全文获取类型
收费全文 | 287篇 |
免费 | 31篇 |
出版年
2022年 | 3篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 5篇 |
2015年 | 5篇 |
2014年 | 8篇 |
2013年 | 18篇 |
2012年 | 6篇 |
2011年 | 13篇 |
2010年 | 2篇 |
2009年 | 6篇 |
2008年 | 11篇 |
2007年 | 10篇 |
2006年 | 12篇 |
2005年 | 11篇 |
2004年 | 14篇 |
2003年 | 13篇 |
2002年 | 7篇 |
2001年 | 14篇 |
2000年 | 9篇 |
1999年 | 6篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1996年 | 8篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1986年 | 6篇 |
1985年 | 8篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 7篇 |
1979年 | 7篇 |
1978年 | 5篇 |
1975年 | 2篇 |
1974年 | 5篇 |
1973年 | 2篇 |
1972年 | 6篇 |
1969年 | 3篇 |
1966年 | 4篇 |
1955年 | 2篇 |
1954年 | 2篇 |
1935年 | 2篇 |
1924年 | 2篇 |
排序方式: 共有318条查询结果,搜索用时 171 毫秒
51.
Rhodanese activity from crude extracts of Thiobacillus sp. strain IV-85 was demonstrated in polyacrylamide gels after incubation in the reaction mixture by staining with dichloroindophenol in the presence of methylphenazonium methosulfate. The sensitivity of the staining system was found to be 8 × 10-7 moles of sulfite. 相似文献
52.
Samuel Gee John Langton Dyce Duckworth Harrison Cripps T. Lauder Brunton W. Bruce Clarke Norman Moore Anthony Bowlby Samuel West C. B. Lockwood J. A. Ormerod D'Arcy Power W. P. Herringham H. J. Waring H. H. Tooth W. McAdam Eccles A. E. Garrod R. C. Bailey James Calvert W. H. H. Jessop F. H. Champneys T. Holmes Spicer W. S. A. Griffith A. E. Cumberbatch 《BMJ (Clinical research ed.)》1903,2(2242):1622-1623
53.
54.
55.
56.
57.
58.
VanMeter AJ Rodriguez AS Bowman ED Jen J Harris CC Deng J Calvert VS Silvestri A Fredolini C Chandhoke V Petricoin EF Liotta LA Espina V 《Molecular & cellular proteomics : MCP》2008,7(10):1902-1924
Little is known about lung carcinoma epidermal growth factor (EGF) kinase pathway signaling within the context of the tissue microenvironment. We quantitatively profiled the phosphorylation and abundance of signal pathway proteins relevant to the EGF receptor within laser capture microdissected untreated, human non-small cell lung cancer (NSCLC) (n = 25) of known epidermal growth factor receptor (EGFR) tyrosine kinase domain mutation status. We measured six phosphorylation sites on EGFR to evaluate whether EGFR mutation status in vivo was associated with the coordinated phosphorylation of specific multiple phosphorylation sites on the EGFR and downstream proteins. Reverse phase protein array quantitation of NSCLC revealed simultaneous increased phosphorylation of EGFR residues Tyr-1148 (p < 0.044) and Tyr-1068 (p < 0.026) and decreased phosphorylation of EGFR Tyr-1045 (p < 0.002), HER2 Tyr-1248 (p < 0.015), IRS-1 Ser-612 (p < 0.001), and SMAD Ser-465/467 (p < 0.011) across all classes of mutated EGFR patient samples compared with wild type. To explore which subset of correlations was influenced by ligand induction versus an intrinsic phenotype of the EGFR mutants, we profiled the time course of 115 cellular signal proteins for EGF ligand-stimulated (three dosages) NSCLC mutant and wild type cultured cell lines. EGFR mutant cell lines (H1975 L858R) displayed a pattern of EGFR Tyr-1045 and HER2 Tyr-1248 phosphorylation similar to that found in tissue. Persistence of phosphorylation for AKT Ser-473 following ligand stimulation was found for the mutant. These data suggest that a higher proportion of the EGFR mutant carcinoma cells may exhibit activation of the phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (MTOR) pathway through Tyr-1148 and Tyr-1068 and suppression of IRS-1 Ser-612, altered heterodimerization with ERBB2, reduced response to transforming growth factor beta suppression, and reduced ubiquitination/degradation of the EGFR through EGFR Tyr-1045, thus providing a survival advantage. This is the first comparison of multiple, site-specific phosphoproteins with the EGFR tyrosine kinase domain mutation status in vivo. 相似文献
59.
Daniel Hind Neill Calvert Richard McWilliams Andrew Davidson Suzy Paisley Catherine Beverley Steven Thomas 《BMJ (Clinical research ed.)》2003,327(7411):361
Objectives To assess the evidence for the clinical effectiveness of ultrasound guided central venous cannulation.Data sources 15 electronic bibliographic databases, covering biomedical, science, social science, health economics, and grey literature.Design Systematic review and meta-analysis of randomised controlled trials.Populations Patients scheduled for central venous access.Intervention reviewed Guidance using real time two dimensional ultrasonography or Doppler needles and probes compared with the anatomical landmark method of cannulation.Data extraction Risk of failed catheter placement (primary outcome), risk of complications from placement, risk of failure on first attempt at placement, number of attempts to successful catheterisation, and time (seconds) to successful catheterisation.Data synthesis 18 trials (1646 participants) were identified. Compared with the landmark method, real time two dimensional ultrasound guidance for cannulating the internal jugular vein in adults was associated with a significantly lower failure rate both overall (relative risk 0.14, 95% confidence interval 0.06 to 0.33) and on the first attempt (0.59, 0.39 to 0.88). Limited evidence favoured two dimensional ultrasound guidance for subclavian vein and femoral vein procedures in adults (0.14, 0.04 to 0.57 and 0.29, 0.07 to 1.21, respectively). Three studies in infants confirmed a higher success rate with two dimensional ultrasonography for internal jugular procedures (0.15, 0.03 to 0.64). Doppler guided cannulation of the internal jugular vein in adults was more successful than the landmark method (0.39, 0.17 to 0.92), but the landmark method was more successful for subclavian vein procedures (1.48, 1.03 to 2.14). No significant difference was found between these techniques for cannulation of the internal jugular vein in infants. An indirect comparison of relative risks suggested that two dimensional ultrasonography would be more successful than Doppler guidance for subclavian vein procedures in adults (0.09, 0.02 to 0.38).Conclusions Evidence supports the use of two dimensional ultrasonography for central venous cannulation. 相似文献
60.
Alexander I. Taylor Rebecca L. Beavil Brian J. Sutton Rosaleen A. Calvert 《The Journal of biological chemistry》2009,284(36):24168-24175
IgY is the principal serum antibody in birds and reptiles, and an IgY-like molecule was the evolutionary precursor of both mammalian IgG and IgE. A receptor for IgY on chicken monocytes, chicken leukocyte receptor AB1 (CHIR-AB1), lies in the avian leukocyte receptor cluster rather than the classical Fc receptor cluster where the genes for mammalian IgE and IgG receptors are found. IgG and IgE receptors bind to the lower hinge region of their respective antibodies with 1:1 stoichiometry, whereas the myeloid receptor for IgA, FcαRI, and the IgG homeostasis receptor, FcRn, which are found in the mammalian leukocyte receptor cluster, bind with 2:1 stoichiometry between the heavy chain constant domains 2 and 3 of each heavy chain. In this paper, the extracellular domain of CHIR-AB1 was expressed in a soluble form and shown to be a monomer that binds to IgY-Fc with 2:1 stoichiometry. The two binding sites have similar affinities: Ka1 = 7.22 ± 0.22 × 105 m−1 and Ka2 = 3.63 ± 1.03 × 106 m−1 (comparable with the values reported for IgA binding to its receptor). The affinity constants for IgY and IgY-Fc binding to immobilized CHIR-AB1 are 9.07 ± 0.07 × 107 and 6.11 ± 0.02 × 108 m−1, respectively, in agreement with values obtained for IgY binding to chicken monocyte cells and comparable with reported values for human IgA binding to neutrophils. Although the binding site for CHIR-AB1 on IgY is not known, the data reported here with a monomeric receptor binding to IgY at two sites with low affinity suggest an IgA-like interaction.Fc receptors link the specificity of the adaptive immune system with the effector mechanisms of innate immune cells. In birds and reptiles, IgY is the principal serum antibody, and both mammalian IgG and IgE have evolved from an IgY-like ancestor, so studies of IgY offer insights into their origins (1). The historical contribution of chicken immunology to a wider understanding of the subject has been considerable (2), and recently several chicken IgY-Fc receptors have been identified. In this paper, the chicken antibody, IgY, is shown to bind to a chicken leukocyte receptor, CHIR-AB1,4 in a different manner from that of its mammalian orthologues, IgG and IgE, to their respective Fc receptors.Phagocytosis, mediated in mammals by IgG, and passive cutaneous anaphylaxis, mediated by both IgG and IgE in mammals, have been observed in chickens (3, 4), presumably both effected by IgY. In vitro, IgY binds to monocyte cell lines (5, 6), and an IgY receptor (CHIR-AB1) has been identified that is able to mediate the influx of calcium into cells (5).The genes for the mammalian high affinity IgE receptor, and several IgG receptors, are located in the classical Fc receptor cluster, whereas in chickens, this cluster is represented by a single gene, the product of which has been expressed and found not to bind IgY (7). Intriguingly, the first IgY leukocyte receptor, CHIR-AB1, was found to be a member of the chicken leukocyte receptor cluster (LRC) (5), adjacent to over 100 genes with high intersequence homology (8). This finding, together with phylogenetic analysis of the orthologous Fc receptor gene clusters (7, 9), implies that during the evolution of the IgY-like ancestor of both IgG and IgE, antibody-Fc binding function migrated from proteins expressed in the LRC to those in the classical Fc receptor cluster. The human LRC is the site of FcαRI, the leukocyte receptor for IgA (an antibody involved in mucosal immunity), the fetal IgG receptor (FcRn, involved in adult IgG homeostasis), and also a number of natural killer cell receptors including the HLA-G ligand, KIR2DL4 (10). A further leukocyte receptor for chicken IgY, also related to LRC receptors, was identified recently, on chromosome 20 (11), and remains to be characterized.Typically, the stoichiometry of the receptor-antibody complex differs for receptors located in the classical Fc receptor cluster and the LRC. Crystal structures of IgG complexes with FcγRIII and of IgE with FcϵRI show 1:1 receptor:antibody stoichiometry, with the receptor binding across both heavy chains in the lower hinge (12). In contrast, the crystal structure of FcαRI complexed with IgA shows 2:1 stoichiometry (13) as does that of FcRn with IgG (14), with the two receptors binding between the heavy chain constant domains 2 and 3 on each heavy chain. The IgY/receptor interaction could have either stoichiometry; on the one hand, IgY is an orthologue of IgG and IgE, which can both show 1:1 stoichiometry, but on the other hand, the location of the IgY receptor, CHIR-AB1, in the same gene cluster as the IgA and FcRn receptors suggests the possibility of a 2:1 stoichiometry. Consistent with either of these binding modes, the crystal structure of IgY-Fc reveals that many of the residues located in the receptor-binding sites in human IgE, IgG, and IgA are present and accessible in IgY (15).The single extracellular domain of the chicken leukocyte IgY receptor, CHIR-AB1, has been expressed in insect cells by Arnon et al. (16), who showed that this preparation consists of a mixture of soluble monomer and dimer. Because of the heterogeneity of the protein, it was not possible to ascertain whether the observed 2:1 stoichiometry of receptor binding to antibody involved two monomers or a single dimer binding to IgY. Thus, it was not possible to answer the question of whether the antibody-receptor complex most resembles that of human IgA or of IgG and IgE. We have expressed the extracellular domain of CHIR-AB1 in human HEK cells. It is a monomer, and we report here that it binds to IgY and IgY-Fc with 2:1 stoichiometry. 相似文献