全文获取类型
收费全文 | 3713篇 |
免费 | 226篇 |
国内免费 | 35篇 |
专业分类
3974篇 |
出版年
2024年 | 5篇 |
2023年 | 14篇 |
2022年 | 38篇 |
2021年 | 52篇 |
2020年 | 34篇 |
2019年 | 32篇 |
2018年 | 43篇 |
2017年 | 52篇 |
2016年 | 76篇 |
2015年 | 127篇 |
2014年 | 153篇 |
2013年 | 261篇 |
2012年 | 263篇 |
2011年 | 250篇 |
2010年 | 147篇 |
2009年 | 140篇 |
2008年 | 259篇 |
2007年 | 261篇 |
2006年 | 256篇 |
2005年 | 252篇 |
2004年 | 250篇 |
2003年 | 245篇 |
2002年 | 225篇 |
2001年 | 41篇 |
2000年 | 37篇 |
1999年 | 37篇 |
1998年 | 47篇 |
1997年 | 47篇 |
1996年 | 26篇 |
1995年 | 28篇 |
1994年 | 22篇 |
1993年 | 23篇 |
1992年 | 18篇 |
1991年 | 21篇 |
1990年 | 17篇 |
1989年 | 17篇 |
1988年 | 23篇 |
1987年 | 8篇 |
1986年 | 17篇 |
1985年 | 11篇 |
1984年 | 9篇 |
1983年 | 16篇 |
1982年 | 12篇 |
1981年 | 10篇 |
1980年 | 11篇 |
1979年 | 5篇 |
1978年 | 5篇 |
1973年 | 3篇 |
1970年 | 4篇 |
1968年 | 5篇 |
排序方式: 共有3974条查询结果,搜索用时 15 毫秒
91.
Daiki Miki Hidenori Ochi Atsushi Takahashi C. Nelson Hayes Yuji Urabe Hiromi Abe Tomokazu Kawaoka Masataka Tsuge Nobuhiko Hiraga Michio Imamura Yoshiiku Kawakami Hiroshi Aikata Shoichi Takahashi Norio Akuta Fumitaka Suzuki Kenji Ikeda Hiromitsu Kumada Yoshiyasu Karino Joji Toyota Tatsuhiko Tsunoda Michiaki Kubo Naoyuki Kamatani Yusuke Nakamura Kazuaki Chayama 《PloS one》2013,8(12)
Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10-5). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (P
combined = 3.59 × 10−16, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype. 相似文献
92.
93.
94.
95.
Quanhai Li Kiyoko Kawamura Shan Yang Shinya Okamoto Hiroshi Kobayashi Yuji Tada Ikuo Sekine Yuichi Takiguchi Masato Shingyouji Koichiro Tatsumi Hideaki Shimada Kenzo Hiroshima Masatoshi Tagawa 《PloS one》2013,8(8)
Interferons (IFNs) have been tested for the therapeutic effects in various types of malignancy, but mechanisms of the anti-tumors effects and the differential biological activities among IFN members are dependent on respective cell types. In this study, we examined growth inhibitory activities of type I and III IFNs on 5 kinds of human mesothelioma cells bearing wild-type p53 gene, and showed that type I IFNs but not type III IFNs decreased the cell viabilities. Moreover, growth inhibitory activities and up-regulated expression levels of the major histocompatibility complexes class I antigens were greater with IFN-β than with IFN-α treatments. Cell cycle analyses demonstrated that type I IFNs increased S- and G2/M-phase populations, and subsequently sub-G1-phase fractions. The cell cycle changes were also greater with IFN-β than IFN-α treatments, and these data collectively showed that IFN-β had stronger biological activities than IFN-α in mesothelioma. Type I IFNs-treated cells increased p53 expression and the phosphorylation levels, and activated apoptotic pathways. A combinatory use of IFN-β and cisplatin or pemetrexed, both of which are the current first-line chemotherapeutic agents for mesothelioma, produced synergistic anti-tumor effects, which were also evidenced by increased sub-G1-phase fractions. These data demonstrated firstly to our knowledge that IFN-β produced synergistic anti-tumor effects with cisplatin or pemetrexed on mesothelioma through up-regulated p53 expression. 相似文献
96.
Daisuke Takagi Atsuko Miyagi Youshi Tazoe Mao Suganami Maki Kawai-Yamada Akihiro Ueda Yuji Suzuki Ko Noguchi Naoki Hirotsu Amane Makino 《Plant, cell & environment》2020,43(9):2033-2053
Phosphorus (P) is an essential mineral nutrient for plants. Nevertheless, excessive P accumulation in leaf mesophyll cells causes necrotic symptoms in land plants; this phenomenon is termed P toxicity. However, the detailed mechanisms underlying P toxicity in plants have not yet been elucidated. This study aimed to investigate the molecular mechanism of P toxicity in rice. We found that under excessive inorganic P (Pi) application, Rubisco activation decreased and photosynthesis was inhibited, leading to lipid peroxidation. Although the defence systems against reactive oxygen species accumulation were activated under excessive Pi application conditions, the Cu/Zn-type superoxide dismutase activities were inhibited. A metabolic analysis revealed that excessive Pi application led to an increase in the cytosolic sugar phosphate concentration and the activation of phytic acid synthesis. These conditions induced mRNA expression of genes that are activated under metal-deficient conditions, although metals did accumulate. These results suggest that P toxicity is triggered by the attenuation of both photosynthesis and metal availability within cells mediated by phytic acid accumulation. Here, we discuss the whole phenomenon of P toxicity, beginning from the accumulation of Pi within cells to death in land plants. 相似文献
97.
98.
Sciichi Uesugi Bok Luel Lee Morio Ikehara Yuji Kobayashi Yoshimasa Kyogoku 《Journal of biomolecular structure & dynamics》2013,31(2):339-347
Abstract It has been shown by us that oligonucleotides containing cyclonucleosides with a high anti glycosidic conformation take left-handed, single and double helical structures (S. Uesugi, J. Yano, E. Yano and M. Ikehara, J. Am. Chem. Soc. 99, 2313 (1977) and references therein). In order to see whether DNA can adopt the high anti left-handed double helical structure or not, a self-complementary hexanucleotide containing 6,2′-O-cyclocytidine (C○), 8,2′-O-cyclo- guanosine (G○), deoxycytidine and deoxyguanosine, C○G○dCdGC ○G○, was synthesized. Corresponding hexanucleotide containing only cyclonucleosides, C○G○C○G○C○G○, was also synthesized. Their conformation was examined by UV, CD and 1H NMR spectroscopy. C○G○C○G○C○G○ forms an unusually stable, left-handed duplex. Imino proton NMR spectra and the results of nuclear Overhauser effect experiments strongly suggest that C○G○dCdGC○G○ take a left-handed double helical structure where the deoxynucleoside residues are involved in hydrogen bonding and take a high anti glycosidic conformation. Thus it is revealed that DNA could form a high anti, left-handed double helix which is different from that of Z-DNA under some constrained conditions. 相似文献
99.
Yudai Nagata Jae Man Lee Hiroaki Mon Shigeo Imanishi Sun Mee Hong Shoji Komatsu Yuji Oshima Takahiro Kusakabe 《Biotechnology letters》2013,35(7):1009-1016
Glycoproteins have various biological functions including enzymatic activity, protein stability and others. Due to the presence of paucimannosidic N-linked glycans, recombinant proteins from an insect cell expression system may not be suitable for therapeutic use. Because baculovirus expression systems (BESs) are used to produce recombinant proteins, it is of interest to modify the endogenous N-glycosylation pathway in insects to mimic that of mammals. Using a soaking RNAi sensitive cell line, BmN4-SID1, has enabled us to suppress Bombyx mori FDL (BmFDL), an N-linked glycan-specific β-N-acetylglucosaminidase. Western blotting and MALDI-TOF MS demonstrated that the BmFDL depletion almost completely converted the paucimannosidic structures of the recombinant proteins produced by BES into a complex-type structure. This highly efficient, simple and low-cost method can be used for mass production of secretion proteins with complex-type N-linked glycans. 相似文献
100.
Ichiro Kawasaki Yuji Suzuki Hiroyuki Yanagisawa 《Biological trace element research》2013,154(1):120-126
The aim of the present study was to examine whether zinc (Zn) deficiency augmented the frequency of micronuclei, an indicator of chromosome aberration, and the induction of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of cellular DNA damage derived from oxidative stress, in rat bone marrow cells or not. Both the frequency of micronuclei and the induction of 8-OHdG were significantly increased in rats fed with a Zn-deficient versus a standard diet for 6 weeks (p?<?0.005). The supplementation of Zn with a standard diet for 4 weeks to rats fed with a Zn-deficient diet for 6 weeks restored the enhanced induction of micronuclei and 8-OHdG to levels comparable to those seen in rats fed with a standard diet for 10 weeks, indicating that the shortage of Zn in the body is involved in the induction of micronuclei and 8-OHdG. Again, the membrane-permeable superoxide dismutase mimetic superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, treatment (100 μmol/kg, twice a day) for 10 days prior to the termination of dietary treatment reduced the induction of micronuclei and 8-OHdG in rats fed with a Zn-deficient diet for 6 weeks to levels comparable to those in rats fed with a standard diet for 6 weeks, indicating that superoxide radical participates in the induction of micronuclei and 8-OHdG. In fact, the endogenous superoxide scavenger, Cu/Zn superoxide dismutase, was significantly reduced in the bone marrow cells of rats fed with a Zn-deficient diet for 6 weeks when compared to those of rats fed with a standard diet for 6 weeks (p?<?0.005). These observations demonstrate that Zn deficiency elevates the frequency of micronuclei and the induction of 8-OHdG through an increase in the biological action of the superoxide radical. This suggests an increase in carcinogenic initiation resulting from Zn deficiency-induced oxidative stress. 相似文献