全文获取类型
收费全文 | 122748篇 |
免费 | 2628篇 |
国内免费 | 3015篇 |
出版年
2024年 | 65篇 |
2023年 | 445篇 |
2022年 | 1085篇 |
2021年 | 1778篇 |
2020年 | 1172篇 |
2019年 | 1572篇 |
2018年 | 12895篇 |
2017年 | 11371篇 |
2016年 | 8689篇 |
2015年 | 2565篇 |
2014年 | 2666篇 |
2013年 | 2896篇 |
2012年 | 6944篇 |
2011年 | 15116篇 |
2010年 | 13262篇 |
2009年 | 9471篇 |
2008年 | 11259篇 |
2007年 | 12636篇 |
2006年 | 1418篇 |
2005年 | 1412篇 |
2004年 | 1712篇 |
2003年 | 1728篇 |
2002年 | 1316篇 |
2001年 | 738篇 |
2000年 | 618篇 |
1999年 | 454篇 |
1998年 | 274篇 |
1997年 | 277篇 |
1996年 | 264篇 |
1995年 | 230篇 |
1994年 | 224篇 |
1993年 | 179篇 |
1992年 | 219篇 |
1991年 | 216篇 |
1990年 | 134篇 |
1989年 | 106篇 |
1988年 | 98篇 |
1987年 | 82篇 |
1986年 | 39篇 |
1985年 | 44篇 |
1984年 | 31篇 |
1983年 | 47篇 |
1982年 | 18篇 |
1981年 | 18篇 |
1972年 | 246篇 |
1971年 | 274篇 |
1965年 | 14篇 |
1962年 | 24篇 |
1944年 | 12篇 |
1940年 | 10篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
981.
982.
Yan Wang Yu Hong Man Li Jiang Long Yan-Ping Zhao Jun-Xia Zhang Qian Li Hong You Wei-Min Tong Ji-Dong Jia Jian Huang 《PloS one》2013,8(12)
Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The NBS1 gene codes for a protein, Nbs1(p95/Nibrin), involved in the processing/repair of DNA double-strand breaks. Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. Recent studies have shown that heterozygous NBS1 mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC). Eight missense NBS1 mutations were identified in six of 64 (9.4%) HCCs and two of 18 (11.1%) ICCs, whereas only one synonymous mutation was found in 89 control cases of cirrhosis and chronic hepatitis B. Analysis of the functional consequences of the identified NBS1 mutations in Mre11-binding domain showed loss of nuclear localization of Nbs1 partner Mre11, one of the hallmarks for Nbs1 deficiency, in one HCC and two ICCs with NBS1 mutations. Moreover, seven of the eight tumors with NBS1 mutations had at least one genetic alteration in the TP53 pathway, including TP53 mutation, MDM2 amplification, p14ARF homozygous deletion and promoter methylation, implying a synergistic effect of Nbs1 disruption and p53 inactivation. Our findings provide novel insight on the molecular pathogenesis of primary liver cancer characterized by mutation inactivation of NBS1, a DNA repair associated gene. 相似文献
983.
Sedimentation velocity analytical ultracentrifugation (SV) is a powerful first-principle technique for the study of protein interactions, and allows a rigorous characterization of binding stoichiometry and affinities. A recently introduced commercial fluorescence optical detection system (FDS) permits analysis of high-affinity interactions by SV. However, for most proteins the attachment of an extrinsic fluorophore is an essential prerequisite for analysis by FDS-SV. Using the glutamate receptor GluA2 amino terminal domain as a model system for high-affinity homo-dimerization, we demonstrate how the experimental design and choice of fluorescent label can impact both the observed binding constants as well as the derived hydrodynamic parameter estimates for the monomer and dimer species. Specifically, FAM (5,6-carboxyfluorescein) was found to create different populations of artificially high-affinity and low-affinity dimers, as indicated by both FDS-SV and the kinetics of dimer dissociation studied using a bench-top fluorescence spectrometer and Förster Resonance Energy Transfer. By contrast, Dylight488 labeled GluA2, as well as GluA2 expressed as an EGFP fusion protein, yielded results consistent with estimates for unlabeled GluA2. Our study suggests considerations for the choice of labeling strategies, and highlights experimental designs that exploit specific opportunities of FDS-SV for improving the reliability of the binding isotherm analysis of interacting systems. 相似文献
984.
A dispersed particle gel (DPG) was successfully prepared from a polymer gel at room temperature. The polymer gel system, morphology, viscosity changes, size distribution, and zeta potential of DPG particles were investigated. The results showed that zirconium gel systems with different strengths can be cross-linked within 2.5 h at low temperature. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) results showed that the particles were polygonal particles with nano-size distribution. According to the viscosity changes, the whole preparation process can be divided into two major stages: the bulk gel cross-linking reaction period and the DPG particle preparation period. A polymer gel with a 3-dimensional network was formed in the bulk gel cross-linking reaction period whereas shearing force and frictional force were the main driving forces for the preparation of DPG particles, and thus affected the morphology of DPG particles. High shearing force and frictional force reduced the particle size distribution, and then decreased the zeta potential (absolute value). The whole preparation process could be completed within 3 h at room temperature. It could be an efficient and energy-saving technology for preparation of DPG particles. 相似文献
985.
Severe retinal ischemia causes persistent visual impairments in eye diseases. Retinal pigment epithelium (RPE) cells are located near the choroidal capillaries, and are easily affected by ischemic or hypoxia. Ginsenoside Rg-1 has shown significant neuroprotective effects. This study was performed to test the cytoprotective effect of ginsenoside Rg-1 in RPE cells against hypoxia and cobalt chloride (CoCl2) assaults, and to understand the underlying mechanisms. We found that Rg-1 pre-administration significantly inhibited CoCl2- and hypoxia-induced RPE cell death and apoptosis. Reactive oxygen specisis (ROS)-dependent p38 and c-Jun NH(2)-terminal kinases (JNK) MAPK activation was required for CoCl2-induced RPE cell death, and Rg-1 pre-treatment significantly inhibited ROS production and following p38/JNK activation. Further, CoCl2 suppressed pro-survival mTOR complex 1 (mTORC1) activation in RPE cells through activating of AMP-activated protein kinase (AMPK), while Rg-1 restored mTORC1 activity through inhibiting AMPK activation. CoCl2-induced AMPK activation was also dependent on ROS production, and anti-oxidant N-acetylcysteine (NAC) prevented AMPK activation and RPE cell death by CoCl2. Our results indicated that Rg-1 could be further investigated as a novel cell-protective agent for retinal ischemia. 相似文献
986.
Wei Chen Wei Wang Beibei Zhu Hui Guo Yu Sun Jie Ming Na Shen Zhi Li Zhenling Wang Lifeng Liu Bingxi Cai Jiayu Duan Jiaoyuan Li Cheng Liu Rong Zhong Weiguo Hu Tao Huang Xiaoping Miao 《PloS one》2013,8(11)
Background
To investigate the association between rs1820453 which located in the promoter region of yes-associated protein 1 (YAP1) gene and breast cancer (BC) risk.Method and Findings
We conducted a hospital-based case-control study including a total of 480 BC cases and 545 cancer-free controls in Chinese population. Then the expression quantitative trait locus (e-QTL) analysis was performed to explore the possible function of rs1820453 to the YAP1 gene expression. The association between rs1820453 and BC risk was significantly identified with the odds ratio (OR) was 1.27 (95 % confidence interval (CI) =1.03-1.57) under allelic model when adjusted by age and menopausal status. In addition, the correlation analysis of rs1820453 and YAP1 expression level found that this variant was significantly associated with the gene expression in Chinese population. When compared with level of mRNA expression of the AA genotype (6.011±0.046), the mRNA expression level in CC genotype (5.903±0.026) was statistically lower (P=0.024).Conclusion
The results from this study suggested that rs1820453 A>C change may affect the gene expression and contribute to the risk of developing BC in Chinese population though larger sample-size studies along with functional experiments were anticipated to warrant the results. 相似文献987.
Yufeng Cheng Qian Wang Zhanjie Li Jianmin Cui Shengwu Hu Huixian Zhao Mingshun Chen 《PloS one》2013,8(11)
Male sterility induced by a chemical hybridization agent (CHA) is an important tool for utilizing crop heterosis. Monosulphuron ester sodium (MES), a new acetolactate synthase-inhibitor herbicide belonging to the sulphonylurea family, has been developed as an effective CHA to induce male sterility in rapeseed (Brassica napus L.). To understand MES-induced male sterility in rapeseed better, comparative cytological and proteomic analyses were conducted in this study. Cytological analysis indicated that defective tapetal cells and abnormal microspores were gradually generated in the developing anthers of MES-treated plants at various development stages, resulting in unviable microspores and male sterility. A total of 141 differentially expressed proteins between the MES-treated and control plants were revealed, and 131 of them were further identified by MALDI-TOF/TOF MS. Most of these proteins decreased in abundance in tissues of MES-treated rapeseed plants, and only a few increased. Notably, some proteins were absent or induced in developing anthers after MES treatment. These proteins were involved in several processes that may be crucial for tapetum and microspore development. Down-regulation of these proteins may disrupt the coordination of developmental and metabolic processes, resulting in defective tapetum and abnormal microspores that lead to male sterility in MES-treated plants. Accordingly, a simple model of CHA-MES-induced male sterility in rapeseed was established. This study is the first cytological and dynamic proteomic investigation on CHA-MES-induced male sterility in rapeseed, and the results provide new insights into the molecular events of male sterility. 相似文献
988.
Background
No attention has been paid on comparing a set of genome sequences crossing genetic components and biological categories with far divergence over large size range. We define it as the systematic comparative genomics and aim to develop the methodology.Results
First, we create a method, GenomeFingerprinter, to unambiguously produce a set of three-dimensional coordinates from a sequence, followed by one three-dimensional plot and six two-dimensional trajectory projections, to illustrate the genome fingerprint of a given genome sequence. Second, we develop a set of concepts and tools, and thereby establish a method called the universal genome fingerprint analysis (UGFA). Particularly, we define the total genetic component configuration (TGCC) (including chromosome, plasmid, and phage) for describing a strain as a systematic unit, the universal genome fingerprint map (UGFM) of TGCC for differentiating strains as a universal system, and the systematic comparative genomics (SCG) for comparing a set of genomes crossing genetic components and biological categories. Third, we construct a method of quantitative analysis to compare two genomes by using the outcome dataset of genome fingerprint analysis. Specifically, we define the geometric center and its geometric mean for a given genome fingerprint map, followed by the Euclidean distance, the differentiate rate, and the weighted differentiate rate to quantitatively describe the difference between two genomes of comparison. Moreover, we demonstrate the applications through case studies on various genome sequences, giving tremendous insights into the critical issues in microbial genomics and taxonomy.Conclusions
We have created a method, GenomeFingerprinter, for rapidly computing, geometrically visualizing, intuitively comparing a set of genomes at genome fingerprint level, and hence established a method called the universal genome fingerprint analysis, as well as developed a method of quantitative analysis of the outcome dataset. These have set up the methodology of systematic comparative genomics based on the genome fingerprint analysis. 相似文献989.
990.