全文获取类型
收费全文 | 375篇 |
免费 | 36篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 7篇 |
2020年 | 7篇 |
2019年 | 8篇 |
2018年 | 4篇 |
2017年 | 7篇 |
2016年 | 14篇 |
2015年 | 23篇 |
2014年 | 20篇 |
2013年 | 30篇 |
2012年 | 26篇 |
2011年 | 35篇 |
2010年 | 11篇 |
2009年 | 18篇 |
2008年 | 18篇 |
2007年 | 22篇 |
2006年 | 16篇 |
2005年 | 9篇 |
2004年 | 23篇 |
2003年 | 15篇 |
2002年 | 7篇 |
2001年 | 8篇 |
2000年 | 4篇 |
1998年 | 4篇 |
1997年 | 6篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1992年 | 9篇 |
1991年 | 1篇 |
1990年 | 7篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1973年 | 2篇 |
1969年 | 1篇 |
1963年 | 2篇 |
排序方式: 共有411条查询结果,搜索用时 31 毫秒
101.
J Diao H Pantua H Ngu L Komuves L Diehl G Schaefer SB Kapadia 《Journal of virology》2012,86(20):10935-10949
While epidermal growth factor receptor (EGFR) has been shown to be important in the entry process for multiple viruses, including hepatitis C virus (HCV), the molecular mechanisms by which EGFR facilitates HCV entry are not well understood. Using the infectious cell culture HCV model (HCVcc), we demonstrate that the binding of HCVcc particles to human hepatocyte cells induces EGFR activation that is dependent on interactions between HCV and CD81 but not claudin 1. EGFR activation can also be induced by antibody mediated cross-linking of CD81. In addition, EGFR ligands that enhance the kinetics of HCV entry induce EGFR internalization and colocalization with CD81. While EGFR kinase inhibitors inhibit HCV infection primarily by preventing EGFR endocytosis, antibodies that block EGFR ligand binding or inhibitors of EGFR downstream signaling have no effect on HCV entry. These data demonstrate that EGFR internalization is critical for HCV entry and identify a hitherto-unknown association between CD81 and EGFR. 相似文献
102.
Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling 总被引:9,自引:0,他引:9
Angiopoietins are ligands of the Tie2 receptor that control angiogenic remodeling in a context-dependent manner. Tie signaling is involved in multiple steps of the angiogenic remodeling process during development, including destabilization of existing vessels, endothelial cell migration, tube formation and the subsequent stabilization of newly formed tubes by mesenchymal cells. Beyond this critical role in blood vessel development, recent studies suggest a wider role for Tie2 and angiopoietins in lymphangiogenesis and the development of the hematopoietic system, as well as a possible role in the regulation of certain non-endothelial cells. The outcome of Tie signaling depends on which vascular bed is involved, and crosstalk between different VEGFs has an important modulating effect on the properties of the angiopoietins. Signaling through the Tie1 receptor is not well understood, but Tie1 may have both angiopoietin-dependent and ligand-independent functions. Changes in the expression of Tie receptors and angiopoietins occur in many pathological conditions, and mutations in the Tie2 gene are found in familial cases of vascular disease. 相似文献
103.
L'Ecuyer T Sanjeev S Thomas R Novak R Das L Campbell W Heide RV 《American journal of physiology. Heart and circulatory physiology》2006,291(3):H1273-H1280
Anthracyclines are antitumor agents the main clinical limitation of which is cardiac toxicity. The mechanism of this cardiotoxicity is thought to be related to generation of oxidative stress, causing lethal injury to cardiac myocytes. Although protein and lipid oxidation have been documented in anthracycline-treated cardiac myocytes, DNA damage has not been directly demonstrated. This study was undertaken to determine whether anthracyclines induce cardiac myocyte DNA damage and whether this damage is linked to a signaling pathway culminating in cell death. H9c2 cardiac myocytes were treated with the anthracycline doxorubicin at clinically relevant concentrations, and DNA damage was assessed using the alkaline comet assay. Doxorubicin induced DNA damage, as shown by a significant increase in the mean tail moment above control, an effect ameliorated by inclusion of a free radical scavenger. Repair of DNA damage was incomplete after doxorubicin treatment in contrast to the complete repair observed in H2O2-treated myocytes after removal of the agent. Immunoblot analysis revealed that p53 activation occurred subsequent in time to DNA damage. By a fluorescent assay, doxorubicin induced loss of mitochondrial membrane potential after p53 activation. Chemical inhibition of p53 prevented doxorubicin-induced cell death and loss of mitochondrial membrane potential without preventing DNA damage, indicating that DNA damage was proximal in the events leading from doxorubicin treatment to cardiac myocyte death. Specific doxorubicin-induced DNA lesions included oxidized pyrimidines and 8-hydroxyguanine. DNA damage therefore appears to play an important early role in anthracycline-induced lethal cardiac myocyte injury through a pathway involving p53 and the mitochondria. 相似文献
104.
Florina Vlad Marie‐Jo Droillard Benoît Valot Mehdi Khafif Americo Rodrigues Mathias Brault Michel Zivy Pedro L. Rodriguez Sylvain Merlot Christiane Laurière 《The Plant journal : for cell and molecular biology》2010,63(5):778-790
Snf1‐related protein kinases 2 (SnRK2s) are major positive regulators of drought stress tolerance. The kinases of this family are activated by hyperosmotic stress, but only some of them are also responsive to abscisic acid (ABA). Moreover, genetic evidence has indicated the ABA‐independence of SnRK2 activation in the fast response to osmotic stress. Although phosphorylation was demonstrated to be crucial for the activation or activity of the kinases of both subgroups, different phosphorylation mechanisms were suggested. Here, using one kinase from each subgroup (SnRK2.6 and SnRK2.10), two phosphorylation sites within the activation loop were identified by mass spectrometry after immunoprecipitation from Arabidopsis cells treated by ABA or osmolarity. By site‐directed mutagenesis, the phosphorylation of only one of the two sites was shown to be necessary for the catalytic activity of the kinase, whereas both sites are necessary for the full activation of the two SnRK2s by hyperosmolarity or ABA. Phosphoprotein staining together with two‐dimensional PAGE followed by immunoblotting indicated distinct phosphorylation mechanisms of the two kinases. While SnRK2.6 seems to be activated through the independent phosphorylation of these two sites, a sequential process occurs in SnRK2.10, where phosphorylation of one serine is required for the phosphorylation of the other. In addition, a subgroup of protein phosphatases 2C which interact and participate in the regulation of SnRK2.6 do not interact with SnRK2.10. Taken together, our data bring evidence for the involvement of distinct phosphorylation mechanisms in the activation of SnRK2.6 and SnRK2.10, which may be conserved between the two subgroups of SnRK2s depending on their ABA‐responsiveness. 相似文献
105.
Marko Mutanen Niklas Wahlberg Lauri Kaila 《Proceedings. Biological sciences / The Royal Society》2010,277(1695):2839-2848
Lepidoptera (butterflies and moths) represent one of the most diverse animals groups. Yet, the phylogeny of advanced ditrysian Lepidoptera, accounting for about 99 per cent of lepidopteran species, has remained largely unresolved. We report a rigorous and comprehensive analysis of lepidopteran affinities. We performed phylogenetic analyses of 350 taxa representing nearly 90 per cent of lepidopteran families. We found Ditrysia to be a monophyletic taxon with the clade Tischerioidea + Palaephatoidea being the sister group of it. No support for the monophyly of the proposed major internested ditrysian clades, Apoditrysia, Obtectomera and Macrolepidoptera, was found as currently defined, but each of these is supported with some modification. The monophyly or near-monophyly of most previously identified lepidopteran superfamilies is reinforced, but several species-rich superfamilies were found to be para- or polyphyletic. Butterflies were found to be more closely related to ‘microlepidopteran’ groups of moths rather than the clade Macrolepidoptera, where they have traditionally been placed. There is support for the monophyly of Macrolepidoptera when butterflies and Calliduloidea are excluded. The data suggest that the generally short diverging nodes between major groupings in basal non-tineoid Ditrysia are owing to their rapid radiation, presumably in correlation with the radiation of flowering plants. 相似文献
106.
Sarah K. Coleman Tommi M?ykkynen Sami Hinkkuri Lauri Vaahtera Esa R. Korpi Olli T. Pentik?inen Kari Kein?nen 《The Journal of biological chemistry》2010,285(46):36032-36039
AMPA receptors (AMPARs) are tetrameric ion channels that mediate rapid glutamate signaling in neurons and many non-neuronal cell types. Endoplasmic reticulum (ER) quality control mechanisms permit only correctly folded functional receptors to be delivered to the cell surface. We analyzed the biosynthetic maturation and transport of all 12 GluA1–4 subunit splice variants as homomeric receptors and observed robust isoform-dependent differences in ER exit competence and surface expression. In contrast to inefficient ER exit of both GluA3 splice forms and the flop variants of GluA1 and GluA4, prominent plasma membrane expression was observed for the other AMPAR isoforms. Surprisingly, deletion of the entire N-terminal domain did not alter the transport phenotype, nor did the different cytosolic C-terminal tail splice variants. Detailed analysis of mutant receptors led to the identification of distinct residues in the ligand-binding domain as primary determinants for isoform-specific maturation. Considered together with the essential role of bound agonist, our findings reveal the ligand-binding domain as the critical quality control target in AMPAR biogenesis. 相似文献
107.
Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma 总被引:8,自引:0,他引:8 下载免费PDF全文
Vanharanta S Buchta M McWhinney SR Virta SK Peçzkowska M Morrison CD Lehtonen R Januszewicz A Järvinen H Juhola M Mecklin JP Pukkala E Herva R Kiuru M Nupponen NN Aaltonen LA Neumann HP Eng C 《American journal of human genetics》2004,74(1):153-159
Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance. 相似文献
108.
Gresl TA Colman RJ Havighurst TC Byerley LO Allison DB Schoeller DA Kemnitz JW 《American journal of physiology. Regulatory, integrative and comparative physiology》2003,285(6):R1340-R1354
The minimal model of glucose disappearance (MINMOD version 3; MM3) and both the one-compartment (1CMM) and the two-compartment (2CMM) minimal models were used to analyze stable isotope-labeled intravenous glucose tolerance test (IVGTT) data from year 10 of a study of the effect of dietary restriction (DR) in male rhesus monkeys. Adult monkeys were energy restricted (R; n = 12) on a semipurified diet to approximately 70% of control (C) intake (ad libitum-fed monkeys; n = 12). Under ketamine anesthesia, fasting insulin levels were greater among C monkeys. Insulin sensitivity estimates from all models were greater in R than C monkeys, whereas glucose effectiveness estimates were not consistently greater in R monkeys. Fasting plasma glucose as well as hepatic glucose production and clearance rates did not differ between groups. Body fat, in part, statistically mediated the effect of DR to enhance insulin sensitivity indexes. Precision of estimation and intermodel relationships among insulin sensitivity and glucose effectiveness estimates were in the ranges of those reported previously for humans and dogs, suggesting that the models may provide valid estimates for rhesus monkeys as well. The observed insulin sensitivity indexes from all models, elevated among R vs. C monkeys, may be explained, at least in part, by the difference in body fat content between these groups after chronic DR. 相似文献
109.
Lack of collagen XVIII/endostatin results in eye abnormalities 总被引:21,自引:0,他引:21
Fukai N Eklund L Marneros AG Oh SP Keene DR Tamarkin L Niemelä M Ilves M Li E Pihlajaniemi T Olsen BR 《The EMBO journal》2002,21(7):1535-1544
Mice lacking collagen XVIII and its proteolytically derived product endostatin show delayed regression of blood vessels in the vitreous along the surface of the retina after birth and lack of or abnormal outgrowth of retinal vessels. This suggests that collagen XVIII/endostatin is critical for normal blood vessel formation in the eye. All basement membranes in wild-type eyes, except Descemet's membrane, showed immunogold labeling with antibodies against collagen XVIII. Labeling at sites where collagen fibrils in the vitreous are connected with the inner limiting membrane and separation of the vitreal matrix from the inner limiting membrane in mutant mice indicate that collagen XVIII is important for anchoring vitreal collagen fibrils to the inner limiting membrane. The findings provide an explanation for high myopia, vitreoretinal degeneration and retinal detachment seen in patients with Knobloch syndrome caused by loss-of-function mutations in collagen XVIII. 相似文献
110.
Anne-Claire Cazalé Marie-Aude Rouet-Mayer Hélène Barbier-Brygoo Yves Mathieu Christiane Laurière 《Plant physiology》1998,116(2):659-669
Oxidative burst constitutes an early response in plant defense reactions toward pathogens, but active oxygen production may also be induced by other stimuli. The oxidative response of suspension-cultured tobacco (Nicotiana tabacum cv Xanthi) cells to hypoosmotic and mechanical stresses was characterized. The oxidase involved in the hypoosmotic stress response showed similarities by its NADPH dependence and its inhibition by iodonium diphenyl with the neutrophil NADPH oxidase. Activation of the oxidative response by hypoosmotic stress needed protein phosphorylation and anion effluxes, as well as opening of Ca2+ channels. Inhibition of the oxidative response impaired Cl− efflux, K+ efflux, and extracellular alkalinization, suggesting that the oxidative burst may play a role in ionic flux regulation. Active oxygen species also induced the cross-linking of a cell wall protein, homologous to a soybean (Glycine max L.) extensin, that may act as part of cell volume and turgor regulation through modification of the physical properties of the cell wall. 相似文献