全文获取类型
收费全文 | 1563篇 |
免费 | 119篇 |
国内免费 | 1篇 |
出版年
2022年 | 7篇 |
2021年 | 16篇 |
2020年 | 7篇 |
2019年 | 11篇 |
2018年 | 20篇 |
2017年 | 11篇 |
2016年 | 19篇 |
2015年 | 27篇 |
2014年 | 45篇 |
2013年 | 79篇 |
2012年 | 74篇 |
2011年 | 94篇 |
2010年 | 43篇 |
2009年 | 54篇 |
2008年 | 88篇 |
2007年 | 89篇 |
2006年 | 79篇 |
2005年 | 81篇 |
2004年 | 89篇 |
2003年 | 60篇 |
2002年 | 72篇 |
2001年 | 49篇 |
2000年 | 49篇 |
1999年 | 49篇 |
1998年 | 24篇 |
1997年 | 22篇 |
1996年 | 16篇 |
1995年 | 19篇 |
1994年 | 15篇 |
1993年 | 21篇 |
1992年 | 38篇 |
1991年 | 37篇 |
1990年 | 31篇 |
1989年 | 25篇 |
1988年 | 32篇 |
1987年 | 21篇 |
1986年 | 18篇 |
1985年 | 17篇 |
1984年 | 30篇 |
1983年 | 8篇 |
1982年 | 12篇 |
1981年 | 7篇 |
1980年 | 7篇 |
1979年 | 14篇 |
1978年 | 11篇 |
1977年 | 4篇 |
1974年 | 5篇 |
1972年 | 8篇 |
1969年 | 7篇 |
1965年 | 4篇 |
排序方式: 共有1683条查询结果,搜索用时 578 毫秒
61.
Hiroyuki Morimoto Hirohiko Okamura Kaya Yoshida Seiichiro Kitamura Tatsuji Haneji 《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):327-331
The reversible phosphorylation of proteins mediates cellular signals in eukaryotic cells. RNA interference inhibits the expression of genes and proteins in a sequence-specific manner and provides a tool to study the functions of target molecules. The effect of RNA interference on protein phosphatase isoforms in HEK-293 cells was examined. Protein phosphatase 1 delta (PP1δ) sequence-specific double-stranded RNA (dsRNA) inhibited mRNA and protein expression of the PP18. This RNA interference did not affect the expression of α and γ1 isoforms of PP1. Transfection of antisense RNA specific for PP1δ also suppressed the expression of PP1δ. It was further demonstrated by an in vitro RNA cleavage assay that extracts of HEK-293 cells catalyzed the processing of dsRNA. This cell line had much stronger mRNA expression of Dicer, an RNase III-like enzyme, than did human osteoblastic MG63 cells. The present results show that RNA interference is a useful tool to distinguish between PP1 isoforms. 相似文献
62.
Keiko Kishimoto-Yamada Fujio Hyodo Masayuki Matsuoka Yoshiaki Hashimoto Masahiro Kon Teruo Ochi Seiki Yamane Reiichiro Ishii Takao Itioka 《Journal of Insect Conservation》2013,17(3):591-605
Tropical landscape structures have been transformed into mosaic structures consisting of small patches of primary and secondary forests, and areas of other land use. Diversity of insect assemblages is often higher in primary forests than in surrounding secondary forests. However, little is known about how the primary forests affect diversity in surrounding secondary forests in a landscape. In Sarawak, Malaysia, the typical landscape in areas from which lowland tropical rainforests had originally spread consists mainly of primary and secondary forests, with small areas of cultivation. In this study, we examined how the proportion of remnant primary forests in a landscape affects species diversity and species composition of ants and dung beetles in Macaranga-dominated secondary forests. The proportions were quantified based on remote-sensing data at various spatial scales, ranging from 100- to 5,000-m radius from each of the target forests. We found that the proportions of remnant primary forests within a 100-m radius had a significant positive effect on ant species diversity, and those within 100-, 300-, and 500-m radii significantly affected species compositions. However, the proportions of remnant primary forests had no significant relationship with dung beetle diversity, while those within 100- and 1,000-m radii had significant effects on species composition. The different responses to the remnant primary forests are likely to be related to differences in the movement and dispersal traits between the two taxa. 相似文献
63.
64.
Masayasu Naito Ursula Hainz Ute E. Burkhardt Buyin Fu Deborah Ahove Kristen E. Stevenson Mohini Rajasagi Baogong Zhu Anselmo Alonso Elizabeth Witten Ken-ichi Matsuoka Donna Neuberg Jonathan S. Duke-Cohan Catherine J. Wu Gordon J. Freeman 《Cancer immunology, immunotherapy : CII》2013,62(2):347-357
CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker. 相似文献
65.
Yasuyuki Mitani Junko Yarimizu Hiroki Akashiba Yoshitsugu Shitaka Keni Ni Nobuya Matsuoka 《Journal of neurochemistry》2013,125(3):465-472
Given that amyloid‐β 42 (Aβ42) is believed to be a culprit in Alzheimer's disease (AD), reducing Aβ42 production should be a potential therapeutic approach. γ‐Secretase modulators (GSMs) cause selective reduction of Aβ42 or both reduction of Aβ42 and Aβ40 without affecting total Aβ through shifting the γ‐cleavage position in amyloid precursor protein. We recently reported on GSM‐2, one of the second‐generation GSMs, that selectively reduced brain Aβ42 level and significantly ameliorated cognitive deficits in plaque‐free 5.5‐month‐old Tg2576 AD model mice. Here, we investigated the effects of GSM‐2 on 10‐, 14‐, and 18‐month‐old mice which had age‐dependent increase in amyloid plaques. Eight‐day treatment with GSM‐2 significantly ameliorated cognitive deficits measured by Y‐maze task in the mice of any age. However, GSM‐2 reduced brain soluble Aβ42 only in 10‐month‐old mice. In contrast, GSM‐2 markedly reduced newly synthesized soluble Aβ42 in both 10‐ and 18‐month‐old mice with similar efficacy when measured using the stable isotope‐labeling technique, suggesting that nascent Aβ42 plays a more significant role than plaque‐associated soluble Aβ42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Aβ42 synthesis in AD therapeutic regimens. 相似文献
66.
Luca Caracciolo S. Sakura Minami Takako Niikura Yasuji Matsuoka R. Scott Turner Mark P. Mattson Francesca Bosetti 《Journal of neurochemistry》2013,124(1):59-68
Several epidemiological and preclinical studies suggest that non‐steroidal anti‐inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β‐amyloid (Aβ) production and inhibit neuroinflammation. However, follow‐up clinical trials, mostly using selective cyclooxygenase (COX)‐2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX‐1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro‐inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX‐1 inhibition, rather than COX‐2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20‐month‐old triple transgenic AD (3 × Tg‐AD) mice with the COX‐1 selective inhibitor SC‐560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC‐560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg‐AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX‐1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg‐AD mice. Thus, selective COX‐1 inhibition should be further investigated as a potential therapeutic approach for AD. 相似文献
67.
68.
69.
Tatsuji Sakamoto Misako Inui Kana Yasui Sachiko Hosokawa Hideshi Ihara 《Applied microbiology and biotechnology》2013,97(3):1121-1130
We previously isolated two α-l-arabinofuranosidases (ABFs), termed AFQ1 and AFS1, from the culture filtrate of Penicillium chrysogenum 31B. afq1 and afs1 complementary DNAs encoding AFQ1 and AFS1 were isolated by in vitro cloning. The deduced amino acid sequences of AFQ1 and AFS1 are highly similar to those of Penicillium purpurogenum ABF 2 and ABF 1, respectively, which belong to glycoside hydrolase (GH) families 51 and 54, respectively. Pfam analysis revealed an “Alpha-L-AF_C” domain in AFQ1 and “ArabFuran-catal” and “AbfB” domains in AFS1. Semi-quantitative RT-PCR analysis indicated that the afq1 gene was constitutively expressed in P. chrysogenum 31B at a low level, although the expression was slightly induced with arabinose, arabinitol, arabinan, and arabinoxylan. In contrast, expression of the afs1 gene was strongly expressed by the above four carbohydrates and less strongly induced by galactan. Recombinant enzymes (rAFQ1 and rAFS1) expressed in Escherichia coli were active against both p-nitrophenyl α-l-arabinofuranoside and polysaccharides with different specificities. 1H-NMR analysis revealed that rAFS1 degraded arabinofuranosyl side chains that were both singly and doubly linked to the backbones of arabinoxylan and l-arabinan. On the other hand, rAFQ1 preferentially released arabinose linked to C-3 of single-substituted xylose or arabinose residues in the two polysaccharides. 相似文献
70.
Tsukasa Mizuhara Shinya Oishi Hiroaki Ohno Kazuya Shimura Masao Matsuoka Nobutaka Fujii 《Bioorganic & medicinal chemistry》2013,21(7):2079-2087
To investigate the mechanism of action of the potent antiviral compound PD 404182, three novel photoaffinity probes equipped with a biotin or alkyne indicator were designed and synthesized based on previous structure–activity relationship studies. These probes retained the potent anti-HIV activity of the original pyrimidobenzothiazine derivatives. In photoaffinity labeling studies using HIV-1-infected H9 cells (H9IIIB), eight potential proteins were observed to bind PD 404182. 相似文献