全文获取类型
收费全文 | 2416篇 |
免费 | 197篇 |
国内免费 | 121篇 |
专业分类
2734篇 |
出版年
2023年 | 22篇 |
2022年 | 57篇 |
2021年 | 90篇 |
2020年 | 51篇 |
2019年 | 66篇 |
2018年 | 75篇 |
2017年 | 56篇 |
2016年 | 85篇 |
2015年 | 155篇 |
2014年 | 173篇 |
2013年 | 171篇 |
2012年 | 227篇 |
2011年 | 180篇 |
2010年 | 121篇 |
2009年 | 97篇 |
2008年 | 125篇 |
2007年 | 121篇 |
2006年 | 118篇 |
2005年 | 91篇 |
2004年 | 99篇 |
2003年 | 60篇 |
2002年 | 59篇 |
2001年 | 28篇 |
2000年 | 34篇 |
1999年 | 42篇 |
1998年 | 22篇 |
1997年 | 29篇 |
1996年 | 22篇 |
1995年 | 24篇 |
1994年 | 17篇 |
1993年 | 20篇 |
1992年 | 21篇 |
1991年 | 12篇 |
1990年 | 16篇 |
1989年 | 15篇 |
1988年 | 13篇 |
1987年 | 10篇 |
1986年 | 13篇 |
1985年 | 14篇 |
1984年 | 6篇 |
1983年 | 12篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1980年 | 9篇 |
1976年 | 6篇 |
1974年 | 6篇 |
1973年 | 3篇 |
1972年 | 4篇 |
1966年 | 3篇 |
1965年 | 6篇 |
排序方式: 共有2734条查询结果,搜索用时 0 毫秒
81.
Gao J Li X Gu G Sun B Cui M Ji M Lou HX 《Bioorganic & medicinal chemistry letters》2011,21(2):622-627
To investigate the relationship of cytotoxicity and saponins with varied aglycones, based on the structure of indioside E 1, a natural derived anti-tumor active ingredient from Chinese medicinal plant Solanum indicum L., five novel saponins 2-6 bearing the same trisaccharide moiety together with 1 were efficiently synthesized via a transglycosylation strategy. MTT assay revealed the killing effects to tumor cells of the synthesized saponins are varied with the change of aglycones. Furthermore, time-lapse microscopy, LDH release, PI staining, and immunocytochemical investigations demonstrated that the cell death caused by neosaponin 2 was through oncotic necrosis involving plasma membrane perturbation and destruction of cytoskeleton. 相似文献
82.
Wang Y Keck ZY Saha A Xia J Conrad F Lou J Eckart M Marks JD Foung SK 《The Journal of biological chemistry》2011,286(51):44218-44233
A potent neutralizing antibody to a conserved hepatitis C virus (HCV) epitope might overcome its extreme variability, allowing immunotherapy. The human monoclonal antibody HC-1 recognizes a conformational epitope on the HCV E2 glycoprotein. Previous studies showed that HC-1 neutralizes most HCV genotypes but has modest potency. To improve neutralization, we affinity-matured HC-1 by constructing a library of yeast-displayed HC-1 single chain Fv (scFv) mutants, using for selection an E2 antigen from one of the poorly neutralized HCVpp. We developed an approach by parallel mutagenesis of the heavy chain variable (VH) and κ-chain variable (Vk) genes separately, then combining the optimized VH and Vk mutants. This resulted in the generation of HC-1-related scFv variants exhibiting improved affinities. The best scFv variant had a 92-fold improved affinity. After conversion to IgG1, some of the antibodies exhibited a 30-fold improvement in neutralization activity. Both surface plasmon resonance and solution kinetic exclusion analysis showed that the increase in affinity was largely due to a lowering of the dissociation rate constant, Koff. Neutralization against a panel of HCV pseudoparticles and infectious 2a HCV virus improved with the affinity-matured IgG1 antibodies. Interestingly, some of these antibodies neutralized a viral isolate that was not neutralized by wild-type HC-1. Moreover, propagating 2a HCVcc under the selective pressure of WT HC-1 or affinity-matured HC-1 antibodies yielded no viral escape mutants and, with the affinity-matured IgG1, needed 100-fold less antibody to achieve complete virus elimination. Taken together, these findings suggest that affinity-matured HC-1 antibodies are excellent candidates for therapeutic development. 相似文献
83.
MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals 总被引:14,自引:0,他引:14
Lou Z Minter-Dykhouse K Franco S Gostissa M Rivera MA Celeste A Manis JP van Deursen J Nussenzweig A Paull TT Alt FW Chen J 《Molecular cell》2006,21(2):187-200
MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1-/- mice recapitulated many phenotypes of H2AX-/- mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability. 相似文献
84.
糙叶败酱挥发油镇静作用的研究 总被引:3,自引:1,他引:3
本文观察了败酱科植物糙叶败酱(Patrinia scabra Bunge)根和根茎中制得的挥发油的镇静作用,井与黄花败酱挥发油做了比较。结果表明,此油灌胃给予数组小鼠,剂量0.45ml/kg,显示如下的作用:[1]能显著延长由于腹腔注射戊巴比妥钠(50mg/kg)引起的小鼠睡眠时间,但其作用强度弱于黄花败酱挥发油。(2)一次灌胃给予小鼠大剂量10.46g/kg的糙叶败酱挥发油,连续观察10天,动物外观正常,无一死亡,体重增加与对照组相似。 相似文献
85.
86.
Fallas JL Tobin HM Lou O Guo D Sant'Angelo DB Denzin LK 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(3):1549-1560
The MHC class II-like molecule HLA-DM (DM) (H-2M in mice) catalyzes the exchange of CLIP for antigenic peptides in the endosomes of APCs. HLA-DO (DO) (H-2O in mice) is another class II-like molecule that is expressed in B cells, but not in other APCs. Studies have shown that DO impairs or modifies the peptide exchange activity of DM. To further evaluate the role of DO in Ag processing and presentation, we generated transgenic mice that expressed the human HLA-DOA and HLA-DOB genes under the control of a dendritic cell (DC)-specific promoter. Our analyses of DCs from these mice showed that as DO levels increased, cell surface levels of A(b)-CLIP also increased while class II-peptide levels decreased. The presentation of some, but not all, exogenous Ags to T cells or T hybridomas was significantly inhibited by DO. Surprisingly, H-2M accumulated in DO-expressing DCs and B cells, suggesting that H-2O/DO prolongs the half-life of H-2M. Overall, our studies showed that DO expression impaired H-2M function, resulting in Ag-specific down-modulation of class II Ag processing and presentation. 相似文献
87.
88.
Premature aging in vitamin D receptor mutant mice 总被引:1,自引:0,他引:1
Tiina Keisala Anna Minasyan Yan-Ru Lou Jing Zou Allan V. Kalueff Ilmari Pyykk Pentti Tuohimaa 《The Journal of steroid biochemistry and molecular biology》2009,115(3-5):91-97
Hypervitaminosis vitamin D3 has been recently implicated in premature aging through the regulation of 1alpha hydroxylase expression by klotho and fibroblast growth factor-23 (Fgf-23). Here we examined whether the lack of hormonal function of vitamin D3 in mice is linked to aging phenomena. For this, we used vitamin D3 receptor (VDR) “Tokyo” knockout (KO) mice (fed with a special rescue diet) and analyzed their growth, skin and cerebellar morphology, as well as overall motor performance. We also studied the expression of aging-related genes, such as Fgf-23, nuclear factor kappaB (NF-kappaB), p53, insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), in liver, as well as klotho in liver, kidney and prostate tissues. Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts. There was no difference either in the structure of cerebellum or in the number of Purkinje cells. Unlike the wildtype controls, VDR KO mice lose their ability to swim after 6 months of age. Expression of all the genes was lower in old VDR KO mice, but only NF-kappaB, Fgf-23, p53 and IGF1R were significantly lower. Since the phenotype of aged VDR knockout mice is similar to mouse models with hypervitaminosis D3, our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D3 homeostasis regulates physiological aging. 相似文献
89.
从甘松(Nardostachys chinensis.Batal)的根中分离到了一个新的倍半萜过氧化物——甘松醛(Nardosaldehyde),并通过J-分解谱等二维核磁共振技术鉴定了其结构。 相似文献
90.
异育淇鲫及其双亲同工酶的比较研究 总被引:14,自引:0,他引:14
用4.5%聚丙烯酰胺凝胶平板电泳研究了异育淇鲫及其母本淇鲫和父本兴国红鲤的肌可溶性蛋白以及肾、肝、眼、背白肌和心等五种组织的乳酸脱氢酶(LDH)、苹果酸脱氢酶(MDH)和酯酶(EST)。结果发现:异育淇鲫的肌可溶性蛋白以及同工酶的电泳图谱与母本淇鲫相同而与父本兴国红鲤显著不同,因而认为异育淇鲫是淇鲫雌核发育的产物,父本基因对子代基本无影响。在此基础上,本文对异源精子在雌核发育中所起的生物学作用进行了初步探讨。 相似文献