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71.
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73.
Luca Mazzei Michele Cianci Stefano Benini Stefano Ciurli 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(52):12145-12158
Urease uses a cluster of two NiII ions to activate a water molecule for urea hydrolysis. The key to this unsurpassed enzyme is a change in the conformation of a flexible structural motif, the mobile flap, which must be able to move from an open to a closed conformation to stabilize the chelating interaction of urea with the NiII cluster. This conformational change brings the imidazole side chain functionality of a critical histidine residue, αHis323, in close proximity to the site that holds the transition state structure of the reaction, facilitating its evolution to the products. Herein, we describe the influence of the solution pH in modulating the conformation of the mobile flap. High-resolution crystal structures of urease inhibited in the presence of N-(n-butyl)phosphoric triamide (NBPTO) at pH 6.5 and pH 7.5 are described and compared to the analogous structure obtained at pH 7.0. The kinetics of urease in the absence and presence of NBPTO are investigated by a calorimetric assay in the pH 6.0–8.0 range. The results indicate that pH modulates the protonation state of αHis323, which was revealed to have pKa=6.6, and consequently the conformation of the mobile flap. Two additional residues (αAsp224 and αArg339) are shown to be key factors for the conformational change. The role of pH in modulating the catalysis of urea hydrolysis is clarified through the molecular and structural details of the interplay between protein conformation and solution acidity in the paradigmatic case of a metalloenzyme. 相似文献
74.
Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers
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Alberto Dal Corso Dr. Michele Caruso Dr. Laura Belvisi Dr. Daniela Arosio Prof. Dr. Umberto Piarulli Dr. Clara Albanese Dr. Fabio Gasparri Dr. Aurelio Marsiglio Dr. Francesco Sola Dr. Sonia Troiani Dr. Barbara Valsasina Dr. Luca Pignataro Dr. Daniele Donati Prof. Dr. Cesare Gennari 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(18):6921-6929
Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala and Phe–Lys peptide sequences) were synthesized by conjugation of the αvβ3‐integrin ligand cyclo[DKP–RGD]‐CH2NH2 ( 2 ) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker ( 8 ) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVβ3‐integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8 , which possesses a nonpeptide “uncleavable” linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF‐CEM (αVβ3?) and its subclone CCRF‐CEM αVβ3 (αVβ3+). Fairly effective integrin targeting was displayed by the cyclo[DKP–RGD]–Val–Ala–PTX conjugate ( 6 ), which was found to differentially inhibit proliferation in antigen‐positive CCRF‐CEM αVβ3 versus antigen‐negative isogenic CCRF‐CEM cells. The total lack of activity displayed by the “uncleavable” cyclo[DKP–RGD]–PTX conjugate ( 8 ) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload. 相似文献
75.
Michele Zilletti Stephen J. Elliott Emiliano Rustighi 《Journal of sound and vibration》2012,331(18):4093-4100
The tuning of a dynamic vibration absorber is considered such that either the kinetic energy of the host structure is minimised or the power dissipation within the absorber is maximised. If the host structure is approximated as a damped single degree of freedom, the optimal values for the ratio of the absorber's natural frequency to the host structure and the optimal damping ratio of the absorber are shown to be the same whether the kinetic energy of the host structure is minimised or the power dissipation of the absorber is maximised. It is also demonstrated that the total power input into the system does not depend on the two parameters but only on the host structure's mass. 相似文献
76.
We describe a parallel implementation of a block triangular preconditioner based on the modified augmented Lagrangian approach to the steady incompressible Navier–Stokes equations. The equations are linearized by Picard iteration and discretized with various finite element and finite difference schemes on two- and three-dimensional domains. We report strong scalability results for up to 64 cores. 相似文献
77.
Jose Castro‐Perez Nathan Hatcher Nana Kofi Karikari Sheng‐Ping Wang Vivienne Mendoza Henry Shion Alan Millar John Shockcor Mark Towers David McLaren Vinit Shah Stephen Previs Karen Akinsanya Michele Cleary Thomas P. Roddy Douglas G. Johns 《Rapid communications in mass spectrometry : RCM》2014,28(22):2471-2479
78.
Structural and Dynamic Characterization of the Molecular Hub Early Region 1A (E1A) from Human Adenovirus
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Marcela Oliveira Nogueira Michele Salvi Dr. Talita Duarte Pagani Prof. Isabella C. Felli Prof. Roberta Pierattelli 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(37):13010-13013
The small‐DNA human adenovirus encodes one of the most versatile molecular hubs, the E1A protein. This protein is essential for productive viral infection in human cells and a vast amount of biologically relevant data are available on its interactions with host proteins. Up to now, however, no high‐resolution structural and dynamic information on E1A is available despite its important biological role. Among the different spliced variants of E1A, two are expressed at high level in the early stage of infection. These are 243 and 289 residues isoforms. Herein, we present their NMR characterization, showing that they are both highly disordered, but also demonstrate a certain heterogeneous behavior in terms of structural and dynamic properties. Furthermore, we present the characterization of the isolated domain of the longer variant, known as CR3. This study opens the way to understanding at the molecular level how E1A functions. 相似文献
79.
We study geometric properties of complete non-compact bounded self-shrinkers and obtain natural restrictions that force these hypersurfaces to be compact. Furthermore, we observe that, to a certain extent, complete self-shrinkers intersect transversally a hyperplane through the origin. When such an intersection is compact, we deduce spectral information on the natural drifted Laplacian associated to the self-shrinker. These results go in the direction of verifying the validity of a conjecture by H.D. Cao concerning the polynomial volume growth of complete self-shrinkers. A finite strong maximum principle in case the self-shrinker is confined into a cylindrical product is also presented. 相似文献
80.
Coronary artery diseases are a leading cause of mortality and are increasingly prevalent with age. However, the large number of age-increasing co-morbidities make difficult to understand the impact of cardiovascular ageing alone on the coronary flow pattern. The present study aims to shed light on the effect of arterial and ventricular ageing on the coronary circulation, which is here studied by means of a validated mathematical model. Forward and backward pressure and flow waves are analysed, as well as their intensity. Results highlight a complex spatiotemporal coronary wave pattern, where intense waves originate from the aorta (particularly in systole) and from the deep myocardium, during both the isovolumic compression and the diastolic phase. The subendocardial viability ratio decreases with age, the total coronary flow is slightly reduced, and the left-ventricular work increases. Consequently, the left-ventricular work per unit of blood flow increases, thus limiting the cell oxygen availability abundance, and therefore increasing the risk of myocardial infarction. Our results highlight a physiological age-induced supply/demand unbalance, which can augment the risk of myocardial ischemia and can contribute to pave the way to other typical coronary pathological processes. 相似文献