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101.
102.
Richter A Rose R Hedberg C Waldmann H Ottmann C 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(21):6520-6527
Modulation of protein-protein interactions (PPIs) is a highly demanding, but also a very promising approach in chemical biology and targeted drug discovery. In contrast to inhibiting PPIs with small, chemically tractable molecules, stabilisation of these interactions can only be achieved with complex natural products, like rapamycin, FK506, taxol, forskolin, brefeldin and fusicoccin. Fusicoccin stabilises the activatory complex of the plant H(+)-ATPase PMA2 and 14-3-3 proteins. Recently, we have shown that the stabilising effect of fusicoccin could be mimicked by a trisubstituted pyrrolinone (pyrrolidone1, 1). Here, we report the synthesis, functional activity and crystal structure of derivatives of 1 that stabilise the 14-3-3-PMA2 complex. With a limited compound collection three modifications that are important for activity enhancement could be determined: 1) conversion of the pyrrolinone scaffold into a pyrazole, 2) introduction of a tetrazole moiety to the phenyl ring that contacts PMA2, and 3) addition of a bromine to the phenyl ring that exclusively contacts the 14-3-3 protein. The crystal structure of a pyrazole derivative of 1 in complex with 14-3-3 and PMA2 revealed that the more rigid core of this molecule positions the stabiliser deeper into the rim of the interface, enlarging especially the contact surface to PMA2. Combination of the aforementioned features gave rise to a molecule (37) that displays a threefold increase in stabilising the 14-3-3-PMA2 complex over 1. Compound 37 and the other active derivatives show no effect on two other important 14-3-3 protein-protein interactions, that is, with CRaf and p53. This is the first study that describes the successful optimisation of a PPI stabiliser identified by screening. 相似文献
103.
Anna Luise Grab Dirk Hose Patrick Horn Elisabetta Ada Cavalcanti-Adam Anja Seckinger Martin Müller 《Particle & Particle Systems Characterization》2021,38(3):2000263
In the malignant plasma cell disease multiple myeloma (MM), bone lesions and resulting fractures caused by MM cell (MMC) accumulation represent a major cause of morbidity and mortality. Despite recent advantages in systemic treatment, residual MMCs remain, especially in bone lesions. Therefore an interfacial delivery system for local treatment of MM and induced bone disease based on polyelectrolyte complex nanoparticles (PEC NP) loaded with bone morphogenetic protein 6 (BMP-6) inducing de-novo bone formation and MMC apoptosis is presented herein. BMP-6 loaded PEC NP are fabricated by defined mixing bio-related cationic and anionic polysaccharides and BMP-6 according to molar ratio of BMP-6/PEC-NP of 1/3. BMP-6/PEC NP bound to a model substrate releases 10% BMP-6 sustainably within two weeks as accessed by infrared spectroscopy. BMP-6 loaded PEC NP adheres to cell membranes of MMCs and MSCs and activated phosphorylation of Smad 1/5. Osteogenic differentiation (ALP-concentration) is enhanced in MSCs (p < 0.05). All patient samples (10/10) of MMCs show significant induction of apoptosis (median 84%, p < 0.05). Finally, BMP-6/PEC NP are successfully integrated in a commercial hyaluronic acid based hydrogel material revealing MMC death as principal proof for the local treatment of MM induced bone lesions. 相似文献
104.
Loquet A Laage S Gardiennet C Elena B Emsley L Böckmann A Lesage A 《Journal of the American Chemical Society》2008,130(32):10625-10632
A two-dimensional proton-mediated carbon-carbon correlation experiment that relies on through-bond heteronuclear magnetization transfers is demonstrated in the context of solid-state NMR of proteins. This new experiment, dubbed J-CHHC by analogy to the previously developed dipolar CHHC techniques, is shown to provide selective and sensitive correlations in the methyl region of 2D spectra of crystalline organic compounds. The method is then demonstrated on a microcrystalline sample of the dimeric protein Crh (2 x 10.4 kDa). A total of 34 new proton-proton contacts involving side-chain methyl groups were observed in the J-CHHC spectrum, which had not been observed with the conventional experiment. The contacts were then used as additional distance restraints for the 3D structure determination of this microcrystalline protein. Upon addition of these new distance restraints, which are in large part located in the hydrophobic core of the protein, the root-mean-square deviation with respect to the X-ray structure of the backbone atom coordinates of the 10 best conformers of the new ensemble of structures is reduced from 1.8 to 1.1 A. 相似文献
105.
106.
Wolfgang Wiesner 《Mikrochimica acta》1978,70(3-4):247-254
Zusammenfassung Ein Verfahren wurde vorgestellt, das die Herabsetzung der Informationstiefe bei der quantitativen Elektronenstrahlmikroanalyse rauher Oxidschichten durch Aufbringen von Goldschichten gestattet. Probenbereiche, deren Dicke geringer als die Austrittstiefe der Röntgenstrahlung ist, können mit einer relativen Genauigkeit von ca. ±5% analysiert werden. Die Auswertung der Spektren nach diesem Verfahren liefert neben den Konzentrationen der Elemente auch die Dicke der Goldschicht.
On the reduction of information depth of oxide layers, using quantitative energy-dispersive X-ray microanalysis
Summary The information depth can be reduced by coating the specimen with gold. A simple quantitative approach is made for the correction of measured intensities which allows determination of elements with a relative efficiency of about ±5% within a certain range of gold thickness. Evaluation of concentrations is combined with determination of gold layer thickness.相似文献
107.
108.
109.
Karl Cammann Udo Lemke Anja Rohen Jürgen Sander Hildegard Wilken Babette Winter 《Angewandte Chemie (International ed. in English)》1991,30(5):516-539
Chemical and environmental engineering and biotechnology are among the fields now being transformed by continually increasing levels of automation. Whereas the objective in other sectors of industry is simply to increase efficiency, here considerations of system theory or safety demand a high level of automation. Either the processes are too complex and require multifunctional control with feedback, or an analysis of the safety requirements shows the necessity for a certain degree of redundancy in the safety measures, and for elimination of human error as a risk factor. With regard to quality control, cost-benefit analyses lead to striking conclusions which again indicate the need for highly automated, and above all reliable, systems to eliminate rejects. The crux of any automated system is the measurement and control technology; of central importance is the rapid, reliable, and in some cases continuous, measurement and interpretation of key processes or control variables. For this purpose a wide variety of recording instruments and sensors are used to give as accurate a picture as possible of the state of the system. It is obvious from this that the performance of the control system is critically dependent on the sensors. Errors in the measured quantities can become amplified in the control variables or, in dynamic systems, can lead to undesirable operating conditions. Moreover, as a consequence of great advances in microelectronics, “intelligent sensors” which can calibrate and control themselves will be one of the key technologies of the nineties. Unless fast and immediate information on the true current status of a system is available, microprocessors as control devices react blindly and unpredictably to errors in input information. New discoveries in the fields of electronic, electrochemical, and optical transducers are now being applied in heterogeneous catalysis and surface physics, and in biochemistry (enzymology and immunology); in these fields new chemical sensor principles are being tested, which could revolutionize instrumental methods of molecular analysis in particular, owing to their very favorable cost-performance relationship. This article aims to give an up-to-date overview of the current state of the art in these developments, with emphasis on their importance for analysis and their significance in relation to the chemist's interest in mechanisms for identifying substances. 相似文献
110.
Karel Wiesner Thomas Y. R. Tsai Ravindra Kumar Harihran Sivaramakrishnan 《Helvetica chimica acta》1984,67(4):1128-1135
Two efficient preparations of the title compound, one from common C19-steroids, the other frm digitoxigenin, are described. The less active minor epimer (21S)-methyldigitoxigenin was also obtained and characterized. The positive inotropic effects and margins of safety of the two C(21)-epimers (tested as glucosides) are discussed in terms of the topological properties of the Digitalis receptors. 相似文献