全文获取类型
收费全文 | 26492篇 |
免费 | 2421篇 |
国内免费 | 638篇 |
出版年
2023年 | 143篇 |
2022年 | 389篇 |
2021年 | 604篇 |
2020年 | 439篇 |
2019年 | 564篇 |
2018年 | 687篇 |
2017年 | 525篇 |
2016年 | 872篇 |
2015年 | 1386篇 |
2014年 | 1526篇 |
2013年 | 1805篇 |
2012年 | 2084篇 |
2011年 | 2022篇 |
2010年 | 1335篇 |
2009年 | 1096篇 |
2008年 | 1464篇 |
2007年 | 1381篇 |
2006年 | 1265篇 |
2005年 | 1164篇 |
2004年 | 1101篇 |
2003年 | 979篇 |
2002年 | 885篇 |
2001年 | 616篇 |
2000年 | 521篇 |
1999年 | 487篇 |
1998年 | 274篇 |
1997年 | 226篇 |
1996年 | 209篇 |
1995年 | 179篇 |
1994年 | 164篇 |
1993年 | 129篇 |
1992年 | 250篇 |
1991年 | 251篇 |
1990年 | 212篇 |
1989年 | 223篇 |
1988年 | 191篇 |
1987年 | 157篇 |
1986年 | 147篇 |
1985年 | 171篇 |
1984年 | 124篇 |
1983年 | 101篇 |
1982年 | 93篇 |
1981年 | 98篇 |
1979年 | 114篇 |
1978年 | 92篇 |
1977年 | 74篇 |
1976年 | 70篇 |
1975年 | 90篇 |
1974年 | 92篇 |
1973年 | 81篇 |
排序方式: 共有10000条查询结果,搜索用时 93 毫秒
31.
Bo Ram Kim Ji-Young Park Hyung Jae Jeong Hyung-Jun Kwon Su-Jin Park In-Chul Lee 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):1256-1265
Sialidases are key virulence factors that remove sialic acid from the host cell surface glycan, unmasking receptors that facilitate bacterial adherence and colonisation. In this study, we developed potential agents for treating bacterial infections caused by Streptococcus pneumoniae Nan A that inhibit bacterial sialidase using Turmeric and curcumin analogues. Design, synthesis, and structure analysis relationship (SAR) studies have been also described. Evaluation of the synthesised derivatives demonstrated that compound 5e was the most potent inhibitor of S. pneumoniae sialidase (IC50?=?0.2?±?0.1?µM). This compound exhibited a 3.0-fold improvement in inhibitory activity over that of curcumin and displayed competitive inhibition. These results warrant further studies confirming the antipneumococcal activity 5e and indicated that curcumin derivatives could be potentially used to treat sepsis by bacterial infections. 相似文献
32.
Advanced hepatic fibrosis therapy using drug-delivering nanoparticles is a relatively unexplored area. Angiotensin type 1 (AT1) receptor blockers such as losartan can be delivered to hepatic stellate cells (HSC), blocking their activation and thereby reducing fibrosis progression in the liver. In our study, we analyzed the possibility of utilizing drug-loaded vehicles such as hyaluronic acid (HA) micelles carrying losartan to attenuate HSC activation. Losartan, which exhibits inherent lipophilicity, was loaded into the hydrophobic core of HA micelles with a 19.5% drug loading efficiency. An advanced liver fibrosis model was developed using C3H/HeN mice subjected to 20 weeks of prolonged TAA/ethanol weight-adapted treatment. The cytocompatibility and cell uptake profile of losartan-HA micelles were studied in murine fibroblast cells (NIH3T3), human hepatic stellate cells (hHSC) and FL83B cells (hepatocyte cell line). The ability of these nanoparticles to attenuate HSC activation was studied in activated HSC cells based on alpha smooth muscle actin (α-sma) expression. Mice treated with oral losartan or losartan-HA micelles were analyzed for serum enzyme levels (ALT/AST, CK and LDH) and collagen deposition (hydroxyproline levels) in the liver. The accumulation of HA micelles was observed in fibrotic livers, which suggests increased delivery of losartan compared to normal livers and specific uptake by HSC. Active reduction of α-sma was observed in hHSC and the liver sections of losartan-HA micelle-treated mice. The serum enzyme levels and collagen deposition of losartan-HA micelle-treated mice was reduced significantly compared to the oral losartan group. Losartan-HA micelles demonstrated significant attenuation of hepatic fibrosis via an HSC-targeting mechanism in our in vitro and in vivo studies. These nanoparticles can be considered as an alternative therapy for liver fibrosis. 相似文献
33.
Pasupathi Sundaramoorthy Jae Jun Sim Yeong-Su Jang Siddhartha Kumar Mishra Keun-Yeong Jeong Poonam Mander Oh Byung Chul Won-Sik Shim Seung Hyun Oh Ky-Youb Nam Hwan Mook Kim 《PloS one》2015,10(1)
Cancer cell motility is a key phenomenon regulating invasion and metastasis. Focal adhesion kinase (FAK) plays a major role in cellular adhesion and metastasis of various cancers. The relationship between dietary supplementation of calcium and colon cancer has been extensively investigated. However, the effect of calcium (Ca2+) supplementation on calpain-FAK-motility is not clearly understood. We sought to identify the mechanism of FAK cleavage through Ca2+ bound lactate (CaLa), its downstream signaling and role in the motility of human colon cancer cells. We found that treating HCT116 and HT-29 cells with CaLa immediately increased the intracellular Ca2+ (iCa2+) levels for a prolonged period of time. Ca2+ influx induced cleavage of FAK into an N-terminal FAK (FERM domain) in a dose-dependent manner. Phosphorylated FAK (p-FAK) was also cleaved in to its p-N-terminal FAK. CaLa increased colon cancer cells motility. Calpeptin, a calpain inhibitor, reversed the effects of CaLa on FAK and pFAK cleavage in both cancer cell lines. The cleaved FAK translocates into the nucleus and modulates p53 stability through MDM2-associated ubiquitination. CaLa-induced Ca2+ influx increased the motility of colon cancer cells was mediated by calpain activity through FAK and pFAK protein destabilization. In conclusion, these results suggest that careful consideration may be given in deciding dietary Ca2+ supplementation to patient undergoing treatment for metastatic cancer. 相似文献
34.
35.
The detection of sequence variation with restriction fragment length polymorphisms is advancing our knowledge of plant genetics on several fronts. In the past year, there has been progress in genetic map construction, phylogeny studies, and the dissection of multigenic traits. In addition, new methods that are independent of restriction sites are being developed for polymorphism detection. 相似文献
36.
Corinna Richter Ron L. Dy Rebecca E. McKenzie Bridget N.J. Watson Corinda Taylor James T. Chang Matthew B. McNeil Raymond H.J. Staals Peter C. Fineran 《Nucleic acids research》2014,42(13):8516-8526
Clustered regularly interspaced short palindromic repeats (CRISPR), in combination with CRISPR associated (cas) genes, constitute CRISPR-Cas bacterial adaptive immune systems. To generate immunity, these systems acquire short sequences of nucleic acids from foreign invaders and incorporate these into their CRISPR arrays as spacers. This adaptation process is the least characterized step in CRISPR-Cas immunity. Here, we used Pectobacterium atrosepticum to investigate adaptation in Type I-F CRISPR-Cas systems. Pre-existing spacers that matched plasmids stimulated hyperactive primed acquisition and resulted in the incorporation of up to nine new spacers across all three native CRISPR arrays. Endogenous expression of the cas genes was sufficient, yet required, for priming. The new spacers inhibited conjugation and transformation, and interference was enhanced with increasing numbers of new spacers. We analyzed ∼350 new spacers acquired in priming events and identified a 5′-protospacer-GG-3′ protospacer adjacent motif. In contrast to priming in Type I-E systems, new spacers matched either plasmid strand and a biased distribution, including clustering near the primed protospacer, suggested a bi-directional translocation model for the Cas1:Cas2–3 adaptation machinery. Taken together these results indicate priming adaptation occurs in different CRISPR-Cas systems, that it can be highly active in wild-type strains and that the underlying mechanisms vary. 相似文献
37.
38.
39.
40.
The Korean species of the genus Eudorylas Aczél have been studied. A total of 16 species are arranged herein. Among them, E. paraappendiculatus sp. nov. is new to science, and E. nomurai Morakote et Yano, 1990 is newly recorded in the Korean fauna. 相似文献