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81.
82.
Anna M. Schoepf Dr. Stefan Salcher Verena Hohn Florina Veider Prof. Dr. Petra Obexer Prof. Dr. Ronald Gust 《ChemMedChem》2020,15(12):1067-1077
New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death-modulating effects of the telmisartan-derived lead 4′-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid ( 3 b ) was investigated. Inspired by the pharmacodynamics of HYL-6d and the selective PPARγ ligand VSP-51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2-COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60-100 % activation. Among the 2-CO2CH3 derivatives, only the ester of the lead ( 2 b ) slightly activated PPARγ. Sensitizing effects were further observed for this non-cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5-Br-substituted ester of the benzimidazoles ( 5 b ). 相似文献
83.
Ulrich Koller Stefan Hainzl Thomas Kocher Clemens Hüttner Alfred Klausegger Christina Gruber Elisabeth Mayr Verena Wally Johann W. Bauer Eva M. Murauer 《International journal of molecular sciences》2015,16(1):1179-1191
Spliceosome-mediated RNA trans-splicing has become an emergent tool for the repair of mutated pre-mRNAs in the treatment of genetic diseases. RNA trans-splicing molecules (RTMs) are designed to induce a specific trans-splicing reaction via a binding domain for a respective target pre-mRNA region. A previously established reporter-based screening system allows us to analyze the impact of various factors on the RTM trans-splicing efficiency in vitro. Using this system, we are further able to investigate the potential of antisense RNAs (AS RNAs), presuming to improve the trans-splicing efficiency of a selected RTM, specific for intron 102 of COL7A1. Mutations in the COL7A1 gene underlie the dystrophic subtype of the skin blistering disease epidermolysis bullosa (DEB). We have shown that co-transfections of the RTM and a selected AS RNA, interfering with competitive splicing elements on a COL7A1-minigene (COL7A1-MG), lead to a significant increase of the RNA trans-splicing efficiency. Thereby, accurate trans-splicing between the RTM and the COL7A1-MG is represented by the restoration of full-length green fluorescent protein GFP on mRNA and protein level. This mechanism can be crucial for the improvement of an RTM-mediated correction, especially in cases where a high trans-splicing efficiency is required. 相似文献
84.
85.
Katharina Panten Bernadette F. van Heel Jan M. Fliervoet Riyan J. G. van den Born 《Water Resources Management》2018,32(12):4063-4078
Integrated river basin management (IRBM) calls for participatory practices involving stakeholders along transnational river landscapes. Understanding the complex and diverse views regarding participation is a prerequisite for meaningful involvement of civil actors, especially in a transnational context. In a case study along the Lower Rhine river, we assessed and compared cognitive perceptions towards IRBM of citizen initiatives and nature organizations from Germany and the Netherlands and their previous experiences with participation processes.We found large differences between the four actor groups in motivations to participate as well as in levels of trust towards institutions. This study also showed different views on participation between the two countries with regard to the problem definition, nature images and the perceived relationships between government organisations on the one hand and citizen initiatives and nature organisations on the other hand.The findings suggest that views vary between citizen initiatives and nature organizations within a country and that cultural notions add to the complexity of transnational participation. In transnational participation processes, the varying views between actor groups should be taken into account, as well as the complexities among countries even within actor groups. 相似文献
86.
Nina Kubatova Dr. Hendrik R. A. Jonker Dr. Krishna Saxena Dr. Christian Richter Verena Vogel Sandra Schreiber Prof. Dr. Anita Marchfelder Prof. Dr. Harald Schwalbe 《Chembiochem : a European journal of chemical biology》2020,21(1-2):149-156
Past sequencing campaigns overlooked small proteins as they seemed to be irrelevant due to their small size. However, their occurrence is widespread, and there is growing evidence that these small proteins are in fact functionally very important in organisms found in all kingdoms of life. Within a global proteome analysis for small proteins of the archaeal model organism Haloferax volcanii, the HVO_2922 protein has been identified. It is differentially expressed in response to changes in iron and salt concentrations, thus suggesting that its expression is stress-regulated. The protein is conserved among Haloarchaea and contains an uncharacterized domain of unknown function (DUF1508, UPF0339 family protein). We elucidated the NMR solution structure, which shows that the isolated protein forms a symmetrical dimer. The dimerization is found to be concentration-dependent and essential for protein stability and most likely for its functionality, as mutagenesis at the dimer interface leads to a decrease in stability and protein aggregation. 相似文献
87.
García de la Cruz Lucía Domenges Bernadette Divinski Sergiy V. Wilde Gerhard Hug Eric 《Metallurgical and Materials Transactions A》2020,51(7):3425-3434
Metallurgical and Materials Transactions A - Short-circuit diffusion in fine-grained Ni samples processed by Spark Plasma sintering has been investigated by the radiotracer technique. Ni grain... 相似文献
88.
Companies have long used various approaches for organizing their employees' time for creative and routine tasks in order to improve innovative performance. In this paper, we examine how work schedule autonomy affects individuals' creative and routine performance. We then evaluate non‐commissioned time models. Results of laboratory experiments with 233 participants reveal that while average routine performance is not affected by schedule autonomy, the effect of schedule autonomy on creative performance depends on the subject's impulsiveness. There is evidence of an inverse relationship between schedule autonomy and creative performance among subjects of low impulsiveness. Hence, our results indicate that the optimal management policy depends on the manager's focus on creative or routine performance and the types of employees the manager supervises. For routine performance, the creativity time model has no significant impact. 相似文献
89.
Guo‐Feng Luo Yonatan Biniuri Margarita Vzquez‐Gonzlez Verena Wulf Michael Fadeev Ronit Lavi Itamar Willner 《Advanced functional materials》2019,29(33)
A series of metal ion‐terpyridine‐modified L‐tyrosinamide aptamers (Mn + = Cu2+ or Fe3+) act as enzyme‐mimicking catalysts (nucleoapzymes) for oxygen‐insertion into C? H bonds and the transformation of L‐tyrosinamide into amidodopachrome. The reaction proceeds in the presence of H2O2 and coadded L‐ascorbic acid. In one series of experiments, the catalyzed oxidation of L‐tyrosinamide to amidodopachrome by a set of nucleoapzymes consisting of Fe3+‐ or Cu2+‐terpyridine complexes tethered directly or through a 4 × thymidine (4 × T) bridge, to the 5′‐ or 3′‐end of the 49‐mer L‐tyrosinamide aptamer or to a shorter 23‐mer L‐tyrosinamide aptamer is examined. All nucleoapzymes reveal catalytic Michaelis–Menten enzyme‐like activities and the separated Fe3+‐ or Cu2+‐terpyridine and L‐tyrosinamide aptamer units show only minute catalytic properties. The catalytic activities of the nucleoapzymes are attributed to the concentration of the L‐tyrosinamide substrate by the aptamer units in proximity to the catalytic sites (Kd = (14 ± 0.1) × 10?6 m for all 49‐mer catalysts and Kd = (2.5 ± 0.1) × 10?6 m and Kd = (0.8 ± 0.04) × 10?6 m for the 23‐mer catalysts). Electron spin resonance experiments reveal that ?OH radicals and ascorbate radicals participate in the transformation of tyrosine derivatives to catechol products. An autocatalytic feedback mechanism for the amplified generation of the two radicals is suggested. 相似文献