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961.
Binding profile of a novel cardioselective muscarine receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat 总被引:25,自引:0,他引:25
The heterogeneity of muscarine receptors was examined in two brain regions (cerebral cortex and cerebellum) and in some parasympathetically innervated peripheral tissues (heart, salivary gland and intraorbital lacrimal gland), by in vitro binding techniques. As a tool, we used a new antimuscarinic compound, AF-DX 116 (see text for structural formula and chemical name). In competition experiments against 3H-N-methylscopolamine (3H-NMS) or 3H-pirenzepine (3H-PZ), AF-DX 116 was found to bind with high affinity to muscarine receptors in the heart and cerebellum (KD's approximately equal to 115 nM), with intermediate affinity to M1 receptors in neuronal tissue (KD = 760 nM) and with low affinity to receptors in exocrine glands (KD's approximately equal to 3200 nM). Its receptor interaction was found to be of the simple, competitive type. Thus, AF-DX 116 shows a novel cardioselective profile. On the basis of the results which demonstrate that the muscarine receptors in the heart and exocrine glands are clearly distinct, it is proposed that these receptors may be subclassified as M2 cardiac type and M2 glandular type muscarine receptors. 相似文献
962.
Tissue-specific posttranslational processing of pre-prosomatostatin encoded by a metallothionein-somatostatin fusion gene in transgenic mice 总被引:17,自引:0,他引:17
The somatostatins are neuropeptides of 14 and 28 amino acids that inhibit the release of growth hormone and other hypophyseal and gastrointestinal peptides. These neuropeptides are cleaved posttranslationally from a common precursor, pre-prosomatostatin. We report here the production and processing of pre-prosomatostatin by transgenic mice carrying a metallothionein-somatostatin fusion gene. The most active site of somatostatin production, as determined by hormone concentrations in the tissues, is the anterior pituitary, a tissue that does not normally synthesize somatostatin-like peptides. Anterior pituitary processed pre-prosomatostatin almost exclusively to the two biologically active peptides, somatostatin-14 and somatostatin-28, whereas the liver and kidney synthesized much smaller quantities of predominantly a 6000 dalton somatostatin-like peptide. The growth of the transgenic mice was normal despite high plasma levels of the somatostatin-like peptides. These studies indicate that proteases which cleave prosomatostatin to somatostatin-28 and somatostatin-14 are not specific to tissues that normally express somatostatin. 相似文献
963.
964.
Somatostatin is targeted to the regulated secretory pathway of gonadotrophs in transgenic mice expressing a metallothionein-somatostatin gene 总被引:2,自引:0,他引:2
M J Low P J Stork R E Hammer R L Brinster M J Warhol G Mandel R H Goodman 《The Journal of biological chemistry》1986,261(34):16260-16263
The pituitaries of transgenic mice that express a metallothionein-somatostatin fusion gene contain high concentrations of somatostatin-14 exclusively in the gonadotrophic cells. The purpose of this study was to determine whether somatostatin expressed from the foreign fusion gene enters the normal secretory pathway within these cells. Immuno-gold labeling of serial thin sections localized somatostatin to the secretory granules of gonadotropin-producing cells. The gonadotroph-specific hypophysiotropic factor, luteinizing hormone-releasing hormone caused a dose-dependent secretion of somatostatin when applied to primary pituitary cultures from these mice. Growth hormone-releasing hormone, thyrotropin-releasing hormone, corticotropin releasing factor, and dopamine did not affect somatostatin secretion. These experiments demonstrate that a neurosecretory peptide encoded by a foreign gene can enter the regulated secretory pathway of pituitary cells from transgenic mice. 相似文献
965.
966.
This study was undertaken to determine the effects of different incubation conditions on human granulocyte (PMN) bactericidal, phagocytic, and chemotactic functions. Specifically, (1) how long may a patient's blood be held before assay and maintain original PMN function, and (2) how long may isolated PMNs be incubated for the purpose of exposure to various agents and still maintain original function? PMNs isolated following storage of whole heparinized blood at 4 degrees C for 24 and 48 hr phagocytized as well as fresh cells and their bactericidal activity was 96 and 85% of control values after 24 and 48 hr, respectively. Chemotaxis decreased to 62% of control after 24 hr. The bactericidal capacity of isolated PMNs stored at 4 degrees C for 24, 48, and 72 hr decreased to 85, 81, and 78% of controls, respectively. Phagocytosis after 24 hr storage was equal to controls. Chemotaxis was decreased to 59 and 34% of controls after 24 and 48 hr, respectively. Isolated PMNs incubated at 37 degrees C demonstrated impairment in phagocytic capacity after only 4 hr. 相似文献
967.
NMR microscopy--a new biological tool 总被引:1,自引:0,他引:1
968.
969.
Tjeerd Barf Fredrik Lehmann Kristin Hammer Saba Haile Eva Axen Carmen Medina Jonas Uppenberg Stefan Svensson Lena Rondahl Thomas Lundbäck 《Bioorganic & medicinal chemistry letters》2009,19(6):1745-1748
Small molecule inhibitors of adipocyte fatty-acid binding protein (A-FABP) have gained renewed interest following the recent publication of pharmacologically beneficial effects of such inhibitors. Despite the potential utility of selective A-FABP inhibitors within the fields of metabolic disease, inflammation and atherosclerosis, there are few examples of useful A-FABP inhibitors in the public domain. Herein, we describe the optimization of N-benzyl-tetrahydrocarbazole derivatives through the use of co-crystal structure guided medicinal chemistry efforts. This led to the identification of a potent and selective class of A-FABP inhibitors as illustrated by N-benzyl-hexahydrocyclohepta[b]indole 30. 相似文献
970.
In our previous work, we routinely observed that a combined cocaine-exercise challenge results in an abnormally rapid muscle glycogen depletion and excessive blood lactacidosis. These phenomena occur simultaneously with a rapid rise in norepinephrine and in the absence of any rise in epinephrine. We postulated that norepinephrine may cause vasoconstriction of the muscle vasculature through activation of alpha-1 receptors during cocaine-exercise, thus inducing hypoxia and a concomitant rise in glycogenolysis and lactate accumulation. To test this hypothesis, rats were pretreated with the selective alpha-1-receptor antagonist prazosin (P) (0.1 mg/kg iv) or saline (S). Ten minutes later, the animals were treated with cocaine (-C) (5 mg/kg iv) or saline (-S) and run for 4 or 15 min at 22 m/min at 10% grade. In the S-S group, glycogen content of the white vastus lateralis muscle was unaffected by exercise at both time intervals, whereas in S-C rats glycogen was reduced by 47%. This effect of cocaine-exercise challenge was not attenuated by P. Similarly, blood lactate concentration in S-C rats was threefold higher than that of S-S after exercise, a response also not altered by pretreatment with P. On the basis of these observations, we conclude that the excessive glycogenolysis and lactacidosis observed during cocaine-exercise challenge is not the result of vasoconstriction secondary to norepinephrine activation of alpha-1 receptors. 相似文献