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11.
Stereospecific synthesis of "para-hydroxymexiletine" and sodium channel blocking activity evaluation
Catalano A Carocci A Fracchiolla G Franchini C Lentini G Tortorella V De Luca A De Bellis M Desaphy JF Conte Camerino D 《Chirality》2004,16(2):72-78
Both enantiomers of "para-hydroxymexiletine" (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)- and (S)-PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na(+) channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4-position, as in PHM, reduced potency with respect to mexiletine in reducing I(Na max). However, PHM showed clear use-dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use-dependent block. Chirality 16:72-78, 2004. 相似文献
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The present study was performed to investigate the effect of previous fasting and lifting of the abdomen of the ewes during transrectal ultrasonographic scanning on the results of early pregnancy diagnosis. Ewes of four flocks (A, B, C and D; all Awassi x Merino ewes, n = 1247 ) aged 0.7-10 years were used in this study. These ewes were estrus synchronized and artificially inseminated. From 2 weeks later onwards, fertile rams were kept with the ewes of flocks A, B and C ( n=949 ) for natural breeding, while ewes of flock D ( n=298 ) were re-inseminated 17 days later. Transrectal ultrasonography (5 MHz) was carried out in ewes of flocks A, B and C on four separate occasions but only once in ewes of flock D. For final analysis, animals were divided over two groups: ewes of Group 1 ( n=949 scans) were scanned in a standing position within the milking parlor. Animals of Group 2 ( n=764 scans) were scanned by the same operator and with the same scanning technique, but these ewes were fasted for 12h prior to scanning and the abdominal wall was lifted, just in front of the udder during scanning. The sensitivity of the test for diagnosing pregnancy at Days 18-24, 25-30, 31-40 and 41-50 was 21.8, 32.3, 63.3 and 50% in Group 1, and 46, 92.5, 92.3 and 96.8% in Group 2, respectively. Only within Group 1, the sensitivity of the test was higher in young ewes (0.7-2 years) than in older ones (>2-10 years). Significant differences were observed at scan periods Days 18-24 and Days 41-50 of gestation. It is concluded that, fasting prior to scanning and lifting the abdomen during scanning significantly improve the accuracy of transrectal ultrasonographic pregnancy diagnosis in Awassi x Merino ewes. 相似文献
14.
Tillie-Leblond I Guery BP Janin A Leberre R Just N Pittet JF Tonnel AB Gosset P 《American journal of physiology. Lung cellular and molecular physiology》2002,283(6):L1303-L1309
Bronchial inflammation in allergic asthma is associated with active exudation from the bronchial tree into the interstitial space of both mucosa and submucosa. The aim of this study was to evaluate epithelial and endothelial permeability as well as alveolar fluid movement in a model of chronic allergic inflammation in Brown-Norway rats sensitized and challenged with ovalbumin (OA). Control groups were challenged with saline solution (C), and rats were immunized by OA but not challenged (Se). Lung sections showed a marked inflammatory infiltrate associated with perivascular and peribronchiolar edema in OA. To measure alveolar liquid clearance, a 5% bovine albumin solution with 1 microCi of (125)I-labeled human albumin was instilled into the air spaces. Alveolar-capillary barrier permeability was evaluated by intravascular injection of 1 microCi of (131)I-labeled albumin. Endothelial permeability was significantly increased in OA, from 0.08 +/- 0.01 in the C group to 0.19 +/- 0.03 in OA group (P < 0.05). Final-to-initial protein ratio was also statistically higher in OA (1.6 +/- 0.05) compared with C (1.38 +/- 0.03, P = 0.01) and Se groups (1.42 +/- 0.03, P = 0.04). Administration of anti-tumor necrosis factor-alpha antibodies within the instillate significantly decreased this ratio (1.32 +/- 0.08, P = 0.003 vs. OA). To conclude, we demonstrated a tumor necrosis factor-alpha-dependent increase in alveolar fluid movement in a model of severe bronchial allergic inflammation associated with endothelial and epithelial leakage. 相似文献
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Gao Yuansheng; Tolsa Jean-Francois; Shen Hai; Raj J. Usha 《Journal of applied physiology》1998,84(1):13-18
Gao, Yuansheng, Jean-François Tolsa, Hai Shen, and J. Usha Raj. Effect of selective phosphodiesteraseinhibitors on response of ovine pulmonary arteries to prostaglandinE2. J. Appl. Physiol. 84(1): 13-18, 1998.Several adenosine3,5-cyclic monophosphate (cAMP)-hydrolyzingphosphodiesterase isozymes are present in the pulmonary vasculature.The present study was designed to determine the effect of selectiveinhibitors of phosphodiesterase subtypes on prostaglandinE2(PGE2)-induced relaxation ofisolated fourth- generation pulmonary arteries of newborn lambs.PGE2 and forskolin causedpulmonary arteries to relax and induced an increase in theintracellular cAMP content in the vessels. The relaxation and change incAMP content were augmented by milrinone and rolipram, inhibitors ofphosphodiesterase type 3 (PDE3) and type 4 (PDE4), respectively. Theaugmentation in relaxation and the increase in cAMP content caused bymilrinone plus rolipram was greater than the sum of theresponses caused by either of the inhibitors alone.8-Methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine, an inhibitor of phosphodiesterase type 1, had no effect on relaxation andchange in cAMP induced by PGE2 andforskolin. Acetylcholine alone had no effect on cAMP content in thevessels but augmented the relaxation and the increase in cAMP inducedby PGE2 and forskolin in arterieswith endothelium. This effect was not observed in arteries withoutendothelium or in arteries with endothelium treated withNG-nitro-L-arginine.These results suggest that PDE3 and PDE4 are the primary enzymeshydrolyzing cAMP of pulmonary arteries of newborn lambs and that aninhibition of both PDE3 and PDE4 would result in a greater effect thanthat caused by inhibition of either one of the subtype isozymes alone.Furthermore, endothelium-derived nitric oxide may enhance cAMP-mediatedrelaxation by inhibition of PDE3. 相似文献
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Tereza Krejcova Miroslava Smelcova Jaroslav Petr Jean-Francois Bodart Marketa Sedmikova Jan Nevoral Marketa Dvorakova Alena Vyskocilova Ivona Weingartova Veronika Kucerova-Chrpova Eva Chmelikova Lenka Tumova Frantisek Jilek 《PloS one》2015,10(1)
Porcine oocytes that have matured in in vitro conditions undergo the process of aging during prolonged cultivation, which is manifested by spontaneous parthenogenetic activation, lysis or fragmentation of aged oocytes. This study focused on the role of hydrogen sulfide (H2S) in the process of porcine oocyte aging. H2S is a gaseous signaling molecule and is produced endogenously by the enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). We demonstrated that H2S-producing enzymes are active in porcine oocytes and that a statistically significant decline in endogenous H2S production occurs during the first day of aging. Inhibition of these enzymes accelerates signs of aging in oocytes and significantly increases the ratio of fragmented oocytes. The presence of exogenous H2S from a donor (Na2S.9H2O) significantly suppressed the manifestations of aging, reversed the effects of inhibitors and resulted in the complete suppression of oocyte fragmentation. Cultivation of aging oocytes in the presence of H2S donor positively affected their subsequent embryonic development following parthenogenetic activation. Although no unambiguous effects of exogenous H2S on MPF and MAPK activities were detected and the intracellular mechanism underlying H2S activity remains unclear, our study clearly demonstrates the role of H2S in the regulation of porcine oocyte aging. 相似文献
18.
Yuling Chi Jean-Francois Jasmin Yoshinori Seki Michael P. Lisanti Maureen J. Charron David J. Lefer Victor L. Schuster 《PloS one》2015,10(6)
Inhibiting the synthesis of endogenous prostaglandins with nonsteroidal anti-inflammatory drugs exacerbates arterial hypertension. We hypothesized that the converse, i.e., raising the level of endogenous prostaglandins, might have anti-hypertensive effects. To accomplish this, we focused on inhibiting the prostaglandin transporter PGT (SLCO2A1), which is the obligatory first step in the inactivation of several common PGs. We first examined the role of PGT in controlling arterial blood pressure blood pressure using anesthetized rats. The high-affinity PGT inhibitor T26A sensitized the ability of exogenous PGE2 to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE2 T26A administered alone to anesthetized rats dose-dependently lowered blood pressure, and did so to a greater degree in spontaneously hypertensive rats than in Wistar-Kyoto control rats. In mice, T26A added chronically to the drinking water increased the urinary excretion and plasma concentration of PGE2 over several days, confirming that T26A is orally active in antagonizing PGT. T26A given orally to hypertensive mice normalized blood pressure. T26A increased urinary sodium excretion in mice and, when added to the medium bathing isolated mouse aortas, T26A increased the net release of PGE2 induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE2. We conclude that pharmacologically inhibiting PGT-mediated prostaglandin metabolism lowers blood pressure, probably by prostaglandin-induced natriuresis and vasodilation. PGT is a novel therapeutic target for treating hypertension. 相似文献
19.
In this study, we investigated the kinetic and the magnitude of dehydrations on yeast plasma membrane (PM) modifications because this parameter is crucial to cell survival. Functional (permeability) and structural (morphology, ultrastructure, and distribution of the protein Sur7-GFP contained in sterol-rich membrane microdomains) PM modifications were investigated by confocal and electron microscopy after progressive (non-lethal) and rapid (lethal) hyperosmotic perturbations. Rapid cell dehydration induced the formation of many PM invaginations followed by membrane internalization of low sterol content PM regions with time. Permeabilization of the plasma membrane occurred during the rehydration stage because of inadequacies in the membrane surface and led to cell death. Progressive dehydration conducted to the formation of some big PM pleats without membrane internalization. It also led to the modification of the distribution of the Sur7-GFP microdomains, suggesting that a lateral rearrangement of membrane components occurred. This event is a function of time and is involved in the particular deformations of the PM during a progressive perturbation. The maintenance of the repartition of the microdomains during rapid perturbations consolidates this assumption. These findings highlight that the perturbation kinetic influences the evolution of the PM organization and indicate the crucial role of PM lateral reorganization in cell survival to hydric perturbations. 相似文献