全文获取类型
收费全文 | 2808篇 |
免费 | 142篇 |
国内免费 | 1篇 |
专业分类
2951篇 |
出版年
2022年 | 14篇 |
2021年 | 21篇 |
2020年 | 12篇 |
2019年 | 24篇 |
2018年 | 29篇 |
2017年 | 20篇 |
2016年 | 38篇 |
2015年 | 71篇 |
2014年 | 83篇 |
2013年 | 222篇 |
2012年 | 164篇 |
2011年 | 170篇 |
2010年 | 121篇 |
2009年 | 115篇 |
2008年 | 192篇 |
2007年 | 156篇 |
2006年 | 152篇 |
2005年 | 159篇 |
2004年 | 139篇 |
2003年 | 148篇 |
2002年 | 148篇 |
2001年 | 39篇 |
2000年 | 41篇 |
1999年 | 43篇 |
1998年 | 40篇 |
1997年 | 41篇 |
1996年 | 33篇 |
1995年 | 34篇 |
1994年 | 20篇 |
1993年 | 37篇 |
1992年 | 41篇 |
1991年 | 32篇 |
1990年 | 20篇 |
1989年 | 23篇 |
1988年 | 17篇 |
1987年 | 24篇 |
1986年 | 15篇 |
1985年 | 22篇 |
1984年 | 18篇 |
1983年 | 25篇 |
1982年 | 21篇 |
1981年 | 16篇 |
1980年 | 14篇 |
1979年 | 11篇 |
1978年 | 16篇 |
1977年 | 15篇 |
1976年 | 15篇 |
1975年 | 12篇 |
1973年 | 10篇 |
1970年 | 15篇 |
排序方式: 共有2951条查询结果,搜索用时 10 毫秒
941.
Kitamura H Yamamoto S Nakase H Matsuura M Honzawa Y Matsumura K Takeda Y Uza N Nagata K Chiba T 《Biochemical and biophysical research communications》2011,(2):599-604
Background and aims
Intestinal fibrosis is a clinically important issue of inflammatory bowel disease (IBD). It is unclear whether or not heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in intestinal fibrosis. The aim of this study is to investigate the role of HSP47 in intestinal fibrosis of murine colitis.Methods
HSP47 expression and localization were evaluated in interleukin-10 knockout (IL-10KO) and wild-type (WT, C57BL/6) mice by immunohistochemistry. Expression of HSP47 and transforming growth factor-β1 (TGF-β1) in colonic tissue was measured. In vitro studies were conducted in NIH/3T3 cells and primary culture of myofibroblasts separated from colonic tissue of IL-10KO (PMF KO) and WT mice (PMF WT) with stimulation of several cytokines. We evaluated the inhibitory effect of administration of small interfering RNA (siRNA) targeting HSP47 on intestinal fibrosis in IL-10KO mice in vivo.Results
Immunohistochemistry revealed HSP47 positive cells were observed in the mesenchymal and submucosal area of both WT and IL-10 KO mice. Gene expressions of HSP47 and TGF-β1 were significantly higher in IL-10KO mice than in WT mice and correlated with the severity of inflammation. In vitro experiments with NIH3T3 cells, TGF-β1 only induced HSP47 gene expression. There was a significant difference of HSP47 gene expression between PMF KO and PMF WT. Administration of siRNA targeting HSP47 remarkably reduced collagen deposition in colonic tissue of IL-10KO mice.Conclusions
Our results indicate that HSP47 plays an essential role in intestinal fibrosis of IL-10KO mice, and may be a potential target for intestinal fibrosis associated with IBD. 相似文献942.
Recent studies have revealed that Ca2+ not only regulates the contraction of cardiomyocytes, but can also function as a signaling agent to stimulate ATP production by the mitochondria. However, the spatiotemporal resolution of current experimental techniques limits our investigative capacity to understand this phenomenon. Here, we created a detailed three-dimensional (3D) cardiomyocyte model to study the subcellular regulatory mechanisms of myocardial energetics. The 3D cardiomyocyte model was based on the finite-element method, with detailed subcellular structures reproduced, and it included all elementary processes involved in cardiomyocyte electrophysiology, contraction, and ATP metabolism localized to specific loci. The simulation results were found to be reproducible and consistent with experimental data regarding the spatiotemporal pattern of cytosolic, intrasarcoplasmic-reticulum, and mitochondrial changes in Ca2+; as well as changes in metabolite levels. Detailed analysis suggested that although the observed large cytosolic Ca2+ gradient facilitated uptake by the mitochondrial Ca2+ uniporter to produce cyclic changes in mitochondrial Ca2+ near the Z-line region, the average mitochondrial Ca2+ changes slowly. We also confirmed the importance of the creatine phosphate shuttle in cardiac energy regulation. In summary, our 3D model provides a powerful tool for the study of cardiac function by overcoming some of the spatiotemporal limitations of current experimental approaches. 相似文献
943.
Hai-Tuong Le Valérie Gautier Fatoum Kthiri Masamichi Kohiyama Tsutomu Katayama Gilbert Richarme 《Biochemical and biophysical research communications》2011,405(1):19459
Escherichia coli contains two thioredoxins, Trx1 and Trx2, and a thioredoxin-like protein, YbbN, that displays both redox and chaperone properties. Since three out of the six proteins of the YbbN interactome (Butland et al., 2005) are components of DNA polymerase 3 holoenzyme (i.e. the β-clamp DnaN, the θ subunit HolE and the δ′ subunit HolB), we investigated whether the ybbN mutant presents DNA replication defects. We found that this mutant incorporates 3H-thymidine at higher rates than the parental strain and displays overinitiation, hypermutator and filamentation phenotypes with the occurrence of anucleated cells. Moreover, YbbN functions as a bona fide chaperone in the refolding of the urea-unfolded β-clamp. These results suggest that the DNA replication and cell division defects of the ybbN mutant might best be explained by chaperone functions of YbbN in the biogenesis of DNA polymerase 3 holoenzyme. 相似文献
944.
Ting Gang Chew Tzer Chyn Lim Yumi Osaki Junqi Huang Anton Kamnev Tomoyuki Hatano Masako Osumi Mohan K. Balasubramanian 《Molecular biology of the cell》2020,31(21):2306
Eukaryotic cells assemble actomyosin rings during cytokinesis to function as force-generating machines to drive membrane invagination and to counteract the intracellular pressure and the cell surface tension. How the extracellular matrix affects actomyosin ring contraction has not been fully explored. While studying the Schizosaccharomyces pombe 1,3-β-glucan-synthase mutant cps1-191, which is defective in division septum synthesis and arrests with a stable actomyosin ring, we found that weakening of the extracellular glycan matrix caused the generated spheroplasts to divide under the nonpermissive condition. This nonmedial slow division was dependent on a functional actomyosin ring and vesicular trafficking, but independent of normal septum synthesis. Interestingly, the high intracellular turgor pressure appears to play a minimal role in inhibiting ring contraction in the absence of cell wall remodeling in cps1-191 mutants, as decreasing the turgor pressure alone did not enable spheroplast division. We propose that during cytokinesis, the extracellular glycan matrix restricts actomyosin ring contraction and membrane ingression, and remodeling of the extracellular components through division septum synthesis relieves the inhibition and facilitates actomyosin ring contraction. 相似文献
945.
946.
947.
Tomoko Fuke Seiji Mizuno Toshiro Nagai Tomonobu Hasegawa Reiko Horikawa Yoko Miyoshi Koji Muroya Tatsuro Kondoh Chikahiko Numakura Seiji Sato Kazuhiko Nakabayashi Chiharu Tayama Kenichiro Hata Shinichiro Sano Keiko Matsubara Masayo Kagami Kazuki Yamazawa Tsutomu Ogata 《PloS one》2013,8(3)
Background
Recent studies have revealed relative frequency and characteristic phenotype of two major causative factors for Silver-Russell syndrome (SRS), i.e. epimutation of the H19-differentially methylated region (DMR) and uniparental maternal disomy 7 (upd(7)mat), as well as multilocus methylation abnormalities and positive correlation between methylation index and body and placental sizes in H19-DMR epimutation. Furthermore, rare genomic alterations have been found in a few of patients with idiopathic SRS. Here, we performed molecular and clinical findings in 138 Japanese SRS patients, and examined these matters.Methodology/Principal Findings
We identified H19-DMR epimutation in cases 1–43 (group 1), upd(7)mat in cases 44–52 (group 2), and neither H19-DMR epimutation nor upd(7)mat in cases 53–138 (group 3). Multilocus analysis revealed hyper- or hypomethylated DMRs in 2.4% of examined DMRs in group 1; in particular, an extremely hypomethylated ARHI-DMR was identified in case 13. Oligonucleotide array comparative genomic hybridization identified a ∼3.86 Mb deletion at chromosome 17q24 in case 73. Epigenotype-phenotype analysis revealed that group 1 had more reduced birth length and weight, more preserved birth occipitofrontal circumference (OFC), more frequent body asymmetry and brachydactyly, and less frequent speech delay than group 2. The degree of placental hypoplasia was similar between the two groups. In group 1, the methylation index for the H19-DMR was positively correlated with birth length and weight, present height and weight, and placental weight, but with neither birth nor present OFC.Conclusions/Significance
The results are grossly consistent with the previously reported data, although the frequency of epimutations is lower in the Japanese SRS patients than in the Western European SRS patients. Furthermore, the results provide useful information regarding placental hypoplasia in SRS, clinical phenotypes of the hypomethylated ARHI-DMR, and underlying causative factors for idiopathic SRS. 相似文献948.
949.
Seiichi Mawatari Hirofumi Uto Akio Ido Kenji Nakashima Tetsuro Suzuki Shuji Kanmura Kotaro Kumagai Kohei Oda Kazuaki Tabu Tsutomu Tamai Akihiro Moriuchi Makoto Oketani Yuko Shimada Masayuki Sudoh Ikuo Shoji Hirohito Tsubouchi 《PloS one》2013,8(12)