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61.
Baciu M Sebai SC Ces O Mulet X Clarke JA Shearman GC Law RV Templer RH Plisson C Parker CA Gee A 《Philosophical transactions. Series A, Mathematical, physical, and engineering sciences》2006,364(1847):2597-2614
Drug molecules must cross multiple cell membrane barriers to reach their site of action. We present evidence that one of the largest classes of pharmaceutical drug molecules, the cationic amphiphilic drugs (CADs), does so via a catalytic reaction that degrades the phospholipid fabric of the membrane. We find that CADs partition rapidly to the polar-apolar region of the membrane. At physiological pH, the protonated groups on the CAD catalyse the acid hydrolysis of the ester linkage present in the phospholipid chains, producing a fatty acid and a single-chain lipid. The single-chain lipids rapidly destabilize the membrane, causing membranous fragments to separate and diffuse away from the host. These membrane fragments carry the drug molecules with them. The entire process, from drug adsorption to drug release within micelles, occurs on a time-scale of seconds, compatible with in vivo drug diffusion rates. Given the rate at which the reaction occurs, it is probable that this process is a significant mechanism for drug transport. 相似文献
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63.
Biochemical properties and cellular localization of the Drosophila DG1 cGMP-dependent protein kinase
The protein encoded by the Drosophila cGMP-dependent protein kinase gene, DG1, was expressed in Sf9 cells. cGMP (10 microM) stimulated histone H2B phosphorylation by the DG1 protein kinase 20-fold. Maximal activity was observed at 40-50 mM Mg2+. The concentrations of cGMP, cAMP, cIMP, 8-bromo-cGMP, and 8-bromo-cAMP that gave 50% activation were 0.19 +/- 0.06, 11.7 +/- 2.8, 5.3 +/- 1.5, 0.04 +/- 0. 01, and 0.62 +/- 0.06 microM, respectively. cGMP activation was cooperative with a Hill coefficient (nH) of 1.28 +/- 0.10, whereas activation by cAMP was not cooperative. DG1 kinase expressed in Sf9 cells was found to be a dimer with an amino-terminal dimerization domain. It also autophosphorylated in a reaction stimulated by cGMP and cAMP. Immunoadsorbed DG1 protein from fly extracts was also capable of autophosphorylation, and this assay was used to quantitate the DG1 kinase in extracts from heads and bodies of adults and whole embryos. Activity was highest in heads of either sex and male bodies, intermediate in female bodies, and lowest in embryos. These results were in accord with DG1 mRNA abundance. Tissue distribution of the DG1 kinase was investigated by immunohistochemistry. In embryos, specific immunoreactivity was observed in large cells scattered along the anterior-posterior axis at stage 13. Prominent staining of adult heads was restricted to the proximal level of the lamina cortex. 相似文献
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The regulation of would healing is one of the most important fields of research in ophthalmology today. Rabbit corneal fibroblast cultures were used to study the effects of interleukin-1 (IL-1) blockers on the proliferation of fibroblasts which is closely related to the wound healing. It was found that IL-1 blockers, such as CK-17, CK-101A, CK-2 and CK-103A, suppress fibroblast proliferation in a concentration-dependent manner. DNA synthesis was significantly inhibited by CK-17 and CK-103A but not by CK-101A and CK1-102. Although the synthesis of mRNA was reduced by all CK-compounds at most concentration tested, the synthesis of protein was only slightly reduced or unaffected. These results indicate that CK-compounds are potent fibroblast inhibitors but not cytolytic agents. 相似文献
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The present nationwide, multicenter clinical study was carried out in 26 departments of surgery to define the incidence and attendant mortality of intestinal infarction following abdominal aortic surgery, and to identify patients at risk of it. The data consist of 1752 patients who underwent abdominal aortic reconstruction during 1991-1993 as recorded in the Finnish national vascular registry (FINNVASC). Among the 1752 operations, 27 patients treated at 14 different hospitals had intestinal ischemia, and the complete patient records of all 27 cases were reanalyzed. The incidence of bowel infarction was 1.2%. Among patients operated on for a ruptured aneurysm it was 3.1%, whereas 1.0% of patients with nonruptured aneurysm and 0.6% of those operated on for aortoiliac occlusive disease developed intestinal infarction. In 14 patients (67%) the lesion affected the left colon. The overall 30-day mortality rate was 13% but reached 67% among those with intestinal infarction. We conclude that acute intestinal ischemia with bowel infarction is an infrequent but serious complication of abdominal aortic surgery. It is mainly related to surgery due to aneurysmal disease, and patients with occlusive aortoiliac disease present ischemic complications in the intestines less often. Hypotensive patients being treated for ruptured aneurysm are at greatest risk of intestinal ischemia. 相似文献
68.
A Kurimasa H Ouyang LJ Dong S Wang X Li C Cordon-Cardo DJ Chen GC Li 《Canadian Metallurgical Quarterly》1999,96(4):1403-1408
The DNA-dependent protein kinase (DNA-PK) consists of a heterodimer DNA-binding complex, Ku70 and Ku80, and a large catalytic subunit, DNA-PKcs. To examine the role of DNA-PKcs in lymphocyte development, radiation sensitivity, and tumorigenesis, we disrupted the mouse DNA-PKcs by homologous recombination. DNA-PKcs-null mice exhibit neither growth retardation nor a high frequency of T cell lymphoma development, but show severe immunodeficiency and radiation hypersensitivity. In contrast to the Ku70-/- and Ku80-/- phenotype, DNA-PKcs-null mice are blocked for V(D)J coding but not for signal-end joint formation. Furthermore, inactivation of DNA-PKcs leads to hyperplasia and dysplasia of the intestinal mucosa and production of aberrant crypt foci, suggesting a novel role of DNA-PKcs in tumor suppression. 相似文献
69.
P69 is an isozyme of the medium size class of human 2'-5' oligoadenylate synthetases. In this study, recombinant P69 was expressed and used for enzymological and structural investigations. Bacterially expressed P69 was inactive whereas the same protein expressed in insect cells was highly active. Whether this difference could be due to differential post-translational modifications of the protein was investigated. Mutations of appropriate residues showed that myristoylation of the protein was not necessary for enzyme activity. In contrast, inhibition of glycosylation of P69, by tunicamycin treatment of the insect cells, produced an enzymatically inactive protein. Recombinant P69 produced in insect cells was purified by affinity chromatography. It was a dimeric glycoprotein, very stable and completely dependent on double stranded (ds) RNA for activity. The enzyme catalyzed the non-processive synthesis of 2'-5'-linked oligoadenylate products containing up to 30 residues. 2'-O-Methylated dsRNA was incapable of activating P69 and a 25-base pair dsRNA was as effective as larger dsRNA. This expression system will be useful for large scale production of P69 and its mutants for structural studies. 相似文献
70.
1. Growing pullets were reared on constant 8, 11 or 14 h photoperiods or given 12 daily increments of 30 min followed by an abrupt 6 h decrease in photoperiod in 14 d cycles from 2 d of age to sexual maturity. 2. Birds on the experimental lighting programme matured earlier than constant 8-h controls, later than 11-h controls but at the same age and body weight as constant 14-h controls. 3. Weight of the first egg was correlated with age at first egg. 4. It is assumed that potential advances in maturity for the experimental birds from the 30 min increments in photoperiod were cancelled by the retarding influences of 6 h decreases in photoperiod, resulting in their maturity being similar to that of birds reared on a constant daylength equal to the longest photoperiod reached during the cycle. 相似文献