全文获取类型
收费全文 | 232篇 |
免费 | 24篇 |
专业分类
256篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 6篇 |
2020年 | 3篇 |
2019年 | 1篇 |
2018年 | 5篇 |
2017年 | 6篇 |
2016年 | 5篇 |
2015年 | 17篇 |
2014年 | 12篇 |
2013年 | 27篇 |
2012年 | 18篇 |
2011年 | 23篇 |
2010年 | 12篇 |
2009年 | 12篇 |
2008年 | 9篇 |
2007年 | 22篇 |
2006年 | 14篇 |
2005年 | 10篇 |
2004年 | 8篇 |
2003年 | 18篇 |
2002年 | 8篇 |
2000年 | 3篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1993年 | 1篇 |
1992年 | 4篇 |
1990年 | 1篇 |
1989年 | 1篇 |
排序方式: 共有256条查询结果,搜索用时 15 毫秒
81.
82.
Kalluri SR Rothhammer V Staszewski O Srivastava R Petermann F Prinz M Hemmer B Korn T 《PloS one》2011,6(1):e16083
Background
Antibodies to the water channel protein aquaporin-4 (AQP4), which is expressed in astrocytic endfeet at the blood brain barrier, have been identified in the serum of Neuromyelitis optica (NMO) patients and are believed to induce damage to astrocytes. However, AQP4 specific T helper cell responses that are required for the generation of anti-AQP4 antibodies and most likely also for the formation of intraparenchymal CNS lesions have not been characterized.Methodology/Principal Findings
Using overlapping 15-meric peptides of AQP4, we identified the immunogenic T cell epitopes of AQP4 that are restricted to murine major histocompatibility complex (MHC) I-Ab. The N-terminal region of AQP4 was highly immunogenic. More precisely, the intracellular epitope AQP422–36 was detected as major immunogenic determinant. AQP482–108 (located in the second transmembrane domain), AQP4139–153 (located in the second extracellular loop), AQP4211–225 (located in the fifth transmembrane domain), AQP4235–249 (located in the sixth transmembrane domain), as well as AQP4289–306 in the intracellular C-terminal region were also immunogenic epitopes. AQP422–36 and AQP4289–303 specific T cells were present in the natural T cell repertoire of wild type C57BL/6 mice and T cell lines were raised. However, active immunization with these AQP4 peptides did not induce signs of spinal cord disease. Rather, sensitization with AQP4 peptides resulted in production of IFN-γ, but also IL-5 and IL-10 by antigen-specific T cells. Consistent with this cytokine profile, the AQP4 specific antibody response upon immunization with full length AQP4 included IgG1 and IgG2, which are associated with a mixed Th2/Th1 T cell response.Conclusions and Significance
AQP4 is able to induce an autoreactive T cell response. The identification of I-Ab restricted AQP4 specific T cell epitopes will allow us to investigate how AQP4 specific autoimmune reactions are regulated and to establish faithful mouse models of NMO that include both cellular and humoral responses against AQP4. 相似文献83.
The tectorial membrane (TM) is an extracellular matrix of the cochlea whose prominent role in hearing has been demonstrated through mutation studies. The C1509G mutation of the Tecta gene, which encodes for the α-tectorin protein, leads to hearing loss. The heterozygote TM only attaches to the first row of outer hair cells (OHCs), and the homozygote TM does not attach to any OHCs. Here we measured the morphology and mechanical properties of wild-type, heterozygous, and homozygous Tecta TMs. Morphological analyses conducted with second- and third-harmonic imaging, scanning electron microscopy, and immunolabeling revealed marked changes in the collagen architecture and stereocilin-labeling patterns of the mutant TMs. The mechanical properties of the mutant TM were measured by force spectroscopy. Whereas the axial Young's modulus of the low-frequency (apical) region of Tecta mutant TM samples was similar to that of wild-type TMs, it significantly decreased in the basal region to a value approaching that found at the apex. Modeling simulations suggest that a reduced TM Young's modulus is likely to reduce OHC stereociliary deflection. These findings argue that the heterozygote C1509G mutation results in a lack of attachment of the TM to the OHCs, which in turn reduces both the overall number of OHCs that are involved in mechanotransduction and the degree of mechanotransduction exhibited by the OHCs that remain attached to the TM. 相似文献
84.
Xingjuan Shi Yu Zhang Ru Chen Yijie Gong Mingming Zhang Rui Guan Ori D. Rotstein Xiangdong Liu XiaoYan Wen 《Journal of cellular and molecular medicine》2020,24(22):13151
Cardiac hypertrophy is a common pathological change in patients with progressive cardiac function failure, which can be caused by hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) or arterial hypertension. Despite years of study, there is still limited knowledge about the underlying molecular mechanisms for cardiac hypertrophy. NDUFA7, a subunit of NADH:ubiquinone oxidoreductase (complex I), has been reported to be a novel HCM associated gene. However, the biological role of NDUFA7 in heart remains unknown. In this study, we found that NDUFA7 exhibited high expression in the heart, and its level was significantly decreased in mice model of cardiac hypertrophy. Moreover, we demonstrated that ndufa7 knockdown in developing zebrafish embryos resulted in cardiac development and functional defects, associated with increased expression of pathological hypertrophy biomarkers nppa (ANP) and nppb (BNP). Mechanistic study demonstrated that ndufa7 depletion promoted ROS production and calcineurin signalling activation. Moreover, NDUFA7 depletion contributed to cardiac cell hypertrophy. Together, these results report for the first time that ndufa7 is implicated in pathological cardiac hypertrophy. 相似文献
85.
Tobias Ruck Stefan Bittner Catharina C. Gross Johanna Breuer Stefanie Albrecht Sabrina Korr Kerstin G?bel Susann Pankratz Christian M. Henschel Nicholas Schwab Ori Staszewski Marco Prinz Tanja Kuhlmann Sven G. Meuth Heinz Wiendl 《PloS one》2013,8(11)
Migration of encephalitogenic CD4+ T lymphocytes across the blood-brain barrier is an essential step in the pathogenesis of multiple sclerosis (MS). We here demonstrate that expression of the co-stimulatory receptor NKG2D defines a subpopulation of CD4+ T cells with elevated levels of markers for migration, activation, and cytolytic capacity especially when derived from MS patients. Furthermore, CD4+NKG2D+ cells produce high levels of proinflammatory IFN-γ and IL-17 upon stimulation. NKG2D promotes the capacity of CD4+NKG2D+ cells to migrate across endothelial cells in an in vitro model of the blood-brain barrier. CD4+NKG2D+ T cells are enriched in the cerebrospinal fluid of MS patients, and a significant number of CD4+ T cells in MS lesions coexpress NKG2D. We further elucidated the role of CD4+NKG2D+ T cells in the mouse system. NKG2D blockade restricted central nervous system migration of T lymphocytes in vivo, leading to a significant decrease in the clinical and pathologic severity of experimental autoimmune encephalomyelitis, an animal model of MS. Blockade of NKG2D reduced killing of cultivated mouse oligodendrocytes by activated CD4+ T cells. Taken together, we identify CD4+NKG2D+ cells as a subpopulation of T helper cells with enhanced migratory, encephalitogenic and cytotoxic properties involved in inflammatory CNS lesion development. 相似文献
86.
Anat Gafter-Gvili Boris Zingerman Benaya Rozen-Zvi Yaacov Ori Hefziba Green Ido Lubin Tsipora Malachi Uzi Gafter Michal Herman-Edelstein 《PloS one》2013,8(7)
Background
DNA repair is a cellular defence mechanism responding to DNA damage caused in large part by oxidative stress. There is a controversy with regard to the effect of red blood cells on DNA damage and cellular response.Aim
To investigate the effect of red blood cells on H2O2-induced DNA damage and repair in human peripheral blood mononuclear cells.Methods
DNA breaks were induced in peripheral blood mononuclear cells by H2O2 in the absence or presence of red blood cells, red blood cells hemolysate or hemoglobin. DNA repair was measured by 3H-thymidine uptake, % double-stranded DNA was measured by fluorometric assay of DNA unwinding. DNA damage was measured by the comet assay and by the detection of histone H2AX phosphorylation.Results
Red blood cells and red blood cells hemolysate reduced DNA repair in a dose-dependent manner. Red blood cells hemolysate reduced % double-stranded DNA, DNA damage and phosphorylation of histone H2AX. Hemoglobin had the same effect as red blood cells hemolysate on % double-stranded DNA.Conclusion
Red blood cells, via red blood cells hemolysate and hemoglobin, reduced the effect of oxidative stress on peripheral blood mononuclear cell DNA damage and phosphorylation of histone H2AX. Consequently, recruitment of DNA repair proteins diminished with reduction of DNA repair. This suggests that anemia predisposes to increased oxidative stress induced DNA damage, while a higher hemoglobin level provides protection against oxidative-stress-induced DNA damage. 相似文献87.
88.
89.
90.
Encephalopathy caused by ablation of very long acyl chain ceramide synthesis may be largely due to reduced galactosylceramide levels 总被引:1,自引:0,他引:1
Ben-David O Pewzner-Jung Y Brenner O Laviad EL Kogot-Levin A Weissberg I Biton IE Pienik R Wang E Kelly S Alroy J Raas-Rothschild A Friedman A Brügger B Merrill AH Futerman AH 《The Journal of biological chemistry》2011,286(34):30022-30033
Sphingolipids (SLs) act as signaling molecules and as structural components in both neuronal cells and myelin. We now characterize the biochemical, histological, and behavioral abnormalities in the brain of a mouse lacking very long acyl (C22-C24) chain SLs. This mouse, which is defective in the ability to synthesize C22-C24-SLs due to ablation of ceramide synthase 2, has reduced levels of galactosylceramide (GalCer), a major component of myelin, and in particular reduced levels of non-hydroxy-C22-C24-GalCer and 2-hydroxy-C22-C24- GalCer. Noteworthy brain lesions develop with a time course consistent with a vital role for C22-C24-GalCer in myelin stability. Myelin degeneration and detachment was observed as was abnormal motor behavior originating from a subcortical region. Additional abnormalities included bilateral and symmetrical vacuolization and gliosis in specific brain areas, which corresponded to some extent to the pattern of ceramide synthase 2 expression, with astrogliosis considerably more pronounced than microglial activation. Unexpectedly, unidentified storage materials were detected in lysosomes of astrocytes, reminiscent of the accumulation that occurs in lysosomal storage disorders. Together, our data demonstrate a key role in the brain for SLs containing very long acyl chains and in particular GalCer with a reduction in their levels leading to distinctive morphological abnormalities in defined brain regions. 相似文献