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41.
Müller glial cells inhibit proliferation of retinal endothelial cells via TGF‐β2 and Smad signaling
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Yousef Yafai Ianors Iandiev Johannes Lange Jan Darius Unterlauft Peter Wiedemann Andreas Bringmann Andreas Reichenbach Wolfram Eichler 《Glia》2014,62(9):1476-1485
Neovascularization is a sight‐threatening complication of ischemic proliferative retinopathies. Transforming growth factor (TGF)‐β, a cytokine with multiple functions in the retina, participates in the control of pathological angiogenesis and neovascularization. Retinal glial (Müller) cells produce TGF‐β2 under physiological and post‐ischemic conditions. To characterize glial cell‐derived mediators of angiogenesis regulation in glial‐endothelial interactions in the retina, we co‐cultured primary Müller cells and bovine microvascular retinal endothelial cells (BRECs). Müller cell‐derived TGF‐β2 was bound by the BRECs, which were found to express serine/threonine kinase TGF‐β receptors, and stimulated TGF‐β‐dependent anti‐proliferative signaling pathways. The proliferation of BRECs was attenuated by exogenous TGF‐β2 as well as by the presence of Müller cell culture media. The following intracellular signaling mechanisms were found to be involved in the anti‐angiogenic action of Müller cell‐derived TGF‐β2: (i) binding of TGF‐β2 to BRECs is mediated by the type‐II TGF‐β receptor, leading to (ii) activation and phosphorylation of receptor‐activated Smads; (iii) Müller cell‐derived TGF‐β2 activates Smad2 and Smad3 to (iv) attenuate the phosphorylation state of the MAP kinases, extracellular signal‐regulated kinase (ERK)‐1/‐2. Neutralizing TGF‐β or TGF‐β type‐II receptor or blocking the activation of Smads partially abrogated the effect of Müller cell‐conditioned media on BRECs. Together, our data suggest that Müller cells release TGF‐β2, inhibiting the proliferation of retinal endothelial cells via activation of Smad2/Smad3 and attenuation of ERK signaling. Given the context‐dependent action of TGF‐β2 on angiogenesis, our results may have implications for understanding the pathogenesis of retinal angiopathies, such as diabetic retinopathy, and the anti‐angiogenic role of TGF‐β therein. GLIA 2014;62:1476–1485 相似文献
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Geert Vandeweyer Céline Helsmoortel Anke Van Dijck Anneke T. Vulto-van Silfhout Bradley P. Coe Raphael Bernier Jennifer Gerdts Liesbeth Rooms Jenneke van den Ende Madhura Bakshi Meredith Wilson Ann Nordgren Laura G. Hendon Omar A. Abdulrahman Corrado Romano Bert B.A. de Vries Tjitske Kleefstra Evan E. Eichler Nathalie Van der Aa R. Frank Kooy 《American journal of medical genetics. Part C, Seminars in medical genetics》2014,166(3):315-326
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Gongshe Han Sita D. Gupta Kenneth Gable Somashekarappa Niranjanakumari Prasun Moitra Florian Eichler Robert H. Brown Jr. Jeffrey M. Harmon Teresa M. Dunn 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(20):8186-8191
Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis. In yeast, SPT is composed of a heterodimer of 2 highly-related subunits, Lcb1p and Lcb2p, and a third subunit, Tsc3p, which increases enzyme activity markedly and is required for growth at elevated temperatures. Higher eukaryotic orthologs of Lcb1p and Lcb2p have been identified, but SPT activity is not highly correlated with coexpression of these subunits and no ortholog of Tsc3p has been identified. Here, we report the discovery of 2 proteins, ssSPTa and ssSPTb, which despite sharing no homology with Tsc3p, each substantially enhance the activity of mammalian SPT expressed in either yeast or mammalian cells and therefore define an evolutionarily conserved family of low molecular weight proteins that confer full enzyme activity. The 2 ssSPT isoforms share a conserved hydrophobic central domain predicted to reside in the membrane, and each interacts with both hLCB1 and hLCB2 as assessed by positive split ubiquitin 2-hybrid analysis. The presence of these small subunits, along with 2 hLCB2 isofoms, suggests that there are 4 distinct human SPT isozymes. When each SPT isozyme was expressed in either yeast or CHO LyB cells lacking endogenous SPT activity, characterization of their in vitro enzymatic activities, and long-chain base (LCB) profiling revealed differences in acyl-CoA preference that offer a potential explanation for the observed diversity of LCB seen in mammalian cells. 相似文献
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Laurent Frenzel Rose-Marie Javier Francoise Eichler Goerg Zollner Jean Sibilia 《Joint, bone, spine : revue du rhumatisme》2010,77(2):171-173
Bone metastases are usually seen on imaging studies as lytic lesions and less often as sclerotic or mixed lesions. We report an exceedingly unusual case of breast cancer identified after magnetic resonance imaging showed bone metastases with fluid-fluid levels in the spine and sacrum. Bone images containing fluid-fluid levels are usually solitary abnormalities produced by aneurismal bone cysts. The fluid-fluid level is due to bleeding within the tumor followed by layering of the blood components based on density differences. Only two other cases of bone metastases with multiple fluid-fluid levels have been reported. Although fluid-fluid levels are exceedingly rare, clinicians should be aware that they might indicate a malignancy, particularly when they are multiple. 相似文献
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Observations on cyclical variations in the nasal resistance were made using active anterior rhinomanometry. About 80% of 40 healthy individuals showed a nasal cycle with a mean period of 2.5 h. Measurements were made during a 8 h at intervals of 30 min. Quantitative values for the variations of the flow volume V1.5 at 1.5 hPa are given and discussed. 相似文献
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Modulation of matrix metalloproteinase and TIMP-1 expression by cytokines in human RPE cells 总被引:10,自引:0,他引:10
Eichler W Friedrichs U Thies A Tratz C Wiedemann P 《Investigative ophthalmology & visual science》2002,43(8):2767-2773
PURPOSE: The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) is crucial for homeostasis of ocular extracellular matrices. To assess altered MMP activity as a determinant in the migration of human retinal pigment epithelial (RPE) cells, expression characteristics of several MMPs and TIMP-1 in RPE cell cultures were investigated. METHODS: Expression studies were performed with RT-PCR, ELISA, and immunofluorescence analysis. Secretion of MMP-2 was demonstrated by zymography. Migration of cytokine-stimulated RPE cells was evaluated with microporous membranes of permeable chambers. RESULTS: MMP-1, -2, -3, and -9; MT2-MMP; and TIMP-1 were expressed in cultured RPE cells. MMP-2 was detected on the cell surface and in secreted inactive and active forms. TGF-beta(2), IL-1beta, and TNF-alpha enhanced secretion of MMP-1, -2, and -3. TGF-beta(2) also stimulated MT2-MMP cell surface expression and release of TIMP-1. The mRNA levels of MMP-1, -2, and -3 and TIMP-1 were markedly increased by TNF-alpha and TGF-beta(2). MMP-2 mRNA levels were also upregulated by PDGF-BB. Migration of RPE cells stimulated by TGF-beta(2) or PDGF-BB was inhibited in presence of a synthetic MMP inhibitor. CONCLUSIONS: Proinflammatory cytokines and TGF-beta(2) play an important role in the upregulation of expression of MMP-1, -2, and -3 in RPE cells and account for a directional shift in the balance between MMPs and TIMPs. Facilitation of RPE cell migration stimulated by cytokines (i.e., TGF-beta(2) or PDGF-BB) in ocular diseases may be due to increased release of MMPs, in the presence of comparatively lower levels of their inhibitors. 相似文献