全文获取类型
收费全文 | 2383篇 |
免费 | 144篇 |
国内免费 | 2篇 |
专业分类
2529篇 |
出版年
2022年 | 10篇 |
2021年 | 24篇 |
2020年 | 13篇 |
2019年 | 21篇 |
2018年 | 33篇 |
2017年 | 24篇 |
2016年 | 38篇 |
2015年 | 56篇 |
2014年 | 67篇 |
2013年 | 127篇 |
2012年 | 138篇 |
2011年 | 138篇 |
2010年 | 77篇 |
2009年 | 65篇 |
2008年 | 125篇 |
2007年 | 110篇 |
2006年 | 126篇 |
2005年 | 116篇 |
2004年 | 117篇 |
2003年 | 111篇 |
2002年 | 95篇 |
2001年 | 86篇 |
2000年 | 65篇 |
1999年 | 76篇 |
1998年 | 19篇 |
1997年 | 24篇 |
1996年 | 15篇 |
1995年 | 21篇 |
1994年 | 18篇 |
1993年 | 13篇 |
1992年 | 46篇 |
1991年 | 37篇 |
1990年 | 39篇 |
1989年 | 30篇 |
1988年 | 58篇 |
1987年 | 41篇 |
1986年 | 19篇 |
1985年 | 28篇 |
1984年 | 24篇 |
1983年 | 24篇 |
1982年 | 13篇 |
1979年 | 18篇 |
1978年 | 19篇 |
1977年 | 12篇 |
1976年 | 13篇 |
1975年 | 13篇 |
1974年 | 17篇 |
1973年 | 17篇 |
1972年 | 10篇 |
1969年 | 18篇 |
排序方式: 共有2529条查询结果,搜索用时 0 毫秒
91.
Zolzaya Tumurgan Haruhiko Kanasaki Tuvshintugs Tumurbaatar Aki Oride Hiroe Okada Satoru Kyo 《Biochemistry and Biophysics Reports》2020
Hypothalamic kisspeptin, encoded by the Kiss-1 gene, governs the hypothalamic-pituitary-gonadal axis by directly regulating the release of gonadotropin-releasing hormone. In this study, we examined the roles of activin, inhibin, and follistatin in the regulation of Kiss-1 gene expression using primary cultures of fetal rat neuronal cells, which express the Kiss-1 gene and kisspeptin. Stimulation with activin significantly increased Kiss-1 gene expression in these cultures by 2.02 ± 0.39-fold. In contrast, a significant decrease in Kiss-1 gene expression was observed with inhibin A and follistatin treatment. Inhibin B did not modulate Kiss-1 gene expression. Activin, inhibin, and follistatin were also expressed in fetal rat brain cultures and their expression was controlled by estradiol (E2). The inhibin α, βA, and βB subunits were upregulated by E2. Similarly, follistatin gene expression was significantly increased by E2 in these cells. Our results suggest the possibility that activin, inhibin, and follistatin expressed in the brain participate in the E2-induced feedback control of the hypothalamic-pituitary-gonadal axis. 相似文献
92.
Deguchi Ryo Fujimoto Moe Sekiyama Hiroshi Sawamura Shigehito 《Sleep and biological rhythms》2021,19(3):277-283
Sleep and Biological Rhythms - Patients with chronic pain develop peripheral neuropathy and experience sleep disturbance. Yokukansan is used to treat insomnia and control neuropathic pain. We... 相似文献
93.
94.
Takaaki Oteki Sohji Nagase Homare Shimohata Aki Hirayama Atsushi Ueda Hidekatsu Yokoyama 《Free radical research》2013,47(2):154-161
It is well known that oxidative stress is related to the pathogenesis of adriamycin (ADR) nephropathy. However, it is unclear how nitric oxide (NO) is associated with the pathophysiological process after ADR administration. The NO level in a kidney homogenate was assayed by electron paramagnetic resonance (EPR) spectrometry using a direct in vivo NO trapping technique after ADR administration. N-(3-(aminomethyl)benzyl)acetamidine (1400W) was used as a specific, inducible nitric oxide synthase (iNOS) inhibitor. The levels of NO after ADR administration gradually increased for 6 h and then decreased until 24 h after ADR administration. The fractional excretion of Na (FENa) in the urine was elevated in the ADR group on day 1. Pre-treatment of the animals with 1400W attenuated the increase in NO levels despite further elevation of FENa. These findings suggest that iNOS-derived NO does not produce a harmful effect but rather protects the ADR-treated kidney against sodium excretion. 相似文献
95.
Florian Wilfling Huajin Wang Joel T. Haas Natalie Krahmer Travis J. Gould Aki Uchida Ji-Xin Cheng Morven Graham Romain Christiano Florian Fröhlich Xinran Liu Kimberly K. Buhman Rosalind A. Coleman Joerg Bewersdorf Robert V. Farese Tobias C. Walther 《Developmental cell》2013,24(4):384-399
- Download : Download high-res image (442KB)
- Download : Download full-size image
96.
Yasuhito Hamaguchi Manabu Fujimoto Takashi Matsushita Kenzo Kaji Kazuhiro Komura Minoru Hasegawa Masanari Kodera Eiji Muroi Keita Fujikawa Mariko Seishima Hidehiro Yamada Ryo Yamada Shinichi Sato Kazuhiko Takehara Masataka Kuwana 《PloS one》2013,8(4)
Objective
To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs).Methods
This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009.Results
Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron’s sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset.Conclusion
Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the “anti-synthetase syndrome.” 相似文献97.
Zui Fujimoto Rintaro Suzuki Takahiro Shiotsuki Wataru Tsuchiya Akira Tase Mitsuru Momma Toshimasa Yamazaki 《PloS one》2013,8(2)
Juvenile hormones (JHs) control a diversity of crucial life events in insects. In Lepidoptera which major agricultural pests belong to, JH signaling is critically controlled by a species-specific high-affinity, low molecular weight JH-binding protein (JHBP) in hemolymph, which transports JH from the site of its synthesis to target tissues. Hence, JHBP is expected to be an excellent target for the development of novel specific insect growth regulators (IGRs) and insecticides. A better understanding of the structural biology of JHBP should pave the way for the structure-based drug design of such compounds. Here, we report the crystal structure of the silkworm Bombyx mori JHBP in complex with two molecules of 2-methyl-2,4-pentanediol (MPD), one molecule (MPD1) bound in the JH-binding pocket while the other (MPD2) in a second cavity. Detailed comparison with the apo-JHBP and JHBP-JH II complex structures previously reported by us led to a number of intriguing findings. First, the JH-binding pocket changes its size in a ligand-dependent manner due to flexibility of the gate α1 helix. Second, MPD1 mimics interactions of the epoxide moiety of JH previously observed in the JHBP-JH complex, and MPD can compete with JH in binding to the JH-binding pocket. We also confirmed that methoprene, which has an MPD-like structure, inhibits the complex formation between JHBP and JH while the unepoxydated JH III (methyl farnesoate) does not. These findings may open the door to the development of novel IGRs targeted against JHBP. Third, binding of MPD to the second cavity of JHBP induces significant conformational changes accompanied with a cavity expansion. This finding, together with MPD2-JHBP interaction mechanism identified in the JHBP-MPD complex, should provide important guidance in the search for the natural ligand of the second cavity. 相似文献
98.
Shigeyuki Fujimoto Naoya Itsumura Tokuji Tsuji Yasumi Anan Natsuko Tsuji Yasumitsu Ogra Tomoki Kimura Yusaku Miyamae Seiji Masuda Masaya Nagao Taiho Kambe 《PloS one》2013,8(10)
The activation process of secretory or membrane-bound zinc enzymes is thought to be a highly coordinated process involving zinc transport, trafficking, transfer and coordination. We have previously shown that secretory and membrane-bound zinc enzymes are activated in the early secretory pathway (ESP) via zinc-loading by the zinc transporter 5 (ZnT5)-ZnT6 hetero-complex and ZnT7 homo-complex (zinc transport complexes). However, how other proteins conducting zinc metabolism affect the activation of these enzymes remains unknown. Here, we investigated this issue by disruption and re-expression of genes known to be involved in cytoplasmic zinc metabolism, using a zinc enzyme, tissue non-specific alkaline phosphatase (TNAP), as a reporter. We found that TNAP activity was significantly reduced in cells deficient in ZnT1, Metallothionein (MT) and ZnT4 genes (ZnT1
−/−
MT
−/−
ZnT4
−/− cells), in spite of increased cytosolic zinc levels. The reduced TNAP activity in ZnT1
−/−
MT
−/−
ZnT4
−/− cells was not restored when cytosolic zinc levels were normalized to levels comparable with those of wild-type cells, but was reversely restored by extreme zinc supplementation via zinc-loading by the zinc transport complexes. Moreover, the reduced TNAP activity was adequately restored by re-expression of mammalian counterparts of ZnT1, MT and ZnT4, but not by zinc transport-incompetent mutants of ZnT1 and ZnT4. In ZnT1
−/−
MT
−/−
ZnT4
−/− cells, the secretory pathway normally operates. These findings suggest that cooperative zinc handling of ZnT1, MT and ZnT4 in the cytoplasm is required for full activation of TNAP in the ESP, and present clear evidence that the activation process of zinc enzymes is elaborately controlled. 相似文献
99.
100.
Muhammad Farooq Hiroyuki Nakai Atsushi Fujimoto Hiroki Fujikawa Klaus Wilbrandt Kjaer Shahid Mahmood Baig Yutaka Shimomura 《Human genetics》2013,132(11):1253-1264
All TGF-beta family members have a prodomain that is important for secretion. Lack of secretion of a TGF-beta family member GDF5 is known to underlie some skeletal abnormalities, such as brachydactyly type C that is characterized by a huge and unexplained phenotypic variability. To search for potential phenotypic modifiers regulating secretion of GDF5, we compared cells overexpressing wild type (Wt) GDF5 and GDF5 with a novel mutation in the prodomain identified in a large Pakistani family with Brachydactyly type C and mild Grebe type chondrodyslplasia (c527T>C; p.Leu176Pro). Initial in vitro expression studies revealed that the p.Leu176Pro mutant (Mut) GDF5 was not secreted outside the cells. We subsequently showed that GDF5 was capable of forming a complex with latent transforming growth factor binding proteins, LTBP1 and LTBP2. Furthermore, secretion of LTBP1 and LTBP2 was severely impaired in cells expressing the Mut-GDF5 compared to Wt-GDF5. Finally, we demonstrated that secretion of Wt-GDF5 was inhibited by the Mut-GDF5, but only when LTBP (LTBP1 or LTBP2) was co-expressed. Based on these findings, we suggest a novel model, where the dosage of secretory co-factors or stabilizing proteins like LTBP1 and LTBP2 in the microenvironment may affect the extent of GDF5 secretion and thereby function as modifiers in phenotypes caused by GDF5 mutations. 相似文献