全文获取类型
收费全文 | 6965篇 |
免费 | 550篇 |
国内免费 | 1篇 |
专业分类
7516篇 |
出版年
2023年 | 45篇 |
2022年 | 121篇 |
2021年 | 196篇 |
2020年 | 124篇 |
2019年 | 137篇 |
2018年 | 160篇 |
2017年 | 128篇 |
2016年 | 228篇 |
2015年 | 400篇 |
2014年 | 436篇 |
2013年 | 507篇 |
2012年 | 637篇 |
2011年 | 567篇 |
2010年 | 373篇 |
2009年 | 357篇 |
2008年 | 471篇 |
2007年 | 429篇 |
2006年 | 371篇 |
2005年 | 310篇 |
2004年 | 278篇 |
2003年 | 296篇 |
2002年 | 264篇 |
2001年 | 55篇 |
2000年 | 40篇 |
1999年 | 68篇 |
1998年 | 52篇 |
1997年 | 50篇 |
1996年 | 29篇 |
1995年 | 37篇 |
1994年 | 42篇 |
1993年 | 33篇 |
1992年 | 31篇 |
1991年 | 23篇 |
1990年 | 9篇 |
1989年 | 15篇 |
1988年 | 20篇 |
1987年 | 7篇 |
1986年 | 13篇 |
1984年 | 14篇 |
1983年 | 9篇 |
1982年 | 12篇 |
1981年 | 7篇 |
1979年 | 7篇 |
1978年 | 6篇 |
1977年 | 5篇 |
1976年 | 5篇 |
1974年 | 9篇 |
1973年 | 7篇 |
1970年 | 5篇 |
1969年 | 8篇 |
排序方式: 共有7516条查询结果,搜索用时 15 毫秒
81.
Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses 下载免费PDF全文
In response to transforming growth factor beta (TGF-beta), Smad4 forms complexes with activated Smad2 and Smad3, which accumulate in the nucleus, where they both positively and negatively regulate TGF-beta target genes. Mutation or deletion of Smad4 is found in about 50% of pancreatic tumors and in about 15% of colorectal tumors. As Smad4 is a central component of the TGF-beta/Smad pathway, we have determined whether Smad4 is absolutely required for all TGF-beta responses, to evaluate the effect of its loss during human tumor development. We have generated cell lines from the immortalized human keratinocyte cell line HaCaT or the pancreatic tumor cell line Colo-357, which stably express a tetracyline-inducible small interfering RNA targeted against Smad4. In response to tetracycline, Smad4 expression is effectively silenced. Large-scale microarray analysis identifies two populations of TGF-beta target genes that are distinguished by their dependency on Smad4. Some genes absolutely require Smad4 for their regulation, while others do not. Functional analysis also indicates a differential Smad4 requirement for TGF-beta-induced functions; TGF-beta-induced cell cycle arrest and migration, but not epithelial-mesenchymal transition, are abolished after silencing of Smad4. Altogether our results suggest that loss of Smad4 might promote TGF-beta-mediated tumorigenesis by abolishing tumor-suppressive functions of TGF-beta while maintaining some tumor-promoting TGF-beta responses. 相似文献
82.
Lamberto I Qin H Noberini R Premkumar L Bourgin C Riedl SJ Song J Pasquale EB 《The Biochemical journal》2012,445(1):47-56
The EphA4 receptor tyrosine kinase interacts with ephrin ligands to regulate many processes, ranging from axon guidance and nerve regeneration to cancer malignancy. Thus antagonists that inhibit ephrin binding to EphA4 could be useful for a variety of research and therapeutic applications. In the present study we characterize the binding features of three antagonistic peptides (KYL, APY and VTM) that selectively target EphA4 among the Eph receptors. Isothermal titration calorimetry analysis demonstrated that all three peptides bind to the ephrin-binding domain of EphA4 with low micromolar affinity. Furthermore, the effects of a series of EphA4 mutations suggest that the peptides interact in different ways with the ephrin-binding pocket of EphA4. Chemical-shift changes observed by NMR spectroscopy upon binding of the KYL peptide involve many EphA4 residues, consistent with extensive interactions and possibly receptor conformational changes. Additionally, systematic replacement of each of the 12 amino acids of KYL and VTM identify the residues critical for EphA4, binding. The peptides exhibit a long half-life in cell culture medium which, with their substantial binding affinity and selectivity for EphA4, makes them excellent research tools to modulate EphA4 function. 相似文献
83.
Lorenzo Galluzzi Ilio Vitale Laura Senovilla Tobias Eisenberg Didac Carmona-Gutierrez Erika Vacchelli Thomas Robert Hugues Ripoche Nora J?gemann Caroline Paccard Nicolas Servant Philippe Hupé Vladimir Lazar Philippe Dessen Emmanuel Barillot Hans Zischka Frank Madeo Guido Kroemer 《Cell cycle (Georgetown, Tex.)》2012,11(18):3472-3480
84.
Guillaume Lentendu Paulo Roberto Bressan Buosi Adalgisa Fernada Cabral Bianca Trevizan Segvia Bianca Ramos Meira Fernando Miranda Lansac‐Tha Luiz Felipe Machado Velho Camila D. Ritter Micah Dunthorn 《The Journal of eukaryotic microbiology》2019,66(4):592-599
The biodiversity and biogeography of protists inhabiting many ecosystems have been intensely studied using different sequencing approaches, but tropical ecosystems are relatively under‐studied. Here, we sampled planktonic waters from 32 lakes associated with four different river–floodplains systems in Brazil, and sequenced the DNA using a metabarcoding approach with general eukaryotic primers. The lakes were dominated by the largely free‐living Discoba (mostly the Euglenida), Ciliophora, and Ochrophyta. There was low community similarity between lakes even within the same river–floodplain. The protists inhabiting these floodplain systems comprise part of the large and relatively undiscovered diversity in the tropics. 相似文献
85.
Knowledge of the target cells is fundamental to maximise efficiency in attempts at immortalisation of specific cell types. It is also important to optimise the primary cell culture system to promote the survival of the target cell population. Other important factors that may influence the success in obtaining immortalised cells include the toxicity and efficiency of the immortalisation procedure. These can be assessed experimentally and if necessary appropriate techniques can be employed to purify the target cells. When cell lines have been established it is vital to assess them at an early stage for desired scientific and practical features as well as determining their stability and life-span. Furthermore, early characterisation of cell line authenticity (e.g. genetic characters, species of origin) and quality control testing will avoid wasted time and resources should contamination with micro-organisms or another cell line occur. Establishing a programme of immortalisation is a serious undertaking that should only be considered when there are no candidate continuous cell lines available. However, new approaches to modify the biology of cells to give extended life-span, whilst retaining the characteristics of differentiated cells in vivo, will hopefully provide valuable new substrates for in vitro toxicology. 相似文献
86.
87.
Mitochondrial dysfunction in a transgenic mouse model expressing human amyloid precursor protein (APP) with the Arctic mutation 下载免费PDF全文
88.
Isabelle Huvent Amina Kamah François-Xavier Cantrelle Nicolas Barois Christian Slomianny Caroline Smet-Nocca Isabelle Landrieu Guy Lippens 《Biochemical and biophysical research communications》2014
We study the aggregation of a fragment of the neuronal protein Tau that contains part of the proline rich domain and of the microtubule binding repeats. When incubated at 37 °C with heparin, the fragment readily forms fibers as witnessed by Thioflavin T fluorescence. Electron microscopy and NMR spectroscopy show bundled ribbon like structures with most residues rigidly incorporated in the fibril. Without its cysteines, this fragment still forms fibers of a similar morphology, but with lesser Thioflavin T binding sites and more mobility for the C-terminal residues. 相似文献
89.
The chemical forms of phosphorus (P) in sediments are routinely measured in studies of P in modern and ancient marine environments. However, samples for such analyses are often exposed to atmospheric oxygen during storage and handling. Recent work suggests that long-term exposure of pyrite-bearing sediments can lead to a decline in apatite P and an increase in ferric Fe-bound P. Here, we report on alterations in P speciation in reducing modern Baltic Sea sediments that we deliberately exposed to atmospheric oxygen for a period of either one week or one year. During oxidation of the sediment, extensive changes occurred in all measured P reservoirs. Exchangeable P all but disappeared during the first week of exposure, likely reflecting adsorption of porewater PO4 by Fe(III) (oxyhydr)oxides (i.e. ferric Fe-bound P formation). Detrital and organic P were also rapidly affected: decreases in both reservoirs were already observed after the first week of exposure to atmospheric oxygen. This was likely because of acidic dissolution of detrital apatite and oxidation of organic matter, respectively. These processes produced dissolved PO4 that was then scavenged by Fe(III) (oxyhydr)oxides. Interestingly, P in authigenic calcium phosphates (i.e. apatite: authigenic Ca-P) remained unaffected after the first week of exposure, which we attributed to the shielding effect of microfossils in which authigenic Ca-P occurs in Baltic Sea sediments. This effect was transient; a marked decrease in the authigenic Ca-P pool was observed in the sediments after one year of exposure to oxygen. In summary, we show that handling and storage of wet sediments under oxic conditions can lead to rapid and extensive alteration of the original sediment P speciation. 相似文献
90.
Franziska Heidemann Anna Schildt Katharina Schmid Oliver T. Bruns Kristoffer Riecken Caroline Jung Harald Ittrich Daniel Wicklein Rudolph Reimer Boris Fehse Joerg Heeren Georg Lüers Udo Schumacher Markus Heine 《PloS one》2014,9(4)
Metastasis formation is the major reason for the extremely poor prognosis in small cell lung cancer (SCLC) patients. The molecular interaction partners regulating metastasis formation in SCLC are largely unidentified, however, from other tumor entities it is known that tumor cells use the adhesion molecules of the leukocyte adhesion cascade to attach to the endothelium at the site of the future metastasis. Using the human OH-1 SCLC line as a model, we found that these cells expressed E- and P-selectin binding sites, which could be in part attributed to the selectin binding carbohydrate motif sialyl Lewis A. In addition, protein backbones known to carry these glycotopes in other cell lines including PSGL-1, CD44 and CEA could be detected in in vitro and in vivo grown OH1 SCLC cells. By intravital microscopy of murine mesenterial vasculature we could capture SCLC cells while rolling along vessel walls demonstrating that SCLC cells mimic leukocyte rolling behavior in terms of selectin and selectin ligand interaction in vivo indicating that this mechanism might indeed be important for SCLC cells to seed distant metastases. Accordingly, formation of spontaneous distant metastases was reduced by 50% when OH-1 cells were xenografted into E-/P-selectin-deficient mice compared with wild type mice (p = 0.0181). However, as metastasis formation was not completely abrogated in selectin deficient mice, we concluded that this adhesion cascade is redundant and that other molecules of this cascade mediate metastasis formation as well. Using several of these adhesion molecules as interaction partners presumably make SCLC cells so highly metastatic. 相似文献