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941.
Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity 下载免费PDF全文
Dr. Philipp M. Toth Dr. Sonja Lieber Dr. Frithjof M. Scheer Tim Schumann Dr. Yvonne Schober Dr. Wolfgang A. Nockher Dr. Till Adhikary Dr. Sabine Müller‐Brüsselbach Prof. Dr. Rolf Müller Prof. Dr. Wibke E. Diederich 《ChemMedChem》2016,11(5):488-496
Based on 3‐(((4‐(hexylamino)‐2‐methoxyphenyl)amino)sulfonyl)‐2‐thiophenecarboxylic acid methyl ester (ST247, compound 2 ), a recently described peroxisome proliferator‐activated receptor (PPAR)β/δ‐selective inverse agonist, we designed and synthesized a series of structurally related ligands. The structural modifications presented herein ultimately resulted in a series of ligands that display increased cellular activity relative to 2 . Moreover, with methyl 3‐(N‐(2‐(2‐ethoxyethoxy)‐4‐(hexylamino)phenyl)sulfamoyl)thiophene‐2‐carboxylate (PT‐S264, compound 9 u ), biologically relevant plasma concentrations in mice were achieved. The compounds presented in this study will provide useful novel tools for future investigations addressing the role of PPARβ/δ in physiological and pathophysiological processes. 相似文献
942.
Cover Picture: Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity (ChemMedChem 5/2016) 下载免费PDF全文
943.
Endo‐β‐Glucosidase Tag Allows Dual Detection of Fusion Proteins by Fluorescent Mechanism‐Based Probes and Activity Measurement 下载免费PDF全文
Dr. Wouter W. Kallemeijn Saskia Scheij Tineke M. Voorn‐Brouwer Dr. Martin D. Witte Marri Verhoek Prof. Dr. Hermen S. Overkleeft Dr. Rolf G. Boot Prof. Dr. Johannes M. F. G. Aerts 《Chembiochem : a European journal of chemical biology》2016,17(18):1698-1704
β‐Glucoside‐configured cyclophellitols are activity‐based probes (ABPs) that allow sensitive detection of β‐glucosidases. Their applicability to detect proteins fused with β‐glucosidase was investigated in the cellular context. The tag was Rhodococcus sp. M‐777 endoglycoceramidase II (EGCaseII), based on its lack of glycans and ability to hydrolyze fluorogenic 4‐methylumbelliferyl β‐d ‐lactoside (an activity absent in mammalian cells). Specific dual detection of fusion proteins was possible in vitro and in situ by using fluorescent ABPs and a fluorogenic substrate. Pre‐blocking with conduritol β‐epoxide (a poor inhibitor of EGCaseII) eliminated ABP labeling of endogenous β‐glucosidases. ABPs equipped with biotin allowed convenient purification of the fusion proteins. Diversification of ABPs (distinct fluorophores, fluorogenic high‐resolution detection moieties) should assist further research in living cells and organisms. 相似文献
944.
Dr. Marie‐Pierre Collin Dr. Mario Lobell Dr. Walter Hübsch Dr. Dirk Brohm Dr. Hartmut Schirok Dr. Rolf Jautelat Dr. Klemens Lustig Dr. Ulf Bömer Dr. Verena Vöhringer Dr. Mélanie Héroult Dr. Sylvia Grünewald Dr. Holger Hess‐Stumpp 《ChemMedChem》2018,13(5):437-445
Rogaratinib (BAY 1163877) is a highly potent and selective small‐molecule pan‐fibroblast growth factor receptor (FGFR) inhibitor (FGFR1–4) for oral application currently being investigated in phase 1 clinical trials for the treatment of cancer. In this publication, we report its discovery by de novo structure‐based design and medicinal chemistry optimization together with its pharmacokinetic profile. 相似文献
945.
Development of an Ultraviolet‐Spectrophotometric Method for Analysis of Esterquat‐Containing Flotation Collectors in Aqueous Solutions 下载免费PDF全文
In this study, a rapid and simple ultraviolet‐spectrophotometric method was developed and validated for the quantitative determination of esterquat‐containing flotation collector FLOT 2015 in aqueous solutions. This method is based on the formation of an ion pair by FLOT 2015 and bromocresol purple, an anionic dye, and the subsequent measurement of the reduction in absorbance without extraction by organic solvents. The optimum conditions for FLOT 2015 detection and analysis were established. Sample solutions were stable up to 3 h. Maximum absorbance was obtained at 574 nm. The proposed method showed linearity in the range of 5–45 μg mL?1 with a correlation coefficient of 0.9917. Standard and relative standard deviation obtained by intraday and interday precision tests of the proposed method were within the permissible bias range and considered satisfactory. This method was found to be selective and specific for successful determination of FLOT 2015 in aqueous flotation systems. 相似文献
946.
Filter algorithm for influence functions in the computer controlled polishing of high-quality optical lenses 总被引:1,自引:0,他引:1
Markus Schinhaerl Rolf Rascher Richard Stamp Gordon Smith Lyndon Smith Elmar Pitschke Peter Sperber 《International Journal of Machine Tools and Manufacture》2007,47(1):107-111
Computer controlled polishing (CCP) is widely used in the production of high-quality optical lenses. CCP enables surface error-profile-dependent calculation of polishing sequences prior to processing, and facilitates the cost-effective manufacture of high-quality optical surfaces. Calculation of an individual polishing sequence requires knowledge of the surface error-profile in addition to knowledge of the material removal characteristic (influence function) of the polishing tool. Measurement errors during both determination of the surface error-profile, and the influence function, may lead to an incorrect polishing sequence calculation, which in turn may result in an inadequate product quality. A new method has been developed which minimises the effects of measurement errors on the influence function. The resulting algorithm renders an influence function symmetrical and filters noisy data. Practical polishing tests with magnetorheological finishing have been performed to verify this new technique. The improvement of the peak-valley (PV) value of the surfaces polished with the symmetrical rendered influence function was observed to average 14% greater than that which related to the PV value improvement of those surfaces which were polished with the unmodified influence function. The algorithm developed is based on software and is easily implemented. Thus, artificial enhancement of an influence function is a straightforward technique to improve the result of the polishing process. 相似文献
947.
Borlinghaus RT 《Microscopy research and technique》2006,69(9):689-692
True confocal microscopy requires point-shaped illumination and detection. To generate an image, a diffraction limited spot is moved over the sample. Single spot scanning has suffered in the past from low image rates; a solution is the employment of very fast scanning devices (resonant scanners) for x-movement. In the process of introducing resonant scanning devices, it was found that both signal yield is improved and bleaching is decreased-in contrary to the assumed performance. This article will show by a simple and well understood model a straightforward explanation for the potential increase of signal yield and decrease in photobleaching. The time that is ruling the dose-rate effects is the effective time; a fluorochrome is illuminated. This time depends on the diameter of the spot that is moved over the sample and the speed at which the spot moves. In essence, the scan process causes a pulsed illumination of the fluorochromes. Various schemes of pulsed illumination are simulated with a fluorescence model. The model includes a dark state, where fluorochromes will exit the fluorescence process and slowly decay back into the ground state. Upon splitting a single dose into two pulses separated by a dark time-reflecting an increased scan speed-the amount of fluorescence emission is increased and bleaching is reduced. These results show a potential increase of fluorescence and a lower photobleaching upon higher scan speed. As illumination during the bleach-phase in a FRAP-experiment is similar to a light pulse, the findings also suggest to critically consider the very beginning of fluorescence recovery in terms of triplet relaxation process that potentially could falsify the measurements. 相似文献
948.
NiAl-Ni3Al intermetallic composites (IC) and intermetallic matrix composites (IMC) with TiC and WC reinforcement were laser clad to increase the liquid impact erosion resistance of AISI 420 Martensitic stainless steel. Laser process parameter optimisation and pre- and post-heat treatment of the laser clad specimens were carried out to minimise porosity and sensitivity to crack formation. The coatings were characterised by optical microscopy (OM), scanning electron microscopy (SEM), X-ray diffraction (XRD) and energy-dispersive spectroscopy (EDS). The erosion resistance of the substrate material at a water droplet exit velocity of up to 150 m/s was improved from 116.9 to 838.7 min/mm3 for the nickel aluminide IC coating and from 855 to 1446 min/mm3 for the IMC coating with TiC and WC reinforcement. The pseudo-elasticity combined with the high work hardening ability was attributed to the excellent erosion resistance of nickel aluminide IC coatings. The IMC coatings with ceramic reinforcement extended significantly the initial resistance against liquid impact erosion. However, once damage occurred the erosion accelerated rapidly. No direct correlation could be established between the erosion resistance and the mechanical properties. The influence of hardness, elastic modulus, strain-hardening coefficient and the reversible penetration ratio on the erosion resistance was discussed. 相似文献
949.
Valence electron energy-loss spectroscopy in the scanning transmission electron microscope can provide detailed information on the electronic structure of individual nanostructures. By employing the latest advances in electron optical devices, such as a probe aberration corrector and an electron monochromator, the probe size, spectroscopic resolution, probe current and primary electron energy can be varied over a large range. This flexibility is particularly important for nanostructures where each of these variables needs to be carefully counterbalanced in order to collect spectroscopic data without altering the integrity of the sample. Here the implementation of valence electron energy-loss spectroscopy to the study of nanostructures is discussed, with particular mention to the theoretical understanding of each of the contributions to the overall spectrum. 相似文献
950.
Hydrolysis Activity of Pyloric Cecal Enterocytes of Brown Trout (Salmo trutta) toward Monoacylglycerol and Lysophosphatidylcholine 下载免费PDF全文
Some lipid digestion pathways in fish deviate from those in mammals, and many differences may also be species dependent. This report describes a pathway for monoacylglycerol (MAG) and lysophospholipid absorption by intestinal enterocytes in brown trout that may be of significance in salmonids. When culturing primary cells in a medium containing 1‐ and 2‐MAG, we observed a massive hydrolysis of unesterified fatty acids. The hydrolysis activity was retained in the medium even after the removal of the cells. To further characterize these activities, both extracellular and isolated membrane proteins were tested for lipase activity toward triacylglycerol (TAG), diacylglycerol (DAG), MAG, phosphatidylcholine (PtdCho), and lysoPtdCho. In both cases, the main hydrolyzing activity was toward MAG followed by lysoPtdCho with very little activity toward DAG, TAG, or PtdCho. The extracellular and membrane proteins were partially purified by fast protein liquid chromatography and identified by proteomics (liquid chromatography–tandem mass spectrometry) focusing on lipase/hydrolase enzymes. In the membrane protein fraction, the data suggested that MAG was produced as an intermediate in the hydrolysis of lysoPtdCho by either lysophospholipase C or lysophospholipase D activity. Both abhydrolase‐domain‐containing protein 6 and abhydrolase‐domain‐containing protein 12 were identified in the membrane protein and they could be responsible for the hydrolysis of MAG. In the culture medium, low‐peptide matches were found for ABHD6 and phospholipases and further studies are needed. In summary, trout enterocytes are capable of hydrolyzing MAG and lysoPtdCho. The enzymes are both extracellular and membrane bound. The pathways may be of significance during lipid absorption in fish lacking a 1,3 specific pancreatic lipase. 相似文献