全文获取类型
收费全文 | 2709篇 |
免费 | 268篇 |
国内免费 | 341篇 |
出版年
2024年 | 4篇 |
2023年 | 38篇 |
2022年 | 97篇 |
2021年 | 161篇 |
2020年 | 99篇 |
2019年 | 144篇 |
2018年 | 124篇 |
2017年 | 100篇 |
2016年 | 122篇 |
2015年 | 161篇 |
2014年 | 189篇 |
2013年 | 180篇 |
2012年 | 236篇 |
2011年 | 201篇 |
2010年 | 145篇 |
2009年 | 153篇 |
2008年 | 159篇 |
2007年 | 125篇 |
2006年 | 120篇 |
2005年 | 110篇 |
2004年 | 90篇 |
2003年 | 87篇 |
2002年 | 76篇 |
2001年 | 57篇 |
2000年 | 65篇 |
1999年 | 49篇 |
1998年 | 30篇 |
1997年 | 18篇 |
1996年 | 24篇 |
1995年 | 20篇 |
1994年 | 17篇 |
1993年 | 8篇 |
1992年 | 11篇 |
1991年 | 13篇 |
1990年 | 13篇 |
1989年 | 9篇 |
1988年 | 10篇 |
1987年 | 9篇 |
1986年 | 4篇 |
1985年 | 6篇 |
1984年 | 4篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 4篇 |
1974年 | 2篇 |
1972年 | 2篇 |
1970年 | 2篇 |
1948年 | 1篇 |
排序方式: 共有3318条查询结果,搜索用时 890 毫秒
991.
992.
Quan Wang Peilin Jia Karen T. Cuenco Zhen Zeng Eleanor Feingold Mary L. Marazita Lily Wang Zhongming Zhao 《PloS one》2013,8(8)
Gene set-based analysis of genome-wide association study (GWAS) data has recently emerged as a useful approach to examine the joint effects of multiple risk loci in complex human diseases or phenotypes. Dental caries is a common, chronic, and complex disease leading to a decrease in quality of life worldwide. In this study, we applied the approaches of gene set enrichment analysis to a major dental caries GWAS dataset, which consists of 537 cases and 605 controls. Using four complementary gene set analysis methods, we analyzed 1331 Gene Ontology (GO) terms collected from the Molecular Signatures Database (MSigDB). Setting false discovery rate (FDR) threshold as 0.05, we identified 13 significantly associated GO terms. Additionally, 17 terms were further included as marginally associated because they were top ranked by each method, although their FDR is higher than 0.05. In total, we identified 30 promising GO terms, including ‘Sphingoid metabolic process,’ ‘Ubiquitin protein ligase activity,’ ‘Regulation of cytokine secretion,’ and ‘Ceramide metabolic process.’ These GO terms encompass broad functions that potentially interact and contribute to the oral immune response related to caries development, which have not been reported in the standard single marker based analysis. Collectively, our gene set enrichment analysis provided complementary insights into the molecular mechanisms and polygenic interactions in dental caries, revealing promising association signals that could not be detected through single marker analysis of GWAS data. 相似文献
993.
Background
Haplotype analysis of closely associated markers has proven to be a powerful tool in kinship analysis, especially when short tandem repeats (STR) fail to resolve uncertainty in relationship analysis. STR located on the X chromosome show stronger linkage disequilibrium compared with autosomal STR. So, it is necessary to estimate the haplotype frequencies directly from population studies as linkage disequilibrium is population-specific.Methodology and Findings
Twenty-six X-STR loci including six clusters of linked markers DXS6807-DXS8378-DXS9902(Xp22), DXS7132-DXS10079-DXS10074-DXS10075-DXS981 (Xq12), DXS6801-DXS6809-DXS6789-DXS6799(Xq21), DXS7424-DXS101-DXS7133(Xq22), DXS6804-GATA172D05(Xq23), DXS8377-DXS7423 (Xq28) and the loci DXS6800, DXS6803, DXS9898, GATA165B12, DXS6854, HPRTB and GATA31E08 were typed in four nationality (Han, Uigur, Kazakh and Mongol) samples from China (n = 1522, 876 males and 646 females). Allele and haplotype frequency as well as linkage disequilibrium data for kinship calculation were observed. The allele frequency distribution among different populations was compared. A total of 5–20 alleles for each locus were observed and altogether 289 alleles for all the selected loci were found. Allele frequency distribution for most X-STR loci is different in different populations. A total of 876 male samples were investigated by haplotype analysis and for linkage disequilibrium. A total of 89, 703, 335, 147, 39 and 63 haplotypes were observed. Haplotype diversity was 0.9584, 0.9994, 0.9935, 0.9736, 0.9427 and 0.9571 for cluster I, II, III, IV, V and VI, respectively. Eighty-two percent of the haplotype of cluster IIwas found only once. And 94% of the haplotype of cluster III show a frequency of <1%.Conclusions
These results indicate that allele frequency distribution for most X-STR loci is population-specific and haplotypes of six clusters provide a powerful tool for kinship testing and relationship investigation. So it is necessary to obtain allele frequency and haplotypes data of the linked loci for forensic application. 相似文献994.
995.
Niloufar Fozouni Michael Chopp Siamak P. Nejad-Davarani Zheng Gang Zhang Norman L. Lehman Steven Gu Yuji Ueno Mei Lu Guangliang Ding Lian Li Jiani Hu Hassan Bagher-Ebadian David Hearshen Quan Jiang 《PloS one》2013,8(10)
Background
To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon''s entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat.Methods
Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities'' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining.Results
Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining.Conclusions
Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease. 相似文献996.
Jia-fu Feng Ling Qiu Lin Zhang Xue-mei Li Yu-wei Yang Ping Zeng Xiu-zhi Guo Yan Qin Hong-chun Liu Xing-min Han Yan-peng Li Wei Xu Shu-yan Sun Li-qiang Wang Hui Quan Li-jun Xia Hong-zhang Hu Fang-cai Zhong Rong Duan 《PloS one》2013,8(3)
Objective
To establish equations for the estimation of glomerular filtration rates (eGFRs) based on serum creatinine (SCr) and/or serum cystatin C (SCysC) in Chinese patients with chronic kidney disease (CKD), and to compare the new equations with both the reference GFR (rGFR) and the literature equations to evaluate their applicability.Methods
The 788 Chinese CKD patients were randomly divided into two groups, the training group and the testing group, to establish new eGFR-formulas based on serum CysC and to validate the established formulas, respectively. 99mTc-DTPA clearance (as the rGFR), serum Cr, and serum CysC were determined for all patients, and GFR was calculated using the Cockcroft-Gault equation (eGFR1), the MDRD formula (eGFR2), the CKD-EPI formulas (eGFR3, eGFR4), and the Chinese eGFR Investigation Collaboration formulas (eGFR5, eGFR6). The accuracy of each eGFR was compared with the rGFR.Results
The training and testing groups'' mean GFRs were 50.84±31.36 mL/min/1.73 m2 and 54.16±29.45 mL/min/1.73 m2, respectively. The two newly developed eGFR formulas were fitted using iterative computation: and . Significant correlation was observed between each eGFR and the rGFR. However, proportional errors and constant errors were observed between rGFR and eGFR1, eGFR2, eGFR4, eGFR5 or eGFR6, and constant errors were observed between eGFR3 and rGFR, as revealed by the Passing & Bablok plot analysis. The Bland-Altman analysis illustrated that the 95% limits of agreement of all equations exceeded the previously accepted limits of <60 mL/min •1.73 m2, except the equations of eGFR7 and eGFR8.Conclusion
The newly developed formulas, eGFR7 and eGFR8, provide precise and accurate GFR estimation using serum CysC detection alone or in combination with serum Cr detection. Differences in detection methods should be carefully considered when choosing literature eGFR equations to avoid misdiagnosis and mistreatment. 相似文献997.
Lina Wang Chunshan Quan Baoquan Liu Jianfeng Wang Wen Xiong Pengchao Zhao Shengdi Fan 《PloS one》2013,8(11)
The integral membrane protein AgrC is a histidine kinase whose sensor domains interact with an autoinducing peptide, resulting in a series of downstream responses. In this study, truncated AgrCTM5-6C and AgrCTM5-6C-GFP with GFP as a reporter gene were produced using a bacterial system. Purified AgrCTM5-6C and AgrCTM5-6C-GFP were reconstituted into liposomes by a detergent-mediated method. To achieve high-yield protein incorporation, we investigated the effect of different detergents on protein reconstitution efficiency. The highest incorporation was found with N,N-dimethyldode-cylamine N-oxide during complete liposome solubilization, which resulted in a yield of 85±5%. The COOH-terminus of the protein AgrCTM5-6C was almost exclusively oriented towards the inside of the vesicles. AgrCTM5-6C in proteoliposomes exhibited approximately a 6-fold increase in constitutive activity compared with AgrCTM5-6C in detergent micelles. The reconstitution of AgrCTM5-6C or AgrCTM5-6C-GFP was characterized using dynamic light scattering, fluorescence microscopy, and transmission electron microscopy. Based on the results, the optimal conditions for protein incorporation were defined. These findings contribute to the study of membrane protein structure and function in vitro using a reconstitution system. 相似文献
998.
Christelle Moreau Qun Liu Richard Graeff Gerd K. Wagner Mark P. Thomas Joanna M. Swarbrick Satoshi Shuto Hon Cheung Lee Quan Hao Barry V. L. Potter 《PloS one》2013,8(6)
Few inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca2+-mobilizing second messenger cyclic adenosine 5′-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5′-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 µM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 µM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 µM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR “northern” ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5′-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 µM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design. 相似文献
999.
Dapeng Yan Heming Quan Lin Wang Feng Liu Haipeng Liu Jianxia Chen Xuetao Cao Baoxue Ge 《Cellular signalling》2013,25(9):1887-1894
Immune responses to pathogens are regulated by immune receptors containing either an immunoreceptor tyrosine-based activation motif (ITAM) or an immunoreceptor tyrosine-based inhibitory motif (ITIM). The important diarrheal pathogen enteropathogenic Escherichia coli (EPEC) require delivery and insertion of the bacterial translocated intimin receptor (Tir) into the host plasma membrane for pedestal formation. The C-terminal region of Tir, encompassing Y483 and Y511, shares sequence similarity with cellular ITIMs. Here, we show that EPEC Tir suppresses the production of inflammatory cytokines by recruitment of SHP-2 and subsequent deubiquitination of TRAF6 in an ITIM dependent manner. Our findings revealed a novel mechanism by which the EPEC utilize its ITIM motifs to suppress and evade the host innate immune response, which could lead to the development of novel therapeutics to prevent bacterial infection. 相似文献
1000.
Yangfeng Peng Quan He Bin Zuo Haibo Niu Tianzhong Tong Hongliang Zhao 《Chirality》2013,25(12):952-956
Enantioselective liquid–liquid extraction of zopiclone was conducted by employing a series of (R)‐mandelic acid esters as chiral extractants. The effects of concentration of extractant, concentration of zopiclone, type of organic solvent, pH value, and temperature on the extraction efficiency were investigated. (R)‐o‐chloromandelic acid propyl ester was demonstrated to be an efficient chiral extractant for zopiclone resolution with a maximum enantioselectivity of 1.6. Chirality 25:952–956, 2013. © 2013 Wiley Periodicals, Inc. 相似文献