全文获取类型
收费全文 | 9275篇 |
免费 | 827篇 |
国内免费 | 16篇 |
出版年
2023年 | 38篇 |
2022年 | 29篇 |
2021年 | 159篇 |
2020年 | 115篇 |
2019年 | 144篇 |
2018年 | 198篇 |
2017年 | 187篇 |
2016年 | 268篇 |
2015年 | 479篇 |
2014年 | 485篇 |
2013年 | 602篇 |
2012年 | 730篇 |
2011年 | 662篇 |
2010年 | 433篇 |
2009年 | 415篇 |
2008年 | 574篇 |
2007年 | 517篇 |
2006年 | 457篇 |
2005年 | 419篇 |
2004年 | 391篇 |
2003年 | 351篇 |
2002年 | 324篇 |
2001年 | 187篇 |
2000年 | 168篇 |
1999年 | 136篇 |
1998年 | 81篇 |
1997年 | 69篇 |
1996年 | 53篇 |
1995年 | 76篇 |
1994年 | 46篇 |
1993年 | 54篇 |
1992年 | 86篇 |
1991年 | 75篇 |
1990年 | 79篇 |
1989年 | 83篇 |
1988年 | 80篇 |
1987年 | 78篇 |
1986年 | 65篇 |
1985年 | 73篇 |
1984年 | 53篇 |
1983年 | 45篇 |
1982年 | 36篇 |
1980年 | 31篇 |
1979年 | 50篇 |
1978年 | 45篇 |
1977年 | 30篇 |
1976年 | 42篇 |
1975年 | 33篇 |
1974年 | 32篇 |
1973年 | 26篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
991.
A liquid chromatography stationary phase containing immobilized membranes obtained from a cell line that expresses the human organic cation transporter (hOCT1-IAM) has been used to study the binding of the enantiomers of propranolol, atenolol, pseudoephedrine, and alpha-methylbenzylamine to the immobilized hOCT1. Frontal displacement chromatography was used to determine the binding affinities (K(d) values), and the data demonstrate that there was an enantioselective difference in the K(d) values of the enantiomers of propranolol, atenolol, and pseudoephedrine, while alpha-methylbenzylamine did not significantly bind to the transporter. Competitive inhibition studies with the cell line used to create the chromatographic column demonstrated that, for the enantiomers of propranolol, the ratio of the chromatographically determined K(d) values [K(d (+)-(R)-propranolol)/K(d (-)-(S)-propranolol) = 2.98] reflected an enantioselective difference in the functional activity of the two enantiomers [IC(50 (+)-(R)-propranolol)/IC(50 (-)-(S)-propranolol) = 2.75]. The chromatographically determined K(d) values were used to construct an initial pharmacophore which contains a hydrogen bond donating site that appears to be responsible for the observed enantioselectivity. 相似文献
992.
The in vitro effect of desipramine on renal tubular cell is unknown. In Madin-Darby canine kidney (MDCK) cells, the effect of desipramine on intracellular Ca2+ concentration ([Ca2+]i) was measured by using fura-2. Desipramine (>25 microM) caused a rapid and sustained rise of [Ca2+]i in a concentration-dependent manner (EC50=50 microM). Desipramine-induced [Ca2+]i rise was prevented by 40% by removal of extracellular Ca2+ but was not altered by L-type Ca2+ channel blockers. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which desipramine failed to release more Ca2+; in addition, pretreatment with desipramine partly decreased thapsigargin-induced [Ca2+]i increase. U73122, an inhibitor of phospholipase C, did not change desipramine-induced [Ca2+]i rise. Incubation with 10-100 microM desipramine enhances or inhibits cell proliferation in a concentration- and time-dependent manner. The inhibitory effect of desipramine on proliferation was not extracellular Ca2+-dependent. Apoptosis appears to contribute to desipramine-induced cell death. Together, these findings suggest that desipramine increases baseline [Ca2+]i in renal tubular cells by evoking both extracellular Ca2+ influx and intracellular Ca2+ release, and can cause apoptosis. 相似文献
993.
Inhibitory effect of Aucubin isolated from Eucommia ulmoides against UVB-induced matrix metalloproteinase-1 production in human skin fibroblasts 总被引:2,自引:0,他引:2
Ho JN Lee YH Lee YD Jun WJ Kim HK Hong BS Shin DH Cho HY 《Bioscience, biotechnology, and biochemistry》2005,69(11):2227-2231
Of 30 herbal plants tested, the methanol extracts of Eucommia ulmoides (52%), Evodia officinalis (45%), and Pleuropterus multiflorus (41%) each showed a potent inhibitory effect on the matrix metalloproteinase-1 (MMP-1) production in ultraviolet B (UVB)-irradiated human fibroblasts. Aucubin was isolated as the MMP-1 inhibitor from E. ulmoides, and significantly suppressed the production of MMP-1 by nearly 57% compared to the control. It also reduced MMP-1 mRNA expression. These results suggest that aucubin is a photoprotective phytochemical, and could be used as a potential agent in preventing photoaging. 相似文献
994.
Sphingosylphosphorylcholine (SPC) is a bioactive lipid molecule involved in numerous biological processes. Treatment of MS1 pancreatic islet endothelial cells with SPC increased phospholipase D (PLD) activity in a time- and dose-dependent manner. In addition, treatment of the MS1 cells with 10 microM SPC induced stimulation of phospholipase C (PLC) activity and transient elevation of intracellular Ca2+. The SPC-induced PLD activation was prevented by pretreatment of the MS1 cells with a PLC inhibitor, U73122, and an intracellular Ca2+-chelating agent, BAPTA-AM. This suggests that PLC-dependent elevation of intracellular Ca2+ is involved in the SPC-induced activation of PLD. The SPC-dependent PLD activity was also almost completely prevented by pretreatment with pan-specific PKC inhibitors, GF109203X and RO-31-8220, and with a PKCdelta-specific inhibitor, rottlerin, but not by pretreatment with GO6976, a conventional PKC isozymes-specific inhibitor. Adenoviral overexpression of a kinase-deficient mutant of PKCdelta attenuated the SPC-induced PLD activity. These results suggest that PKCdelta plays a crucial role for the SPC-induced PLD activation. The SPC-induced PLD activation was preferentially potentiated in COS-7 cells transfected with PLD2 but not with PLD1, suggesting a specific implication of PLD2 in the SPC-induced PLD activation. SPC treatment induced phosphorylation of PLD2 in COS-7 cells, and overexpression of the kinase-deficient mutant of PKCdelta prevented the SPC-induced phosphorylation of PLD2. Furthermore, SPC treatment generated reactive oxygen species (ROS) in MS1 cells and the SPC induced production of ROS was inhibited by pretreatment with U73122, BAPTA-AM, and rottlerin. In addition, pretreatment with a PLD inhibitor 1-butanol and overexpression of a lipase-inactive mutant of PLD2 but not PLD1 attenuated the SPC-induced generation of ROS. These results suggest that PLC-, Ca2+-, PKCdelta-, and PLD2-dependent pathways are essentially required for the SPC induced ROS generation. 相似文献
995.
996.
Park JY Kim HY Lee JY Kim KH Jang MK Lee JH Yoo JY Han DS Hahm JS 《FEMS immunology and medical microbiology》2005,44(2):171-176
Macrolide antibiotics have an anti-inflammatory effect by suppressing lipopolysaccharide-induced IL-8 production. IL-8 secretion from monocytes is observed in Helicobacter pylori infection. Although cag gene products are known to induce IL-8 secretion, whether other bacterial substances can initiate the reaction is not determined. In this study, we show that clarithromycin induced down-regulation of Toll-like receptor 4 expression and did not lead to a decrease in IL-8 production and H. pylori lipopolysaccharide. However, Toll-like receptor 4 activation was possibly not the main cause in the induction of inflammation during H. pylori infection. 相似文献
997.
Summary. The study was designed to investigate the effects of NMDA receptor agonist on the behavioral activity in rats with experimental hyperammonemia. The experiments were performed on adult male Wistar rats. Experimental hyperammonemia was induced by intraperitoneal injections of tioacetamide (TAA, 200mg/kg) for three consecutive days. Rats treated with saline (0.9%) served as control. Stimulation of the NMDA glutamatergic receptor was evoked by ip. injection of agonist N-methyl-D-aspartate acid (NMDA) in a dose of 30mg/kg thirty minutes before experiments. Memory motivated affectively was evaluated in the passive avoidance responses. The speculative influence of the treatment on anxiety and motor activity was tested in elevated plus-maze and in open field respectively.To show change of NMDA receptor function after various doses of agonist, the seizures evoked by N-methyl-D-aspartate acid was carried out. This experiment showed that with rise of dose of NMDA time to appear of convulsions was contracted in rats with hyperammonemia as well as in control rats. Dose of NMDA caused convulsions was three times as less in rats with hyperammonemia than dose in control. Time of duration of convulsions was proportional to applied dose of NMDA and it lengthened with rise of agonists dose in both groups of studied animals.Furthermore, we observed that NMDA increased motor activity of control rats in open field test, but not in rats with hyperammonemia (treated tioacetamide). Hyperammonemia did not have significant influence on motor activity and on a passive avoidance latency. The NMDA given in control and in hyperammonemia, increased acquisition, consolidation and recall of a passive avoidance responses. Moreover, NMDA had anxiogenic-like profile in elevated plus-maze.In rats with hyperammonemia NMDA had no influence on locomotor activity but it significantly increased memory in a passive avoidance responses. Furthermore, we observed that reactivity of NMDA glutamate receptor in rats with hyperammonemia was higher than in control rats. 相似文献
998.
Filek M Hołda M Machácková I Krekule J 《Zeitschrift für Naturforschung. C, Journal of biosciences》2005,60(11-12):876-882
The influence of electric field treatment on dedifferentiation and calli formation on rape hypocotyls was investigated. Segments, 10 mm long, of the upper part of rape (Brassica napus L., cv. Góczański) hypocotyls were stimulated by different combinations of voltage/time (1.5 V/120 h, 3 V/3 h, 10 V/15 min and 30 V/30 s) under in vitro conditions. With all electric field treatments, segments oriented with their apical part towards the cathode produced more calli as compared to control (non-treated with electric field). Under opposite orientation slight inhibition of callus growth was observed. As the strongest effect on callus growth was observed after treatment with 30 V/30 s, this electric field treatment was selected for following analyses: the incorporation of [14C]-2,4-D (2,4-dichlorophenoxyacetic acid) and [14C]-BAP (benzylaminopurine) from the culture medium, changes in ACC (1-aminocyclopropane-1-carboxylic acid) level and the redox activity in apical and bottom parts of hypocotyls during 18 d of culture. In contrast to changes in fresh weight, electric field treatment (30 V/30 s) stimulated a higher accumulation of 2,4-D and BAP in basal parts of hypocotyls than in apical ones. Moreover, orienting the apical part towards the cathode resulted in lower uptake of hormones as compared with the opposite orientation. The ACC concentration increased, especially in the basal parts of hypocotyls, independently on electric field application. However, the highest level was observed after electric field treatment with orientation of the apical part towards the anode. The distribution of oxidative substances (measured as the amount of ferric ions) between the apical and bottom part of hypocotyls was not changed when the apical parts were oriented towards the cathode. Under these conditions a decrease in apical and an increase in basal parts was observed during culture. Opposite orientation influenced the redistribution of oxidative substances from the first day of electric field treatment. Based on these results we suggest that electric field action can be connected with its influence on specific concentration of oxidative substances and hormone distribution in cells. 相似文献
999.
Molecular characterization of FK-506 binding protein 38 and its potential regulatory role on the anti-apoptotic protein Bcl-2 总被引:4,自引:0,他引:4
Kang CB Feng L Chia J Yoon HS 《Biochemical and biophysical research communications》2005,337(1):30-38
The immunosuppressant FK-506 binding protein 38 (FKBP38) is localized at the mitochondrial membrane and appears to play an important role in apoptosis. Recent reports about the potential functions of FKBP38 in apoptosis appear to be controversial. To further understand the biological function of FKBP38, here, we studied its molecular characteristics and a potential regulatory role on the anti-apoptotic protein Bcl-2. Our results suggest that FKBP38 appears to show chaperone activities in the citrate synthase aggregation assays during thermal denaturation and affect solubility of Bcl-2 when they are co-expressed. The FKBP family proteins bind the immunosuppressive drug FK-506 through the FK-506 binding domain and consequently inhibit the activity of calcineurin. In this study, from our NMR studies and calcineurin assays in vitro, we demonstrate that the N-terminal fragment of FKBP38 which contains the FK-506 binding domain does not bind FK-506 at molecular level. Lastly, to investigate the effect of FKBP38 on Bcl-2, we suppressed FKBP38 by RNA interference (RNAi) of FKBP38. Our results suggest that the suppression of FKBP38 appears to make Bcl-2 unstable or unprotected from degradation in an unknown mechanism. 相似文献
1000.
c-Jun N-terminal kinase is involved in the suppression of adiponectin expression by TNF-alpha in 3T3-L1 adipocytes 总被引:5,自引:0,他引:5
Kim KY Kim JK Jeon JH Yoon SR Choi I Yang Y 《Biochemical and biophysical research communications》2005,327(2):460-467
Adiponectin, one of adipokines that is secreted from adipocytes, plays an important role in the regulation of glucose and lipid metabolism. Paradoxically, serum concentrations of adiponectin are decreased in obese and type 2 diabetic patients, although it is produced in adipose tissue. On the other hand, plasma TNF-alpha levels are increased in such subjects. In the present study, the mechanism by which adiponectin is regulated by TNF-alpha was investigated. The decreased adiponectin mRNA levels by TNF-alpha were partially recovered by treatment with a c-Jun N-terminal kinase (JNK) inhibitor or the PPAR-gamma agonist rosiglitazone in 3T3-L1 adipocytes. Interestingly, however, cotreatment with the JNK inhibitor and rosiglitazone led to a recovery of TNF-alpha-mediated adiponectin suppression to the control level. The JNK inhibitor regulated the expression of adiponectin by the increase of PPAR-gamma DNA binding activity and the recovery of its mRNA expression while rosiglitazone acted via a PPAR-gamma independent pathway which remains to be elucidated. These findings suggest that the JNK signaling pathway, activated by TNF-alpha, is involved in the regulation of adiponectin expression. 相似文献