全文获取类型
收费全文 | 1281篇 |
免费 | 140篇 |
国内免费 | 32篇 |
专业分类
1453篇 |
出版年
2022年 | 12篇 |
2021年 | 16篇 |
2020年 | 23篇 |
2019年 | 19篇 |
2018年 | 28篇 |
2017年 | 23篇 |
2016年 | 23篇 |
2015年 | 45篇 |
2014年 | 40篇 |
2013年 | 62篇 |
2012年 | 67篇 |
2011年 | 77篇 |
2010年 | 50篇 |
2009年 | 45篇 |
2008年 | 63篇 |
2007年 | 61篇 |
2006年 | 60篇 |
2005年 | 47篇 |
2004年 | 61篇 |
2003年 | 55篇 |
2002年 | 39篇 |
2001年 | 45篇 |
2000年 | 30篇 |
1999年 | 42篇 |
1998年 | 23篇 |
1997年 | 25篇 |
1996年 | 19篇 |
1995年 | 16篇 |
1994年 | 20篇 |
1993年 | 11篇 |
1992年 | 25篇 |
1991年 | 17篇 |
1990年 | 18篇 |
1989年 | 22篇 |
1988年 | 21篇 |
1987年 | 16篇 |
1986年 | 12篇 |
1985年 | 12篇 |
1983年 | 7篇 |
1982年 | 12篇 |
1981年 | 12篇 |
1980年 | 9篇 |
1979年 | 9篇 |
1978年 | 9篇 |
1977年 | 10篇 |
1975年 | 6篇 |
1974年 | 8篇 |
1973年 | 8篇 |
1971年 | 8篇 |
1949年 | 5篇 |
排序方式: 共有1453条查询结果,搜索用时 15 毫秒
1.
Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist 总被引:15,自引:0,他引:15
T R Jones R Zamboni M Belley E Champion L Charette A W Ford-Hutchinson R Frenette J Y Gauthier S Leger P Masson 《Canadian journal of physiology and pharmacology》1989,67(1):17-28
L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 microM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 x 10(-8)M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). L-660,711 (1.9 x 10(-5)M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2 alpha, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 x 10(-5)M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2-12.8 micrograms/kg)-induced bronchoconstriction in guinea pigs, and p.o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions. 相似文献
2.
Phosphofructokinase 2 and glycolysis in HT29 human colon adenocarcinoma cell line. Regulation by insulin and phorbol esters.
下载免费PDF全文
![点击此处可从《The Biochemical journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Kinetic properties of phosphofructokinase 2 (PFK2) and regulation of glycolysis by phorbol 12-myristate 13-acetate (PMA) and insulin were investigated in highly glycolytic HT29 colon cancer cells. PFK2 was found to be inhibited by citrate and, to a lesser extent, by phosphoenolpyruvate and ADP, but to be insensitive to inhibition by sn-glycerol phosphate. From these kinetic data, PFK2 from HT29 cells appears different from the liver form, but resembles somewhat the heart isoenzyme. Fructose 2,6-bisphosphate (Fru-2,6-P2) levels, glucose consumption and lactate production are increased in a dose-dependent manner in HT29 cells treated with PMA or insulin. The increase in Fru-2,6-P2 can be related to an increase in the Vmax. of PFK2, persisting after the enzyme has been precipitated with poly(ethylene glycol), without change in the Km for fructose 6-phosphate. The most striking effects of PMA and insulin on Fru-2,6-P2 production are observed after long-term treatment (24 h) and are abolished by actinomycin, cycloheximide and puromycin, suggesting that protein synthesis is involved. Furthermore, the effects of insulin and PMA on glucose consumption, lactate production, Fru-2,6-P2 levels and PFK2 activity are additive, and the effect of insulin on Fru-2,6-P2 production is not altered by pre-treatment of the cells with the phorbol ester. This suggests that these effects are exerted by separate mechanisms. 相似文献
3.
4.
Payant V; Abukashawa S; Sasseville M; Benkel BF; Hickey DA; David J 《Molecular biology and evolution》1988,5(5):560-567
Nuclear DNA was extracted from each of the eight species comprising the
Drosophila melanogaster species subgroup. Southern hybridization of this
DNA by using a molecular probe specific for the alpha-amylase coding region
showed that the duplicated structure of the amylase locus, first found in
D. melanogaster, is conserved among all species of the melanogaster
subgroup. Evidence is also presented for the concerted evolution of the
duplicated genes within each species. In addition, it is shown that the
glucose repression of amylase gene expression, which has been extensively
studied in D. melanogaster, is not confined to this species but occurs in
all eight members of the species subgroup. Thus, both the duplicated gene
structure and the glucose repression of Drosophila amylase gene activity
are stable over extended periods of evolutionary time.
相似文献
5.
J. M. White D. D. Jones D. Huang J. J. Gauthier 《Journal of industrial microbiology & biotechnology》1988,3(5):263-272
Summary A cyanide-degrading pseudomonad was isolated by selective enrichment in a chemostat inoculated with coke-plant activated sludge and maintained at a dilution rate of 0.042/h for 60 days with a feed of 10 mg/l cyanide. The isolate, a facultative methylotroph capable of growth on methanol and methylamine, degraded cyanide to formate and ammonia; it could utilize the released ammonia as a nitrogen source but did not further metabolize formate under the experimental conditions employed. Both cyanide-degrading enzyme activity and respiratory resistance to cyanide were inducible and were enhanced by repeated exposure to the compound. Cell-free extracts stoichiometrically converted cyanide to formate and ammonia in a reaction that did not require oxygen. Enzyme activity, lost upon dialysis, was restored by less than equimolar ratios of NAD(P)H or ascorbate to cyanide, indicating that the reductants did not function directly as co-enzymes. 相似文献
6.
Cysteine-proteinase-inhibiting function of T kininogen and of its proteolytic fragments 总被引:1,自引:0,他引:1
T Moreau F Esnard N Gutman P Degand F Gauthier 《European journal of biochemistry》1988,173(1):185-190
Previous attempts to liberate T kinin from T kininogen [Moreau et al. (1986) Eur. J. Biochem. 159, 341-346; Gutman et al. (1988) Eur. J. Biochem. 171, 577-582] have shown that complete fragmentation of the precursor molecule into inhibitory peptides was achieved before any vasoactive peptide was released, suggesting a possible physiological significance for this phenomenon. In this study, cysteine-proteinase-inhibiting properties of rat T kininogen and of its proteolytic fragments issuing from trypsin and submaxillary gland endopeptidase k hydrolysis, have been investigated using rat lysosomal cathepsins B, H and L, papain and bovine calpains I and II. All three lysosomal cathepsins were inhibited by T kininogen but tighter interactions were observed with cathepsin L and papain. Though higher Ki values were obtained for cathepsins B and H, rate constants for association were found to have high and almost similar values (in the 10(6) M-1 s-1 range) whatever the enzyme used. Proteolytic fragments also inhibited cathepsin L and papain very strongly and even better than the entire molecule for some of them, but no significant inhibition of cathepsins B and H was observed. Bovine calpains were not inhibited by T kininogen nor by its proteolytic fragments. From the results of this kinetic analysis, which indicates that both the association and the dissociation of lysosomal cysteine proteinases with T kininogen may occur rapidly, an hypothesis has been put forward on the possible in vivo functioning of T kininogen as a proteinase inhibitor. 相似文献
7.
Two rat homologues of human cystatin C 总被引:1,自引:0,他引:1
Two immunochemically related forms of cystatin C-like inhibitors which differ in their Mr app and isoelectric point have been found both in urine and seminal vesicles of rats. Amino-terminal sequences of these two cystatins are identical within the same fluid and exhibit a high degree of homology with that of human cystatin C. However, cystatins C purified from urine lack eight residues at their amino-terminal end when compared to those of seminal vesicles. The occurrence of two cystatin C-like components in rat fluids has been found to be due to the presence of a glycosylated form reported here as cystatin Cg which specifically binds concanavalin A and is susceptible to endo-beta-N-acetylglucosaminidase treatment. 相似文献
8.
P Gauthier 《Canadian journal of physiology and pharmacology》1988,66(3):213-221
Electrical stimulation (100 Hz, 1 ms, 150 microA, 10 s) of the anterior hypothalamus in chloralose-anesthetized rats evoked a biphasic pressor response consisting of an initial sharp rise in arterial pressure at the onset of stimulation, followed by a second elevation after cessation of the stimulus. This response was accompanied by an increase in plasma noradrenaline and adrenaline levels. Peripheral sympathectomy with guanethidine selectively abolished the primary phase of the biphasic pressor response, while bilateral removal of the adrenal medulla eliminated only the secondary component. After alpha-adrenergic blockade with phentolamine, the primary phase of the stimulation-induced response was reduced while the secondary pressor component was blocked and replaced by a significant hypotension. The intravenous administration of sotalol enhanced the secondary pressor component without affecting the stimulation-induced plasma noradrenaline and adrenaline responses. After treatment with atropine, the secondary pressor effect was also potentiated, as the reflex bradycardia normally associated with the response was eliminated. A subsequent administration of sotalol in these rats further potentiated the secondary pressor component to stimulation. In rats treated with atropine and sotalol, the sympathetic vasomotor and the adrenomedullary pressor responses could be dissociated according to thresholds and stimulus frequency or current-response characteristics. The results suggest that in intact rats, adrenaline-induced vasodilation and reflex cardiac inhibition contribute to either reduce or mask the adrenomedullary component of the biphasic pressor response evoked by stimulation of the anterior hypothalamus. The study also raises the hypothesis of a dual regulation of both components of the sympathetic system in the anterior hypothalamic region. 相似文献
9.
T R Jones R Young E Champion L Charette D Denis A W Ford-Hutchinson R Frenette J Y Gauthier Y Guindon M Kakushima 《Canadian journal of physiology and pharmacology》1986,64(8):1068-1075
L-649,923, Sodium (beta S*, gamma R*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)- gamma- hydroxy-beta-methylbenzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (Ki value of 400 nM) and to a lesser extent [3H]leukotriene C4 (Ki value of 8.6 microM) binding in guinea-pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotriene C4, D4, E4, and F4 but not those induced by acetylcholine, histamine, serotonin, prostaglandin F2 alpha, or U-44069 (stable endoperoxide analogue). Schild plot analysis indicated a competitive inhibition of contractions of guinea-pig ileum induced by leukotriene D4 (pA2 8.1) and contractions of guinea-pig trachea induced by leukotrienes E4 and F4 (pA2 7.1 and 6.9, respectively). In contrast, contractions of guinea-pig trachea induced by leukotrienes C4 (pA2 7.2; slope 0.6) and D4 (pA2 7.2; slope 0.7) were inhibited in a noncompetitive fashion. In vivo, intravenously administered L-649,923 selectively blocked bronchoconstriction induced in anesthetized guinea pigs by leukotriene C4 and D4 (ED50 values i.v. 0.38 and 0.26 mg/kg, respectively) but not that induced by histamine, arachidonic acid, serotonin, U-44069, or acetylcholine. Following intraduodenal administration, L-649,923, blocked leukotriene D4 induced bronchoconstriction (5 and 10 mg/kg). The present findings indicate that selective antagonists, such as L-649,923, may be useful for defining the role of leukotrienes in diseases such as bronchial asthma. 相似文献
10.
The overall mechanism of interaction with proteinases of alpha 1-inhibitor3, a plasma proteinase inhibitor so far specific to the rat, has been shown to be closely similar to that described for alpha-macroglobulins. This mechanism includes: (i) the cleavage of at least one susceptible peptidic bond which leads to structural changes in the molecule. (ii) The cleavage of a putative thiol ester bond in another site of the molecule which permits the covalent linkage of the enzyme. Moreover, fragmentation of alpha 1-inhibitor3 upon heating as observed for alpha-macroglobulin quarter subunits has been demonstrated. The question is raised of the presence of such a molecule in rat plasma in addition to two alpha-macroglobulin species, all of these proteinase inhibitors being antigenically unrelated. 相似文献