全文获取类型
收费全文 | 3205篇 |
免费 | 227篇 |
出版年
2023年 | 5篇 |
2022年 | 17篇 |
2021年 | 62篇 |
2020年 | 34篇 |
2019年 | 58篇 |
2018年 | 71篇 |
2017年 | 61篇 |
2016年 | 87篇 |
2015年 | 148篇 |
2014年 | 183篇 |
2013年 | 237篇 |
2012年 | 271篇 |
2011年 | 264篇 |
2010年 | 176篇 |
2009年 | 132篇 |
2008年 | 197篇 |
2007年 | 204篇 |
2006年 | 191篇 |
2005年 | 162篇 |
2004年 | 161篇 |
2003年 | 138篇 |
2002年 | 136篇 |
2001年 | 43篇 |
2000年 | 28篇 |
1999年 | 28篇 |
1998年 | 38篇 |
1997年 | 25篇 |
1996年 | 28篇 |
1995年 | 25篇 |
1994年 | 23篇 |
1993年 | 27篇 |
1992年 | 25篇 |
1991年 | 24篇 |
1990年 | 18篇 |
1989年 | 11篇 |
1988年 | 14篇 |
1987年 | 7篇 |
1986年 | 14篇 |
1985年 | 5篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 8篇 |
1981年 | 8篇 |
1978年 | 5篇 |
1976年 | 4篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1969年 | 2篇 |
1966年 | 2篇 |
排序方式: 共有3432条查询结果,搜索用时 46 毫秒
991.
992.
Olianas A Messana I Sanna MT Castagnola M Manconi B Masia D Coluccia E Giardina B Pellegrini M 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2005,141(4):400-407
Cathodic haemoglobins of four species of anguilliform fish were characterized from a functional point of view, with special regard to the interaction with their physiological effectors. A series of oxygen-binding experiments at increasing GTP concentrations was carried out in order to compare GTP-binding activities in the absence and presence of saturating amounts of chloride. The results indicated that the cathodic haemoglobin of three species (Anguilla anguilla, Conger conger and Muraena helena) do have two sites for GTP-binding. In the absence of chloride, the two sites cannot be discriminated, whereas in the presence of chloride, a competition between the two anions occurred for the second GTP-binding site. The cathodic haemoglobin of Gymnothorax unicolor, which showed lower GTP sensitivity than the other haemoglobins examined, displayed only one GTP-binding site. The presence of an additional phosphate-binding site is not exceptional, although the way haemoglobin interacts with the two organic phosphate molecules may differ among species. This property may provide an auxiliary means of haemoglobin modulation for species that inhabit environments where oxygen availability is highly variable and haemoglobin-oxygen affinity needs to be modulated to different extents in order to satisfy physiological oxygen requirements. 相似文献
993.
994.
Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity 总被引:7,自引:0,他引:7
Immunosenescence is the consequence of the continuous attrition caused by chronic antigenic stress. The most important characteristics of immunosenescence (accumulation of memory and effector T cells, reduction of naive T cells, shrinkage of T cell repertoire, reduction of the immunological space) are compatible with this assumption. Immunosenescence can be taken as proof that the beneficial effects of the immune system, devoted to the neutralization of harmful agents early in life, become detrimental late in life, in a period not foreseen by evolution. This perspective could explain the mechanisms of the ageing process as well as the pathogenesis of age-related diseases. 相似文献
995.
Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells 总被引:9,自引:0,他引:9
Mazzocca A Sciammetta SC Carloni V Cosmi L Annunziato F Harada T Abrignani S Pinzani M 《The Journal of biological chemistry》2005,280(12):11329-11339
The hepatitis C virus (HCV) envelope E2 glycoprotein is a key molecule regulating the interaction of HCV with cell surface proteins. E2 binds the major extracellular loop of human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Regardless, information on the biological functions originating from this interaction are largely unknown. Since human hepatic stellate cells (HSC) express high levels of CD81 at the cell surface, we investigated the E2/CD81 interaction in human HSC and the possible effects arising from this interaction. Matrix metalloproteinase-2 (MMP-2; gelatinase A), a major enzyme involved in the degradation of normal hepatic extracellular matrix, was up-regulated following the interaction between E2 and CD81. In particular, by employing zymography and Western blot, we observed that E2 binding to CD81 induces a time-dependent increase in the synthesis and activity of MMP-2. This effect was abolished by preincubating HSC with an anti-CD81 neutralizing antibody. Similar effects were detected in NIH3T3 mouse fibroblasts transfected with human CD81 with identical time course features. In addition, E2/CD81 interaction in human HSC induced the up-regulation of MMP-2 by increasing activator protein-2/DNA binding activity via ERK/MAPK phosphorylation. Finally, suppression of CD81 by RNA interference in human HSC abolished the described effects of E2 on these cells, indicating that CD81 is essential for the activation of the signaling pathway leading to the up-regulation of MMP-2. These results suggest that HSC may represent a potential target for HCV. The interaction of HCV envelope with CD81 on the surface of human HSC induces an increased expression of MMP-2. Increased degradation of the normal hepatic extracellular matrix in areas where HCV is concentrated may favor inflammatory infiltration and further parenchymal damage. 相似文献
996.
Rovida E Lugli B Barbetti V Giuntoli S Olivotto M Dello Sbarba P 《Biological chemistry》2005,386(9):919-929
The macrophage colony-stimulating factor (M-CSF, CSF-1) regulates survival, proliferation and differentiation of mononuclear phagocytes, as well as macrophage motility and morphology. The latter features are usually regulated by ECM-mediated activation of integrins and subsequent tyrosine phosphorylation of cellular proteins, including focal adhesion kinase (FAK). FAK is phosphorylated by downstream receptor tyrosine kinases as well. We addressed the question whether M-CSF regulates FAK tyrosine phosphorylation in macrophages, and found that M-CSF induces FAK phosphorylation at all known tyrosine residues. This phosphorylation was dependent on Src. Extracellularly-regulated kinase (ERK), Jun N-terminal kinase (JNK) and phosphatidylinositol-3-kinase (PI3K) were found to be negatively involved in M-CSF-induced FAK phosphorylation, as their inhibition resulted in FAK hyper-phosphorylation. Following M-CSF treatment, FAK and the active forms of M-CSFR and Src were redistributed to the cytoskeleton, where active ERK, JNK and PI3K were detectable. Immunofluorescence showed the presence of FAK and its active form in focal complexes following M-CSF treatment. Moreover, cell spreading and adhesion were impaired when FAK tyrosine phosphorylation was abrogated by either transfection with FRNK, a dominant negative form of FAK, or treatment with a number of inhibitors of upstream FAK-activating signals. These results point to a relevant role for FAK in the regulation of cell spreading and adhesion in macrophages. 相似文献
997.
Human ether-a-go-go-related gene 1 channels are physically linked to beta1 integrins and modulate adhesion-dependent signaling 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Molecular biology of the cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Cherubini A Hofmann G Pillozzi S Guasti L Crociani O Cilia E Di Stefano P Degani S Balzi M Olivotto M Wanke E Becchetti A Defilippi P Wymore R Arcangeli A 《Molecular biology of the cell》2005,16(6):2972-2983
Adhesive receptors of the integrin family are primarily involved in cell-extracellular matrix adhesion. Additionally, integrins trigger multiple signaling pathways that are involved in cell migration, proliferation, survival, and differentiation. We previously demonstrated that the activation of integrins containing the beta(1) subunit leads to a selective increase in potassium currents carried by the human ether-a-go-go-related gene (hERG) channels in neuroblastoma and leukemia cells; this current activation modulates adhesion-dependent differentiation in these cells. We hypothesized that the cross-talk between integrins and hERG channels could be traced back to the assembly of a macromolecular signaling complex comprising the two proteins. We tested this hypothesis in both SH-SY5Y neuroblastoma cells and in human embryonic kidney 293 cells stably transfected with hERG1 and, therefore, expressing only the full-length hERG1 protein on the plasma membrane. The beta(1) integrin and hERG1 coprecipitate in these cells and colocalize in both intracellular and surface membrane compartments. The two proteins also coprecipitate with caveolin-1, suggesting the localization of the complex in lipid rafts/caveolae. hERG1-transfected cells undergo an activation of hERG currents after beta(1) integrin-mediated adhesion to fibronectin; concomitant with this activation, the focal adhesion kinase associates with the hERG1 protein and becomes tyrosine phosphorylated. Using hERG1-specific inhibitors, we show that the tyrosine phosphorylation of focal adhesion kinase is strictly dependent on hERG channel activity. Similarly, the activity of the small GTPase Rac1 turned out to be dependent on hERG currents. On the whole, these data indicate that the hERG1 protein associates with beta(1) integrins and modulates adhesion receptor signaling. 相似文献
998.
999.
Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells 总被引:1,自引:0,他引:1
Di Giacinto C Marinaro M Sanchez M Strober W Boirivant M 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(6):3237-3246
Recent studies of murine models of mucosal inflammation suggest that, whereas some kinds of bacterial microflora are inducers of disease, others, known as probiotics, prevent disease. In the present study, we analyzed the regulatory cytokine and cell response to probiotic (VSL#3) administration in the context of the Th1 T cell colitis induced by trinitrobenzene sulfonic acid treatment of SJL/J mice. Daily administration of probiotics for 3 wk to mice during a remission period between a first and second course of colitis induced by trinitrobenzene sulfonic acid, resulted in a milder form of recurrent colitis than observed in mice administered PBS during this same period. This protective effect was attributable to effects on the lamina propria mononuclear cell (LPMC) population, because it could be transferred by LPMC from probiotic-treated mice to naive mice. Probiotic administration was associated with an early increase in the production of IL-10 and an increased number of regulatory CD4+ T cells bearing surface TGF-beta in the form of latency-associated protein (LAP) (LAP+ T cells). The latter were dependent on the IL-10 production because administration of anti-IL-10R mAb blocked their appearance. Finally, the LAP+ T cells were essential to the protective effect of probiotics because administration of anti-IL-10R or anti-TGF-beta at the initiation of recurrent colitis induction or depletion of LAP+ T cells from LPMC abolished the latter's capacity to transfer protection to naive recipients. These studies show that probiotic (VSL#3) administration during a remission period ameliorates the severity of recurrent colitis by inducing an immunoregulatory response involving TGF-beta-bearing regulatory cells. 相似文献
1000.