全文获取类型
收费全文 | 3984篇 |
免费 | 163篇 |
国内免费 | 16篇 |
出版年
2024年 | 7篇 |
2023年 | 24篇 |
2022年 | 30篇 |
2021年 | 54篇 |
2020年 | 64篇 |
2019年 | 57篇 |
2018年 | 67篇 |
2017年 | 60篇 |
2016年 | 50篇 |
2015年 | 79篇 |
2014年 | 167篇 |
2013年 | 219篇 |
2012年 | 133篇 |
2011年 | 216篇 |
2010年 | 104篇 |
2009年 | 171篇 |
2008年 | 208篇 |
2007年 | 200篇 |
2006年 | 176篇 |
2005年 | 97篇 |
2004年 | 130篇 |
2003年 | 83篇 |
2002年 | 59篇 |
2001年 | 45篇 |
2000年 | 71篇 |
1999年 | 65篇 |
1998年 | 85篇 |
1997年 | 69篇 |
1996年 | 64篇 |
1995年 | 83篇 |
1994年 | 98篇 |
1993年 | 68篇 |
1992年 | 95篇 |
1991年 | 88篇 |
1990年 | 71篇 |
1989年 | 81篇 |
1988年 | 72篇 |
1987年 | 75篇 |
1986年 | 68篇 |
1985年 | 84篇 |
1984年 | 80篇 |
1983年 | 72篇 |
1982年 | 90篇 |
1981年 | 78篇 |
1980年 | 49篇 |
1976年 | 9篇 |
1974年 | 6篇 |
1973年 | 7篇 |
1972年 | 11篇 |
1970年 | 6篇 |
排序方式: 共有4163条查询结果,搜索用时 31 毫秒
991.
Phosphoglycerates and Protein Phosphorylation: Identification of a Protein Substrate as Glucose-1,6-Bisphosphate Synthetase 总被引:1,自引:1,他引:0
Hideo Morino Carolyn Fischer-Bovenkerk Phillip E. Kish Tetsufumi Ueda† 《Journal of neurochemistry》1991,56(3):1049-1057
We have previously reported the occurrence of two endogenous protein phosphorylation systems in mammalian brain that are enhanced in the presence of 3-phosphoglycerate (3PG) and ATP. We present here a study of one of these systems, the phosphorylation of the 72-kDa protein (3PG-PP72). This system was separated into the substrate, 3PG-PP72, and a kinase by ammonium sulfate fractionation, hydroxyapatite chromatography, and hydrophobic interaction HPLC. The substrate protein was shown to be directly phosphorylated with [1-32P]1,3-bisphosphoglycerate [( 1-32P]1,3BPG) with an apparent Km of 1.1 nM. Nonradioactive 1,3BPG inhibited 32P incorporation in the presence of [gamma-32P]ATP and 3PG. Phosphopeptide mapping and phosphoamino acid analyses indicated that the site of phosphorylation of 3PG-PP72 observed in the presence of 3PG and ATP is a serine residue identical to that observed with [1-32P]1,3BPG. Moreover, [32P]phosphate incorporated into 3PG-PP72 in the presence of 3PG and ATP was removed by subsequent incubation with glucose-1-phosphate or glucose-6-phosphate. Finally, 3PG-PP72 showed chromatographic behaviors identical to those of glucose-1,6-bisphosphate (G1,6P2) synthetase. Based upon these observations, we conclude that 3PG-PP72 is G1,6P2 synthetase and that it is phosphorylated directly by 1,3BPG, which is formed from 3PG and ATP by 3PG kinase present in a crude 3PG-PP72 preparation. 相似文献
992.
Julie A. Blendy David C. Perry Laurie A. Pabreza Kenneth J. Kellar 《Journal of neurochemistry》1991,57(5):1548-1555
Repeated administration of electroconvulsive shock (ECS) increases [3H]prazosin binding to alpha 1-adrenoceptors in rat cerebral cortex. In contrast, [3H]WB4101 binding in cortex has been reported to be unchanged after ECS. [3H]Prazosin labels two alpha 1-adrenoceptor subtypes, termed alpha 1a and alpha 1b, whereas [3H]WB4101 labels the alpha 1a subtype preferentially. The purpose of this study was to determine whether ECS increases one or both alpha 1-adrenoceptor subtypes in rat cerebral cortex. We found that treatment of rats with ECS once daily for 10-12 days increased [3H]prazosin binding in cortex by about 25% but did not significantly alter [3H]WB4101 binding to alpha 1-adrenoceptors. Measurement of alpha 1a and alpha 1b receptors by competition analysis of the selective alpha 1a antagonist 5-methylurapidil against [3H]prazosin and measurement of [3H]prazosin binding in homogenates preincubated with chlorethylclonidine, which alkylates alpha 1b binding sites, also indicated that the ECS-induced increase in alpha 1-adrenoceptors is confined to the alpha 1b subtype. In contrast to its effect on [3H]prazosin binding, ECS did not increase phosphoinositide hydrolysis as measured by [3H]inositol 1-phosphate accumulation in slices of rat cerebral cortex stimulated by either norepinephrine or phenylephrine. The failure of ECS to increase [3H]inositol 1-phosphate accumulation stimulated by phenylephrine, which is a partial agonist for this response, suggests that spare receptors do not account for the apparent absence of effect of ECS on alpha 1-adrenoceptor-mediated phosphoinositide hydrolysis. 相似文献
993.
Phorbol Myristate Acetate Inhibition of Phospholipase C Activation by Carbachol in Slices of Rat Brain Cortex Is a Delayed and Indirect Effect 总被引:2,自引:2,他引:0
We examined the effect of phorbol esters on phospholipase C activation in rat brain cortical slices and membranes. There was little effect of concurrent addition of phorbol 12-myristate 13-acetate (PMA) with carbachol on phosphoinositide breakdown due to carbachol over a 1-h incubation of brain slices. However, if slices were preincubated for 3 h with 1 microM PMA or 200 microM sphingosine before addition of carbachol, there was a 35-50% inhibition of phosphoinositide breakdown. There was also a marked loss of protein kinase C (PKC) activity from both cytosol and membranes after a 3-h exposure to PMA. The loss in responsiveness to the muscarinic agonists in slices was not reflected in carbachol-stimulated phospholipase C activation using isolated membranes. However, the decrease in carbachol-induced phosphoinositide breakdown seen in slices after a 3-h exposure to PMA was abolished if the extracellular K+ concentration was elevated from 5.9 to 55mM. Because elevation of the K+ level induces depolarization and increases Ca2+ entry, we examined the effect of ionomycin, a Ca2+ ionophore. Ionomycin potentiated the effects of carbachol on phosphoinositide breakdown but was unable to reverse the effects of a 3-h incubation with PMA. Because apamin, an inhibitor of Ca2(+)-dependent K+ channels, mimicked the effects of exposure to PMA for 3 h, it is possible that these channels are involved in muscarinic cholinergic regulation of phosphoinositide breakdown in rat brain slices. These results support the hypothesis that prolonged PMA treatment in rat brain cortex has no direct effect on phospholipase C activation by muscarinic cholinergic stimulation. 相似文献
994.
Finn Bengtsson Mogens Bugge Kaj H. Johansen† Roger F. Butterworth‡ 《Journal of neurochemistry》1991,56(3):1069-1074
Regional and whole-brain tryptophan-hydroxylating activity and serotonin turnover were investigated in portacaval shunted (PCS) rats using an in vivo decarboxylase inhibition assay. To saturate tryptophan hydroxylation with amino acid substrate, rats were administered a high dose of tryptophan 1 h prior to analysis of brain tryptophan, 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid. The analysis revealed, as expected, higher brain concentrations of tryptophan and 5-hydroxyindoles and increased serotonin synthesis rate in PCS rats as compared with shamoperated controls. Saturating levels of brain tryptophan were achieved in both PCS and sham animals after exogenous tryptophan administration. The tryptophan load resulted in increased brain serotonin turnover in all regions and in whole brain compared with rats that did not receive a tryptophan load. Tryptophan-loaded PCS rats showed increased brain serotonin turnover compared with tryptophan-loaded sham rats. Regionally, this supranormal tryptophan-hydroxylating activity was most pronounced in the mesencephalon-pons followed by the cortex. It is concluded that, at least in the PCS rat, brain tryptophan hydroxylation is an inducible process. Since it is known that brain tissue from PCS rats undergoes a redox shift toward a reduced state and that the essential cofactor tetrahydrobiopterin is active in tryptophan hydroxylation only when present in its reduced form, it is hypothesized that this is the reason for the supranormal tryptophan-hydroxylating activity displayed by the PCS rats. The hypothesis further suggests that alterations in tetrahydrobiopterin availability may serve as a mechanism by which brain tryptophan hydroxylation, and therefore serotonin turnover, can be regulated with high sensitivity in vivo. 相似文献
995.
Citalopram, a selective serotonin (5-HT) uptake inhibitor with antidepressant properties, was found to bind with high affinity to the 5-HT transporter from human neuronal and platelet membranes. At 20 degrees C, KD was about 1.5 nM in both tissues. [3H]Citalopram bound to rat neuronal membranes with higher affinity than to human neuronal and platelet membranes; at 20 degrees C KD was about 0.7 nM. The Bmax value for the binding of [3H]citalopram to platelet membranes was close to that found using the 5-HT uptake inhibitors [3H]imipramine and [3H]paroxetine, suggesting that all three 5-HT uptake inhibitors bind to the 5-HT transporter. The dissociation rate of [3H]citalopram increased twofold with each 4-5 degree C increase in temperature in both human and rat membranes, although at any given temperature, the dissociation rate was about four times faster in the human neuronal and platelet membranes than in rat neuronal membranes. 相似文献
996.
Francesco Aniello Dominique Couchie Daniel Gripois Jacques Nunez 《Journal of neurochemistry》1991,57(5):1781-1786
Nucleic acid probes derived from the 3' noncoding region of five tubulin cDNAs were used to study the effects of thyroid hormone deficiency on the expression of the mRNAs encoding two alpha (alpha 1 and alpha 2)- and three beta (beta 2, beta 4, and beta 5)-tubulin isotypes in the developing cerebral hemispheres and cerebellum. The content of alpha 1, which markedly declines during development in both brain regions, is maintained at high levels in the hypothyroid cerebellum, whereas it is decreased in the cerebral hemispheres. The alpha 2 level also declines during development and is decreased in both regions by thyroid hormone deficiency, but only during the two first postnatal weeks. Thyroid hormone deficiency slightly increases at all stages the beta 2 level in the cerebellum, whereas a decrease is observed at early stages in the cerebral hemispheres. The beta 5 level seems to be independent of thyroid hormone in the cerebral hemispheres, whereas it decreases at early stages in the hypothyroid cerebellum. Finally, the expression of the brain-specific beta 4 isotype is markedly depressed by thyroid hormone deficiency, particularly in the cerebellum. These data suggest that the genes encoding the tubulin isotypes are, directly or not, differently regulated by thyroid hormone during brain development. This might contribute to abnormal neurite outgrowth seen in the hypothyroid brain and therefore to impairment in brain functions produced by thyroid hormone deficiency. 相似文献
997.
Summary An ACTH-like peptidergic system was demonstrated in the brain of three teleost species by immunocytochemistry. In order to investigate the origin of brain ACTH and factors modulating its synthesis, similar techniques were applied to the brain of eels (1) submitted to hypothysectomy in order to suppress pituitary ACTH and plasma cortisol, (2) injected with cortisol to inhibit pituitary ACTH synthesis and release, and (3) injected with metopirone to block cortisol synthesis and stimulate ACTH synthesis and release. Hypophysectomized eels showed a normal distribution of immunoreactive perikarya in the ventral hypothalamus and fibers in the brain, suggesting that brain ACTH does not arise from the pituitary. In cortisol-treated eels immunostaining was markedly reduced in brain perikarya and pituitary corticotropes, suggesting a reduced synthesis. In metopirone-injected eels, one third of the animals showed an increased immunostaining in perikarya and a dense network of immunoreactive fibers, suggesting that ACTH synthesis was increased. Brain ACTH was not affected in other animals. Pituitary corticotropes were rapidly degranulated. Responses of ACTH in the brain and pituitary occur independently when cortisol synthesis is inhibited. These responses are compared to those of the corticotropin-releasing factor system in the same eels. 相似文献
998.
Barbara P. Barna Lisa R. Rogers Mary Jane Thomassen Gene H. Barnett Melinda L. Estes 《Cancer immunology, immunotherapy : CII》1991,33(5):314-318
Summary Monocyte-mediated tumoricidal activity, tumor necrosis factor (TNF) secretion and gene expression were examined in astrocytoma patients, patients with other types of brain tumors (primary or metastatic), and normal individuals. The spontaneous monocyte-mediated tumoricidal activity of either patient group against an astrocytoma cell line was significantly greater than normal. There was no difference between patient groups. When monocytes were stimulated with lipopolysaccharide in vitro, tumoricidal activity increased in all patient groups. Patient monocyte activity tested shortly (48 h) after surgery was not different from that before surgery. Both spontaneous and stimulated monocyte cytocidal activities were tumor-cell-restricted: melanoma and astrocytoma cells were equally susceptible but non-neoplastic glial cells were not affected. Examination of monocyte TNF secretion and mRNA expression indicated that patient activity was comparable to or greater than normal. These results demonstrate that, despite steroid therapy, circulating monocytes in astrocytoma and other brain tumor patients retain intact functional activity.Supported in part by grant CA-49 950 from the National Cancer Institute (B.P.B) and grant 1454-HL from the National Institutes of Health (M.L.E.) 相似文献
999.
In brain cortex, low concentrations of GTP or Gpp(NH)p activated the membrane-bound low Km cyclic AMP phosphodiesterase while higher concentrations of GTP, but not of Gpp(NH)p, reversed this activation. The adenosine analog N6-phenylisopropyladenosine (N6-PIA) elicited biphasic effect on this enzyme (activation up to 10(-8) M, complete reversion at 10(-5) M), provided that GTP was present. N6-PIA activation was reduced in the presence of Gpp(NH)p and blocked by sodium (80 mM). In contrast, the soluble low Km cyclic AMP phosphodiesterase was insensitive to GTP or N6-PIA. This study suggests that guanine nucleotides and N6-PIA exert their effects on the membrane-bound enzyme through guanine nucleotide regulatory proteins. 相似文献
1000.
Competitive Inhibition of Human Brain Hexokinase by Metrizamide and Related Compounds 总被引:1,自引:1,他引:0
Abstract: We have compared the competitive inhibitory effects of 2-deoxyglucose, glucosamine, N -acetylglucosamine, N -benzoylglucosamine, and the commonly used radiographic and density gradient agent metrizamide (2-[3 - acetamido - 2,4,6 - triiodo -5-( N - methylacetamido) benzamido]-2-deoxyglucose) on the mitochondrial and soluble forms of human brain hexokinase. Metrizamide produces a classical competitive inhibition with glucose for human brain hexokinase, with K i s of 2.8 and 2.5 m M , respectively, for the mitochondrial and soluble forms. Glucosamine exhibited K i s of 0.58 and 0.29 m M , while 2-deoxyglucose exhibited K i s of 0.074 and 0.15 m M and N -acetylglucosamine 0.098 and 0.092 m M for these two forms, respectively. N -Benzoylglucosamine was by far the most effective inhibitor tested, with K i values of 0.0086 and 0.022 m M , respectively. In order of increasing potency as a competitive inhibitor for mitochondrial hexokinase are metrizamide, glucosamine, N -acetylglucosamine, 2-deoxyglucose, and N -benzoylglucosamine. For the soluble form of the enzyme in increasing potency are metrizamide, glucosamine, 2-deoxyglucose, N -acetylglucosamine, and N -benzoylglucosamine. Since N -benzoylglucosamine was over 100 times more potent than metrizamide, some of the effects of metrizamide could be due to contamination by N -benzoylglucosamine. However, gas chromatography-mass spectrometry analysis of metrizamide did not indicate the presence of N -benzoylglucosamine. In addition, column chromatographic separation of commercially available metrizamide and reconstitution of freeze-dried eluate fractions localized the inhibitory effect to the metrizamide peak. 相似文献