全文获取类型
收费全文 | 8223篇 |
免费 | 531篇 |
国内免费 | 12篇 |
出版年
2023年 | 17篇 |
2022年 | 75篇 |
2021年 | 153篇 |
2020年 | 95篇 |
2019年 | 119篇 |
2018年 | 174篇 |
2017年 | 154篇 |
2016年 | 280篇 |
2015年 | 412篇 |
2014年 | 547篇 |
2013年 | 583篇 |
2012年 | 678篇 |
2011年 | 618篇 |
2010年 | 351篇 |
2009年 | 345篇 |
2008年 | 486篇 |
2007年 | 477篇 |
2006年 | 451篇 |
2005年 | 406篇 |
2004年 | 388篇 |
2003年 | 333篇 |
2002年 | 290篇 |
2001年 | 212篇 |
2000年 | 189篇 |
1999年 | 137篇 |
1998年 | 57篇 |
1997年 | 42篇 |
1996年 | 43篇 |
1995年 | 52篇 |
1994年 | 31篇 |
1993年 | 22篇 |
1992年 | 64篇 |
1991年 | 45篇 |
1990年 | 49篇 |
1989年 | 42篇 |
1988年 | 34篇 |
1987年 | 28篇 |
1986年 | 25篇 |
1985年 | 28篇 |
1984年 | 27篇 |
1983年 | 16篇 |
1982年 | 19篇 |
1981年 | 11篇 |
1979年 | 19篇 |
1978年 | 18篇 |
1976年 | 10篇 |
1975年 | 11篇 |
1974年 | 16篇 |
1973年 | 17篇 |
1972年 | 10篇 |
排序方式: 共有8766条查询结果,搜索用时 187 毫秒
191.
Fumiaki Nakayama Sachiko Umeda Tomomi Ichimiya Shin Kamiyama Masaharu Hazawa Takeshi Yasuda Shoko Nishihara Takashi Imai 《FEBS letters》2013,587(2):231-237
This study focuses on clarifying the contribution of sulfation to radiation-induced apoptosis in human Burkitt’s lymphoma cell lines, using 3′-phosphoadenosine 5′-phosphosulfate transporters (PAPSTs). Overexpression of PAPST1 or PAPST2 reduced radiation-induced apoptosis in Namalwa cells, whereas the repression of PAPST1 expression enhanced apoptosis. Inhibition of PAPST slightly decreased keratan sulfate (KS) expression, so that depletion of KS significantly increased radiation-induced apoptosis. In addition, the repression of all three N-acetylglucosamine-6-O-sulfotransferases (CHST2, CHST6, and CHST7) increased apoptosis. In contrast, PAPST1 expression promoted the phosphorylation of p38 MAPK and Akt in irradiated Namalwa cells. These findings suggest that 6-O-sulfation of GlcNAc residues in KS reduces radiation-induced apoptosis of human Burkitt’s lymphoma cells. 相似文献
192.
Flagellar filament self‐assembles from the component protein, flagellin or FliC, with the aid of the capping protein, HAP2 or FliD. Depending on the helical parameters of filaments, flagella from various species are divided into three groups, family I, II, and III. Each family coincides with the traditional classification of flagella, peritrichous flagella, polar flagella, and lateral flagella, respectively. To elucidate the physico‐chemical properties of flagellin to separate families, we chose family I flagella and family II flagella and examined how well the exchangeability of a combination of FliC and/or FliD from different families is kept in filament formation. FliC or FliD of Salmonella enterica serovar Typhimurium (Salty; family I) were exchanged with those of Escherichia coli (Escco; family I) or Pseudomonas aeruginosa (Pseae; family II). In a Salty fliC deletion mutant, Escco FliC formed short filaments, but Pseae FliC did not form filaments. In a Salty fliD deletion mutant, both Escco FliD and Pseae FliD allowed Salty FliC to polymerize into short filaments. In conclusion, FliC can be exchanged among the same family but not between different families, while FliD serves as the cap protein even in different families, confirming that FliC is essential for determining families, but FliD plays a subsidiary role in filament formation. © 2012 Wiley Periodicals, Inc. 相似文献
193.
Md. Golam Sharoar Md. Shahnawaz Md. Imamul Islam Vijay Sankar Ramasamy Song Yub Shin Il-Seon Park 《Archives of biochemistry and biophysics》2013
The aggregation of β-amyloid (Aβ) peptide from its monomeric to its fibrillar form importantly contributes to the development of Alzheimer’s disease. Here, we investigated the effects of Escherichia coli maltose binding protein (MBP), which has been previously used as a fusion protein, on Aβ42 fibrillization, in order to improve understanding of the self-assembly process and the cytotoxic mechanism of Aβ42. MBP, at a sub-stoichiometric ratio with respect to Aβ42, was found to have chaperone-like inhibitory effects on β-sheet fibril formation, due to the accumulation of Aβ42 aggregates by sequestration of active Aβ42 species as Aβ42-MBP complexes. Furthermore, MBP increased the lag time of Aβ42 polymerization, decreased the growth rate of fibril extension, and suppressed Aβ42 mediated toxicity in human neuroblastoma SH-SY5Y cells. It appears that MBP decreases the active concentration of Aβ42 by sequestering it as Aβ42-MBP complex, and that this sequestration suppresses ongoing nucleation and retards the growth rate of Aβ42 species required for fibril formation. We speculate that inhibition of the growth rate of potent Aβ42 species by MBP suppresses Aβ42-mediated toxicity in SH-SY5Y cells. 相似文献
194.
Elin Grundberg Eshwar Meduri Johanna?K. Sandling ?sa?K. Hedman Sarah Keildson Alfonso Buil Stephan Busche Wei Yuan James Nisbet Magdalena Sekowska Alicja Wilk Amy Barrett Kerrin?S. Small Bing Ge Maxime Caron So-Youn Shin the Multiple Tissue Human Expression Resource Consortium Mark Lathrop Emmanouil T. Dermitzakis Mark I. McCarthy Timothy D. Spector Jordana T. Bell Panos Deloukas 《American journal of human genetics》2013,93(5):876-890
Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h2median = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner. 相似文献
195.
Hyun Myung Ko So Yeon Kim So Hyun Joo Jae Hoon Cheong Sung-Il Yang Chan Young Shin Bon Nyeo Koo 《Biochemical and biophysical research communications》2013
Despite the extensive use of propofol in general anesthetic procedures, the effects of propofol on glial cell were not completely understood. In lipopolysaccharide (LPS)-stimulated rat primary astrocytes and BV2 microglial cell lines, co-treatment of propofol synergistically induced inflammatory activation as evidenced by the increased production of NO, ROS and expression of iNOS, MMP-9 and several cytokines. Propofol augmented the activation of JNK and p38 MAPKs induced by LPS and the synergistic activation of glial cells by propofol was prevented by pretreatment of JNK and p38 inhibitors. When we treated BV2 cell culture supernatants treated with LPS plus propofol on cultured rat primary neuron, it induced a significant neuronal cell death. The results suggest that the repeated use of propofol in immunologically challenged situation may induce glial activation in brain. 相似文献
196.
Hyehyeon Lee Jin Bae SohnSoo Shin Kim Kyung Lib Jang 《Biochemical and biophysical research communications》2013
We here report a simple assay system for DNA methyltransferase (DNMT) inhibitors based on the HBx-induced DNA methylation of E-cadherin. A stable cell line named G1 was generated by co-transfecting E-cadherin luciferase reporter and HBx-expression plasmid into HepG2 cells. Treatment of G1 cells with DNMT inhibitors, 5-azacytidine, 5-aza-2′-deoxycytidine, and procainamaid, dose-dependently inhibited DNA methylation of E-cadherin promoter in the reporter, resulting in up-regulation of luciferase levels and its enzyme activity. Treatment with all-trans retinoic acid that is known to inhibit DNMT expression, also induced similar effects. Our system can be useful for development of epi-drugs targeting DNA methylation in malignancies. 相似文献
197.
Rong Jiang Bozena Frackowiak Youseung Shin Xinyi Song Weimin Chen Li Lin Michael D. Cameron Derek R. Duckett Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2013,23(9):2683-2687
Starting from pyrazole HTS hit (1), a series of 1-aryl-1H-indazoles have been synthesized as JNK3 inhibitors with moderate selectivity against JNK1. SAR studies led to the synthesis of 5r as double digital nanomolar JNK3 inhibitor with good in vivo exposure. 相似文献
198.
Non hemolytic short peptidomimetics as a new class of potent and broad-spectrum antimicrobial agents
Ravichandran N. Murugan Binu Jacob Eun-Hee Kim Mija Ahn Hoik Sohn Ji-Hyung Seo Chaejoon Cheong Jae-Kyung Hyun Kyung S. Lee Song Yub Shin Jeong Kyu Bang 《Bioorganic & medicinal chemistry letters》2013,23(16):4633-4636
Since the bacterial resistance to antibiotics is increasing rapidly, numerous studies have contributed to the design and synthesis of potent synthetic mimics of antimicrobial peptides (AMPs). In an attempt to find the pharmacophore of short antimicrobial peptidomimetics through systematic tuning of hydrophobic and hydrophilic patterns, we have identified a set of short histidine-derived antimicrobial peptides (SAMPs) with potent and broad-spectrum activity. A combination of high antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), without hemolytic activity and proteolytic stability makes these molecules promising candidates for novel antimicrobial therapeutics. 相似文献
199.
Ping Sun John C. Clamp Dapeng Xu Bangqin Huang Mann Kyoon Shin Franziska Turner 《Proceedings. Biological sciences / The Royal Society》2013,280(1771)
Vorticella includes more than 100 currently recognized species and represents one of the most taxonomically challenging genera of ciliates. Molecular phylogenetic analysis of Vorticella has been performed so far with only sequences coding for small subunit ribosomal RNA (SSU rRNA); only a few of its species have been investigated using other genetic markers owing to a lack of similar sequences for comparison. Consequently, phylogenetic relationships within the genus remain unclear, and molecular discrimination between morphospecies is often difficult because most regions of the SSU rRNA gene are too highly conserved to be helpful. In this paper, we move molecular systematics for this group of ciliates to the infrageneric level by sequencing additional molecular markers—fast-evolving internal transcribed spacer (ITS) regions—in a broad sample of 66 individual samples of 28 morphospecies of Vorticella collected from Asia, North America and Europe. Our phylogenies all featured two strongly supported, highly divergent, paraphyletic clades (I, II) comprising the morphologically defined genus Vorticella. Three major lineages made up clade I, with a relatively well-resolved branching order in each one. The marked divergence of clade II from clade I confirms that the former should be recognized as a separate taxonomic unit as indicated by SSU rRNA phylogenies. We made the first attempt to elucidate relationships between species in clade II using both morphological and multi-gene approaches, and our data supported a close relationship between some morphospecies of Vorticella and Opisthonecta, indicating that relationships between species in the clade are far more complex than would be expected from their morphology. Different patterns of helix III of ITS2 secondary structure were clearly specific to clades and subclades of Vorticella and, therefore, may prove useful for resolving phylogenetic relationships in other groups of ciliates. 相似文献
200.
Masaki Setoguchi Shin Iimura Yuuichi Sugimoto Yoshiyuki Yoneda Jun Chiba Toshiyuki Watanabe Fumihito Muro Yutaka Iigo Gensuke Takayama Mika Yokoyama Tomoe Taira Misato Aonuma Tohru Takashi Atsushi Nakayama Nobuo Machinaga 《Bioorganic & medicinal chemistry》2013,21(1):42-61
We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5 mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 μg/mL; JP2, 462 μg/mL). Furthermore, this compound showed good oral bioavailability (F = 54%) in monkeys. 相似文献