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81.
82.
Serial serum thyroglobulin (Tg) measurements with a highly sensitive enzyme-linked immunosorbent assay (ELISA; functional sensitivity 0.03 ng/mL) in 126 patients (Tg autoantibody negative) with treated differentiated thyroid cancer (DTC) are described. At the beginning of the retrospective study, all 126 patients were in remission and Tg was detectable by ELISA in 92 (73%; range, 0.03-0.8 ng/mL). Over the following 4-year period, Tg levels remained essentially unchanged (i.e., any increases were less than 2 times the Tg level at the start of the study) in 121 of 126 (96%) and all 121 patients remained well. In 5 patients, Tg levels increased to more than 2 times the starting Tg level over the study period and in 4 of these 5, there was recurrence of DTC. The fifth patient in this group remains well as evidenced by extensive diagnostic imaging, although his serum Tg level continues to increase and can be stimulated by thyrotropin (TSH). Our results suggest that serial measurements of low levels of Tg by ELISA in treated patients with DTC enable detection of recurrence (without using TSH stimulation) 6-12 months earlier than would have been possible using a conventional Tg immuno-radiometric assay (IRMA). A prospective study is now needed to confirm these observations. 相似文献
83.
Dmitry Namgaladze Sebastian Lips Thomas J. Leiker Robert C. Murphy Kim Ekroos Nerea Ferreiros Gerd Geisslinger Bernhard Brüne 《Diabetologia》2014,57(5):1067-1077
Aims/hypothesis
Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid β-oxidation (FAO) affects macrophage responses to SFA.Methods
We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures.Results
To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD.Conclusions/interpretation
Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO. 相似文献84.
Florian Grahammer Nora Haenisch Frederic Steinhardt Lukas Sandner Malte Roerden Frederic Arnold Tomke Cordts Nicola Wanner Wilfried Reichardt Dontscho Kerjaschki Markus A. Ruegg Michael N. Hall Pierre Moulin Hauke Busch Melanie Boerries Gerd Walz Ferruh Artunc Tobias B. Huber 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(27):E2817-E2826
85.
86.
Simon Pape Tom J. G. Gevers Jan Maarten Vrolijk Bart van Hoek Gerd Bouma Carin M. J. van Nieuwkerk Richard Taubert Elmar Jaeckel Michael P. Manns Maria Papp Nora Sipeki Felix Stickel Cumali Efe Ersan Ozaslan Tugrul Purnak Frederik Nevens Dominik J. N. Kessener Alisan Kahraman Heiner Wedemeyer Johannes Hartl Christoph Schramm Ansgar W. Lohse Michael A. Heneghan Joost P. H. Drenth 《Liver international》2020,40(9):2164-2171
87.
88.
Kunnath-Velayudhan S Davidow AL Wang HY Molina DM Huynh VT Salamon H Pine R Michel G Perkins MD Xiaowu L Felgner PL Flynn JL Catanzaro A Gennaro ML 《The Journal of infectious diseases》2012,206(5):697-705
Background.Biomarkers of progression from latent Mycobacterium tuberculosis infection to active tuberculosis are needed. We assessed correlations between infection outcome and antibody responses in macaques and humans by high-throughput, proteome-scale serological studies. Methods.Mycobacterium tuberculosis proteome microarrays were probed with serial sera from macaques representing various infection outcomes and with single-point human sera from tuberculosis suspects. Fluorescence intensity data were analyzed by calculating Z scores and associated P values. Temporal changes in macaque antibody responses were analyzed by polynomial regression. Correlations between human responses and sputum bacillary burden were assessed by quantile and hurdle regression. Results.Macaque outcome groups exhibited distinct antibody profiles: early, transient responses in latent infection and stable antibody increase in active and reactivation disease. In humans, antibody levels and reactive protein numbers increased with bacillary burden. Responses to a subset of 10 proteins were more tightly associated with disease state than reactivity to the broader reactive proteome. Conclusions.Integration of macaque and human data reveals dynamic properties of antibody responses in relation to outcome and leads to actionable findings for translational research. These include the potential of antibody responses to detect acute infection and preclinical tuberculosis and to identify serodiagnostic proteins for the spectrum of bacillary burden in tuberculosis. 相似文献
89.
Heusch G 《Journal of molecular and cellular cardiology》2012,52(4):832-839
Activation of coronary vascular α-adrenoceptors results in vasoconstriction which competes with metabolic vasodilation during sympathetic activation. Epicardial conduit vessel constriction is largely mediated by α(1)-adrenoceptors; the constriction of the resistive microcirculation largely by α(2)-adrenoceptors, but also by α(1)-adrenoceptors. There is no firm evidence that α-adrenergic coronary vasoconstriction exerts a beneficial effect on transmural blood flow distribution. In fact, α-blockade in anesthetized and conscious dogs improves blood flow to all transmural layers, during normoperfusion and hypoperfusion. Also, in patients with coronary artery disease, blockade of α(1)- and α(2)-adrenoceptors improves coronary blood flow, myocardial function and metabolism. This article is part of a Special Issue entitled "Coronary Blood Flow". 相似文献
90.
Stewart JD Marchan R Lesjak MS Lambert J Hergenroeder R Ellis JK Lau CH Keun HC Schmitz G Schiller J Eibisch M Hedberg C Waldmann H Lausch E Tanner B Sehouli J Sagemueller J Staude H Steiner E Hengstler JG 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(21):8155-8160
Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention. 相似文献