全文获取类型
收费全文 | 808篇 |
免费 | 29篇 |
出版年
2024年 | 1篇 |
2023年 | 1篇 |
2022年 | 3篇 |
2021年 | 10篇 |
2020年 | 6篇 |
2019年 | 4篇 |
2018年 | 9篇 |
2017年 | 7篇 |
2016年 | 12篇 |
2015年 | 27篇 |
2014年 | 33篇 |
2013年 | 51篇 |
2012年 | 59篇 |
2011年 | 49篇 |
2010年 | 28篇 |
2009年 | 29篇 |
2008年 | 65篇 |
2007年 | 49篇 |
2006年 | 47篇 |
2005年 | 40篇 |
2004年 | 51篇 |
2003年 | 49篇 |
2002年 | 49篇 |
2001年 | 8篇 |
2000年 | 7篇 |
1999年 | 10篇 |
1998年 | 17篇 |
1997年 | 14篇 |
1996年 | 9篇 |
1995年 | 16篇 |
1994年 | 3篇 |
1992年 | 5篇 |
1991年 | 5篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1988年 | 2篇 |
1987年 | 7篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1983年 | 9篇 |
1982年 | 12篇 |
1981年 | 4篇 |
1980年 | 1篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1975年 | 1篇 |
排序方式: 共有837条查询结果,搜索用时 15 毫秒
61.
Wu B Iwakiri R Tsunada S Utsumi H Kojima M Fujise T Ootani A Fujimoto K 《Free radical biology & medicine》2002,33(5):649-658
The aim of this study was to demonstrate (i) the role of iNOS (inducible nitric oxide synthase) on apoptosis in the rat intestinal mucosa after ischemia-reperfusion, and (ii) the effect of iNOS on the release of cytochrome c from mitochondria. The superior mesenteric artery was occluded for 60 min and was followed by a 60 min reperfusion. Rats were pretreated with an intraperitoneal injection of the following iNOS inhibitors: N-nitro-L-arginine methyl ester, aminoguanidine, and (1S,5S,6R,7R)-7- chloro-3-imino-5-methyl-2-azabicyclo [4. 1. 0] heptane hydrochloride (ONO-1714). Apoptosis was evaluated and NO(X) in the portal vein was assayed. The amount of iNOS, caspase-3, and cytochrome c were determined by a Western blot analysis. Intestinal mucosal epithelial mitochondrial dehydrogenase activity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoilium bromide. Ischemia-reperfusion increased intestinal mucosal apoptosis, NO(X) production in the portal vein, the amount of iNOS protein, and the release of cytochrome c, but not caspase-3. Inhibitors of iNOS significantly attenuated the induction of apoptosis, increased NO(X) production, and release of cytochrome c. Mitochondrial dysfunction was induced by ischemia-reperfusion, which was ameliorated by iNOS inhibitors. Our results indicate that iNOS is related to increased mucosal apoptosis in the rat small intestine after ischemia-reperfusion, which is partly explained by the release of cytochrome c from mitochondria to cytosols following mitochondrial dysfunction. 相似文献
62.
Nishigaki R Shinohara T Toda T Omori A Ichinose S Itoh M Shirayoshi Y Kurimasa A Oshimura M 《Biochemical and biophysical research communications》2002,295(1):112-118
An extra copy of human chromosome 21 (Chr 21) causes Down syndrome (DS), which is characterized by mental retardation and congenital heart disease (CHD). Chimeric mice containing Chr 21 also exhibit phenotypic traits of DS including CHD. In this study, to identify genes contributing to DS phenotypes, we compared the overall protein expression patterns in hearts of Chr 21 chimeras and wild type mice by two-dimensional electrophoresis. The endogenous mouse atrial specific isoform of myosin light chain-2 (mlc-2a) protein was remarkably downregulated in the hearts of chimeric mice. We also confirmed that the human MLC-2A protein level was significantly lower in a human DS neonate heart, as compared to that of a normal control. Since mouse mlc-2a is involved in heart morphogenesis, our data suggest that the downregulation of this gene plays a crucial role in the CHD observed in DS. The dosage imbalance of Chr 21 has a trans-acting effect which lowers the expression of other genes encoded elsewhere in the genome. 相似文献
63.
Nakamoto T Suzuki T Huang J Matsumura T Seo S Honda H Sakai R Hirai H 《Biochemical and biophysical research communications》2002,294(3):635-641
p130(Cas) (Cas) is a docking protein that becomes tyrosine phosphorylated in v-Src- or v-Crk-transformed cells and in integrin-stimulated cells. Cas -/- fibroblasts show defects in stress fiber formation, cell spreading, cell migration, and transformation by activated Src. To further characterize the role of Cas in signaling, we compared the expression profile in Cas -/- fibroblasts with that in Cas-re-expressing fibroblasts using the microarray methods. In Cas -/- fibroblasts, the expression of heme oxygenase 1 and caveolin-1 was reduced, but the expression of procollagen 1 alpha 1, procollagen 3 alpha 1, procollagen 11 alpha 1, elastin, periostin, TSC-36, and MARCKS was enhanced. The domains in Cas necessary for the change varied among these genes. Activated Src reduced the expression of most of these genes both in Cas -/- and in Cas +/+ fibroblasts. These results suggest the existence of signaling pathways that emanate from Cas to gene expression. 相似文献
64.
Kamino H Hiratsuka M Toda T Nishigaki R Osaki M Ito H Inoue T Oshimura M 《Cell structure and function》2003,28(6):495-503
It is known that replicative senescence of endothelium in vivo contributes at least partially to age-related vascular disorders such as arteriosclerosis. However, the genes involved in this process remain to be identified. In this study, we employed a proteomics-based approach to identify candidate genes using in vitro cultured human umbilical vein endothelial cells (HUVECs) as an experimental model for replicative senescence. By comparing protein spots from young and senescent HUVECs using two-dimensional electrophoresis, we identified three up-regulated proteins and five down-regulated proteins in senescent HUVECs as compared to young HUVECs, whose alteration was not observed during replicative senescence of primary human fibroblasts. Consistent results were obtained in Western blotting analysis using specific antibodies raised against some of these proteins, whereas there were no significant changes in the mRNA levels of these genes during senescence of HUVECs. Among them, cathepsin B, a protease participating in both intracellular proteolysis and extracellular matrix remodeling was observed to be dramatically up-regulated in senescent HUVECs and whose activity is known to be up-regulated in atherosclerotic lesions with senescence-associated phenotypes in vivo. Additional proteins, including cytoskeletal proteins and proteins involved in the processes of synthesis, turnover and modification of protein, were identified, whose function in endothelium was previously unsuspected. These proteins identified by a proteomics-based approach using cultured HUVECs may be involved not only in replicative senescence but also in functional alterations in vascular endothelial cells with senescence-associated phenotypes and may serve as molecular markers for these processes. 相似文献
65.
A functional polymorphism in the promoter/enhancer region of the<Emphasis Type="Italic"> FOXP3/Scurfin</Emphasis> gene associated with type 1 diabetes 总被引:20,自引:0,他引:20
FOXP3/Scurfin, a member of forkhead/winged-helix proteins, is involved in the regulation of T-cell activation, and essential for normal immune homeostasis. The FOXP3/Scurfin gene is located on chromosome Xp11.23, which includes one of the type 1 diabetes susceptible loci. Therefore, we investigated whether the human FOXP3/Scurfin gene might be a new candidate gene for type 1 diabetes. We first screened the human FOXP3/Scurfin gene for microsatellite and single nucleotide polymorphisms. Next, we performed an association study between the FOXP3/Scurfin gene and type 1 diabetes. Then, the evaluation of promoter/enhancer activity of the intron with (GT)(n) polymorphism was performed by dual luciferase reporter assay. We demonstrated two regions contained microsatellite polymorphisms; one was (GT)(n), located on intron zero and the other (TC)(n) on intron 5, which were under linkage-disequilibrium. The (GT)(15) allele showed a significantly higher frequency in patients with type 1 diabetes than in controls (43.1% vs 32.6%, P=0.0027). The genotype frequencies of (GT)(15)/(GT)(15) in female patients and of (GT)(15) in male patients tended to be higher than those in female ( P=0.064) and male ( P=0.061) controls, respectively. A significant difference in the enhancer activity between (GT)(15) and (GT)(16) dinucleotide repeats was detected. In conclusion, the FOXP3/Scurfin gene appears to confer a significant susceptibility to type 1 diabetes in the Japanese population. 相似文献
66.
67.
Tanabe T Murata I Karasuyama M Shin M Ueoka R Fujiwara K 《Histochemistry and cell biology》2003,120(5):401-408
The enterochromaffin-like (ECL) cells of the gastric mucosa in animals play an important role in gastric acid secretion. They contain few granules and numerous secretory vesicles and microvesicles. They operate under the control of circulating gastrin. In the present study, we conducted an immunoelectron microscopic study for histamine (HA) in the ECL cells of rats given the proton pump inhibitor lansoprazole (LP), which is known to induce hypergastrinemia. The pre-embedding indirect immunoperoxidase procedure utilized a mouse monoclonal antibody AHA-2 against glutaraldehyde-conjugated HA. Rats received LP (50 g/kg per day, subcutaneously) over a period of a month, and developed hypertrophy of the ECL cells in the stomach. It was clearly demonstrated that HA was located to a much higher degree in the cytoplasm of ECL cells of LP-treated rats than in normal rats. HA immunoreactivity was observed in the cores of the granules and secretory vesicles of the ECL cells in all the rats, but in the LP-treated rats it was observed in the cores of the newly developed vacuoles as well. These results may suggest that HA may be actively generated in the cytoplasm of the hypertrophic ECL cells of LP-treated rats. Also suggested in the present study is that HA is instrumental in the transformation of granules into secretory vesicles and in their consequent enlargement, and that vacuoles are formed by the fusion of large secretory vesicles. Furthermore, the finding that relatively little HA immunoreactivity existed in the vacuoles may suggest that the vacuoles actively degrade superfluous secretory products (for example, HA) through enhanced autophagocytosis and/or oxidative stress. Another possibility may be that the membrane-bounded structure regarded as the vacuoles in this study might actually be an invagination structure produced as a result of successive series of exocytosis through which the secretory vesicles actively and rapidly release HA. 相似文献
68.
Yamada R Mizutani-Koseki Y Hasegawa T Osumi N Koseki H Takahashi N 《Development (Cambridge, England)》2003,130(9):1759-1770
The mab-21 gene was first identified because of its requirement for ray identity specification in Caenorhabditis elegans. It is now known to constitute a family of genes that are highly conserved from vertebrates to invertebrates, and two homologs, Mab21l1 and Mab21l2, have been identified in many species. We describe the generation of Mab21l1-deficient mice with defects in eye and preputial gland formation. The mutant mouse eye has a rudimentary lens resulting from insufficient invagination of the lens placode caused by deficient proliferation. Chimera analyses suggest that the lens placode is affected in a cell-autonomous manner, although Mab21l1 is expressed in both the lens placode and the optic vesicle. The defects in lens placode development correlate with delayed and insufficient expression of Foxe3, which is also required for lens development, while Maf, Sox2, Six3 and PAX6 levels are not significantly affected. Significant reduction of Mab21l1 expression in the optic vesicle and overlying surface ectoderm in Sey homozygotes indicates that Mab21l1 expression in the developing eye is dependent upon the functions of Pax6 gene products. We conclude that Mab21l1 expression dependent on PAX6 is essential for lens placode growth and for formation of the lens vesicle; lack of Mab21l1 expression causes reduced expression of Foxe3 in a cell-autonomous manner. 相似文献
69.
Unequal cleavage in the early Tubifex embryo 总被引:1,自引:0,他引:1
Takashi Shimizu Ryuichi Ishii Hirokazu Takahashi 《Development, growth & differentiation》1998,40(3):257-266
Unequal cleavage that produces two blastomeres of different size is a cleavage pattern that many animals in a variety of phyla, particularly in Spiralia, adopt during early development. This cleavage pattern is apparently instrumental for asymmetric segregation of developmental potential, but it is also indispensable for normal embryogenesis in many animals. Mechanically, unequal cleavage is achieved by either simple unequal cytokinesis or by forming a polar lobe at the egg's vegetal pole. In the present paper, the mechanisms for unequal cytokinesis involved in the first three cleavages in the oligochaete annelid Tubifex are reviewed. The three unequal cleavages are all brought about by an asymmetrically organized mitotic apparatus (MA). The MA of the first cleavage is monastral in that an aster is present at one pole of a bipolar spindle but not at the other. This monastral form, which arises as a result of the involvement of a single centrosome in the MA assembly, is both necessary and sufficient for unequal first cleavage. The egg cortex during the first mitosis is devoid of the ability to remodel spindle poles. In contrast to the non-cortical mechanisms for the first cleavage, asymmetry in the MA organization at the second and third cleavages depends solely on specialized properties of the cell cortex, to which one spindle pole is physically connected. A cortical attachment site for the second cleavage spindle is generated de novo at the cleavage membrane resulting from the first cleavage; it is an actin-based, cell contact-dependent structure. The cortical microtubule attachment site for the third cleavage, which functions independently of contact with other cells, is not generated at the cleavage membrane resulting from the second cleavage, but is located at the animal pole; it may originate from the second polar body formation and become functional at the 4-cell stage. 相似文献
70.
Yasunori Machida Marina Nakashima Kayoko Morikiyo Hiroharu Banno Masaki Ishikawa Takashi Soyano Ryuichi Nishihama 《Journal of plant research》1998,111(2):243-246
The tobaccoNPK1 gene encodes a homolog of mitogenactivated protein kinase kinase kinases. We have recently identified tobacco kinesin-like
proteins (NACK1/2) as activators for NPK1. Immunochemical analyses of NPK1 and NACK1 proteins suggest that NPK1 is involved
in the regulation of some process in the M phase of the plant cell cycle.
The extended abstract of a paper presented at the 13th International Symposium in Conjugation with Award of the International
Prize for Biology “Frontier of Plant Biology” 相似文献