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991.
Juliane H. Fröhner Stephan Ripke Sarah Jurk Shu-Chen Li Tobias Banaschewski Arun L.W. Bokde Erin Burke Quinlan Sylvane Desrivières Herta Flor Antoine Grigis Hugh Garavan Andreas Heinz Rüdiger Brühl Jean-Luc Martinot Marie-Laure Paillère Martinot Eric Artiges Frauke Nees Dimitri Papadopoulos Orfanos Luise Poustka Sarah Hohmann Henrik Walter Robert Whelan Gunter Schumann Michael N. Smolka the IMAGEN Consortium 《Alcoholism, clinical and experimental research》2022,46(4):667-681
Background
While drinking alcohol, one must choose between the immediate rewarding effects and the delayed reward of a healthier lifestyle. Individuals differ in their devaluation of a delayed reward based on the time required to receive it, i.e., delay discounting (DD). Previous studies have shown that adolescents discount more steeply than adults and that steeper DD is associated with heavier alcohol use in both groups.Methods
In a large-scale longitudinal study, we investigated whether higher rates of DD are an antecedent or a consequence of alcohol use during adolescent development. As part of the IMAGEN project, 2220 adolescents completed the Monetary Choice Questionnaire as a DD measure, the Alcohol Use Disorders Identification Test, and the Timeline Follow Back interview at ages 14, 16, 18, and 22. Bivariate latent growth curve models were applied to investigate the relationship between DD and drinking. To explore the consequences of drinking, we computed the cumulative alcohol consumption and correlated it with the development of discounting. A subsample of 221 participants completed an intertemporal choice task (iTeCh) during functional magnetic resonance imaging at ages 14, 16, and 18. Repeated-measures ANOVA was used to differentiate between high-risk and low-risk drinkers on the development of neural processing during intertemporal choices.Results
Overall, high rates of DD at age 14 predicted a greater increase in drinking over 8 years. In contrast, on average, moderate alcohol use did not affect DD from ages 14 to 22. Of note, we found indicators for less brain activity in top-down control areas during intertemporal choices in the participants who drank more.Conclusions
Steep DD was shown to be a predictor rather than a consequence of alcohol use in low-level drinking adolescents. Important considerations for future longitudinal studies are the sampling strategies to be used and the reliability of the assessments.992.
Rebecca Grayston Gabriela Czanner Kareim Elhadd Andreas Goebel Bernhard Frank Nurcan Üçeyler Rayaz A Malik Uazman Alam 《Seminars in arthritis and rheumatism》2019,48(5):933-940
Objectives
Fibromyalgia is a condition which exhibits chronic widespread pain with neuropathic pain features and has a major impact on health-related quality of life. The pathophysiology remains unclear, however, there is increasing evidence for involvement of the peripheral nervous system with a high prevalence of small fiber pathology (SFP). The aim of this systematic literature review is to establish the prevalence of SFP in fibromyalgia.Methods
An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL and the Cochrane Library databases. Published full-text, English language articles that provide SFP prevalence data in studies of fibromyalgia of patients over 18years old were included. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using the critical appraisal tool by Munn et al. Overall and subgroup pooled prevalence were calculated by random-effects meta-analysis with 95% CI.Results
Database searches found 935 studies; 45 articles were screened of which 8 full text articles satisfied the inclusion criteria, providing data from 222 participants. The meta-analysis demonstrated the pooled prevalence of SFP in fibromyalgia is 49% (95% CI: 38–60%) with a moderate degree of heterogeneity, (I2=?68%). The prevalence estimate attained by a skin biopsy was 45% (95% CI: 32–59%, I2=?70%) and for corneal confocal microscopy it was 59% (95% CI: 40–78%, I2=?51%).Conclusion
There is a high prevalence of SFP in fibromyalgia. This study provides compelling evidence of a distinct phenotype involving SFP in fibromyalgia. Identifying SFP will aid in determining its relationship to pain and potentially facilitate the development of future interventions and pharmacotherapy. 相似文献993.
Schulz B Pruessmeyer J Maretzky T Ludwig A Blobel CP Saftig P Reiss K 《Circulation research》2008,102(10):1192-1201
Vascular endothelial (VE)-cadherin is the major adhesion molecule of endothelial adherens junctions. It plays an essential role in controlling endothelial permeability, vascular integrity, leukocyte transmigration, and angiogenesis. Elevated levels of soluble VE-cadherin are associated with diseases like coronary atherosclerosis. Previous data showed that the extracellular domain of VE-cadherin is released by an unknown metalloprotease activity during apoptosis. In this study, we used gain-of-function analyses, inhibitor studies, and RNA interference experiments to analyze the proteolytic release of VE-cadherin in human umbilical vein endothelial cells (HUVECs). We found that VE-cadherin is specifically cleaved by the disintegrin and metalloprotease ADAM10 in its ectodomain, releasing a soluble fragment and generating a carboxyl-terminal membrane-bound stub, which is a substrate for a subsequent gamma-secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca(2+) influx and staurosporine treatment, indicating that ADAM10-mediated VE-cadherin cleavage contributes to the dissolution of adherens junctions during endothelial cell activation and apoptosis, respectively. In contrast, protein kinase C activation or inhibition did not modulate VE-cadherin processing. Increased ADAM10 expression was functionally associated with an increase in endothelial permeability. Remarkably, our data indicate that ADAM10 activity also contributes to the thrombin-induced decrease of endothelial cell-cell adhesion. Moreover, knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impaired T-cell transmigration. Taken together, our data identify ADAM10 as a novel regulator of vascular permeability and demonstrate a hitherto unknown function of ADAM10 in the regulation of VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration. 相似文献
994.
Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma 总被引:16,自引:1,他引:16
Kaufmann H Raderer M Wöhrer S Püspök A Bankier A Zielinski C Chott A Drach J 《Blood》2004,104(8):2269-2271
We evaluated a treatment strategy targeting both lymphoma cells (by rituximab) and the microenvironment (by thalidomide) in 16 patients with relapsed/refractory mantle cell lymphoma (MCL). Rituximab was administered at 375 mg/m(2) for 4 weekly doses concomitantly with thalidomide (200 mg daily, with a dose increment to 400 mg on day 15), which was continued as maintenance therapy until progression/relapse. Thirteen patients (81%) experienced an objective response, with 5 complete responders (31%). Median progression-free survival (PFS) was 20.4 months (95% confidence interval [CI], 17.3-23.6 months), and estimated 3-year survival was 75%. In patients achieving a complete response, PFS after rituximab plus thalidomide was longer than PFS after the preceding chemotherapy. Severe adverse events included 2 thromboembolic events and 1 grade IV neutropenia associated with thalidomide. Our results suggest that rituximab plus thalidomide has marked antitumor activity in relapsed/refractory MCL and a low toxicity profile, which warrants further evaluation in MCL. 相似文献
995.
Seidl K Rameken M Drögemüller A Vater M Brandt A Schwacke H Bergmeier C Zahn R Senges J 《Journal of the American College of Cardiology》2002,39(9):1436-1442
OBJECTIVES: The primary objective was to evaluate the usefulness of transesophageal echocardiography (TEE)-guided cardioversion to prevent thromboembolic complications in patients with atrial fibrillation (AF) and effective anticoagulation (International Normalized Ratio of 2 or 3) at least three weeks before cardioversion. BACKGROUND: Transesophageal echocardiography has been proposed as a method of screening patients for left atrial thrombi before direct-current cardioversion of AF. The usefulness of TEE as a screening tool has always been evaluated in patients without long-term anticoagulation before cardioversion. METHODS: This prospective, single-center, observational study, performed on an intention-to-cardiovert basis, comprised 1,076 consecutive, unselected patients with AF. The initial two years were designed to be the control phase, during which the conventional approach was used. After that, cardioversion guided by TEE was performed in consecutive patients. RESULTS: The prevalence of left atrial thrombi was 7.7% in patients with persistent AF and effective anticoagulation. During the first four weeks after electrical cardioversion, six thromboembolic complications were observed in patients in whom the TEE-guided approach was employed (6 [0.8%] of 719 patients), compared with three thromboembolic complications in patients in whom the conventional approach was used (3 [0.8%] of 357 patients). None of the patients in whom electrical cardioversion was not performed experienced an embolic event. CONCLUSIONS: There were no differences in the rate of embolic events between the two treatment groups. In patients with AF and effective anticoagulation, TEE-guided electrical cardioversion does not reduce the embolic risk. However, TEE revealed left atrial thrombi in 7.7% of patients with AF and effective anticoagulation, before direct-current cardioversion. 相似文献
996.
Schlumberger MC Müller AJ Ehrbar K Winnen B Duss I Stecher B Hardt WD 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(35):12548-12553
Many pathogenic and symbiotic Gram-negative bacteria employ type III secretion systems to inject "effector" proteins into eukaryotic host cells. These effectors manipulate signaling pathways to initiate symbiosis or disease. By using time-lapse microscopy, we have imaged delivery of the Salmonella type III effector protein SipA/SspA into animal cells in real time. SipA delivery mostly began 10-90 sec after docking and proceeded for 100-600 sec until the bacterial SipA pool (6 +/- 3 x 10(3) molecules) was exhausted. Similar observations were made for the effector protein SopE. This visualization of type III secretion in real time explains the efficiency of host cell manipulation by means of this virulence system. 相似文献
997.
998.
ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes,inferior clinical outcome,and distinct gene expression profile 总被引:25,自引:24,他引:25
999.
1000.
Neumann P Weidner A Pech A Stubbs MT Tittmann K 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(45):17390-17395
The thiamin- and flavin-dependent peripheral membrane enzyme pyruvate oxidase from E. coli catalyzes the oxidative decarboxylation of the central metabolite pyruvate to CO2 and acetate. Concomitant reduction of the enzyme-bound flavin triggers membrane binding of the C terminus and shuttling of 2 electrons to ubiquinone 8, a membrane-bound mobile carrier of the electron transport chain. Binding to the membrane in vivo or limited proteolysis in vitro stimulate the catalytic proficiency by 2 orders of magnitude. The molecular mechanisms by which membrane binding and activation are governed have remained enigmatic. Here, we present the X-ray crystal structures of the full-length enzyme and a proteolytically activated truncation variant lacking the last 23 C-terminal residues inferred as important in membrane binding. In conjunction with spectroscopic results, the structural data pinpoint a conformational rearrangement upon activation that exposes the autoinhibitory C terminus, thereby freeing the active site. In the activated enzyme, Phe-465 swings into the active site and wires both cofactors for efficient electron transfer. The isolated C terminus, which has no intrinsic helix propensity, folds into a helical structure in the presence of micelles. 相似文献