全文获取类型
收费全文 | 1035篇 |
免费 | 61篇 |
国内免费 | 1篇 |
专业分类
1097篇 |
出版年
2023年 | 4篇 |
2022年 | 11篇 |
2021年 | 13篇 |
2020年 | 5篇 |
2019年 | 9篇 |
2018年 | 22篇 |
2017年 | 12篇 |
2016年 | 28篇 |
2015年 | 44篇 |
2014年 | 51篇 |
2013年 | 58篇 |
2012年 | 76篇 |
2011年 | 83篇 |
2010年 | 71篇 |
2009年 | 48篇 |
2008年 | 68篇 |
2007年 | 66篇 |
2006年 | 64篇 |
2005年 | 57篇 |
2004年 | 54篇 |
2003年 | 58篇 |
2002年 | 53篇 |
2001年 | 10篇 |
2000年 | 5篇 |
1999年 | 9篇 |
1998年 | 15篇 |
1997年 | 8篇 |
1996年 | 7篇 |
1995年 | 5篇 |
1994年 | 4篇 |
1993年 | 9篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 9篇 |
1988年 | 5篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 7篇 |
1984年 | 3篇 |
1982年 | 6篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1962年 | 1篇 |
1959年 | 1篇 |
1957年 | 2篇 |
排序方式: 共有1097条查询结果,搜索用时 0 毫秒
51.
Melanie K Bothe Josephine Braun Lars Mundhenk Achim D Gruber 《The journal of histochemistry and cytochemistry》2008,56(5):495-509
The CLCA family of proteins consists of a growing number of structurally and functionally diverse members with distinct expression patterns in different tissues. Several CLCA homologs have been implicated in diseases with secretory dysfunctions in the respiratory and intestinal tracts. Here we present biochemical protein characterization and details on the cellular and subcellular expression pattern of the murine mCLCA6 using specific antibodies directed against the amino- and carboxy-terminal cleavage products of mCLCA6. Computational and biochemical characterizations revealed protein processing and structural elements shared with hCLCA2 including anchorage in the apical cell membrane by a transmembrane domain in the carboxy-terminal subunit. A systematic light- and electron-microscopic immunolocalization found mCLCA6 to be associated with the microvilli of non-goblet cell enterocytes in the murine small and large intestine but in no other tissues. The expression pattern was confirmed by quantitative RT-PCR following laser-capture microdissection of relevant tissues. Confocal laser scanning microscopy colocalized the mCLCA6 protein with the cystic fibrosis transmembrane conductance regulator CFTR at the apical surface of colonic crypt cells. Together with previously published functional data, the results support a direct or indirect role of mCLCA6 in transepithelial anion conductance in the mouse intestine. 相似文献
52.
This paper presents a simple mathematical model for energy transport from the body into the brain and for appetite regulation. Particular properties in appetite regulation are deduced from the general observation of cyclic food intake. These particular properties are the importance of a push component, however small it may be, from the body into the brain, the dependence of the appetite activation on the energy supply level in the brain and a necessary condition for the sensitivity of this dependence. The dominant pull component in the energy transport is accompanied by a smaller push component managing this information transport. The properties listed above correspond to physiological observations. For instance, sensitivity is found in the postnatal development of projections between neuropeptide Y (NPY) neurons and pro-opiomelanocortin (POMC) neurons, which release, respectively, the appetite-amplifying and -reducing neuropeptides NPY and α-melanocyte-stimulating hormone at their nerve terminals. The development of these projections determines the change from the permanent feeding of the foetus into the cyclic ingestive behaviour in later life. The correspondence verifies the mathematically-deduced properties, justifies the simple model and supports the technique of the deductive functional assignment. 相似文献
53.
Achim Brockmeier Manuel Skopnik Brigitte Koch Christian Herrmann Stefan Welti Klaus Scheffzek 《Biochemical and biophysical research communications》2009,388(4):630-636
Eubacteria can import and simultaneously phosphorylate a range of different carbohydrates by means of sugar specific phosphoenolpyruvate (PEP) dependent sugar phosphotransferase systems (PTSs). Here, we report the biochemical characterization of the gluconate specific PTS component EIIAgnt from Enterococcus faecalis and its unexpectedly strong complex with EIIBgnt. We analyze the activity of the complex regarding phosphoryl transfer using kinetic measurements and demonstrate by mutagenesis that His-9 of EIIAgnt is essential for this process and represents most likely the phosphoryl group carrier of EIIAgnt. With a combination of isothermal titration calorimetry (ITC), analytical ultracentrifugation (AUC), native gel electrophoresis and chemical crosslinking experiments we show that EIIAgnt and EIIBgnt form a strong 2:2 heterotetrameric complex, which seems to be destabilized upon phosphorylation of EIIBgnt. 相似文献
54.
Hauser S Bickel L Weinspach D Gerg M Schäfer MK Pfeifer M Hazin J Schelter F Weidle UH Ramser J Volkmann J Meindl A Schmitt M Schrötzlmair F Altevogt P Krüger A 《PloS one》2011,6(4):e18989
Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression. 相似文献
55.
Boltz A Piater B Toleikis L Guenther R Kolmar H Hock B 《The Journal of biological chemistry》2011,286(24):21896-21905
Antibody-dependent cellular cytotoxicity plays a pivotal role in antibody-based tumor therapies and is based on the recruitment of natural killer cells to antibody-bound tumor cells via binding of the Fcγ receptor III (CD16). Here we describe the generation of chimeric DNA aptamers that simultaneously bind to CD16α and c-Met, a receptor that is overexpressed in many tumors. By application of the systematic evolution of ligands by exponential enrichment (SELEX) method, CD16α specific DNA aptamers were isolated that bound with high specificity and affinity (91 pm-195 nm) to their respective recombinant and cellularly expressed target proteins. Two optimized CD16α specific aptamers were coupled to each of two c-Met specific aptamers using different linkers. Bi-specific aptamers retained suitable binding properties and displayed simultaneous binding to both antigens. Moreover, they mediated cellular cytotoxicity dependent on aptamer and effector cell concentration. Displacement of a bi-specific aptamer from CD16α by competing antibody 3G8 reduced cytotoxicity and confirmed the proposed mode of action. These results represent the first gain of a tumor-effective function of two distinct oligonucleotides by linkage into a bi-specific aptamer mediating cellular cytotoxicity. 相似文献
56.
57.
58.
59.
Jürgen?E?Schneider Jens?B?se Simon?D?Bamforth Achim?D?Gruber Carol?Broadbent Kieran?Clarke Stefan?Neubauer Andreas?LengelingEmail author Shoumo?BhattacharyaEmail author 《BMC developmental biology》2004,4(1):16
Background
Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo. 相似文献60.
Solution stability and degradation pathway of deoxyribonucleoside phosphoramidites in acetonitrile 总被引:1,自引:0,他引:1
Krotz AH Rentel C Gorman D Olsen P Gaus HJ McArdle JV Scozzari AN 《Nucleosides, nucleotides & nucleic acids》2004,23(5):767-775
The impuritiy profiles of acetonitrile solutions of the four standard O-cyanoethyl-N,N-diisopropyl-phosphoramidites of 5'-O-dimethoxytrityl (DMT) protected deoxyribonucleosides (dG(ib), dA(bz), dC(bz), T) were analyzed by HPLC-MS. The solution stability of the phosphoramidites decreases in the order T, dC>dA>dG. After five weeks storage under inert gas atmosphere the amidite purity was reduced by 2% (T, dC), 6% (dA), and 39% (dG), respectively. The main degradation pathways involve hydrolysis, elimination of acrylonitrile and autocatalytic acrylonitrile-induced formation of cyanoethyl phosphonoamidates. Consequently, the rate of degradation is reduced by reducing the water concentration in solution with molecular sieves and by lowering the amidite concentration. Acid-catalyzed hydrolysis could also be reduced by addition of small amounts of base. 相似文献