全文获取类型
收费全文 | 1524篇 |
免费 | 112篇 |
国内免费 | 1篇 |
专业分类
1637篇 |
出版年
2023年 | 4篇 |
2022年 | 19篇 |
2021年 | 34篇 |
2020年 | 23篇 |
2019年 | 26篇 |
2018年 | 39篇 |
2017年 | 33篇 |
2016年 | 47篇 |
2015年 | 81篇 |
2014年 | 87篇 |
2013年 | 131篇 |
2012年 | 130篇 |
2011年 | 116篇 |
2010年 | 91篇 |
2009年 | 70篇 |
2008年 | 120篇 |
2007年 | 84篇 |
2006年 | 90篇 |
2005年 | 84篇 |
2004年 | 59篇 |
2003年 | 67篇 |
2002年 | 52篇 |
2001年 | 9篇 |
2000年 | 7篇 |
1999年 | 12篇 |
1998年 | 12篇 |
1997年 | 11篇 |
1996年 | 9篇 |
1995年 | 9篇 |
1994年 | 3篇 |
1993年 | 6篇 |
1992年 | 7篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 3篇 |
1988年 | 7篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 6篇 |
1984年 | 7篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 6篇 |
1980年 | 2篇 |
1977年 | 2篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1970年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1637条查询结果,搜索用时 15 毫秒
61.
A series of coumarins incorporating tert-butyl-dimethylsilyloxy- or allyoxy- moieties in positions 4-, 6 or 7 of the heterocyclic ring have been synthesized and then converted to the corresponding 2-thioxo-coumarins. Other derivatives incorporating hydroxyethyloxy-, tosylethoxy- and 2-fluroethyloxy- moieties in position 7 of the coumarin ring were synthesized together with derivatives of 4-methyl-7-amino coumarin incorporating acetamido, 3,5-dimethylphenylureido- and tert-butyloxycarbonylamido functionalities. All these compounds were assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The human (h) cytosolic isoforms hCA I and II were weakly inhibited (hCA I) or not inhibited at all (hCA II) by these (thioxo)coumarins whereas the tumor-associated transmembrane isoforms hCA IX and XII were inhibited with efficiencies from the submicromolar to the low micromolar range by many of these derivatives. The structure-activity relationship for these classes of less investigated CA inhibitors are delineated, with the potential of using them as leads to obtain isoform-selective inhibitors with excellent affinity for CA IX and XII (validated antitumor targets) which do not significantly inhibit the cytosolic offtarget isoforms hCA I and II. 相似文献
62.
Carnevali S Petruzzelli S Longoni B Vanacore R Barale R Cipollini M Scatena F Paggiaro P Celi A Giuntini C 《American journal of physiology. Lung cellular and molecular physiology》2003,284(6):L955-L963
Cigarette smoke is a mixture of chemicals having direct and/or indirect toxic effects on different lung cells. We investigated the effect of cigarette smoke on human lung fibroblasts (HFL-1) oxidation and apoptosis. Cells were exposed to various concentrations (1, 5, and 10%) of cigarette smoke extract (CSE) for 3 h, and oxidative stress and apoptosis were assessed by fluorescence-activated cell sorting and confocal laser fluorescence microscopy. Both oxidative stress and apoptosis exhibited a dose-response relationship with CSE concentrations. Lung fibroblasts also showed marked DNA fragmentation at the Comet assay after exposure to 10% CSE. Coincubation of HLF-1 cells with N-acetylcysteine (1 mM) during CSE exposure significantly reduced oxidative stress, apoptosis, and DNA fragmentation, whereas preincubation (3 h) with the glutathione-depleting agent buthionine sulfoximine (125 microM) produced a significant increase of oxidative stress. Cigarette smoke is a potent source of oxidative stress, DNA damage, and apoptosis for HFL-1 cells, and we speculate that this could contribute to the development of pulmonary emphysema in the lungs of smokers. 相似文献
63.
Giovanni Piccinini Mariangela Iannello Guglielmo Puccio Federico Plazzi Justin C Havird Fabrizio Ghiselli 《Molecular biology and evolution》2021,38(6):2597
In Metazoa, four out of five complexes involved in oxidative phosphorylation (OXPHOS) are formed by subunits encoded by both the mitochondrial (mtDNA) and nuclear (nuDNA) genomes, leading to the expectation of mitonuclear coevolution. Previous studies have supported coadaptation of mitochondria-encoded (mtOXPHOS) and nuclear-encoded OXPHOS (nuOXPHOS) subunits, often specifically interpreted with regard to the “nuclear compensation hypothesis,” a specific form of mitonuclear coevolution where nuclear genes compensate for deleterious mitochondrial mutations due to less efficient mitochondrial selection. In this study, we analyzed patterns of sequence evolution of 79 OXPHOS subunits in 31 bivalve species, a taxon showing extraordinary mtDNA variability and including species with “doubly uniparental” mtDNA inheritance. Our data showed strong and clear signals of mitonuclear coevolution. NuOXPHOS subunits had concordant topologies with mtOXPHOS subunits, contrary to previous phylogenies based on nuclear genes lacking mt interactions. Evolutionary rates between mt and nuOXPHOS subunits were also highly correlated compared with non-OXPHO-interacting nuclear genes. Nuclear subunits of chimeric OXPHOS complexes (I, III, IV, and V) also had higher dN/dS ratios than Complex II, which is formed exclusively by nuDNA-encoded subunits. However, we did not find evidence of nuclear compensation: mitochondria-encoded subunits showed similar dN/dS ratios compared with nuclear-encoded subunits, contrary to most previously studied bilaterian animals. Moreover, no site-specific signals of compensatory positive selection were detected in nuOXPHOS genes. Our analyses extend the evidence for mitonuclear coevolution to a new taxonomic group, but we propose a reconsideration of the nuclear compensation hypothesis. 相似文献
64.
Carta F Vullo D Maresca A Scozzafava A Supuran CT 《Bioorganic & medicinal chemistry letters》2012,22(6):2182-2185
Considering phenols and coumarins as lead molecules for obtaining non-sulfonamide inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1), we screened a large number of compounds possessing diverse chemotypes, but structural features which resemble the two chemical classes. Here we report an investigation of such derivatives which do not significantly inhibit CA II, but show interesting inhibition profiles against other isozymes. Pyridine-N-oxide-2-thiophenol, thiobenzoic acid, thimerosal, two oximes derived from a six-membered-ring lactone and from coumarin; 2-hydroxyquinoline and coumaphos, were investigated as inhibitors of CA I-XIV. All these compounds did not inhibit CA II, whereas the two oximes and 2-hydroxyquinoline were low nanomolar inhibitors of CA I, IX, XII, XIII and XIV, showing a very different inhibition profile compared to sulfonamides and sulfamates. Some other compounds showed low micromolar inhibition of other isoforms of interest, such as CA VA/VB, CA VI and VII. This study demonstrates that a rather wide range of structures show low nanomolar-micromolar inhibitory activity against many CA isozymes, without inhibiting significantly the offtarget isoform CA II. 相似文献
65.
Subrata Barman Petr S. Krylov Thomas P. Fabrizio John Franks Jasmine C. Turner Patrick Seiler David Wang Jerold E. Rehg Gene A. Erickson Marie Gramer Robert G. Webster Richard J. Webby 《PLoS pathogens》2012,8(7)
North American triple reassortant swine (TRS) influenza A viruses have caused sporadic human infections since 2005, but human-to-human transmission has not been documented. These viruses have six gene segments (PB2, PB1, PA, HA, NP, and NS) closely related to those of the 2009 H1N1 pandemic viruses. Therefore, understanding of these viruses'' pathogenicity and transmissibility may help to identify determinants of virulence of the 2009 H1N1 pandemic viruses and to elucidate potential human health threats posed by the TRS viruses. Here we evaluated in a ferret model the pathogenicity and transmissibility of three groups of North American TRS viruses containing swine-like and/or human-like HA and NA gene segments. The study was designed only to detect informative and significant patterns in the transmissibility and pathogenicity of these three groups of viruses. We observed that irrespective of their HA and NA lineages, the TRS viruses were moderately pathogenic in ferrets and grew efficiently in both the upper and lower respiratory tracts. All North American TRS viruses studied were transmitted between ferrets via direct contact. However, their transmissibility by respiratory droplets was related to their HA and NA lineages: TRS viruses with human-like HA and NA were transmitted most efficiently, those with swine-like HA and NA were transmitted minimally or not transmitted, and those with swine-like HA and human-like NA (N2) showed intermediate transmissibility. We conclude that the lineages of HA and NA may play a crucial role in the respiratory droplet transmissibility of these viruses. These findings have important implications for pandemic planning and warrant confirmation. 相似文献
66.
Roberta Bertelli Fabrizio Ginevri Rosanna Gusmano Gian Marco Ghiggeri 《In vitro cellular & developmental biology. Animal》1991,27(10):799-804
Summary It has been suggested that the generation of toxic radicals plays an important role in toxicity by Adriamycin (ADR) on cancer
cell lines and in vivo. We have examined the role of free radicals in determining toxicity and resistance to ADR of rat glomerular
epithelial cells in culture; this method provides a good model for analyzing the mechanisms responsible for ADR experimental
nephrosis in rats. Three points were established: a) the intra- or extracellular site of ADR toxicity; b) the role of the
superoxide anion and of the hydroxyl radical in determining intra- and-extracellular cytotoxicity; and c) the implication
of oxido-reduction cycling as a potential route for ADR semiquinone transformation. Free ADR was found to induce the same
inhibition of [3H]thymidine incorporation into DNA as ADR bound to an agarose macroporous bed which prevents the intracellular incorporation
of the drug. Specific scavenging of free radical activity by the enzymes catalase and superoxide dismutase, the hydroxyl radical
inhibitors dimethyl sulfoxide and dimethylthiourea (DMTU) and by chelation of intracellular free iron with deferoxamine produced
only a partial restoration of [3H]thymidine incorporation into DNA, which was maximal for DMTU (30% of normal incorporation). DMTU treatment was unsuccessful
in preventing the extracellular cytostatic effect of ADR. Finally, glomerular epithelial cell killing (51Cr-release method) by 5-iminodaunorubicin, an ADR analogue with a modified quinone function that prohibits oxido-reduction
cycling, was higher than unmodified ADR. These results indicate that ADR may exert its cytotoxic effects on glomerular epithelial
cells by interaction at the cell surface, whereas the intracellular compartment, principally DNA, does not seem to be the
target of ADR effects. They also suggest that the free radicals are in part responsible for ADR intracellular cytotoxicity,
but other mechanisms should also be hypothesized. Finally, the participation of the ADR semiquinone radical in oxido-reduction
cycling seems not important for the induction of the cellular damage. 相似文献
67.
Mesoporous TiO2 Beads Offer Improved Mass Transport for Cobalt‐Based Redox Couples Leading to High Efficiency Dye‐Sensitized Solar Cells 下载免费PDF全文
Leo‐Philipp Heiniger Fabrizio Giordano Thomas Moehl Michael Grätzel 《Liver Transplantation》2014,4(12)
Overcoming ionic diffusion limitations is essential for the development of high‐efficiency dye‐sensitized solar cells based on cobalt redox mediators. Here, improved mass transport is reported for photoanodes composed of mesoporous TiO2 beads of varying pore sizes and porosities in combination with the high extinction YD2‐o‐C8 porphyrin dye. Compared to a photoanode made of 20 nm‐sized TiO2 particles, electrolyte diffusion through these films is greatly improved due to the large interstitial pores between the TiO2 beads, resulting in up to 70% increase in diffusion‐limited current. Simultaneously, transient photocurrent measurements reveal no mass transport limitations for films of up to 10 μm thickness. In contrast, standard photoanodes made of 20 nm‐sized TiO2 particles show non‐linear behavior in photocurrent under 1 sun illumination for a film thickness as low as 7 μm. By including a transparent thin mesoporous TiO2 underlayer in order to reduce optical losses at the fluorine‐doped tin oxide (FTO)‐TiO2 interface, an efficiency of 11.4% under AM1.5G 1 sun illumination is achieved. The combination of high surface area, strong scattering behavior, and high porosity makes these mesoporous TiO2 beads particularly suitable for dye‐sensitized solar cells using bulky redox couples and/or viscous electrolytes. 相似文献
68.
69.
Biochemical Origin and Refractory Properties of Humic Acid Extracted from the Maize Plant 总被引:2,自引:1,他引:2
Humic acids (HA) contribute to soil fertility because of their chemical, physical, and biological properties. The origin of
HAs in soils has puzzled scientists for decades, and what HAs are and what their origin is remain unclear. The isolation of
HAs in plants, which have characteristics close to soil HAs, suggests the probable origin of soil-HA is the preservation of
plant tissue, indicating biochemical origin. In this paper HA from maize plant at different stages of maturity is isolated,
from which it was found that the evolution of this fraction depends on and is derived from cell wall formation. Evidence was
also found that HA was above all composed of lignin and cutin residues, and was characterized by low surface area. After 8 months
of incubation in both mineral-artificial and natural soils, humic acid isolated form maize plant could be recovered intact. 相似文献
70.
Bernardetta Maresca Luisa Cigliano Maria Stefania Spagnuolo Fabrizio Dal Piaz Maria M. Corsaro Nicola Balato Massimiliano Nino Anna Balato Fabio Ayala Paolo Abrescia 《PloS one》2012,7(12)
Improved diagnosis of psoriasis, by new biomarkers, is required for evaluating the progression rate of the disease and the response to treatment. Haptoglobin (Hpt), a glycoprotein secreted by hepatocytes and other types of cells including keratinocytes, was found with glycan changes in psoriasis and other diseases. We previously reported that Hpt isolated from plasma of psoriatic patients is more fucosylated than Hpt of healthy subjects. The aim of this study was to compare the glycosylation pattern of Hpt isolated from skin scales or plasma of patients with psoriasis with that of Hpt from cornified epidermal layer or plasma of healthy subjects. High performance liquid chromatography analysis of the glycans isolated from the protein backbone revealed that glycan patterns from skin and plasma of patients were similar, and mostly displayed quantitative rather than qualitative differences from normal pattern. Biotin-labeled lectins were used to evaluate quantitative differences in the glycoforms of Hpt from plasma and psoriatic skin scales. Hpt from skin and plasma of patients showed more fucosylated and branched glycans than Hpt from plasma of healthy subjects. Tryptic glycopeptides of Hpt were also analyzed by mass spectrometry, and a decreased amount of sialylated glycan chains was found in glycopeptides of skin Hpt, as compared with Hpt from plasma. High levels of glycans with fucosylated and tetra-antennary chains were detected on the peptide NLFLNHSENATAK from Hpt of psoriatic patients. Our data demonstrate that specific changes in glycan structures of Hpt, such as enhanced glycan branching and fucose content, are associated with psoriasis, and that differences between circulating and skin Hpt do exist. A lower extent of glycan fucosylation and branching was found in Hpt from plasma of patients in disease remission. Altered glycoforms might reflect changes of Hpt function in the skin, and could be used as markers of the disease. 相似文献