全文获取类型
收费全文 | 1748篇 |
免费 | 139篇 |
国内免费 | 81篇 |
出版年
2023年 | 11篇 |
2022年 | 28篇 |
2021年 | 72篇 |
2020年 | 41篇 |
2019年 | 78篇 |
2018年 | 77篇 |
2017年 | 61篇 |
2016年 | 66篇 |
2015年 | 82篇 |
2014年 | 104篇 |
2013年 | 104篇 |
2012年 | 158篇 |
2011年 | 126篇 |
2010年 | 98篇 |
2009年 | 69篇 |
2008年 | 77篇 |
2007年 | 70篇 |
2006年 | 75篇 |
2005年 | 55篇 |
2004年 | 44篇 |
2003年 | 52篇 |
2002年 | 52篇 |
2001年 | 38篇 |
2000年 | 37篇 |
1999年 | 37篇 |
1998年 | 15篇 |
1997年 | 23篇 |
1996年 | 14篇 |
1995年 | 18篇 |
1994年 | 14篇 |
1993年 | 14篇 |
1992年 | 19篇 |
1991年 | 28篇 |
1990年 | 13篇 |
1989年 | 13篇 |
1988年 | 5篇 |
1987年 | 14篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1971年 | 4篇 |
1967年 | 3篇 |
排序方式: 共有1968条查询结果,搜索用时 15 毫秒
71.
Yingyu Chen Jing Zheng Donghui Gan Yanxin Chen Na Zhang Yuwen Chen Zhenxing Lin Wenfeng Wang Haijun Chen Donghong Lin Jianda Hu 《Journal of cellular physiology》2020,235(11):8023-8034
Leukemia stem cells (LSCs) have critical functions in acute leukemia (AL) pathogenesis, participating in its initiation and relapse. Thus, identifying new molecules to eradicate LSCs represents a high priority for AL management. This work identified E35, a novel Emodin derivative, which strongly inhibited growth and enhanced apoptosis of AL stem cell lines, and primary stem and progenitor cells from AL cases, while sparing normal hematopoietic cells. Furthermore, functional assays in cultured cells and animals suggested that E35 preferentially ablated primitive leukemia cell populations without impairing their normal counterparts. Moreover, molecular studies showed that E35 remarkably downregulated drug-resistant gene and dramatically inhibited the Akt/mammalian target of rapamycin signaling pathway. Notably, the in vivo anti-LSC activity of E35 was further confirmed in murine xenotransplantation models. Collectively, these findings indicate E35 constitutes a novel therapeutic candidate for AL, potentially targeting leukemia stem and progenitor cells. 相似文献
72.
Renli Qi Min Feng Xiao Tan Lu Gan Guoyong Yan Chao Sun 《Molecular biology reports》2013,40(4):2907-2914
FATP1 plays an important role in the trafficking of free fatty acids in adipocytes, however, its precise function and relationship with other fatty acid transporters all remain poorly understood. In this study, FATP1 gene silencing was induced by transfecting siRNA of target sequence into chicken preadipocytes, then the expression of FABP was found down-regulated while the expression of FAT was raised. In addition, differential inhibition of the cells was observed and the expressions of PPARγ and C/EBPα were found down-regulated. Moreover, the silencing also induced the down-regulation of FAS and inhibited the adipogenesis in adipocytes. Of specific interest here was that FATP1 silencing significantly improved the expressions and activities of cell apoptotic factors Caspases 3 and BCL2 associated X protein (Bax). Consequently, FATP1 deficiency prevented the differentiation while induced apoptosis in chicken preadipocytes. 相似文献
73.
74.
Background and Aims
Evidence shows that plants modify their microbial environment leading to the “crop rotation effect”, but little is known about the changes in rhizobacterial community structure and functionality associated with beneficial rotation effects.Methods
Polymerase chain reaction (PCR) and 454 GS FLX amplicon pyrosequencing were used to describe the composition of the rhizobacterial community evolving under the influence of pea, a growth promoting rotation crop, and the influence of three genotypes of chickpea, a plant known as an inferior rotation crop. The growth promoting properties of these rhizobacterial communities were tested on wheat in greenhouse assays.Results
The rhizobacterial communities selected by pea and the chickpea CDC Luna in 2008, a wet year, promoted durum wheat growth, but those selected by CDC Vanguard or CDC Frontier had no growth-promoting effect. In 2009, a dry year, the influence of plants was mitigated, indicated that moisture availability is a major driver of soil bacterial community dynamics.Conclusion
The effect of pulse crops on soil biological quality varies with the crop species and genotypes, and certain chickpea genotypes may induce positive rotation effects on wheat. The strength of a rotation effect on soil biological quality is modulated by the abundance of precipitation. 相似文献75.
Huachen Gan Guibo Wang Qin Hao Q. Jane Wang Hua Tang 《The Journal of biological chemistry》2013,288(52):37343-37354
At the interface between host and external environment, the airway epithelium serves as a major protective barrier. In the present study we show that protein kinase D (PKD) plays an important role in the formation and integrity of the airway epithelial barrier. Either inhibition of PKD activity or silencing of PKD increased transepithelial electrical resistance (TEER), resulting in a tighter epithelial barrier. Among the three PKD isoforms, PKD3 knockdown was the most efficient one to increase TEER in polarized airway epithelial monolayers. In contrast, overexpression of PKD3 wild type, but not PKD3 kinase-inactive mutant, disrupted the formation of apical intercellular junctions and their reassembly, impaired the development of TEER, and increased paracellular permeability to sodium fluorescein in airway epithelial monolayers. We further found that overexpression of PKD, in particular PKD3, markedly suppressed the mRNA and protein levels of claudin-1 but had only minor effects on the expression of other tight junctional proteins (claudin-3, claudin-4, claudin-5, occludin, and ZO-1) and adherent junctional proteins (E-cadherin and β-catenin). Immunofluorescence study revealed that claudin-1 level was markedly reduced and almost disappeared from intercellular contacts in PKD3-overexpressed epithelial monolayers and that claudin-4 was also restricted from intercellular contacts and tended to accumulate in the cell cytosolic compartments. Last, we found that claudin-1 knockdown prevented TEER elevation by PKD inhibition or silencing in airway epithelial monolayers. These novel findings indicate that PKD negatively regulates human airway epithelial barrier formation and integrity through down-regulation of claudin-1, which is a key component of tight junctions. 相似文献
76.
Lai-Ping Wong Rick?Twee-Hee Ong Wan-Ting Poh Xuanyao Liu Peng Chen Ruoying Li Kevin?Koi-Yau Lam Nisha?Esakimuthu Pillai Kar-Seng Sim Haiyan Xu Ngak-Leng Sim Shu-Mei Teo Jia-Nee Foo Linda?Wei-Lin Tan Yenly Lim Seok-Hwee Koo Linda?Seo-Hwee Gan Ching-Yu Cheng Sharon Wee Eric?Peng-Huat Yap Pauline?Crystal Ng Wei-Yen Lim Richie Soong Markus?Rene Wenk Tin Aung Tien-Yin Wong Chiea-Chuen Khor Peter Little Kee-Seng Chia Yik-Ying Teo 《American journal of human genetics》2013,92(1):52-66
Whole-genome sequencing across multiple samples in a population provides an unprecedented opportunity for comprehensively characterizing the polymorphic variants in the population. Although the 1000 Genomes Project (1KGP) has offered brief insights into the value of population-level sequencing, the low coverage has compromised the ability to confidently detect rare and low-frequency variants. In addition, the composition of populations in the 1KGP is not complete, despite the fact that the study design has been extended to more than 2,500 samples from more than 20 population groups. The Malays are one of the Austronesian groups predominantly present in Southeast Asia and Oceania, and the Singapore Sequencing Malay Project (SSMP) aims to perform deep whole-genome sequencing of 100 healthy Malays. By sequencing at a minimum of 30× coverage, we have illustrated the higher sensitivity at detecting low-frequency and rare variants and the ability to investigate the presence of hotspots of functional mutations. Compared to the low-pass sequencing in the 1KGP, the deeper coverage allows more functional variants to be identified for each person. A comparison of the fidelity of genotype imputation of Malays indicated that a population-specific reference panel, such as the SSMP, outperforms a cosmopolitan panel with larger number of individuals for common SNPs. For lower-frequency (<5%) markers, a larger number of individuals might have to be whole-genome sequenced so that the accuracy currently afforded by the 1KGP can be achieved. The SSMP data are expected to be the benchmark for evaluating the value of deep population-level sequencing versus low-pass sequencing, especially in populations that are poorly represented in population-genetics studies. 相似文献
77.
78.
Yanmin Huang Jianguo Cui Sijing Chen Chunfang Gan Qiucui Yao Qifu Lin 《Bioorganic & medicinal chemistry letters》2013,23(7):2265-2267
Using deoxycholic acid as starting materials, a series of 12a-aza-C-homo-12-one 7-deoxycholic acid derivatives were synthesized The antiproliferative activity of the synthesized compounds against some carcinoma cell lines was investigated. The results showed that some 12-oxy-12a-aza-C-homo-7-deoxycholic acid derivatives displayed distinct cytotoxicity to HeLa (human cervical carcinoma) and Tu 686 (laryngocarcinoma) tumor cell lines. In particular, the IC50 values of the compounds 6 and 7 against Tu 686 cells are 16.7 and 19.8 μM/L respectively. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs. 相似文献
79.
Guohua Zhao Chet Kwon Sharon N. Bisaha Philip D. Stein Karen A. Rossi Xueying Cao Thao Ung Ginger Wu Chen-Pin Hung Sarah E. Malmstrom Ge Zhang Qinling Qu Jinping Gan William J. Keim Mary Jane Cullen Kenneth W. Rohrbach James Devenny Mary Ann Pelleymounter Jeffrey A. Robl 《Bioorganic & medicinal chemistry letters》2013,23(13):3914-3919
The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure–activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing. 相似文献
80.
Huanan Wen Jiaxin Zhong Bei Shen Tao Gan Chao Fu Zhihong Zhu Rui Li Xu Yang 《生物学前沿》2013,8(4):444-450
To compare the cytotoxicity on HeLa cells induced by nanosized and microsized tellurium powders, HeLa cells were exposed to different concentrations of tellurium powders (0, 50, 100, 150 and 200 μg/mL) for 12 h. In this study, detection of a series of biomarkers, including reactive oxygen species (ROS), glutathione (GSH), 8-hydroxy-2′-deoxyguanosine (8-OHdG), in addition to DNA and protein crosslink (DPC) and MTTassay, were conducted to evaluate the cytotoxicity. It is indicated that compared with the control group, there was no significant difference in the induced cytotoxicity at concentrations lower than 50 μg/mL for both nanosized and microsized tellurium powders. While there appears a significant difference in the induced cytotoxicity for nanosized tellurium powders when the concentration is higher than 100 μg/mL as well as for microsized tellurium powders when the concentration is higher than 200 μg/mL. Moreover, it is found that the cytotoxicity induced on HeLa cells exhibits a certain dose-effect relationship with the concentration of tellurium powders. A conclusion has been reached that the toxicity on HeLa cells can be induced by both nanosized and microsized tellurium powders, and the toxicity of the nanosized tellurium powders is significantly greater than the microsized one. 相似文献