping with the concept that biologically derived oxidants can potentiate tissue damage by inactivating key but susceptible protein inhibitors such as TIMP-1 which form the major local defence against MMP induced tissue breakdown. 相似文献
TIMP-1 was exposed to HOCl in the presence of a variety of disease modifying anti-rheumatic drugs. TIMP-1 activity was measured by its ability to inhibit BC1 collagenase activity as measured by a fluorimetric assay using the synthetic pEptide substrate (DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg), best cleaved by MMP-1.
The neutrophil derived oxidant HOCl, but not the derived oxidant N-chlorotaurine, can inactivate TIMP-1 at concentrations achieved at sites of inflammation. Anti-rheumatic drugs have the ability to protect hrTIMP-1 from inactivation by HOCl. For D-penicil-lamine, this effect occurs at plasma levels achieved with patients taking the drug but for other anti-rheumatic drugs tested this occurs at relatively high concentrations that are unlikely to be achieved in vivo, except possibly in a microenvironment. These results are in keeping with the concept that biologically derived oxidants can potentiate tissue damage by inactivating key but susceptible protein inhibitors such as TIMP-1 which form the major local defence against MMP induced tissue breakdown. 相似文献
995.
Aiming at estimating the average N2-fixation in a pasture, ap preciating the great variability due to patchy urine and dung deposition, the in fluence of dairy cow excreta on biological N2-fixation in a perennial ryegrass–white clover mixture was studied using natural urine and dung. Application of urine as well as dung affected the N2-fixation by promoting the growth of grass and thereby the proportion of clover was significantly reduced. Also the proportion of clover-N derived from the atmosphere (pNdfa) was significantly reduced. In control plots clover dry matter constituted between 40 and 50% of the total dry matter production and the pNdfa ranged between 0.8 and 0.9. Addition of urine caused a significant increase in the grass growth rates, which was the primary reason for a decrease in proportion of clover. At the same time pNdfa decreased to 0.2–0.4 followed by an increase resulting in a total reduction of 45% in the N2-fixation in urine affected areas over a period of four months. The dung only affected the N2-fixation for a distance of up to 10 cm from the edge of the dung pats. In this border area the pNdfa decreased from 0.85 to 0.75 during one month after application followed by an increase, so that after three months there was no difference between pNdfa at 0–10 and 10–20 cm distance from the dung hill. The proportion of clover was lower in the 0–10 cm than in the 10–20 cm distance, which totally resulted in a total reduction of 20% in the N2-fixation over a period of four months in the 0–10 cm area around the dung pats. Considering the proportion of a pasture which may by affected by excreta at a stocking density of 4–6 cows ha-1, the length of the grazing period, the frequency of excretion and the area covered by individual patches, it was estimated that the N2-fixation in a grass-clover pasture would be reduced by 10–15% compared to the N2-fixation in a grass-clover sward not exposed to animal excreta. 相似文献
996.
997.
Increased Solubility of High-Molecular-Mass Neurofilament Subunit by Suppression of Dephosphorylation: Its Relation to Axonal Transport 总被引:4,自引:1,他引:3
Abstract: To investigate the role of phosphorylation in the turnover and transport of neurofilament (NF) proteins in vivo, we studied their solubility properties and axonal transport in the rat sciatic nerve using phosphatase inhibitors to minimize dephosphorylation during preparation. About 20% of the 200-kDa subunit (NF-H) in the axon was soluble in the 1% Triton-containing buffer under the present conditions, whereas this amount was less and more variable in the absence of phosphatase inhibitors. The 68-kDa subunit (NF-L) was exclusively insoluble and not affected by the inhibitors. Such selective solubilization of NF-H by phosphorylation differed significantly from the in vitro phosphorylation with cyclic AMP-dependent protein kinase, which resulted in NF disassembly. The carboxy-terminal phosphorylation state of NF-H probed with the phosphorylation-sensitive antibodies was also not directly related to solubility. The solubility of NF-H did not differ along the nerve. In contrast, the solubility of l -[35 S]methionine-labeled, transported NF-H was lowest at the peak of radioactivity. Higher solubility at the leading edge, regardless of its location along the nerve, indicates that NF-H solubility is positively correlated with the rate of NF transport. 相似文献
998.
There was little release of extractable SO4-S during four weeks from CS2 applied by injecting into two S-deficient soils. In this incubation experiment, the rate of CS2 was 30 μg S g−, placement was injection at 9 cm depth, soil temperature was 20°C, and soil moisture tension was 33 kPa. The yield of barley
forage after seven weeks in the greenhouse showed only small increases from 10 or 30 μg S g−1 of CS2 as compared to Na2SO4, on the two soils.
While CS2 supplied little plant available S in the short term, it was an effective inhibitor of nitrification. In the laboratory, or
in the field, the injection of CS2 (with N fertilizers) at a point 9 cm into the soils either stopped or reduced nitrification. In one laboratory experiment,
35 μg of CS2 g−1 of soil with urea reduced nitrification for at least four weeks; and in another experiment 20 μg of CS2 g−1 of soil with aqua NH3 nearly or completely inhibited nitrification at 20 days. In two field experiments, 3 and 12 μg of CS2 g−1 of soil (or 6 and 24 kg ha−1) with aqua NH3 inhibited nitrification from October to the subsequent May. In addition, CS2 reduced the amount of ammonium produced from the soil N, both in these two field experiments and in the laboratory experiments.
That is to say, CS2 injected at a point, inhibited both nitrification and ammonification.
In other field experiments, CS2 at a rate of 10 kg ha−1 was injected in bands 9 cm deep with urea in October, and by May there was still reduced nitrification. Less than half of
the fall-applied urea alone was recovered as mineral N, but with the application of CS2 the recovery was increased to three-quarters.
The yield and N uptake of barley grain was increased where fall-applied banded urea or aqua NH3 received banded CS2, (NH4)2CS3, or K2CS3. The average increase in yield from fall-applied fertilizer, from inhibitor with fall-applied fertilizer, and from spring-applied
fertilizer was 800, 1370, and 1900 kg ha−1, respectively. In the same order, the apparent % recovery of fertilizer N in grain was 24, 42, and 60. 相似文献
999.
Gilles Lalmanach Johan Hoebeke Thierry Moreau Michèle Brillard-Bourdet Michèle Ferrer-Di Martino Francisco Borras-Cuesta Francis Gauthier 《Journal of Protein Chemistry》1993,12(1):23-31
The interaction between papain and synthetic peptides which tentatively mimic cystatin surfaces was investigated both enzymatically and structurally. Measurements of dissociation equilibrium constants for the interaction of papain with these peptides modified by successive deletions or substitutions demonstrated that the QVVAG segment, which is highly conserved throughout members of the cystatin superfamily, is essential for the interaction. The glycylcontaining (N-terminal) fragments and PW-containing (C-terminal) fragments were found to be of lesser importance, since each could be deleted without significantly modifying the interaction. These fragments improved the stability of the interacting QVVAG region, which appeared to be substrate-like in all peptides tested, as it was cleaved at the A-G bond upon peptide-papain interaction. Replacement of the A residue at the scissile bond of the QVVAG by a blocked cysteinyl residue reduced the rate of cleavage of the susceptible bond and therefore shifted the resulting peptide from a substrate to an inhibitor. Derivatization of this substituted peptide at its N- and C-terminal ends by fluoresceinyl groups resulted in a dramatic decrease in theK
i to 0.5 µM. This improvement in the inhibitory properties of the substituted and derivatized peptides was correlated with structural changes as analyzed by molecular dynamic calculations. The results were compared to those proposed for the mechanism of inhibition by natural inhibitors of the cystatin superfamily. 相似文献
1000.
DNMT and HDAC are closely related to each other and involved in various human diseases especially cancer. These two enzymes have been widely recognized as antitumor targets for drug discovery. Besides, research has indicated that combination therapy consisting of DNMT and HDAC inhibitors exhibited therapeutic advantages. We have reported a DNMT and HDAC dual inhibitor 15a of which the DNMT enzymatic inhibitory potency needs to be improved. Herein we reported the development of a novel dual DNMT and HDAC inhibitor C02S which showed potent enzymatic inhibitory activities against DNMT1, DNMT3A, DNMT3B and HDAC1 with IC50 values of 2.05, 0.93, 1.32, and 4.16 µM, respectively. Further evaluations indicated that C02S could inhibit DNMT and HDAC at cellular levels, thereby inversing mutated methylation and acetylation and increasing expression of tumor suppressor proteins. Moreover, C02S regulated multiple biological processes including inducing apoptosis and G0/G1 cell cycle arrest, inhibiting angiogenesis, blocking migration and invasion, and finally suppressing tumor cells proliferation in vitro and tumor growth in vivo. 相似文献