全文获取类型
收费全文 | 9988篇 |
免费 | 756篇 |
国内免费 | 2篇 |
专业分类
10746篇 |
出版年
2024年 | 7篇 |
2023年 | 54篇 |
2022年 | 158篇 |
2021年 | 250篇 |
2020年 | 156篇 |
2019年 | 177篇 |
2018年 | 245篇 |
2017年 | 187篇 |
2016年 | 338篇 |
2015年 | 552篇 |
2014年 | 639篇 |
2013年 | 733篇 |
2012年 | 912篇 |
2011年 | 831篇 |
2010年 | 536篇 |
2009年 | 513篇 |
2008年 | 652篇 |
2007年 | 603篇 |
2006年 | 535篇 |
2005年 | 440篇 |
2004年 | 444篇 |
2003年 | 396篇 |
2002年 | 360篇 |
2001年 | 157篇 |
2000年 | 105篇 |
1999年 | 121篇 |
1998年 | 66篇 |
1997年 | 67篇 |
1996年 | 39篇 |
1995年 | 46篇 |
1994年 | 41篇 |
1993年 | 40篇 |
1992年 | 44篇 |
1991年 | 34篇 |
1990年 | 29篇 |
1989年 | 27篇 |
1988年 | 24篇 |
1987年 | 12篇 |
1986年 | 14篇 |
1985年 | 12篇 |
1984年 | 11篇 |
1983年 | 8篇 |
1982年 | 11篇 |
1981年 | 6篇 |
1979年 | 9篇 |
1978年 | 9篇 |
1977年 | 6篇 |
1974年 | 11篇 |
1973年 | 6篇 |
1969年 | 8篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Rajkumar Dorajoo Ruoying Li Mohammad Kamran Ikram Jianjun Liu Philippe Froguel Jeannette Lee Xueling Sim Rick Twee-Hee Ong Wan Ting Tay Chen Peng Terri L. Young Alexandra I. F. Blakemore Ching Yu Cheng Tin Aung Paul Mitchell Jie Jin Wang Caroline C. Klaver Eric Boerwinkle Ronald Klein David S. Siscovick Richard A. Jensen Vilmundur Gudnason Albert Vernon Smith Yik Ying Teo Tien Yin Wong E-Shyong Tai Chew-Kiat Heng Yechiel Friedlander 《PloS one》2013,8(7)
Introduction
C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations.Methods
Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry.Results
Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10−8) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058).Conclusions
Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease. 相似文献992.
阿哈湖深层水中微生物和硫酸还原菌数量及群落结构空间变化 总被引:2,自引:0,他引:2
采用荧光原位杂交法分析了贵州阿哈湖深层水环境中总微生物、真细菌和硫酸盐还原菌数量。结果表明:该湖水中微生物总量为1.6×107个.L-1,真细菌占微生物总量的52.9%,且微生物总量和真细菌数量垂直变化无明显差异。随着水体深度的增加,活性微生物数量增加,且微生物的群落结构更加复杂。阿哈湖深层水体中有一定数量的硫酸盐还原菌存在。 相似文献
993.
Mohammed-Amin Madoui Stefan Engelen Corinne Cruaud Caroline Belser Laurie Bertrand Adriana Alberti Arnaud Lemainque Patrick Wincker Jean-Marc Aury 《BMC genomics》2015,16(1)
Background
Long-read sequencing technologies were launched a few years ago, and in contrast with short-read sequencing technologies, they offered a promise of solving assembly problems for large and complex genomes. Moreover by providing long-range information, it could also solve haplotype phasing. However, existing long-read technologies still have several limitations that complicate their use for most research laboratories, as well as in large and/or complex genome projects. In 2014, Oxford Nanopore released the MinION® device, a small and low-cost single-molecule nanopore sequencer, which offers the possibility of sequencing long DNA fragments.Results
The assembly of long reads generated using the Oxford Nanopore MinION® instrument is challenging as existing assemblers were not implemented to deal with long reads exhibiting close to 30% of errors. Here, we presented a hybrid approach developed to take advantage of data generated using MinION® device. We sequenced a well-known bacterium, Acinetobacter baylyi ADP1 and applied our method to obtain a highly contiguous (one single contig) and accurate genome assembly even in repetitive regions, in contrast to an Illumina-only assembly. Our hybrid strategy was able to generate NaS (Nanopore Synthetic-long) reads up to 60 kb that aligned entirely and with no error to the reference genome and that spanned highly conserved repetitive regions. The average accuracy of NaS reads reached 99.99% without losing the initial size of the input MinION® reads.Conclusions
We described NaS tool, a hybrid approach allowing the sequencing of microbial genomes using the MinION® device. Our method, based ideally on 20x and 50x of NaS and Illumina reads respectively, provides an efficient and cost-effective way of sequencing microbial or small eukaryotic genomes in a very short time even in small facilities. Moreover, we demonstrated that although the Oxford Nanopore technology is a relatively new sequencing technology, currently with a high error rate, it is already useful in the generation of high-quality genome assemblies.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1519-z) contains supplementary material, which is available to authorized users. 相似文献994.
Karoline Schousboe Gonneke Willemsen Kirsten O Kyvik Jakob Mortensen Dorret I Boomsma Belinda K Cornes Chayna J Davis Corrado Fagnani Jacob Hjelmborg Jaakko Kaprio Marlies De Lange Michelle Luciano Nicholas G Martin Nancy Pedersen Kirsi H Pietil?inen Aila Rissanen Suoma Saarni Thorkild I A S?rensen G Caroline M Van Baal Jennifer R Harris 《Twin research》2003,6(5):409-421
Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects. 相似文献
995.
996.
Lars Dölken Georg Malterer Florian Erhard Sheila Kothe Caroline C. Friedel Guillaume Suffert Lisa Marcinowski Natalie Motsch Stephanie Barth Michaela Beitzinger Diana Lieber Susanne M. Bailer Reinhard Hoffmann Zsolt Ruzsics Elisabeth Kremmer Sébastien Pfeffer Ralf Zimmer Ulrich H. Koszinowski Friedrich Grässer Gunter Meister Jürgen Haas 《Cell host & microbe》2010,7(4):324-334
997.
Jesse Hudson Jacqueline R. Ha Valerie Sabourin Ryuhjin Ahn Rachel La Selva Julie Livingstone Lauren Podmore Jennifer Knight Laura Forrest Nicole Beauchemin Michael Hallett Morag Park Josie Ursini-Siegel 《Molecular and cellular biology》2014,34(19):3689-3701
Breast cancers are stratified into distinct subtypes, which influence therapeutic responsiveness and patient outcome. Patients with luminal breast cancers are often associated with a better prognosis relative to that with other subtypes. However, subsets of patients with luminal disease remain at increased risk of cancer-related death. A critical process that increases the malignant potential of breast cancers is the epithelial-to-mesenchymal transition (EMT). The p66ShcA adaptor protein stimulates the formation of reactive oxygen species in response to stress stimuli. In this paper, we report a novel role for p66ShcA in inducing an EMT in HER2+ luminal breast cancers. p66ShcA increases the migratory properties of breast cancer cells and enhances signaling downstream of the Met receptor tyrosine kinase in these tumors. Moreover, Met activation is required for a p66ShcA-induced EMT in luminal breast cancer cells. Finally, elevated p66ShcA levels are associated with the acquisition of an EMT in primary breast cancers spanning all molecular subtypes, including luminal tumors. This is of high clinical relevance, as the luminal and HER2 subtypes together comprise 80% of all newly diagnosed breast cancers. This study identifies p66ShcA as one of the first prognostic biomarkers for the identification of more aggressive tumors with mesenchymal properties, regardless of molecular subtype. 相似文献
998.
Transmodulation between phospholipase D and c-Src enhances cell proliferation 总被引:4,自引:0,他引:4 下载免费PDF全文
Ahn BH Kim SY Kim EH Choi KS Kwon TK Lee YH Chang JS Kim MS Jo YH Min DS 《Molecular and cellular biology》2003,23(9):3103-3115
Phospholipase D (PLD) has been implicated in the signal transduction pathways initiated by several mitogenic protein tyrosine kinases. We demonstrate for the first time that most notably PLD2 and to a lesser extent the PLD1 isoform are tyrosine phosphorylated by c-Src tyrosine kinase via direct association. Moreover, epidermal growth factor induced tyrosine phosphorylation of PLD2 and its interaction with c-Src in A431 cells. Interaction between these proteins is via the pleckstrin homology domain of PLD2 and the catalytic domain of c-Src. Coexpression of PLD1 or PLD2 with c-Src synergistically enhances cellular proliferation compared with expression of either molecule. While PLD activity as a lipid-hydrolyzing enzyme is not affected by c-Src, wild-type PLDs but not catalytically inactive PLD mutants significantly increase c-Src kinase activity, up-regulating c-Src-mediated paxillin phosphorylation and extracellular signal-regulated kinase activity. These results demonstrate the critical role of PLD catalytic activity in the stimulation of Src signaling. In conclusion, we provide the first evidence that c-Src acts as a kinase of PLD and PLD acts as an activator of c-Src. This transmodulation between c-Src and PLD may contribute to the promotion of cellular proliferation via amplification of mitogenic signaling pathways. 相似文献
999.
Hong H Coutanceau E Leclerc M Caleechurn L Leadlay PF Demangel C 《PLoS neglected tropical diseases》2008,2(10):e325
Background
Buruli ulcer (BU) is a progressive disease of subcutaneous tissues caused by Mycobacterium ulcerans. The pathology of BU lesions is associated with the local production of a diffusible substance, mycolactone, with cytocidal and immunosuppressive properties. The defective inflammatory responses in BU lesions reflect these biological properties of the toxin. However, whether mycolactone diffuses from infected tissues and suppresses IFN-γ responses in BU patients remains unclear.Methodology/Principal Findings
Here we have investigated the pharmacodistribution of mycolactone following injection in animal models by tracing a radiolabeled form of the toxin, and by directly quantifying mycolactone in lipid extracts from internal organs and cell subpopulations. We show that subcutaneously delivered mycolactone diffused into mouse peripheral blood and accumulated in internal organs with a particular tropism for the spleen. When mice were infected subcutaneously with M. ulcerans, this led to a comparable pattern of distribution of mycolactone. No evidence that mycolactone circulated in blood serum during infection could be demonstrated. However, structurally intact toxin was identified in the mononuclear cells of blood, lymph nodes and spleen several weeks before ulcerative lesions appear. Importantly, diffusion of mycolactone into the blood of M. ulcerans–infected mice coincided with alterations in the functions of circulating lymphocytes.Conclusion
In addition to providing the first evidence that mycolactone diffuses beyond the site of M. ulcerans infection, our results support the hypothesis that the toxin exerts immunosuppressive effects at the systemic level. Furthermore, they suggest that assays based on mycolactone detection in circulating blood cells may be considered for diagnostic tests of early disease. 相似文献1000.
Rosie A. Fisher Charles D. Koven William R. L. Anderegg Bradley O. Christoffersen Michael C. Dietze Caroline E. Farrior Jennifer A. Holm George C. Hurtt Ryan G. Knox Peter J. Lawrence Jeremy W. Lichstein Marcos Longo Ashley M. Matheny David Medvigy Helene C. Muller‐Landau Thomas L. Powell Shawn P. Serbin Hisashi Sato Jacquelyn K. Shuman Benjamin Smith Anna T. Trugman Toni Viskari Hans Verbeeck Ensheng Weng Chonggang Xu Xiangtao Xu Tao Zhang Paul R. Moorcroft 《Global Change Biology》2018,24(1):35-54
Numerous current efforts seek to improve the representation of ecosystem ecology and vegetation demographic processes within Earth System Models (ESMs). These developments are widely viewed as an important step in developing greater realism in predictions of future ecosystem states and fluxes. Increased realism, however, leads to increased model complexity, with new features raising a suite of ecological questions that require empirical constraints. Here, we review the developments that permit the representation of plant demographics in ESMs, and identify issues raised by these developments that highlight important gaps in ecological understanding. These issues inevitably translate into uncertainty in model projections but also allow models to be applied to new processes and questions concerning the dynamics of real‐world ecosystems. We argue that stronger and more innovative connections to data, across the range of scales considered, are required to address these gaps in understanding. The development of first‐generation land surface models as a unifying framework for ecophysiological understanding stimulated much research into plant physiological traits and gas exchange. Constraining predictions at ecologically relevant spatial and temporal scales will require a similar investment of effort and intensified inter‐disciplinary communication. 相似文献