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71.
Inhibition of 12 mammalian isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA I-XIV, with a series of phenols was investigated. The inhibition profile by phenols of these CAs was distinct from those of the sulfonamides and their isosteres, the main class of clinically used inhibitors. Phenol and some of its 2-, 3- and 4-substituted derivatives incorporating hydroxy-, fluoro-, carboxy-, amino-, cyano- and acetamido-moieties were generally effective low micromolar CA inhibitors, with inhibition constants in the range of 9.8-4003 microM against CA I, of 0.090-870 microM against CA II, of 0.71-885 microM against CA III, of 9.5-809 microM against CA IV, of 8.7-867 microM against CA VA, of 4.2-649 microM against CA VB, of 11.4-658 microM against CA VI, of 9.1-1359 microM against CA VII, of 8.8-517 microM against CA IX, of 4.1-598 microM against CA XII, of 12.2-697 microM against CA XIII and of 10.1-49.8 microM against CA XIV, respectively. The different mechanisms of inhibition by phenols as compared to sulfonamides, and their diverse inhibition profile for these mammalian isozymes, makes this class of derivatives of great interest for the design of compounds with selectivity and/or specificity for some of the medicinal chemistry targets belonging to this enzyme family. 相似文献
72.
Federica Vacondio Caterina Carmi Elena Galvani Michele Bassi Claudia Silva Alessio Lodola Silvia Rivara Andrea Cavazzoni Roberta R. Alfieri Pier Giorgio Petronini Marco Mor 《Bioorganic & medicinal chemistry letters》2013,23(19):5290-5294
In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5–6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols. 相似文献
73.
Epithelial cell polarity depends on mechanisms for targeting proteins to different plasma membrane domains. Here, we dissect the pathway for apical delivery of several raft-associated, glycosyl phosphatidylinositol (GPI)-anchored proteins in polarized MDCK cells using live-cell imaging and selective inhibition of apical or basolateral exocytosis. Rather than trafficking directly from the trans-Golgi network (TGN) to the apical plasma membrane as previously thought, the GPI-anchored proteins followed an indirect, transcytotic route. They first exited the TGN in membrane-bound carriers that also contained basolateral cargo, although the two cargoes were laterally segregated. The carriers were then targeted to and fused with a zone of lateral plasma membrane adjacent to tight junctions that is known to contain the exocyst. Thereafter, the GPI-anchored proteins, but not basolateral cargo, were rapidly internalized, together with endocytic tracer, into clathrin-free transport intermediates that transcytosed to the apical plasma membrane. Thus, apical sorting of these GPI-anchored proteins occurs at the plasma membrane, rather than at the TGN. 相似文献
74.
Ascenzi P Bocedi A Fasano M Gioia M Marini S Coletta M 《Journal of inorganic biochemistry》2005,99(5):1255-1259
The effect of pH on the X-band electron paramagnetic resonance (EPR) spectrum of ferrous nitrosylated human adult tetrameric hemoglobin (HbNO) as well as of ferrous nitrosylated monomeric alpha- and beta-chains has been investigated, at -163 degrees C. At pH 7.3, the X-band EPR spectrum of tetrameric HbNO and ferrous nitrosylated monomeric alpha- and beta-chains displays a rhombic shape. Lowering the pH from 7.3 to 3.0, tetrameric HbNO and ferrous nitrosylated monomeric alpha- and beta-chains undergo a transition towards a species characterized by a X-band EPR spectrum with a three-line splitting centered at 334mT. These pH-dependent spectroscopic changes may be taken as indicative of the cleavage, or the severe weakening, of the proximal HisF8-Fe bond. In tetrameric HbNO, the pH-dependent spectroscopic changes depend on the acid-base equilibrium of two apparent ionizing groups with pK(a) values of 5.8 and 3.8. By contrast, the pH-dependent spectroscopic changes occurring in ferrous nitrosylated monomeric alpha- and beta-chains depend on the acid-base equilibrium of one apparent ionizing group with pK(a) values of 4.8 and 4.7, respectively. The different pK(a) values for the proton-linked spectroscopic transition(s) of tetrameric HbNO and ferrous nitrosylated monomeric alpha- and beta-chains suggest that the quaternary assembly drastically affects the strength of the proximal HisF8-Fe bond in both subunits. This probably reflects a 'quaternary effect', i.e., structural changes in both subunits upon tetrameric assembly, which is associated to a relevant variation of functional properties (i.e., proton affinity). 相似文献
75.
Patterns of rodent species abundance and diversity were examined over a 5 months period in two areas of a Kenyan relict tropical
rainforest. The two areas are subjected to different administrations which lead to various levels of anthropogenic disturbance:
one can be considered relatively disturbed and one relatively undisturbed. Anthropogenic disturbance causes a reduction in
woody stem density between 0 and 1.5 m and reduced understory tree canopy cover. Rodent abundance was estimated using the
program CAPTURE and compared with the number of individuals actually captured. Density was estimated with three different
methods, two of these utilised a boundary strip to estimate effective size of the area trapped. Density resulted in being
relatively high in both areas, so population might have been at a peak. Species richness was higher in the disturbed forest,
while species diversity and evenness was higher in the undisturbed forest. We suggest that in the disturbed forest the increase
in number of species might be due to sporadical entrance in the forest by non-forest species, while the decrease in diversity
might be due to the decrease of lower strata vegetation that occurs in the disturbed forest, hence this factor might affect
species equitability. Bibliographic data supports this hypothesis as rodent species diversity and ground vegetation cover
have been found to be correlated. 相似文献
76.
Laura Zuccaro Cinzia Tesauro Barbara Cerroni Alessio Ottaviani Birgitta Ruth Knudsen Kannan Balasubramanian Alessandro Desideri 《Analytical biochemistry》2014
A high-sensitivity assay has been developed for the detection of human topoisomerase I with single molecule resolution. The method uses magnetic sepharose beads to concentrate rolling circle products, produced by the amplification of DNA molecules circularized by topoisomerase I and detectable with a confocal microscope as single and discrete dots, once reacted with fluorescent probes. Each dot, corresponding to a single cleavage–religation event mediated by the enzyme, can be counted due to its high signal/noise ratio, allowing detection of 0.3 pM enzyme and representing a valid method to detect the enzyme activity in highly diluted samples. 相似文献
77.
Alessio Collalti Mark G. Tjoelker Günter Hoch Annikki Mkel Gabriele Guidolotti Mary Heskel Giai Petit Michael G. Ryan Giovanna Battipaglia Giorgio Matteucci Iain Colin Prentice 《Global Change Biology》2020,26(3):1739-1753
Two simplifying hypotheses have been proposed for whole‐plant respiration. One links respiration to photosynthesis; the other to biomass. Using a first‐principles carbon balance model with a prescribed live woody biomass turnover, applied at a forest research site where multidecadal measurements are available for comparison, we show that if turnover is fast the accumulation of respiring biomass is low and respiration depends primarily on photosynthesis; while if turnover is slow the accumulation of respiring biomass is high and respiration depends primarily on biomass. But the first scenario is inconsistent with evidence for substantial carry‐over of fixed carbon between years, while the second implies far too great an increase in respiration during stand development—leading to depleted carbohydrate reserves and an unrealistically high mortality risk. These two mutually incompatible hypotheses are thus both incorrect. Respiration is not linearly related either to photosynthesis or to biomass, but it is more strongly controlled by recent photosynthates (and reserve availability) than by total biomass. 相似文献
78.
79.
Adeline C Ledoux Hélène Sellier Katie Gillies Alessio Iannetti John James Neil D Perkins 《Cell cycle (Georgetown, Tex.)》2013,12(18):3052-3062
Activation of the NFκB signaling pathway allows the cell to respond to infection and stress and can affect many cellular processes. As a consequence, NFκB activity must be integrated with a wide variety of parallel signaling pathways. One mechanism through which NFκB can exert widespread effects is through controlling the expression of key regulatory kinases. Here we report that NFκB regulates the expression of genes required for centrosome duplication, and that Polo-like kinase 4 (PLK4) is a direct NFκB target gene. RNA interference, chromatin immunoprecipitation, and analysis of the PLK4 promoter in a luciferase reporter assay revealed that all NFκB subunits participate in its regulation. Moreover, we demonstrate that NFκB regulation of PLK4 expression is seen in multiple cell types. Significantly long-term deletion of the NFκB2 (p100/p52) subunit leads to defects in centrosome structure. This data reveals a new component of cell cycle regulation by NFκB and suggests a mechanism through which deregulated NFκB activity in cancer can lead to increased genomic instability and uncontrolled proliferation. 相似文献