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Kornelia Neveling Ilse Feenstra Christian Gilissen Lies H. Hoefsloot Erik‐Jan Kamsteeg Arjen R. Mensenkamp Richard J. T. Rodenburg Helger G. Yntema Liesbeth Spruijt Sascha Vermeer Tuula Rinne Koen L. van Gassen Danielle Bodmer Dorien Lugtenberg Rick de Reuver Wendy Buijsman Ronny C. Derks Nienke Wieskamp Bert van den Heuvel Marjolijn J.L. Ligtenberg Hannie Kremer David A. Koolen Bart P.C. van de Warrenburg Frans P.M. Cremers Carlo L.M. Marcelis Jan A.M. Smeitink Saskia B. Wortmann Wendy A.G. van Zelst‐Stams Joris A. Veltman Han G. Brunner Hans Scheffer Marcel R. Nelen 《Human mutation》2013,34(12):1721-1726
The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene‐specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger‐based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite‐stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost. 相似文献
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Introduction. It has been theorised that patients with persecutory delusions display a lack of covert self‐esteem (formerly termed the ‘inferiority complex’), while at the same time displaying normal or even heightened levels of explicit self‐esteem. However, the empirical basis for this assumption is inconsistent. Methods. In view of apparent shortcomings of prior studies to assess implicit self‐esteem, the Implicit Association Test was utilised to readdress this theory. The Rosenberg scale served as an index of overt self‐esteem. A total of 23 schizophrenic patients, 13 of whom showed current symptoms of persecutory delusions, participated in the study; 41 healthy and 14 depressed participants served as controls. Results. Schizophrenic patients showed decreased levels of both implicit and explicit self‐esteem relative to healthy controls. In line with recent studies, patients with current ideas of persecutory delusions displayed greater explicit self‐esteem than nonparanoid patients. Conclusions. The present study lends partial support for the notion that persecutory delusions serve as a defence against low implicit self‐esteem, although the explicit self‐esteem of these patients is still lower than in normal participants. Apart from abnormalities of attributional style, which have been assumed to convert low into high self‐esteem, the assumption that a ‘feeling of personal significance’ heightens self‐esteem in paranoid schizophrenia deserves further consideration. 相似文献
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Hein J. Verberne Wanda Acampa Constantinos Anagnostopoulos Jim Ballinger Frank Bengel Pieter De Bondt Ronny R. Buechel Alberto Cuocolo Berthe L. F. van Eck-Smit Albert Flotats Marcus Hacker Cecilia Hindorf Philip A. Kaufmann Oliver Lindner Michael Ljungberg Markus Lonsdale Alain Manrique David Minarik Arthur J. H. A. Scholte Riemer H. J. A. Slart Elin Trägårdh Tim C. de Wit Birger Hesse 《European journal of nuclear medicine and molecular imaging》2015,42(12):1929-1940
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Sofie Moyson Raewyn M. Town Steven Joosen Steven J. Husson Ronny Blust 《Journal of applied toxicology : JAT》2019,39(2):282-293
Using the well‐documented model organism Caenorhabditis elegans, a combined analysis of metal speciation in the exposure medium and body burdens of metals (Zn, Cu and Cd) was performed, and factors that are predictive of toxicological endpoints in single metal and mixed metal exposures were identified. Cu, and to a lesser extent Cd, is found to associate with Escherichia coli in the exposure medium (the food source for C. elegans) as evidenced by the observed decrease in both their dissolved and free metal ion concentrations. Together with a critical analysis of literature data, our results suggest that free metal ion concentrations and thus aqueous uptake routes are the best predictor of internal concentrations under all conditions considered, and of metal toxicity in single metal exposures. Additional factors are involved in determining the toxicity of metal mixtures. In general, the eventual adverse effects of metals on biota are expected to be a consequence of the interplay between chemical speciation in the exposure medium, timescale of exposure, exposure route as well as the nature and timescale of the biotic handling pathways. 相似文献
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Piechnick R Ritter E Hildebrand PW Ernst OP Scheerer P Hofmann KP Heck M 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(14):5247-5252
In the retinal binding pocket of rhodopsin, a Schiff base links the retinal ligand covalently to the Lys296 side chain. Light transforms the inverse agonist 11-cis-retinal into the agonist all-trans-retinal, leading to the active Meta II state. Crystal structures of Meta II and the active conformation of the opsin apoprotein revealed two openings of the 7-transmembrane (TM) bundle towards the hydrophobic core of the membrane, one between TM1/TM7 and one between TM5/TM6, respectively. Computational analysis revealed a putative ligand channel connecting the openings and traversing the binding pocket. Identified constrictions within the channel motivated this study of 35 rhodopsin mutants in which single amino acids lining the channel were replaced. 11-cis-retinal uptake and all-trans-retinal release were measured using UV/visible and fluorescence spectroscopy. Most mutations slow or accelerate both uptake and release, often with opposite effects. Mutations closer to the Lys296 active site show larger effects. The nucleophile hydroxylamine accelerates retinal release 80 times but the action profile of the mutants remains very similar. The data show that the mutations do not probe local channel permeability but rather affect global protein dynamics, with the focal point in the ligand pocket. We propose a model for retinal/receptor interaction in which the active receptor conformation sets the open state of the channel for 11-cis-retinal and all-trans-retinal, with positioning of the ligand at the active site as the kinetic bottleneck. Although other G protein-coupled receptors lack the covalent link to the protein, the access of ligands to their binding pocket may follow similar schemes. 相似文献