全文获取类型
收费全文 | 2426篇 |
免费 | 254篇 |
专业分类
2680篇 |
出版年
2023年 | 12篇 |
2022年 | 24篇 |
2021年 | 46篇 |
2020年 | 38篇 |
2019年 | 40篇 |
2018年 | 46篇 |
2017年 | 49篇 |
2016年 | 64篇 |
2015年 | 108篇 |
2014年 | 117篇 |
2013年 | 128篇 |
2012年 | 199篇 |
2011年 | 162篇 |
2010年 | 93篇 |
2009年 | 85篇 |
2008年 | 152篇 |
2007年 | 134篇 |
2006年 | 109篇 |
2005年 | 126篇 |
2004年 | 123篇 |
2003年 | 122篇 |
2002年 | 114篇 |
2001年 | 42篇 |
2000年 | 18篇 |
1999年 | 28篇 |
1998年 | 33篇 |
1997年 | 32篇 |
1996年 | 17篇 |
1995年 | 21篇 |
1994年 | 22篇 |
1993年 | 27篇 |
1992年 | 19篇 |
1991年 | 17篇 |
1990年 | 19篇 |
1989年 | 21篇 |
1988年 | 11篇 |
1987年 | 11篇 |
1986年 | 11篇 |
1985年 | 14篇 |
1984年 | 15篇 |
1983年 | 17篇 |
1981年 | 13篇 |
1980年 | 12篇 |
1979年 | 13篇 |
1977年 | 9篇 |
1974年 | 11篇 |
1973年 | 11篇 |
1971年 | 12篇 |
1967年 | 7篇 |
1966年 | 8篇 |
排序方式: 共有2680条查询结果,搜索用时 15 毫秒
81.
82.
Frequent Long-Range Epigenetic Silencing of Protocadherin Gene Clusters on Chromosome 5q31 in Wilms' Tumor 下载免费PDF全文
Anthony R. Dallosso Anne L. Hancock Marianna Szemes Kim Moorwood Laxmi Chilukamarri Hsin-Hao Tsai Abby Sarkar Jonathan Barasch Raisa Vuononvirta Chris Jones Kathy Pritchard-Jones Brigitte Royer-Pokora Sean Bong Lee Ceris Owen Sally Malik Yi Feng Marcus Frank Andrew Ward Keith W. Brown Karim Malik 《PLoS genetics》2009,5(11)
Wilms'' tumour (WT) is a pediatric tumor of the kidney that arises via failure of the fetal developmental program. The absence of identifiable mutations in the majority of WTs suggests the frequent involvement of epigenetic aberrations in WT. We therefore conducted a genome-wide analysis of promoter hypermethylation in WTs and identified hypermethylation at chromosome 5q31 spanning 800 kilobases (kb) and more than 50 genes. The methylated genes all belong to α-, β-, and γ-protocadherin (PCDH) gene clusters (Human Genome Organization nomenclature PCDHA@, PCDHB@, and PCDHG@, respectively). This demonstrates that long-range epigenetic silencing (LRES) occurs in developmental tumors as well as in adult tumors. Bisulfite polymerase chain reaction analysis showed that PCDH hypermethylation is a frequent event found in all Wilms'' tumor subtypes. Hypermethylation is concordant with reduced PCDH expression in tumors. WT precursor lesions showed no PCDH hypermethylation, suggesting that de novo PCDH hypermethylation occurs during malignant progression. Discrete boundaries of the PCDH domain are delimited by abrupt changes in histone modifications; unmethylated genes flanking the LRES are associated with permissive marks which are absent from methylated genes within the domain. Silenced genes are marked with non-permissive histone 3 lysine 9 dimethylation. Expression analysis of embryonic murine kidney and differentiating rat metanephric mesenchymal cells demonstrates that Pcdh expression is developmentally regulated and that Pcdhg@ genes are expressed in blastemal cells. Importantly, we show that PCDHs negatively regulate canonical Wnt signalling, as short-interfering RNA–induced reduction of PCDHG@ encoded proteins leads to elevated β-catenin protein, increased β-catenin/T-cell factor (TCF) reporter activity, and induction of Wnt target genes. Conversely, over-expression of PCDHs suppresses β-catenin/TCF-reporter activity and also inhibits colony formation and growth of cancer cells in soft agar. Thus PCDHs are candidate tumor suppressors that modulate regulatory pathways critical in development and disease, such as canonical Wnt signaling. 相似文献
83.
Qi L Davis AS Jagger BW Schwartzman LM Dunham EJ Kash JC Taubenberger JK 《Journal of virology》2012,86(17):9211-9220
The 1918-1919 "Spanish" influenza pandemic is estimated to have caused 50 million deaths worldwide. Understanding the origin, virulence, and pathogenic properties of past pandemic influenza viruses, including the 1918 virus, is crucial for current public health preparedness and future pandemic planning. The origin of the 1918 pandemic virus has not been resolved, but its coding sequences are very like those of avian influenza virus. The proteins encoded by the 1918 virus differ from typical low-pathogenicity avian influenza viruses at only a small number of amino acids in each open reading frame. In this study, a series of chimeric 1918 influenza viruses were created in which each of the eight 1918 pandemic virus gene segments was replaced individually with the corresponding gene segment of a prototypical low-pathogenicity avian influenza (LPAI) H1N1 virus in order to investigate functional compatibility of the 1918 virus genome with gene segments from an LPAI virus and to identify gene segments and mutations important for mammalian adaptation. This set of eight "7:1" chimeric viruses was compared to the parental 1918 and LPAI H1N1 viruses in intranasally infected mice. Seven of the 1918 LPAI 7:1 chimeric viruses replicated and caused disease equivalent to the fully reconstructed 1918 virus. Only the chimeric 1918 virus containing the avian influenza PB2 gene segment was attenuated in mice. This attenuation could be corrected by the single E627K amino acid change, further confirming the importance of this change in mammalian adaptation and mouse pathogenicity. While the mechanisms of influenza virus host switch, and particularly mammalian host adaptation are still only partly understood, these data suggest that the 1918 virus, whatever its origin, is very similar to avian influenza virus. 相似文献
84.
85.
86.
Brian Ponnaiya Sally A. Amundson Shanaz A. Ghandhi Lubomir B. Smilenov Charles R. Geard Manuela Buonanno David J. Brenner 《Radiation and environmental biophysics》2013,52(4):523-530
While gene expression studies have proved extremely important in understanding cellular processes, it is becoming more apparent that there may be differences in individual cells that are missed by studying the population as a whole. We have developed a qRT-PCR protocol that allows us to assay multiple gene products in small samples, starting at 100 cells and going down to a single cell, and have used it to study radiation responses at the single-cell level. Since the accuracy of qRT-PCR depends greatly on the choice of “housekeeping” genes used for normalization, initial studies concentrated on determining the optimal panel of such genes. Using an endogenous control array, it was found that for IMR90 cells, common housekeeping genes tend to fall into one of two categories—those that are relatively stably expressed regardless of the number of cells in the sample, e.g., B2M, PPIA, and GAPDH, and those that are more variable (again regardless of the size of the population), e.g., YWHAZ, 18S, TBP, and HPRT1. Further, expression levels in commonly studied radiation-response genes, such as ATF3, CDKN1A, GADD45A, and MDM2, were assayed in 100, 10, and single-cell samples. It is here that the value of single-cell analyses becomes apparent. It was observed that the expression of some genes such as FGF2 and MDM2 was relatively constant over all irradiated cells, while that of others such as FAS was considerably more variable. It was clear that almost all cells respond to ionizing radiation but the individual responses were considerably varied. The analyses of single cells indicate that responses in individual cells are not uniform and suggest that responses observed in populations are not indicative of identical patterns in all cells. This in turn points to the value of single-cell analyses. 相似文献
87.
88.
Bindesh Shrestha Prabhakar Sripadi Brent R. Reschke Holly D. Henderson Matthew J. Powell Sally A. Moody Akos Vertes 《PloS one》2014,9(12)
Xenopus laevis eggs are used as a biological model system for studying fertilization and early embryonic development in vertebrates. Most methods used for their molecular analysis require elaborate sample preparation including separate protocols for the water soluble and lipid components. In this study, laser ablation electrospray ionization (LAESI), an ambient ionization technique, was used for direct mass spectrometric analysis of X. laevis eggs and early stage embryos up to five cleavage cycles. Single unfertilized and fertilized eggs, their animal and vegetal poles, and embryos through the 32-cell stage were analyzed. Fifty two small metabolite ions, including glutathione, GABA and amino acids, as well as numerous lipids including 14 fatty acids, 13 lysophosphatidylcholines, 36 phosphatidylcholines and 29 triacylglycerols were putatively identified. Additionally, some proteins, for example thymosin β4 (Xen), were also detected. On the subcellular level, the lipid profiles were found to differ between the animal and vegetal poles of the eggs. Radial profiling revealed profound compositional differences between the jelly coat vitelline/plasma membrane and egg cytoplasm. Changes in the metabolic profile of the egg following fertilization, e.g., the decline of polyamine content with the development of the embryo were observed using LAESI-MS. This approach enables the exploration of metabolic and lipid changes during the early stages of embryogenesis. 相似文献
89.
Drought consistently alters the composition of soil fungal and bacterial communities in grasslands from two continents 总被引:1,自引:0,他引:1 下载免费PDF全文
Raúl Ochoa‐Hueso Scott L. Collins Manuel Delgado‐Baquerizo Kelly Hamonts William T. Pockman Robert L. Sinsabaugh Melinda D. Smith Alan K. Knapp Sally A. Power 《Global Change Biology》2018,24(7):2818-2827
The effects of short‐term drought on soil microbial communities remain largely unexplored, particularly at large scales and under field conditions. We used seven experimental sites from two continents (North America and Australia) to evaluate the impacts of imposed extreme drought on the abundance, community composition, richness, and function of soil bacterial and fungal communities. The sites encompassed different grassland ecosystems spanning a wide range of climatic and soil properties. Drought significantly altered the community composition of soil bacteria and, to a lesser extent, fungi in grasslands from two continents. The magnitude of the fungal community change was directly proportional to the precipitation gradient. This greater fungal sensitivity to drought at more mesic sites contrasts with the generally observed pattern of greater drought sensitivity of plant communities in more arid grasslands, suggesting that plant and microbial communities may respond differently along precipitation gradients. Actinobateria, and Chloroflexi, bacterial phyla typically dominant in dry environments, increased their relative abundance in response to drought, whereas Glomeromycetes, a fungal class regarded as widely symbiotic, decreased in relative abundance. The response of Chlamydiae and Tenericutes, two phyla of mostly pathogenic species, decreased and increased along the precipitation gradient, respectively. Soil enzyme activity consistently increased under drought, a response that was attributed to drought‐induced changes in microbial community structure rather than to changes in abundance and diversity. Our results provide evidence that drought has a widespread effect on the assembly of microbial communities, one of the major drivers of soil function in terrestrial ecosystems. Such responses may have important implications for the provision of key ecosystem services, including nutrient cycling, and may result in the weakening of plant–microbial interactions and a greater incidence of certain soil‐borne diseases. 相似文献
90.
Sally Nordlund Andersen Dorte Bodin Dresbøll Kristian Thorup-Kristensen 《Plant and Soil》2014,378(1-2):59-72