全文获取类型
收费全文 | 1255篇 |
免费 | 92篇 |
国内免费 | 2篇 |
出版年
2023年 | 10篇 |
2022年 | 22篇 |
2021年 | 29篇 |
2020年 | 21篇 |
2019年 | 26篇 |
2018年 | 32篇 |
2017年 | 27篇 |
2016年 | 49篇 |
2015年 | 68篇 |
2014年 | 71篇 |
2013年 | 109篇 |
2012年 | 94篇 |
2011年 | 106篇 |
2010年 | 63篇 |
2009年 | 60篇 |
2008年 | 87篇 |
2007年 | 76篇 |
2006年 | 70篇 |
2005年 | 50篇 |
2004年 | 54篇 |
2003年 | 50篇 |
2002年 | 37篇 |
2001年 | 41篇 |
2000年 | 20篇 |
1999年 | 25篇 |
1998年 | 5篇 |
1997年 | 7篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1991年 | 8篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
排序方式: 共有1349条查询结果,搜索用时 46 毫秒
991.
Adrian Oo Keivan Zandi Caitlin Shepard Leda C. Bassit Katie Musall Shu Ling Goh Young-Jae Cho Dong-Hyun Kim Raymond F. Schinazi Baek Kim 《The Journal of biological chemistry》2022,298(3)
The lack of antiviral innate immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is characterized by limited production of interferons (IFNs). One protein associated with Aicardi–Goutières syndrome, SAMHD1, has been shown to negatively regulate the IFN-1 signaling pathway. However, it is unclear whether elevated IFN signaling associated with genetic loss of SAMHD1 would affect SARS-CoV-2 replication. In this study, we established in vitro tissue culture model systems for SARS-CoV-2 and human coronavirus OC43 infections in which SAMHD1 protein expression was absent as a result of CRISPR–Cas9 gene KO or lentiviral viral protein X–mediated proteosomal degradation. We show that both SARS-CoV-2 and human coronavirus OC43 replications were suppressed in SAMHD1 KO 293T and differentiated THP-1 macrophage cell lines. Similarly, when SAMHD1 was degraded by virus-like particles in primary monocyte-derived macrophages, we observed lower levels of SARS-CoV-2 RNA. The loss of SAMHD1 in 293T and differentiated THP-1 cells resulted in upregulated gene expression of IFNs and innate immunity signaling proteins from several pathways, with STAT1 mRNA being the most prominently elevated ones. Furthermore, SARS-CoV-2 replication was significantly increased in both SAMHD1 WT and KO cells when expression and phosphorylation of STAT1 were downregulated by JAK inhibitor baricitinib, which over-rode the activated antiviral innate immunity in the KO cells. This further validates baricitinib as a treatment of SARS-CoV-2–infected patients primarily at the postviral clearance stage. Overall, our tissue culture model systems demonstrated that the elevated innate immune response and IFN activation upon genetic loss of SAMHD1 effectively suppresses SARS-CoV-2 replication. 相似文献
992.
Daseul Im Joonhong Jun Jihyun Baek Haejin Kim Dahyun Kang Hyunah Bae Hyunwook Cho Jung-Mi Hah 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):472
Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a–k, 8n–z, and phenyl urea 8l–m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC50 and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics. 相似文献
993.
Hye Jeong Kim Mi-Jin Kim Jung Hun Pak Ho Won Jung Hong Kyu Choi Yeong-Hoon Lee In-Youl Baek Jong-Min Ko Soon-Chun Jeong In Sook Pack Ki Hyun Ryu Young-Soo Chung 《Plant biotechnology reports》2013,7(4):425-433
Soybean mosaic virus (SMV), a species of the Potyvirus genus in the Potyviridae family, is one of the most typical viral diseases and results in yield and quality loss of cultivated soybean. Due to the depletion of genetic resources for resistance breeding, a trial of genetic transformation to improve disease resistance has been performed by introducing the SMV-CP gene by the RNA interference (RNAi) method via Agrobacterium-mediated transformation. Among 30 transgenic plants produced, 7 lines with enough seeds were infected with SMV and two lines (3 and 4) showed viral resistance to SMV infection. In genomic Southern blot analysis, all the lines tested contained at least one T-DNA insertion. Subsequent investigation confirmed that no viral CP gene expression was detected in two SMV-resistant lines after artificial inoculation of SMV, while non-transgenic control and other transgenic lines expressed substantial amounts of the viral gene. Viral symptoms affected seed morphology, and clean seeds were harvested from the resistant lines. Also, strong viral gene expression was detected from the seeds of susceptible lines. In further generations, the same phenotypic appearance was maintained among non-transgenic and transgenic plants. Finally, the presence of helper component-proteinase (HC-Pro), known as a suppressor of gene silencing apparatus, was checked among transgenic lines. No expression of HC-Pro in resistant lines indicated that the viral CP-RNAi transformation into soybean somehow created a functional gene silencing system and resulted in a viral-resistant phenotype. 相似文献
994.
Lee SY Lee MS Lee HY Kim SD Shim JW Jo SH Lee JW Kim JY Choi YW Baek SH Ryu SH Bae YS 《FEBS letters》2008,582(2):273-278
F2L, a peptide derived from heme-binding protein, was originally identified as an endogenous ligand for formyl peptide receptor-like (FPRL)2. Previously, we reported that F2L inhibits FPR and FPRL1-mediated signaling in neutrophils. Since endothelial cells express functional FPRL1, we examined the effect of F2L on LL-37 (an FPRL1 agonist)-induced signaling in human umbilical vein endothelial cells (HUVECs). F2L stimulated the chemotactic migration in HUVECs. However, F2L inhibited FPRL1 activity, resulting in the inhibition of cell proliferation and tube formation induced by LL-37 in HUVECs. We suggest that F2L will potentially be useful in the study of FPRL1 signaling and the development of drugs to treat diseases involving the FPRL1 in the vascular system. 相似文献
995.
996.
Jeong-Woo Seo Mi-Young Seo Baek-Rock Oh Sun-Yeon Heo Jin-Oh Baek Dina Rairakhwada Lian Hua Luo Won-Kyung Hong Chul Ho Kim 《Applied microbiology and biotechnology》2010,85(3):659-666
In a previous study, we showed that 1,3-propanediol (1,3-PD) was still produced from glycerol by the Klebsiella pneumoniae mutant strain defective in 1,3-PD oxidoreductase (DhaT), although the production level was lower compared to the parent strain.
As a potential candidate for another putative 1,3-PD oxidoreductase, we identified and characterized a homolog of Escherichia coli yqhD (88% homology in amino acid sequence), which encodes an alcohol dehydrogenase and is well known to replace the function of
DhaT in E. coli. Introduction of multiple copies of the yqhD homolog restored 1,3-PD production in the mutant K. pneumoniae strain defective in DhaT. In addition, by-product formation was still eliminated in the recombinant strain due to the elimination
of the glycerol oxidative pathway. An increase in NADP-dependent 1,3-PD oxidoreductase activity was observed in the recombinant
strain harboring multiple copies of the yqhD homolog. The level of 1,3-PD production during batch fermentation in the recombinant strain was comparable to that of the
parent strain; further engineering can generate an industrial strain producing 1,3-propanediol. 相似文献
997.
998.
999.
Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression 总被引:7,自引:0,他引:7 下载免费PDF全文
1000.