全文获取类型
收费全文 | 7293篇 |
免费 | 653篇 |
国内免费 | 1021篇 |
出版年
2024年 | 24篇 |
2023年 | 175篇 |
2022年 | 339篇 |
2021年 | 536篇 |
2020年 | 369篇 |
2019年 | 452篇 |
2018年 | 394篇 |
2017年 | 313篇 |
2016年 | 380篇 |
2015年 | 544篇 |
2014年 | 655篇 |
2013年 | 608篇 |
2012年 | 709篇 |
2011年 | 603篇 |
2010年 | 406篇 |
2009年 | 361篇 |
2008年 | 366篇 |
2007年 | 315篇 |
2006年 | 258篇 |
2005年 | 239篇 |
2004年 | 184篇 |
2003年 | 186篇 |
2002年 | 146篇 |
2001年 | 86篇 |
2000年 | 46篇 |
1999年 | 46篇 |
1998年 | 59篇 |
1997年 | 34篇 |
1996年 | 33篇 |
1995年 | 19篇 |
1994年 | 9篇 |
1993年 | 13篇 |
1992年 | 11篇 |
1991年 | 13篇 |
1990年 | 8篇 |
1989年 | 9篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 4篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1974年 | 1篇 |
1950年 | 2篇 |
排序方式: 共有8967条查询结果,搜索用时 234 毫秒
141.
摘要目的:建立一条新的毕赤酵母表达乙肝表面抗原(HepatitisBantigen,HBsAg)柱层析纯化方法,保持HBsAg结构完整性和提高免疫原性。方法:毕赤酵母发酵料液经过菌体破碎、聚乙二醇沉淀、疏水层析、超滤和凝胶分子筛精纯,收集HBsAg合格样品液适当稀释后加入铝佐荆吸附,制成乙肝疫苗半成品免疫BALB/c小鼠。结果:纯化产物经SDS-PAGE银染鉴定得单一条带,分子量在23kD左右,凝胶成像软件分析纯度超过95%;该纯化方法得到的HBsAg颗粒电镜观察得平均直径为22nm病毒样颗粒,结构较均一完整;自制疫苗免疫小鼠后,其血清抗体水平高于葛兰素史克生产的Engerix—B(安在时),存在显著性差异(P〈0.05)。结论:通过该方法纯化的HBsAg结构完整性良好,疫苗免疫效果优于酵母表达的Engerix—B,纯化路径简单高效,易于放大用于工业化生产。 相似文献
142.
Rui Zhang Zhigang Meng Tao Zhou Yong Deng Li Feng Yuan Wang Guoqing Sun Sandui Guo Maozhi Ren 《Plant signaling & behavior》2013,8(11)
FKBP12 encodes a prolyl isomerase and highly conserved in eukaryotic species. In yeasts and animals, FKBP12 can interact with rapamycin and FK506 to form rapamycin-FKBP12 and FK506-FKBP12 complex, respectively. In higher plants, FKBP12 protein lost its function to bind rapamycin and FK506. Early studies showed that yeast and human FKBP12 protein can restore the rapamycin sensitivity in Arabidopsis, but the used concentration is 100–1000 folds higher than that in yeast and animals. High concentration of drugs would increase the cost and cause the potential secondary effects on plant growth and development. Here we further discovered that BP12 plants generated in our previous study are hypersensitive to rapamycin at the concentration as low as that is effective in yeast and animals. It is surprising to observe that WT and BP12 plants are not sensitive to FK506 in normal growth condition. These findings advance the current understanding of rapamycin-TOR signaling in plants. 相似文献
143.
Epithelial cells in the colon are arranged in cylindrical structures called crypts in which cellular proliferation and migration are tightly regulated. We hypothesized that the proliferation patterns of cells may determine the stability of crypts as well as the rates of somatic evolution towards colorectal tumorigenesis. Here, we propose a linear process model of colonic epithelial cells that explicitly takes into account the proliferation kinetics of cells as a function of cell position within the crypt. Our results indicate that proliferation kinetics has significant influence on the speed of cell movement, kinetics of mutation propagation, and sensitivity of the system to selective effects of mutated cells. We found that, of all proliferation curves tested, those with mitotic activities concentrated near the stem cell, including the actual proliferation kinetics determined in in vivo labeling experiments, have a greater ability of delaying the rate of mutation accumulation in colonic stem cells compared to hypothetical proliferation curves with mitotic activities focused near the top of the crypt column. Our model can be used to investigate the dynamics of proliferation and mutation accumulation in spatially arranged tissues. 相似文献
144.
Adam Auton Ying Rui Li Jeffrey Kidd Kyle Oliveira Julie Nadel J. Kim Holloway Jessica J. Hayward Paula E. Cohen John M. Greally Jun Wang Carlos D. Bustamante Adam R. Boyko 《PLoS genetics》2013,9(12)
The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred. 相似文献
145.
146.
hOGG1 Ser326Cys Polymorphism and Risk of Hepatocellular Carcinoma among East Asians: A Meta-Analysis
Wenjun Wang Shuangsuo Dang Yaping Li Mingzhu Sun Xiaoli Jia Rui Wang Jingkun Liu 《PloS one》2013,8(4)
Background
The hOGG1 gene encodes a DNA glycosylase enzyme responsible for DNA repair. The Ser326Cys polymorphism in this gene may influence its repair ability and thus plays a role in carcinogenesis. Several case-control studies have been conducted on this polymorphism and its relationship with the risk of hepatocellular carcinoma (HCC) among East Asians. However, their results are inconsistent.Methods
We performed a meta-analysis of published case-control studies assessing the association of the hOGG1 Ser326Cys polymorphism with HCC risk among East Asians. PubMed, EMBASE, SCI, BIOSIS, CNKI and WanFang databases were searched. A random-effect model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Analyses were conducted for additive, dominant and recessive genetic models.Results
Eight studies were identified involving 2369 cases and 2442 controls assessing the association of the hOGG1 Ser326Cys polymorphism with HCC risk among East Asians. Applying a dominant genetic model, only in the Chinese population, the Cys allele was significantly associated with increased risk of HCC (OR 1.56, 95% CI 1.12–2.17). However, two studies influenced this finding according to sensitivity analysis. Furthermore, considerable heterogeneity and bias existed among Chinese studies.Conclusion
There is limited evidence to support that the hOGG1 Ser326Cys polymorphism is associated with HCC risk among East Asians. Well-designed and large-sized studies are required to determine this relationship. 相似文献147.
Considering IPPC climate change scenarios, it is pertinent to predict situations where coastal ecosystems already impacted with chemical contamination became exposed to an additional stressor under a future scenario of seawater intrusion. Accordingly, the present study aimed at evaluating if a negative association between tolerance to a metal and to saltwater exists among genotypes of a freshwater organism. For this, five clonal lineages of the cladoceran Daphnia longispina O.F. Müller, exhibiting a differential tolerance to lethal levels of copper, were selected. Each clonal lineage was exposed to lethal and sublethal concentrations of sodium chloride (assumed as a protective surrogate to evaluate the toxicity of increased salinity to freshwater organisms). Mortality, time to release the first brood and total number of neonates per female were monitored and the somatic growth rate and intrinsic rate of natural increase were computed for each clonal lineage. Data here obtained were compared with their lethal responses to copper and significant negative correlations were found. These results suggest that genetically eroded populations of D. longispina, due to copper or salinity, may be particularly susceptible to a later exposure to the other contaminant supporting the multiple stressors differential tolerance. 相似文献
148.
Rui Liu Xuguang Guo Yikyung Park Jian Wang Xuemei Huang Albert Hollenbeck Aaron Blair Honglei Chen 《PloS one》2013,8(6)
Background
The epidemiologic evidence on alcohol consumption and Parkinson’s disease (PD) is equivocal. We prospectively examined total alcohol consumption and consumption of specific types of alcoholic beverage in relation to future risk of PD.Methods
The study comprised 306,895 participants (180,235 male and 126,660 female) ages 50–71 years in 1995–1996 from the NIH-AARP Diet and Health Study. Consumption of alcoholic beverages in the past 12 months was assessed in 1995–1996. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models.Results
A total of 1,113 PD cases diagnosed between 2000 and 2006 were included in the analysis. Total alcohol consumption was not associated with PD. However, the association differed by types of alcoholic beverages. Compared with non-beer drinkers, the multivariate ORs for beer drinkers were 0.79 (95% CI: 0.68, 0.92) for <1 drink/day, 0.73 (95% CI: 0.50, 1.07) for 1–1.99 drinks/day, and 0.86 (95% CI: 0.60, 1.21) for ≥2 drinks/day. For liquor consumption, a monotonic increase in PD risk was suggested: ORs (95% CI) were 1.06 (0.91, 1.23), 1.22 (0.94, 1.58), and 1.35 (1.02, 1.80) for <1, 1–1.99, and ≥2 drinks/day, respectively (P for trend <0.03). Additional analyses among exclusive drinkers of one specific type of alcoholic beverage supported the robustness of these findings. The results for wine consumption were less clear, although a borderline lower PD risk was observed when comparing wine drinkers of 1–1.99 drinks/day with none drinkers (OR = 0.74, 95% CI: 0.53, 1.02).Conclusions
Our results suggest that beer and liquor consumption may have opposite associations with PD: low to moderate beer consumption with lower PD risk and greater liquor consumption with higher risk. These findings and potential underlying mechanisms warrant further investigations. 相似文献149.
Hong-xia Chen Zeng-liang Jin Li-ming Zhang Rui Xue Xiao-dan Xu Nan Zhao Zhi-kun Qiu Xian-wang Wang You-zhi Zhang Ri-fang Yang Yun-feng Li 《PloS one》2013,8(12)
It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder. 相似文献
150.