全文获取类型
收费全文 | 1178篇 |
免费 | 83篇 |
专业分类
1261篇 |
出版年
2023年 | 5篇 |
2022年 | 16篇 |
2021年 | 35篇 |
2020年 | 23篇 |
2019年 | 27篇 |
2018年 | 39篇 |
2017年 | 26篇 |
2016年 | 47篇 |
2015年 | 63篇 |
2014年 | 72篇 |
2013年 | 101篇 |
2012年 | 79篇 |
2011年 | 87篇 |
2010年 | 55篇 |
2009年 | 56篇 |
2008年 | 69篇 |
2007年 | 66篇 |
2006年 | 65篇 |
2005年 | 55篇 |
2004年 | 38篇 |
2003年 | 44篇 |
2002年 | 43篇 |
2001年 | 7篇 |
2000年 | 3篇 |
1999年 | 10篇 |
1998年 | 7篇 |
1997年 | 9篇 |
1996年 | 12篇 |
1995年 | 12篇 |
1994年 | 6篇 |
1993年 | 7篇 |
1992年 | 6篇 |
1991年 | 8篇 |
1990年 | 6篇 |
1989年 | 8篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 2篇 |
1985年 | 6篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 5篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1976年 | 3篇 |
1965年 | 1篇 |
1958年 | 1篇 |
1953年 | 1篇 |
1933年 | 1篇 |
排序方式: 共有1261条查询结果,搜索用时 15 毫秒
961.
Gasparetti C Nordlund E Jänis J Buchert J Kruus K 《Biochimica et biophysica acta》2012,1824(4):598-607
Tyrosinase (EC 1.14.18.1) is a widely distributed type 3 copper enzyme participating in essential biological functions. Tyrosinases are potential biotools as biosensors or protein crosslinkers. Understanding the reaction mechanism of tyrosinases is fundamental for developing tyrosinase-based applications. The reaction mechanisms of tyrosinases from Trichoderma reesei (TrT) and Agaricus bisporus (AbT) were analyzed using three diphenolic substrates: caffeic acid, L-DOPA (3,4-dihydroxy-l-phenylalanine), and catechol. With caffeic acid the oxidation rates of TrT and AbT were comparable; whereas with L-DOPA or catechol a fast decrease in the oxidation rates was observed in the TrT-catalyzed reactions only, suggesting end product inhibition of TrT. Dopachrome was the only reaction end product formed by TrT- or AbT-catalyzed oxidation of L-DOPA. We produced dopachrome by AbT-catalyzed oxidation of L-DOPA and analyzed the TrT end product (i.e. dopachrome) inhibition by oxygen consumption measurement. In the presence of 1.5mM dopachrome the oxygen consumption rate of TrT on 8mM L-DOPA was halved. The type of inhibition of potential inhibitors for TrT was studied using p-coumaric acid (monophenol) and caffeic acid (diphenol) as substrates. The strongest inhibitors were potassium cyanide for the TrT-monophenolase activity, and kojic acid for the TrT-diphenolase activity. The lag period related to the TrT-catalyzed oxidation of monophenol was prolonged by kojic acid, sodium azide and arbutin; contrary it was reduced by potassium cyanide. Furthermore, sodium azide slowed down the initial oxidation rate of TrT- and AbT-catalyzed oxidation of L-DOPA or catechol, but it also formed adducts with the reaction end products, i.e., dopachrome and o-benzoquinone. 相似文献
962.
Durum wheat seedling responses to simultaneous high light and salinity involve a fine reconfiguration of amino acids and carbohydrate metabolism 下载免费PDF全文
Pasqualina Woodrow Loredana F. Ciarmiello Maria Grazia Annunziata Severina Pacifico Federica Iannuzzi Antonio Mirto Luisa D'Amelia Emilia Dell'Aversana Simona Piccolella Amodio Fuggi Petronia Carillo 《Physiologia plantarum》2017,159(3):290-312
Durum wheat plants are extremely sensitive to drought and salinity during seedling and early development stages. Their responses to stresses have been extensively studied to provide new metabolic targets and improving the tolerance to adverse environments. Most of these studies have been performed in growth chambers under low light [300–350 µmol m?2 s?1 photosynthetically active radiation (PAR), LL]. However, in nature plants have to face frequent fluctuations of light intensities that often exceed their photosynthetic capacity (900–2000 µmol m?2 s?1). In this study we investigated the physiological and metabolic changes potentially involved in osmotic adjustment and antioxidant defense in durum wheat seedlings under high light (HL) and salinity. The combined application of the two stresses decreased the water potential and stomatal conductance without reducing the photosynthetic efficiency of the plants. Glycine betaine (GB) synthesis was inhibited, proline and glutamate content decreased, while γ‐aminobutyric acid (GABA), amides and minor amino acids increased. The expression level and enzymatic activities of Δ1‐pyrroline‐5‐carboxylate synthetase, asparagine synthetase and glutamate decarboxylase, as well as other enzymatic activities of nitrogen and carbon metabolism, were analyzed. Antioxidant enzymes and metabolites were also considered. The results showed that the complex interplay seen in durum wheat plants under salinity at LL was simplified: GB and antioxidants did not play a main role. On the contrary, the fine tuning of few specific primary metabolites (GABA, amides, minor amino acids and hexoses) remodeled metabolism and defense processes, playing a key role in the response to simultaneous stresses. 相似文献
963.
Emilia Daghir-Wojtkowiak Paweł Wiczling Małgorzata Waszczuk-Jankowska Roman Kaliszan Michał Jan Markuszewski 《Metabolomics : Official journal of the Metabolomic Society》2017,13(3):31
Introduction
Multilevel modeling is a quantitative statistical method to investigate variability and relationships between variables of interest, taking into account population structure and dependencies. It can be used for prediction, data reduction and causal inference from experiments and observational studies allowing for more efficient elucidation of knowledge.Objectives
In this study we introduced the concept of multilevel pharmacokinetics (PK)-driven modelling for large-sample, unbalanced and unadjusted metabolomics data comprising nucleoside and creatinine concentration measurements in urine of healthy and cancer patients.Methods
A Bayesian multilevel model was proposed to describe the nucleoside and creatinine concentration ratio considering age, sex and health status as covariates. The predictive performance of the proposed model was summarized via area under the ROC, sensitivity and specificity using external validation.Results
Cancer was associated with an increase in methylthioadenosine/creatinine excretion rate by a factor of 1.42 (1.09–2.03) which constituted the highest increase among all nucleosides. Age influenced nucleosides/creatinine excretion rates for all nucleosides in the same direction which was likely caused by a decrease in creatinine clearance with age. There was a small evidence of sex-related differences for methylthioadenosine. The individual a posteriori prediction of patient classification as area under the ROC with 5th and 95th percentile was 0.57(0.5–0.67) with sensitivity and specificity of 0.59(0.42–0.76) and 0.57(0.45–0.7), respectively suggesting limited usefulness of 13 nucleosides/creatinine urine concentration measurements in predicting disease in this population.Conclusion
Bayesian multilevel pharmacokinetics-driven modeling in metabolomics may be useful in understanding the data and may constitute a new tool for searching towards potential candidates of disease indicators.964.
Inmaculada Llamas Ana del Moral Victoria Béjar Mara Dolores Girón Rafael Salto Emilia Quesada 《FEMS microbiology letters》1997,156(2):251-257
The moderately halophilic bacterium Halomonas eurihalina strain F2-7, able to produce an exopolysaccharide, was found to contain two plasmids named pVE1 and pVE2, of 8.1 and 5.8 kb respectively. We found no evidence for the involvement of these plasmids in the expression of the mucoid phenotype. Restriction maps of both plasmids were constructed. Southern hybridization revealed similarities between them but excluded the existence of sequences homologous to other plasmids isolated from the Halomonas species. Neither pVE1 nor pVE2 displayed any homology with other plasmids isolated from moderate halophiles. The occurrence of similar plasmids in other strains of Halomonas eurihalina, isolated from hypersaline soils, has been detected. These small plasmids may be useful for the development of cloning vectors for moderately halophilic bacteria. 相似文献
965.
To study spatiotemporal regulation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK1/2) signaling cascade in living cells, a HeLa cell line in which MAPK kinase of ERK kinase (MEK) 2 (MAPK kinase) was knocked down by RNA interference and replaced with the green fluorescent protein (GFP)-tagged MEK2 was generated. In these cells, MEK2-GFP was stably expressed at a level similar to that of the endogenous MEK2 in the parental cells. Upon activation of the EGF receptor (EGFR), a pool of MEK2-GFP was found initially translocated to the plasma membrane and then accumulated in a subset of early and late endosomes. However, activated MEK was detected only at the plasma membrane and not in endosomes. Surprisingly, MEK2-GFP endosomes did not contain active EGFR, suggesting that endosomal MEK2-GFP was separated from the upstream signaling complexes. Knockdown of clathrin by small interfering RNA (siRNA) abolished MEK2 recruitment to endosomes but resulted in increased activation of ERK without affecting the activity of MEK2-GFP. The accumulation of MEK2-GFP in endosomes was also blocked by siRNA depletion of RAF kinases and by the MEK1/2 inhibitor, UO126. We propose that the recruitment of MEK2 to endosomes can be a part of the negative feedback regulation of the EGFR-MAPK signaling pathway by endocytosis. 相似文献
966.
Laura Alcazar-Fuoli Juan L. Rodríguez-Tudela Emilia Mellado 《Current fungal infection reports》2008,2(1):36-42
The incidence of fungal infections has increased over the past decade. In addition to classical pathogens, such as Aspergillus spp, new fungal species are increasingly reported. Despite the availability of new antifungals, mortality of invasive fungal
infections remains very high. The host immune status is the main factor for survival. However, most of these pathogens have
high minimum inhibitory concentrations (MICs) to antifungals, and therefore, the influence of these high MICs in the outcome
of the patients have begun to be addressed. Several strains of Aspergillus fumigatus showing resistance to itraconazole have been isolated, and the molecular-resistance mechanisms have been characterized. In
addition, attempts to correlate high MICs with patient outcome have been performed. Although correlation is far from perfect,
a clear trend between high MICs and poor outcome has been established. Resistance of fungi to antifungals is a health problem
requiring support from research agencies. 相似文献
967.
Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. 总被引:21,自引:0,他引:21
Laura Moro Laura Dolce Sara Cabodi Elena Bergatto Elisabetta Boeri Erba Monica Smeriglio Emilia Turco Saverio Francesco Retta Maria Gabriella Giuffrida Mascia Venturino Jasminka Godovac-Zimmermann Amedeo Conti Erik Schaefer Laura Beguinot Carlo Tacchetti Paolo Gaggini Lorenzo Silengo Guido Tarone Paola Defilippi 《The Journal of biological chemistry》2002,277(11):9405-9414
Integrin-mediated cell adhesion cooperates with growth factor receptors in the control of cell proliferation, cell survival, and cell migration. One mechanism to explain these synergistic effects is the ability of integrins to induce phosphorylation of growth factor receptors, for instance the epidermal growth factor (EGF) receptor. Here we define some aspects of the molecular mechanisms regulating integrin-dependent EGF receptor phosphorylation. We show that in the early phases of cell adhesion integrins associate with EGF receptors on the cell membrane in a macromolecular complex including the adaptor protein p130Cas and the c-Src kinase, the latter being required for adhesion-dependent assembly of the macromolecular complex. We also show that the integrin cytoplasmic tail, c-Src kinase, and the p130Cas adaptor protein are required for phosphorylation of EGF receptor in response to integrin-mediated adhesion. We show that integrins induce phosphorylation of EGF receptor on tyrosine residues 845, 1068, 1086, and 1173, but not on residue 1148, a major site of phosphorylation in response to EGF. In addition we find that integrin-mediated adhesion increases the amount of EGF receptor expressed on the cell surface. Therefore these data indicate that integrin-mediated adhesion induces assembly of a macromolecular complex containing c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosine residues. 相似文献
968.
Long-term implications of industrial pollution stress on lipids composition in Scots pine (Pinus sylvestris L.) roots 总被引:1,自引:0,他引:1
The influence of pollution stress (SO2, Cu2+, Pb2+, Zn2+ and fluoride) on composition changes in cellular membranes of roots of three European of Scots pine (Pinus sylvestris L.) populations were examined. Plant material growing in three experimental areas: Kórnik relatively free of air pollution
(control), Luboń: SO2 and HF and Głogów: SO2 and heavy metals. Analysis of total phospholipids and their composition indicates that the phosphatidylcholine (PC) and phosphatidylethanolamine
(PE) were present in lower concentration in the root tissues from both polluted sites (Luboń and Głogów). The difference in
PC:PE ratio between control and both polluted sites was greater in root of Scots pine population from Russia than in the population
from Slovakia. Under pollution conditions the content of lipid soluble antioxidant α-tocopherol was lower about 220 %, in
comparison to the control. The action of pollution stress also lead to lowering of unsaturated:saturated ratio of total fatty
acid, and lower content of polyunsaturated fatty acids, linoleic acid (18:2) and eicosatrienoic acid (20:3). We concluded
that the long-term pollution stress markedly inhibited lipid biosynthesis in root tissue of Scots pine and it is probably
contribute to the reduction of productivity of forests. These results also suggest that lipid composition can be used as an
indicator of changes in tissue roots of Scots pine caused by air and/or soil long-term pollution. 相似文献
969.
Morandi S Morandi F Caselli E Shoichet BK Prati F 《Bioorganic & medicinal chemistry》2008,16(3):1195-1205
Boronic acids have proved to be promising selective inhibitors of beta-lactamases, acting as transition state analogues. Starting from a previously described nanomolar inhibitor of AmpC beta-lactamase, three new inhibitors were designed to gain interactions with highly conserved residues, such as Asn343, and to bind more tightly to the enzyme. Among these, one was obtained by stereoselective synthesis and succeeded in placing its anionic group into the carboxylate binding site of the enzyme, as revealed by X-ray crystallography of the complex inhibitor/AmpC. Nevertheless, it failed at improving affinity, when compared to the lead from which it was derived. The origins of this structural and energetic discrepancy are discussed. 相似文献
970.
María C de Andrés Emilia Maneiro Miguel A Martín Joaquín Arenas Francisco J Blanco 《Arthritis research & therapy》2013,15(5):R115