全文获取类型
收费全文 | 4704篇 |
免费 | 421篇 |
国内免费 | 207篇 |
出版年
2024年 | 1篇 |
2023年 | 117篇 |
2022年 | 48篇 |
2021年 | 200篇 |
2020年 | 288篇 |
2019年 | 331篇 |
2018年 | 322篇 |
2017年 | 298篇 |
2016年 | 296篇 |
2015年 | 313篇 |
2014年 | 370篇 |
2013年 | 844篇 |
2012年 | 264篇 |
2011年 | 188篇 |
2010年 | 84篇 |
2009年 | 84篇 |
2008年 | 74篇 |
2007年 | 69篇 |
2006年 | 80篇 |
2005年 | 80篇 |
2004年 | 50篇 |
2003年 | 51篇 |
2002年 | 77篇 |
2001年 | 55篇 |
2000年 | 60篇 |
1999年 | 33篇 |
1998年 | 34篇 |
1997年 | 42篇 |
1996年 | 38篇 |
1995年 | 42篇 |
1994年 | 57篇 |
1993年 | 38篇 |
1992年 | 38篇 |
1991年 | 31篇 |
1990年 | 44篇 |
1989年 | 32篇 |
1988年 | 30篇 |
1987年 | 14篇 |
1986年 | 33篇 |
1985年 | 30篇 |
1984年 | 19篇 |
1983年 | 13篇 |
1982年 | 38篇 |
1981年 | 19篇 |
1980年 | 14篇 |
1979年 | 16篇 |
1978年 | 14篇 |
1977年 | 12篇 |
1976年 | 6篇 |
1975年 | 1篇 |
排序方式: 共有5332条查询结果,搜索用时 15 毫秒
1.
Ann K. Rosenthal Claudia M. Gohr Elizabeth Mitton-Fitzgerald Rupinder Grewal James Ninomiya Carolyn B. Coyne William T. Jackson 《The Journal of biological chemistry》2015,290(21):13028-13038
Chondrocyte-derived extracellular organelles known as articular cartilage vesicles (ACVs) participate in non-classical protein secretion, intercellular communication, and pathologic calcification. Factors affecting ACV formation and release remain poorly characterized; although in some cell types, the generation of extracellular vesicles is associated with up-regulation of autophagy. We sought to determine the role of autophagy in ACV production by primary articular chondrocytes. Using an innovative dynamic model with a light scatter nanoparticle counting apparatus, we determined the effects of autophagy modulators on ACV number and content in conditioned medium from normal adult porcine and human osteoarthritic chondrocytes. Healthy articular chondrocytes release ACVs into conditioned medium and show significant levels of ongoing autophagy. Rapamycin, which promotes autophagy, increased ACV numbers in a dose- and time-dependent manner associated with increased levels of autophagy markers and autophagosome formation. These effects were suppressed by pharmacologic autophagy inhibitors and short interfering RNA for ATG5. Caspase-3 inhibition and a Rho/ROCK inhibitor prevented rapamycin-induced increases in ACV number. Osteoarthritic chondrocytes, which are deficient in autophagy, did not increase ACV number in response to rapamycin. SMER28, which induces autophagy via an mTOR-independent mechanism, also increased ACV number. ACVs induced under all conditions had similar ecto-enzyme specific activities and types of RNA, and all ACVs contained LC3, an autophagosome-resident protein. These findings identify autophagy as a critical participant in ACV formation, and augment our understanding of ACVs in cartilage disease and repair. 相似文献
2.
3.
Phytoplankton biomass values in Tavropos Reservoir, ranging from 92 to 1071 mg m–3, are within a range characteristic of oligotrophic waters. The seasonal sequence of biomass shows three annual peaks, differing from the monoacmic pattern seen in oligotrophic lakes. This sequence was profoundly affected by changes in water withdrawal and inflow rates. Diatoms, cryptophytes, chrysophytes and dinoflagellates, in that order, were the major constituents of the reservoir phytoplankton. The succession, from diatoms and chrysophytes in late winter-spring, to centric diatoms in late spring-summer and again to diatom-chrysophytes in late autumn was similar to that in oligotrophic lakes. 相似文献
4.
Chunhui Sun Qiaoqiao Diao Jun Lu Zifeng Zhang Dongmei Wu Xingqi Wang Jun Xie Guihong Zheng Qun Shan Shaohua Fan Bin Hu Yuanlin Zheng 《Journal of cellular physiology》2019,234(5):5926-5939
Autophagy is a vital negative factor regulating cellular senescence. Purple sweet potato color (PSPC), one type of flavonoid, has been demonstrated to suppress endothelial senescence and restore endothelial function in diabetic mice by inhibiting the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome. However, the roles of autophagy in the inflammatory response during endothelial senescence are unknown. Here, we found that PSPC augmented autophagy to restrict high-glucose-induced premature endothelial senescence. In addition, PSPC administration impaired endothelium aging in diabetic mice by increasing autophagy. Inhibition of autophagy accelerated endothelial senescence, while enhancement of autophagy delayed senescence. Moreover, deactivation of the NLRP3 inflammasome triggered by PSPC was autophagy-dependent. Autophagy receptor microtubule-associated protein 1 light chain 3 and p62 interacted with the inflammasome component NLRP3, suggesting that autophagosomes target the NLRP3 inflammasome and deliver it to the lysosome for degradation. Altogether, PSPC amplified cellular autophagy, subsequently attenuated NLRP3 inflammasome activity and finally delayed endothelial senescence to ameliorate cardiovascular complication. These results suggest a potential therapeutic target in senescence-related cardiovascular diseases. 相似文献
5.
6.
7.
8.
Núria Eritja Bo-Juen Chen Ruth Rodríguez-Barrueco Maria Santacana Sònia Gatius August Vidal 《Autophagy》2017,13(3):608-624
Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC. 相似文献
9.
Ida Johansson Vivi Talstad Monsen Kristine Pettersen Jennifer Mildenberger Kristine Misund Kai Kaarniranta Svanhild Sch?nberg Geir Bj?rk?y 《Autophagy》2015,11(9):1636-1651
Accumulation and aggregation of misfolded proteins is a hallmark of several diseases collectively known as proteinopathies. Autophagy has a cytoprotective role in diseases associated with protein aggregates. Age-related macular degeneration (AMD) is the most common neurodegenerative eye disease that evokes blindness in elderly. AMD is characterized by degeneration of retinal pigment epithelial (RPE) cells and leads to loss of photoreceptor cells and central vision. The initial phase associates with accumulation of intracellular lipofuscin and extracellular deposits called drusen. Epidemiological studies have suggested an inverse correlation between dietary intake of marine n-3 polyunsaturated fatty acids (PUFAs) and the risk of developing neurodegenerative diseases, including AMD. However, the disease-preventive mechanism(s) mobilized by n-3 PUFAs is not completely understood. In human retinal pigment epithelial cells we find that physiologically relevant doses of the n-3 PUFA docosahexaenoic acid (DHA) induce a transient increase in cellular reactive oxygen species (ROS) levels that activates the oxidative stress response regulator NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2). Simultaneously, there is a transient increase in intracellular protein aggregates containing SQSTM1/p62 (sequestosome 1) and an increase in autophagy. Pretreatment with DHA rescues the cells from cell cycle arrest induced by misfolded proteins or oxidative stress. Cells with a downregulated oxidative stress response, or autophagy, respond with reduced cell growth and survival after DHA supplementation. These results suggest that DHA both induces endogenous antioxidants and mobilizes selective autophagy of misfolded proteins. Both mechanisms could be relevant to reduce the risk of developing aggregate-associate diseases such as AMD. 相似文献
10.
Wild-type rabies virus induces autophagy in human and mouse neuroblastoma cell lines 总被引:1,自引:0,他引:1
Different rabies virus (RABV) strains have their own biological characteristics, but little is known about their respective impact on autophagy. Therefore, we evaluated whether attenuated RABV HEP-Flury and wild-type RABV GD-SH-01 strains triggered autophagy. We found that GD-SH-01 infection significantly increased the number of autophagy-like vesicles, the accumulation of enhanced green fluorescent protein (EGFP)-LC3 fluorescence puncta and the conversion of LC3-I to LC3-II, while HEP-Flury was not able to induce this phenomenon. When evaluating autophagic flux, we found that GD-SH-01 infection triggers a complete autophagic response in the human neuroblastoma cell line (SK), while autophagosome fusion with lysosomes was inhibited in a mouse neuroblastoma cell line (NA). In these cells, GD-SH-01 led to apoptosis and mitochondrial dysfunction while triggering autophagy, and apoptosis could be decreased by enhancing autophagy. To further identify the virus constituent causing autophagy, 5 chimeric recombinant viruses carrying single genes of HEP-Flury instead of those of GD-SH-01 were rescued. While the HEP-Flury virus carrying the wild-type matrix protein (M) gene of RABV triggered LC3-I to LC3-II conversion in SK and NA cells, replacement of genes of nucleoprotein (N), phosphoprotein (P) and glycoprotein (G) produced only minor autophagy. But no one single structural protein of GD-SH-01 induced autophagy. Moreover, the AMPK signaling pathway was activated by GD-SH-01 in SK. Therefore, our data provide strong evidence that autophagy is induced by GD-SH-01 and can decrease apoptosis in vitro. Furthermore, the M gene of GD-SH-01 may cooperatively induce autophagy. 相似文献