全文获取类型
收费全文 | 3592篇 |
免费 | 242篇 |
国内免费 | 5篇 |
专业分类
3839篇 |
出版年
2024年 | 2篇 |
2023年 | 14篇 |
2022年 | 52篇 |
2021年 | 84篇 |
2020年 | 37篇 |
2019年 | 59篇 |
2018年 | 90篇 |
2017年 | 63篇 |
2016年 | 110篇 |
2015年 | 166篇 |
2014年 | 189篇 |
2013年 | 240篇 |
2012年 | 295篇 |
2011年 | 326篇 |
2010年 | 202篇 |
2009年 | 162篇 |
2008年 | 228篇 |
2007年 | 253篇 |
2006年 | 253篇 |
2005年 | 236篇 |
2004年 | 208篇 |
2003年 | 165篇 |
2002年 | 194篇 |
2001年 | 22篇 |
2000年 | 8篇 |
1999年 | 18篇 |
1998年 | 28篇 |
1997年 | 18篇 |
1996年 | 17篇 |
1995年 | 13篇 |
1994年 | 14篇 |
1993年 | 13篇 |
1992年 | 7篇 |
1991年 | 7篇 |
1990年 | 5篇 |
1988年 | 2篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1978年 | 4篇 |
1976年 | 2篇 |
1972年 | 2篇 |
1951年 | 1篇 |
1950年 | 1篇 |
1942年 | 1篇 |
排序方式: 共有3839条查询结果,搜索用时 15 毫秒
101.
Fitch RW Pei XF Kaneko Y Gupta T Shi D Federova I Daly JW 《Bioorganic & medicinal chemistry》2004,12(1):179-190
Homoepiboxidine (3) and the corresponding N-methyl (4) and N-benzyl (5) derivatives were prepared from a 6beta-carbomethoxynortropane (8). Affinities and functional activities at neuromuscular, central neuronal and ganglionic-type nicotinic receptors were compared to those of epibatidine 1, and epiboxidine 2. Homoepiboxidine had equivalent affinity/activity to epiboxidine at neuromuscular, neuronal alpha4beta2, and most alpha3-containing ganglionic-type nicotinic receptors. The N-substituted derivatives showed reduced affinity/activity at most receptor subtypes. Replacement of the methylisoxazole moiety of 3 and 4 with a methyloxadiazole moiety provided analogues 6 and 7, which had greatly reduced affinity/activity in virtually all assays at nicotinic receptors. Marked analgetic activity in mice occurred at the following ip doses: epibatidine 10 microg/kg; epiboxidine 25 microg/kg; homoepiboxidine 100 microg/kg; N-methylhomoepiboxidine 100 microg/kg; the methyloxadiazole (6) 100 microg/kg. The time course at such ip doses was significantly longer for homoepiboxidine 3 with marked analgesia still manifest at 30 min post-injection. Epiboxidine and the homoepiboxidines were less toxic than epibatidine. 相似文献
102.
Dedova IV Nikolaeva OP Mikhailova VV dos Remedios CG Levitsky DI 《Biophysical chemistry》2004,110(1-2):119-128
Differential scanning calorimetry was used to examine the effects of cofilin on the thermal unfolding of actin. Stoichiometric binding increases the thermal stability of both G- and F-actin but at sub-saturating concentrations cofilin destabilizes F-actin. At actin:cofilin molar ratios of 1.5-6 the peaks corresponding to stabilized (66-67 degrees C) and destabilized (56-57 degrees C) F-actin are observed simultaneously in the same thermogram. Destabilizing effects of sub-saturating cofilin are highly cooperative and are observed at actin:cofilin molar ratios as low as 100:1. These effects are abolished by the addition of phalloidin or aluminum fluoride. Conversely, at saturating concentrations, cofilin prevents the stabilizing effects of phalloidin and aluminum fluoride on the F-actin thermal unfolding. These results suggest that cofilin stabilizes those actin subunits to which it directly binds, but destabilizes F-actin with a high cooperativity in neighboring cofilin-free regions. 相似文献
103.
Correction: Caldendrin–Jacob: A Protein Liaison That Couples NMDA Receptor Signalling to the Nucleus
Daniela C Dieterich Anna Karpova Marina Mikhaylova Irina Zdobnova Imbritt K?nig Marco Landwehr Martin Kreutz Karl-Heinz Smalla Karin Richter Peter Landgraf Carsten Reissner Tobias M Boeckers Werner Zuschratter Christina Spilker Constanze I Seidenbecher Craig C Garner Eckart D Gundelfinger Michael R Kreutz 《PLoS biology》2009,7(1)
104.
Codiţă I Caplan DM Drăgulescu EC Lixandru BE Coldea IL Dragomirescu CC Surdu-Bob C Bădulescu M 《Roumanian archives of microbiology and immunology》2010,69(4):204-212
Contaminated surfaces are possible vehicles in infection transmission. It is known that both Copper (Cu) and Silver (Ag) efficiently inactivate microbes by direct contact. Aiming at using these metals for benefitting from their antimicrobial effect, but to avoid subsequent toxic effects, we evaluated the antimicrobial activity of nanometric thin Silver and Copper films covering less expensive materials. Using a modified version of the Japan Industrial Standard JIS Z 2801:2000, we demonstrated the antimicrobial activity of the surfaces covered with metal ions nanofilms on microorganisms possibly involved in nosocomial infections and on Bacillus anthracis, bacteria with possible implication in bioterrorist attacks. Copper covered surfaces proved to have better antimicrobial activity than Silver surfaces. Silver covered surfaces showed better activity on Gram negative bacteria than on Gram positive cocci. Going deeper with studies on antimicrobial effects using new methods with better direct and/or functional discriminatory capacity is needed in order to provide additional information on the mechanisms of Silver and Copper nanofilms antimicrobial activity. 相似文献
105.
Following incubation of mesophilic methanogenic floccular sludge from a lab-scale upflow anaerobic sludge bed reactor used to treat cattle manure wastewater, a stable 5-aminosalicylate-degrading enrichment culture was obtained. Subsequently, a Citrobacter freundii strain, WA1, was isolated from the 5-aminosalicylate-degrading methanogenic consortium. The methanogenic enrichment culture degraded 5-aminosalicylate completely to CH4, CO2 and NH4
+, while C. freundii strain WA1 reduced 5-aminosalicylate with simultaneous deamination to 2-hydroxybenzyl alcohol during anaerobic growth with electron donors such as pyruvate, glucose or serine. When grown on pyruvate, C. freundii WA1 converted 3-aminobenzoate to benzyl alcohol and also reduced benzaldehyde to benzyl alcohol. Pyruvate was fermented to acetate, CO2, H2 and small amounts of lactate, succinate and formate. Less lactate (30%) was produced from pyruvate when C. freundii WA1 grew with 5-aminosalicylate as co-substrate. 相似文献
106.
Sevostyanova IA Solovjeva ON Kochetov GA 《Biochemical and biophysical research communications》2004,313(3):771-774
Yeast transketolase, in addition to catalyzing the transferase reaction through utilization of two substrates--the donor substrate (ketose) and the acceptor substrate (aldose)--is also able to catalyze a one-substrate reaction with only aldose (glycolaldehyde) as substrate. The interaction of glycolaldehyde with holotransketolase results in formation of the transketolase reaction intermediate, dihydroxyethyl-thiamin diphosphate. Then the glycolaldehyde residue is transferred from dihydroxyethyl-thiamin diphosphate to free glycolaldehyde. As a result, the one-substrate transketolase reaction product, erythrulose, is formed. The specific activity of transketolase was found to be 0.23 U/mg and the apparent Km for glycolaldehyde was estimated as 140 mM. 相似文献
107.
Protein changes and proteolytic degradation in red and white clover plants subjected to waterlogging
Veselin Stoychev Lyudmila Simova-Stoilova Irina Vaseva Anelia Kostadinova Rosa Nenkova Urs Feller K. Demirevska 《Acta Physiologiae Plantarum》2013,35(6):1925-1932
Red (Trifolium pratense L., cv. “Start”) and white clover varieties (Trifolium repens L., cv. “Debut” and cv. “Haifa”) were waterlogged for 14 days and subsequently recovered for the period of 21 days. Physiological and biochemical responses of the clover varieties were distinctive, which suggested different sensitivity toward flooding. The comparative study of morphological and biochemical parameters such as stem length, leaflet area, dry weight, protein content, protein pattern and proteolytic degradation revealed prominent changes under waterlogging conditions. Protease activity in the stressed plants increased significantly, especially in red clover cv. “Start”, which exhibited eightfold higher azocaseinolytic activity compared to the control. Changes in the protein profiles were detected by SDS-PAGE electrophoresis. The specific response of some proteins (Rubisco, Rubisco-binding protein, Rubisco activase, ClpA and ClpP protease subunits) toward the applied stress was assessed by immunoblotting. The results characterized the red clover cultivar “Start” as the most sensitive toward waterlogging, expressing reduced levels of Rubisco large and small subunits, high content of ClpP protease subunits and increased activity of protease isoforms. 相似文献
108.
Iman Azimi Jack U. Flanagan Ralph J. Stevenson Marco Inserra Irina Vetter Gregory R. Monteith William A. Denny 《Bioorganic & medicinal chemistry》2017,25(1):440-449
The Orai1 Ca2+ permeable ion channel is an important component of store operated Ca2+ entry (SOCE) in cells. It’s over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays. The assay was also used in a screening project seeking novel inhibitors. Following a broad literature survey of classes of calcium channel inhibitors we used simplified ligand structures to query the ZINC on-line database, and following two iterations of refinement selected a novel Orai1-selective dichlorophenyltriazole hit compound. Analogues of this were synthesized and evaluated in the FLIPR assay to develop structure–activity relationships (SAR) for the three domains of the hit; triazole (head), dichlorophenyl (body) and substituted phenyl (tail). For this series, the results suggested the need for a lipophilic tail domain and an out-of-plane twist between the body and tail domains. 相似文献
109.
Irina V. Kholodenko Alisa M. Gisina Garik V. Manukyan Alexander G. Majouga Elena V. Svirshchevskaya Roman V. Kholodenko Konstantin N. Yarygin 《Current issues in molecular biology》2022,44(8):3428
Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, presumably by apoptosis. As the mechanisms of MSC apoptosis are not fully understood, in the present work we analyzed MSC sensitivity to Fas-induced apoptosis using MSCs isolated from the biopsies of liver fibrosis patients (L-MSCs). The level of cell death was analyzed by flow cytometry in the propidium iodide test. The luminescent ATP assay was used to measure cellular ATP levels; and the mitochondrial membrane potential was assessed using the potential-dependent dye JC-1. We found that human L-MSCs were resistant to Fas-induced cell death over a wide range of FasL and anti-Fas mAb concentrations. At the same time, intrinsic death signal inducers CoCl2 and staurosporine caused apoptosis of L-MSCs in a dose-dependent manner. Despite the absence of Fas-induced cell death treatment of L-MSCs with low concentrations of FasL or anti-Fas mAb resulted in a cellular ATP level decrease, while high concentrations of the inducers caused a decline of the mitochondrial membrane potential. Pre-incubation of L-MSCs with the pro-inflammatory cytokine TNF-α did not promote L-MSC cell death. Our data indicate that human L-MSCs have increased resistance to receptor-mediated cell death even under inflammatory conditions. 相似文献
110.
Low-dissolved-oxygen nitrifying systems exploit ammonia-oxidizing bacteria with unusually high yields 总被引:1,自引:0,他引:1
Bellucci M Ofiteru ID Graham DW Head IM Curtis TP 《Applied and environmental microbiology》2011,77(21):7787-7796
In wastewater treatment plants, nitrifying systems are usually operated with elevated levels of aeration to avoid nitrification failures. This approach contributes significantly to operational costs and the carbon footprint of nitrifying wastewater treatment processes. In this study, we tested the effect of aeration rate on nitrification by correlating ammonia oxidation rates with the structure of the ammonia-oxidizing bacterial (AOB) community and AOB abundance in four parallel continuous-flow reactors operated for 43 days. Two of the reactors were supplied with a constant airflow rate of 0.1 liter/min, while in the other two units the airflow rate was fixed at 4 liters/min. Complete nitrification was achieved in all configurations, though the dissolved oxygen (DO) concentration was only 0.5 ± 0.3 mg/liter in the low-aeration units. The data suggest that efficient performance in the low-DO units resulted from elevated AOB levels in the reactors and/or putative development of a mixotrophic AOB community. Denaturing gel electrophoresis and cloning of AOB 16S rRNA gene fragments followed by sequencing revealed that the AOB community in the low-DO systems was a subset of the community in the high-DO systems. However, in both configurations the dominant species belonged to the Nitrosomonas oligotropha lineage. Overall, the results demonstrated that complete nitrification can be achieved at low aeration in lab-scale reactors. If these findings could be extended to full-scale plants, it would be possible to minimize the operational costs and greenhouse gas emissions without risk of nitrification failure. 相似文献