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排序方式: 共有227条查询结果,搜索用时 15 毫秒
111.
Brasca MG Albanese C Amici R Ballinari D Corti L Croci V Fancelli D Fiorentini F Nesi M Orsini P Orzi F Pastori W Perrone E Pesenti E Pevarello P Riccardi-Sirtori F Roletto F Roussel P Varasi M Vulpetti A Mercurio C 《ChemMedChem》2007,2(6):841-852
We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma. 相似文献
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The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signalling processes and cell proliferation. It has been reported that an improper amplification or activation of these enzymes is a distinctive feature of a number of human cancers, including breast cancers. Thus, the inhibition of Cdc25 phosphatases might provide a novel approach for the discovery of new and selective antitumor agents. By using the crystal structure of the catalytic domain of Cdc25B, structural models for the interaction of various Cdc25B inhibitors (1-13) with the enzyme were generated by computational docking. The parallel use of two efficient and predictive docking programs, AutoDock and GOLD, allowed mutual validation of the predicted binding poses. To evaluate their quality, the models were validated with known structure-activity relationships and site-directed mutagenesis data. The results provide an improved basis for structure-based ligand design and suggest a possible explanation for the inhibition mechanism of the examined Cdc25B ligands. We suggest that the recurring motif of a tight interaction between the inhibitor and the two arginine residues, 482 and 544, is of prime importance for reversible enzyme inhibition. In contrast, the irreversible inhibition mechanism of 1-4 seems to be associated with the close vicinity of the quinone ring and the Cys473 catalytic thiolate. We believe that this extensive study might provide useful hints to guide the development of new potent Cdc25B inhibitors as novel anticancer drugs. 相似文献
115.
Paizis Christos; Papaxanthis Charalambos; Berret Bastien; Pozzo Thierry 《Canadian Metallurgical Quarterly》2008,122(6):1361
The authors investigated the influence of normal aging upon equilibrium and kinematics features during a whole-body task. Eight young (23±1.51 years) and eight elderly (74.5±4.5 years) adults reached from a standing position an object placed in front of them on the ground. The authors found smaller Center of Masse (CoM) and Center of Pressure (CoP) antero-posterior displacements in elderly than in young adults. Wrist paths were curved in young but straight in elderly adults. Wrist peak velocity and duration were respectively lower and greater in elderly compared to young adults. However, Principal-Component-Analysis did not reveal differences in angle coordination between the two groups, suggesting so that modifications in equilibrium and wrist kinematics reflect an adaptation process that compensates age-related physiological changes. The authors hypothesized that equilibrium preservation in elderly contributes to wrist kinematics modifications. The authors verified this premise by placing young adults under equilibrium restrictions (reduced base of support) and observing that they reproduced the behavior of elderly adults. The authors propose that wrist kinematics is equilibrium dependent and that such a strategy is included in the motor plan of elderly adults. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
116.
Cinzia Maria Chinnici Gioacchin Iannolo Ettore Cittadini Anna Paola Carreca David Nascari Francesca Timoneri Mariangela Di Bella Nicola Cuscino Giandomenico Amico Claudia Carcione Pier Giulio Conaldi 《International journal of molecular sciences》2021,22(4)
Despite low levels of vascular endothelial growth factor (VEGF)-A, the secretome of human Wharton’s jelly (WJ) mesenchymal stromal cells (MSCs) effectively promoted proangiogenic responses in vitro, which were impaired upon the depletion of small (~140 nm) extracellular vesicles (EVs). The isolated EVs shared the low VEGF-A profile of the secretome and expressed five microRNAs, which were upregulated compared to fetal dermal MSC-derived EVs. These upregulated microRNAs exclusively targeted the VEGF-A gene within 54 Gene Ontology (GO) biological processes, 18 of which are associated with angiogenesis. Moreover, 15 microRNAs of WJ-MSC-derived EVs were highly expressed (Ct value ≤ 26) and exclusively targeted the thrombospondin 1 (THBS1) gene within 75 GO biological processes, 30 of which are associated with the regulation of tissue repair. The relationship between predicted microRNA target genes and WJ-MSC-derived EVs was shown by treating human umbilical-vein endothelial cells (HUVECs) with appropriate doses of EVs. The exposure of HUVECs to EVs for 72 h significantly enhanced the release of VEGF-A and THBS1 protein expression compared to untreated control cells. Finally, WJ-MSC-derived EVs stimulated in vitro tube formation along with the migration and proliferation of HUVECs. Our findings can contribute to a better understanding of the molecular mechanisms underlying the proangiogenic responses induced by human umbilical cord-derived MSCs, suggesting a key regulatory role for microRNAs delivered by EVs. 相似文献
117.
Perrone MG Vitale P Malerba P Altomare A Rizzi R Lavecchia A Di Giovanni C Novellino E Scilimati A 《ChemMedChem》2012,7(4):629-641
The COX-1 isoenzyme plays a significant role in a variety of diseases, as it catalyzes the bioprocesses behind many health problems. Among the diarylheterocycle class of COX inhibitors, the isoxazole ring has been widely used as a central heterocycle for the preparation of potent and selective COX-1 inhibitors such as P6 [3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole]. The role of the isoxazole nucleus in COX-1 inhibitor selectivity has been clarified by preparing a set of new diarylheterocycles with various heterocycle cores. Replacement of isoxazole with isothiazole or pyrazole gave a drastic decrease in COX-1 inhibitory activity, whereas the introduction of an electron-donating group (EDG) on the N-aryl pyrazole allowed recovery of COX-1 inhibitory activity and selectivity. The EDG-equipped 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (17) selectively inhibits COX-1 activity (IC(50) =3.4 μM; 28% COX-2 inhibition at 50 μM), in contrast to its inactive analogue, 3-(furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole, which does not bear the methoxy EDG. Molecular docking studies of compound 17 into the binding site of COX-1 shed light on its binding mode. 相似文献
118.
S. Palmas A. Da Pozzo M. Mascia A. Vacca R. Matarrese I. Nova 《Journal of Applied Electrochemistry》2012,42(9):745-751
The results of an experimental study on the photo electrochemical behavior of nanotubular TiO2 structures are presented in this work. TiO2 samples were prepared by electrochemical anodization of Ti foils and submitted to thermal annealing. The influence of the current transient during the anodization, and of the annealing temperature on the photochemical response of the samples at different wavelengths was studied. Different behavior of the samples was observed, which may be attributed to the distributions of defects and to their different sensitivity to the temperature. The analysis of the performance of the samples in absence or in the presence of glycerol, used as hole scavenger, provided more information on the photo-catalytic properties of these structures. 相似文献
119.
Nadia Arcamone Simona Neglia Giuliana Gargiulo Vincenzo Esposito Ettore Varricchio Pietro Battaglini Paolo De Girolamo Finizia Russo 《Microscopy research and technique》2009,72(7):525-533
The occurrence and localization of ghrelin peptide in the gastrointestinal tract of Carassius auratus and Dicentrarchus labrax, two fish species that exhibit different feeding behavior, different habitats, and different anatomical organizations of the gastroenteric tract, were examined by immunohistochemical methods and western blotting analysis. All of the gastrointestinal segments studied displayed immunohistochemical localizations of ghrelin peptide. Numerous single or clustered immunoreactive cells were found along the gastric folds, particularly in the pyloric region of Dicentrarcus labrax, whereas scattered ghrelin immunoreactive cells were observed in the intestinal epithelium of both fish species. Double immunolabeling PGP 9.5/ghrelin demonstrated the localization of ghrelin peptide also in nerve fibers and neuronal cells of the submucosal and myenteric plexuses, often in association with vascular structures. Western blotting analysis confirmed the presence of ghrelin peptide in the gatrointestinal tract of both species studied, whose molecular weight was similar to that of the corresponding mammalian prepro-ghrelin. The findings could support the hypothesis that this peptide is an important appetite regulator in fish and could confirm the presence of the ghrelin peptide, starting from its precursor proteins, in the gastrointestinal tract of the goldfish and the sea bass. Microsc. Res. Tech. 2009. © 2009 Wiley-Liss, Inc. 相似文献
120.
Ettore Fornasini 《Multidimensional Systems and Signal Processing》1991,2(3):233-265
The paper presents some applications of 2-D systems theory to the problem of modeling the river pollution processes and the associated selfpurification phenomena. The dynamical evolution of the biological oxygen demand (BOD) and the dissolved oxygen (DO) in a one-dimensional river model is discussed under various physical assumptions. 相似文献