全文获取类型
收费全文 | 751篇 |
免费 | 45篇 |
专业分类
796篇 |
出版年
2023年 | 2篇 |
2022年 | 14篇 |
2021年 | 20篇 |
2020年 | 10篇 |
2019年 | 13篇 |
2018年 | 12篇 |
2017年 | 19篇 |
2016年 | 23篇 |
2015年 | 41篇 |
2014年 | 45篇 |
2013年 | 66篇 |
2012年 | 44篇 |
2011年 | 61篇 |
2010年 | 35篇 |
2009年 | 28篇 |
2008年 | 44篇 |
2007年 | 44篇 |
2006年 | 31篇 |
2005年 | 36篇 |
2004年 | 32篇 |
2003年 | 31篇 |
2002年 | 41篇 |
2001年 | 7篇 |
1999年 | 5篇 |
1998年 | 8篇 |
1997年 | 6篇 |
1996年 | 5篇 |
1995年 | 9篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1983年 | 4篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1966年 | 1篇 |
1964年 | 1篇 |
1963年 | 2篇 |
1962年 | 3篇 |
1959年 | 1篇 |
1951年 | 2篇 |
1941年 | 1篇 |
1940年 | 1篇 |
排序方式: 共有796条查询结果,搜索用时 15 毫秒
11.
The interaction of the alphaLbeta2 integrin with its cellular ligand the intercellular adhesion molecule-1 (ICAM-1) is critical for the tight binding interaction between most leukocytes and the vascular endothelium before transendothelial migration to the sites of inflammation. In this article we have modeled the alphaL subunit I-domain in its active form, which was computationally docked with the D1 domain of the ICAM-1 to probe potential protein-protein interactions. The experimentally observed key interaction between the carboxylate of Glu 34 in the ICAM-1 D1 domain and the metal ion-dependent adhesion site (MIDAS) in the open alphaL I-domain was consistently reproduced by our calculations. The calculations reveal the nature of the alphaLbeta2/ICAM-1 interaction and suggest an explanation for the increased ligand-binding affinity in the "open" versus the "closed" conformation of the alphaL I-domain. A mechanism for substrate selectivity among alphaL, alphaM, and alpha2 I-domains is suggested whereby the orientation of the loops within the I-domain is critical in mediating the interaction of the Glu 34 carboxylate of ICAM-1 D1 with the MIDAS. 相似文献
12.
Alessandro Furlan Benjamin Roux Fabienne Lamballe Filippo Conti Nathalie Issaly Fabrice Daian Jean-Fran?ois Guillemot Sylvie Richelme Magali Contensin Joan Bosch Daniele Passarella Oreste Piccolo Rosanna Dono Flavio Maina 《PloS one》2012,7(10)
The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by “RTK swapping” by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation. 相似文献
13.
Robert C. Jennings Flavio M. Garlaschi Paolo D. Gerola Rachel Etzion-Katz Giorgio Forti 《BBA》1981,638(1):100-107
Lowering the pH of the incubation medium to pH 5.4 leads to grana formation morphologically similar to that induced by metal cations. The same phenomenon is observed in EDTA-washed chloroplasts, indicating that it is not due in part to electrostatic ‘masking’ by residual cations associated with the membranes. Digitonin fractionation studies have indicated that the distribution of the major chlorophyll-protein complexes between granal and stromal membrane regions is similar at pH 5.4 in the absence of Mg2+, and at pH 7.4 in the presence of Mg2+. Chlorophyll fluorescence induction studies have indicated that the primary photochemistry of Photosystem II (PS II) is stimulated by lowering the pH to 5.4, just as it is upon metal cation addition at higher pH values. The failure to observe such an increase at pH 5.4 by measuring electron transport to ferricyanide is attributed to a combination of an inhibition by this pH of electron transport at a site after Q reduction and an increase in the number of PS II centres detached from the plastoquinone pool. We conclude that the stacked configuration of chloroplast membranes leads to increased PS II primary photochemistry, which is most simply explained in terms of a redistribution of excitation energy towards PS II. 相似文献
14.
Souza DG Fagundes CT Amaral FA Cisalpino D Sousa LP Vieira AT Pinho V Nicoli JR Vieira LQ Fierro IM Teixeira MM 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(12):8533-8543
The appropriate development of an inflammatory response is central for the ability of a host to deal with any infectious insult. However, excessive, misplaced, or uncontrolled inflammation may lead to acute or chronic diseases. The microbiota plays an important role in the control of inflammatory responsiveness. In this study, we investigated the role of lipoxin A4 and annexin-1 for the IL-10-dependent inflammatory hyporesponsiveness observed in germfree mice. Administration of a 15-epi-lipoxin A4 analog or an annexin-1-derived peptide to conventional mice prevented tissue injury, TNF-alpha production, and lethality after intestinal ischemia/reperfusion. This was associated with enhanced IL-10 production. Lipoxin A4 and annexin-1 failed to prevent reperfusion injury in IL-10-deficient mice. In germfree mice, there was enhanced expression of both lipoxin A4 and annexin-1. Blockade of lipoxin A4 synthesis with a 5-lipoxygenase inhibitor or Abs against annexin-1 partially prevented IL-10 production and this was accompanied by partial reversion of inflammatory hyporesponsiveness in germfree mice. Administration of BOC-1, an antagonist of ALX receptors (at which both lipoxin A4 and annexin-1 act), or simultaneous administration of 5-lipoxygenase inhibitor and anti-annexin-1 Abs, was associated with tissue injury, TNF-alpha production, and lethality similar to that found in conventional mice. Thus, our data demonstrate that inflammatory responsiveness is tightly controlled by the presence of the microbiota and that the innate capacity of germfree mice to produce IL-10 is secondary to their endogenous greater ability to produce lipoxin A4 and annexin-1. 相似文献
15.
Flavio De Maio Giuseppe Maulucci Mariachiara Minerva Saber Anoosheh Ivana Palucci Raffaella Iantomasi Valentina Palmieri Serena Camassa Michela Sali Maurizio Sanguinetti Wilbert Bitter Riccardo Manganelli Marco De Spirito Giovanni Delogu 《PloS one》2014,9(11)
PE_PGRS proteins are unique to the Mycobacterium tuberculosis complex and a number of other pathogenic mycobacteria. PE_PGRS30, which is required for the full virulence of M. tuberculosis (Mtb), has three main domains, i.e. an N-terminal PE domain, repetitive PGRS domain and the unique C-terminal domain. To investigate the role of these domains, we expressed a GFP-tagged PE_PGRS30 protein and a series of its functional deletion mutants in different mycobacterial species (Mtb, Mycobacterium bovis BCG and Mycobacterium smegmatis) and analysed protein localization by confocal microscopy. We show that PE_PGRS30 localizes at the mycobacterial cell poles in Mtb and M. bovis BCG but not in M. smegmatis and that the PGRS domain of the protein strongly contributes to protein cellular localization in Mtb. Immunofluorescence studies further showed that the unique C-terminal domain of PE_PGRS30 is not available on the surface, except when the PGRS domain is missing. Immunoblot demonstrated that the PGRS domain is required to maintain the protein strongly associated with the non-soluble cellular fraction. These results suggest that the repetitive GGA-GGN repeats of the PGRS domain contain specific sequences that contribute to protein cellular localization and that polar localization might be a key step in the PE_PGRS30-dependent virulence mechanism. 相似文献
16.
Pedrotta Tiziana Gobet Erika Schwörer Christoph Beffa Giorgia Butz Christoph Henne Paul D. Morales-Molino César Pasta Salvatore van Leeuwen Jacqueline F. N. Vogel Hendrik Zwimpfer Elias Anselmetti Flavio S. Grosjean Martin Tinner Willy 《Vegetation History and Archaeobotany》2021,30(6):789-813
Vegetation History and Archaeobotany - Knowledge about the vegetation history of Sardinia, the second largest island of the Mediterranean, is scanty. Here, we present a new sedimentary record... 相似文献
17.
Summary Irradiation of the principal photosystem II light-harvesting chlorophyll-protein antenna complex, LHC II, with high light intensities brings about a pronounced quenching of the chlorophyll fluorescence. Illumination of isolated thylakoids with high light intensities generates the formation of quenching centres within LHC II in vivo, as demonstrated by fluorescence excitation spectroscopy. In the isolated complex it is demonstrated that the light-induced fluorescence quenching: a) shows a partial, biphasic reversibility in the dark; b) is approximately proportional to the light intensity; c) is almost independent of temperature in the range 0–30°C; d) is substantially insensitive to protein modifying reagents and treatments; e) occurs in the absence of oxygen. A possible physiological importance of the phenomenon is discussed in terms of a mechanism capable of dissipating excess excitation energy within the photosystem II antenna.Abbreviations chla
chlorophyll a
- chlb
chlorophyll b
- F0
fluorescence yield with reaction centers open
- Fm
fluorescence yield with reaction centres closed
- Fi
fluorescence at the plateau level of the fast induction phase
- LHC II
light-harvesting chlorophyll a/b protein complex II
- PS II
photosystem II
- PSI
photosystem I
- Tricine
N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine 相似文献
18.
Colombo F Tintori C Furlan A Borrelli S Christodoulou MS Dono R Maina F Botta M Amat M Bosch J Passarella D 《Bioorganic & medicinal chemistry letters》2012,22(14):4693-4696
The use of Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition permitted the synthesis of a new compound that is able to inhibit the HGF-induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non-small-cell lung cancer) and GTL-16 (human gastric carcinoma). In agreement with biochemical and biological results, docking studies within the ATP binding site of Met suggested for the new synthesized compound a binding mode similar to that of the active compound Triflorcas previously reported. 相似文献
19.
Disturbances, elevation, topography and spatial proximity drive vegetation patterns along an altitudinal gradient of a top biodiversity hotspot 总被引:1,自引:0,他引:1
Pedro V. Eisenlohr Luciana F. Alves Luís Carlos Bernacci Maíra C. G. Padgurschi Roseli B. Torres Eduardo M. B. Prata Flavio Antonio M. dos Santos Marco Antônio Assis Eliana Ramos André Luís C. Rochelle Fernando R. Martins Mariana C. R. Campos Fernando Pedroni Maryland Sanchez Larissa S. Pereira Simone A. Vieira José Ataliba M. A. Gomes Jorge Y. Tamashiro Marcos A. S. Scaranello Cora J. Caron Carlos Alfredo Joly 《Biodiversity and Conservation》2013,22(12):2767-2783
The correlation between vegetation patterns (species distribution and richness) and altitudinal variation has been widely reported for tropical forests, thereby providing theoretical basis for biodiversity conservation. However, this relationship may have been oversimplified, as many other factors may influence vegetation patterns, such as disturbances, topography and geographic distance. Considering these other factors, our primary question was: is there a vegetation pattern associated with substantial altitudinal variation (10–1,093 m a.s.l.) in the Atlantic Rainforest—a top hotspot for biodiversity conservation—and, if so, what are the main factors driving this pattern? We addressed this question by sampling 11 1-ha plots, applying multivariate methods, correlations and variance partitioning. The Restinga (forest on sandbanks along the coastal plains of Brazil) and a lowland area that was selectively logged 40 years ago were floristically isolated from the other plots. The maximum species richness (>200 spp. per hectare) occurred at approximately 350 m a.s.l. (submontane forest). Gaps, multiple stemmed trees, average elevation and the standard deviation of the slope significantly affected the vegetation pattern. Spatial proximity also influenced the vegetation pattern as a structuring environmental variable or via dispersal constraints. Our results clarify, for the first time, the key variables that drive species distribution and richness across a large altitudinal range within the Atlantic Rainforest. 相似文献
20.