全文获取类型
收费全文 | 4619篇 |
免费 | 390篇 |
国内免费 | 336篇 |
出版年
2024年 | 11篇 |
2023年 | 47篇 |
2022年 | 141篇 |
2021年 | 236篇 |
2020年 | 171篇 |
2019年 | 195篇 |
2018年 | 208篇 |
2017年 | 137篇 |
2016年 | 189篇 |
2015年 | 295篇 |
2014年 | 375篇 |
2013年 | 340篇 |
2012年 | 439篇 |
2011年 | 379篇 |
2010年 | 221篇 |
2009年 | 239篇 |
2008年 | 277篇 |
2007年 | 216篇 |
2006年 | 175篇 |
2005年 | 146篇 |
2004年 | 120篇 |
2003年 | 130篇 |
2002年 | 116篇 |
2001年 | 82篇 |
2000年 | 76篇 |
1999年 | 54篇 |
1998年 | 27篇 |
1997年 | 35篇 |
1996年 | 37篇 |
1995年 | 46篇 |
1994年 | 33篇 |
1993年 | 24篇 |
1992年 | 27篇 |
1991年 | 22篇 |
1990年 | 17篇 |
1989年 | 14篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 9篇 |
1985年 | 3篇 |
1984年 | 6篇 |
1983年 | 5篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有5345条查询结果,搜索用时 15 毫秒
81.
Xuemei Cheng Tianliang Zhang Jing Zhao Jingyang Zhou Hua Shao Zhonghua Zhou Fanling Kong Nannan Feng Yuan Sun Baode Shan Zhaolin Xia 《Mutation Research - Genetic Toxicology and Environmental Mutagenesis》2013,750(1-2):139-146
1,3-Butadiene (BD) has been classified as a human carcinogen, group I; however, the relationship between polymorphisms of glutathione S-transferases that metabolize BD and chromosomal damage is not clear. The present study used sister chromatid exchange (SCE) and cytokinesis-block micronucleus (CBMN) assays to detect chromosomal damage in peripheral lymphocytes of 44 BD-exposed workers and 39 non-exposed healthy controls. PCR and PCR-RFLP were employed to detect three known glutathione S-transferase polymorphisms GSTT1, GSTM1, and GSTP1 (Ile105Val). The data demonstrated that the micronucleus (CBMN) frequency in BD-exposed workers was significantly higher than that in controls (frequency ratio (FR) = 1.48, 95% CI: 1.14–1.91, P < 0.01), and the CBMN frequency was higher in workers exposed to higher cumulative BD levels (FR = 1.70, 95% CI: 1.28–2.27, P < 0.01). However, differences in SCE frequency were not observed (FR = 1.14, 95% CI: 0.81–1.61, P > 0.05). Among exposed workers, chromosomal damage was related to BD exposure levels (FR = 1.35, 95% CI: 1.02–1.80, P < 0.05); age, older workers exhibited higher MN frequencies than younger workers (FR = 1.45, 95% CI: 1.14–1.84, P < 0.05); and years of work, those with more years of work exhibited higher MN frequencies than those with fewer years (FR = 1.40, 95% CI: 1.10–1.77, P < 0.05). Multivariate Poisson regression analysis showed that those who carried GSTM1 (?) (FR = 1.48, 95% CI: 1.14–1.92) or GSTT1 (?) (FR = 1.42, 95% CI: 1.10–1.83) genotypes, and especially those who carried both (FR = 2.10, 95% CI: 1.43–3.09) exhibited significantly higher MN frequencies than those carrying GSTM1 (+), GSTT1 (+) genotypes or their combination. The GSTP1 Val genotype did not affect MN frequency (P > 0.05). Our results suggested that higher levels of BD exposure in the workplace resulted in increased chromosomal damage, and that polymorphisms in GSTT1 and GSTM1 genes might modulate the genotoxic effects of BD exposure. Furthermore, the GSTT1 and GSTM1 polymorphisms exhibited an additive effect. Finally, urinary DHBMA was found to provide a biomarker that correlated with airborne BD levels. 相似文献
82.
Norcantharidin (NCTD), a demethylated analog of cantharidin derived from blister beetles, has attracted considerable attentions in recent years due to their definitely toxic properties and the noteworthy advantages in stimulating bone marrow and increasing the peripheral leukocytes. Hence, it is worth studying the anti-tumor effect of NCTD on human prostate cancer cells DU145. It was found that after the treatment of NCTD with different concentrations (25-100 μM), the cell proliferation was significantly inhibited, which led to the appearance of micronucleus (MN). Moreover, the cells could be killed in a dose-/ time-dependent manner along with the reduction of PCNA (proliferating cell nuclear antigen) expression, destruction of mitochondrial membrane potential (MMP), down-regulation of MnSOD, induction of ROS, depletion of ATP, and activation of AMPK (Adenosine 5‘-monophosphate -activated protein kinase) . In addition, a remarkable release of cytochrome c was found in the cells exposed to 100 μM NCTD and exogenous SOD-PEG could eliminate the generation of NCTD-induced MN. In conclusion, our studies indicated that NCTD could induce the collapse of MMP and mitochondria dysfunction. Accumulation of intercellular ROS could eventually switch on the apoptotic pathway by causing DNA damage and depleting ATP. 相似文献
83.
Yong-Liang Yao Jie Shao Chunfu Zhang Jian-Hong Wu Qing-Hui Zhang Jian-Jun Wang Wei Zhu 《PloS one》2013,8(10)
One of the recent breakthroughs in cancer research is the identification of activating mutations in various receptor tyrosine kinase(RTK) pathways in many cancers including colorectal cancer(CRC). We hypothesize that, alternative to mutations, overexpression of various oncogenic RTKs may also underpin CRC pathogenesis, and different RTK may couple with distinct downstream signaling pathways in different subtypes of human CRC. By immunohistochemistry, we show here that RTK members ErbB2, ErbB3 and c-Met were in deed differentially overexpressed in colorectal cancer patient samples leading to constitutive activation of RTK signaling pathways. Using ErbB2 specific inhibitor Lapatinib and c-Met specific inhibitor PHA-665752, we further demonstrated that this constitutive activation of RTK signaling is necessary for the survival of colorectal cancer cells. Furthermore, we show that RTK overexpression pattern dictates the use of downstream AKT and/or MAPK pathways. Our data are important additions to current oncogenic mutation models, and further explain the clinical variation in therapeutic responses of colorectal cancer. Our findings advocate for more personalized therapy tailored to individual patients based on their type of RTK expression in addition to their mutation status. 相似文献
84.
Yang Liu Qiliang Lai Chunming Dong Fengqin Sun Liping Wang Guangyu Li Zongze Shao 《PloS one》2013,8(11)
Bacteria closely related to Bacillus pumilus cannot be distinguished from such other species as B. safensis, B. stratosphericus, B. altitudinis and B. aerophilus simply by 16S rRNA gene sequence. In this report, 76 marine strains were subjected to phylogenetic analysis based on 7 housekeeping genes to understand the phylogeny and biogeography in comparison with other origins. A phylogenetic tree based on the 7 housekeeping genes concatenated in the order of gyrB-rpoB-pycA-pyrE-mutL-aroE-trpB was constructed and compared with trees based on the single genes. All these trees exhibited a similar topology structure with small variations. Our 79 strains were divided into 6 groups from A to F; Group A was the largest and contained 49 strains close to B. altitudinis. Additional two large groups were presented by B. safensis and B. pumilus respectively. Among the housekeeping genes, gyrB and pyrE showed comparatively better resolution power and may serve as molecular markers to distinguish these closely related strains. Furthermore, a recombinant phylogenetic tree based on the gyrB gene and containing 73 terrestrial and our isolates was constructed to detect the relationship between marine and other sources. The tree clearly showed that the bacteria of marine origin were clustered together in all the large groups. In contrast, the cluster belonging to B. safensis was mainly composed of bacteria of terrestrial origin. Interestingly, nearly all the marine isolates were at the top of the tree, indicating the possibility of the recent divergence of this bacterial group in marine environments. We conclude that B. altitudinis bacteria are the most widely spread of the B. pumilus group in marine environments. In summary, this report provides the first evidence regarding the systematic evolution of this bacterial group, and knowledge of their phylogenetic diversity will help in the understanding of their ecological role and distribution in marine environments. 相似文献
85.
Jun Yin Xu Wang Liang Zheng Yijun Shi Liming Wang Aizhong Shao Weifeng Tang Guowen Ding Chao Liu Ruiping Liu Suocheng Chen Haiyong Gu 《PloS one》2013,8(11)
Esophageal cancer is the eighth most common cancer and sixth leading cause of cancer associated death worldwide. Besides environmental risk factors, genetic factors might play an important role in the esophageal cancer carcinogenesis. We conducted a hospital based case–control study to evaluate the genetic susceptibility of functional single nucleotide polymorphisms (SNPs) in the microRNAs on the development of esophageal cancer. A total of 629 esophageal squamous cell carcinoma (ESCC) cases and 686 controls were recruited for this study. The hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A genotypes were determined using Ligation Detection Reaction (LDR) method. Our results demonstrated that hsa-miR-34b/c rs4938723 CC genotype had a decreased risk of ESCC. The association was evident among patients who never drinking. Hsa-miR-423 rs6505162 C>A might associated with a significantly increased risk of ESCC in patients who smoking. These findings indicated that functional polymorphisms hsa-miR-34b/c rs4938723 T>C and hsa-miR-423 rs6505162 C>A might alter individual susceptibility to ESCC. However, our results were obtained with a limited sample size. Future larger studies with other ethnic populations are required to confirm current findings. 相似文献
86.
87.
Lina Josefsson Sarah Palmer Nuno R. Faria Philippe Lemey Joseph Casazza David Ambrozak Mary Kearney Wei Shao Shyamasundaran Kottilil Michael Sneller John Mellors John M. Coffin Frank Maldarelli 《PLoS pathogens》2013,9(6)
Genetic recombination contributes to the diversity of human immunodeficiency virus (HIV-1). Productive HIV-1 recombination is, however, dependent on both the number of HIV-1 genomes per infected cell and the genetic relationship between these viral genomes. A detailed analysis of the number of proviruses and their genetic relationship in infected cells isolated from peripheral blood and tissue compartments is therefore important for understanding HIV-1 recombination, genetic diversity and the dynamics of HIV-1 infection. To address these issues, we used a previously developed single-cell sequencing technique to quantify and genetically characterize individual HIV-1 DNA molecules from single cells in lymph node tissue and peripheral blood. Analysis of memory and naïve CD4+ T cells from paired lymph node and peripheral blood samples from five untreated chronically infected patients revealed that the majority of these HIV-1-infected cells (>90%) contain only one copy of HIV-1 DNA, implying a limited potential for productive recombination in virus produced by these cells in these two compartments. Phylogenetic analysis revealed genetic similarity of HIV-1 DNA in memory and naïve CD4+ T-cells from lymph node, peripheral blood and HIV-1 RNA from plasma, implying exchange of virus and/or infected cells between these compartments in untreated chronic infection. 相似文献
88.
Dong-Sheng Cao Yi-Zeng Liang Zhe Deng Qian-Nan Hu Min He Qing-Song Xu Guang-Hua Zhou Liu-Xia Zhang Zi-xin Deng Shao Liu 《PloS one》2013,8(4)
The identification of interactions between drugs and target proteins plays a key role in genomic drug discovery. In the present study, the quantitative binding affinities of drug-target pairs are differentiated as a measurement to define whether a drug interacts with a protein or not, and then a chemogenomics framework using an unbiased set of general integrated features and random forest (RF) is employed to construct a predictive model which can accurately classify drug-target pairs. The predictability of the model is further investigated and validated by several independent validation sets. The built model is used to predict drug-target associations, some of which were confirmed by comparing experimental data from public biological resources. A drug-target interaction network with high confidence drug-target pairs was also reconstructed. This network provides further insight for the action of drugs and targets. Finally, a web-based server called PreDPI-Ki was developed to predict drug-target interactions for drug discovery. In addition to providing a high-confidence list of drug-target associations for subsequent experimental investigation guidance, these results also contribute to the understanding of drug-target interactions. We can also see that quantitative information of drug-target associations could greatly promote the development of more accurate models. The PreDPI-Ki server is freely available via: http://sdd.whu.edu.cn/dpiki. 相似文献
89.
Xuan He Dan Li Zhenwu Luo Hua Liang Hong Peng Yangyang Zhao Nidan Wang Donghua Liu Chuan Qin Qiang Wei Huimin Yan Yiming Shao 《PloS one》2013,8(2)
Increasing evidence indicates that antibody-dependent cellular cytotoxicity (ADCC) contributes to the control of HIV/SIV infection. However, little is known about the ADCC function of natural killer (NK) cells in non-human primate model. Here we demonstrated that ADCC function of NK cells was significantly compromised in chronic SIV/SHIV infection, correlating closely with the expression of FcγRIIIa receptor (CD16) on NK cells. CD32, another class of IgG Fc receptors, was identified on NK cells with higher expression in the infected macaques and the blockade of CD32 impacted the ability of NK cells to respond to antibody-coated target cells. The inhibition of matrix metalloproteases (MMPs), a group of enzymes normally involved in tissue/receptor remodeling, could restore NK cell-mediated ADCC with increased CD16 expression on macaque NK cells. These data offer a clearer understanding of NK cell-mediated ADCC in rhesus macaques, which will allow us to evaluate the ADCC repertoire arising from preclinical vaccination studies in non-human primates and inform us in the future design of effective HIV vaccination strategies. 相似文献
90.