全文获取类型
收费全文 | 8255篇 |
免费 | 644篇 |
国内免费 | 2篇 |
出版年
2023年 | 56篇 |
2022年 | 39篇 |
2021年 | 191篇 |
2020年 | 157篇 |
2019年 | 172篇 |
2018年 | 214篇 |
2017年 | 212篇 |
2016年 | 312篇 |
2015年 | 480篇 |
2014年 | 475篇 |
2013年 | 626篇 |
2012年 | 749篇 |
2011年 | 617篇 |
2010年 | 443篇 |
2009年 | 394篇 |
2008年 | 481篇 |
2007年 | 512篇 |
2006年 | 441篇 |
2005年 | 396篇 |
2004年 | 377篇 |
2003年 | 329篇 |
2002年 | 333篇 |
2001年 | 91篇 |
2000年 | 66篇 |
1999年 | 71篇 |
1998年 | 79篇 |
1997年 | 65篇 |
1996年 | 49篇 |
1995年 | 59篇 |
1994年 | 50篇 |
1993年 | 42篇 |
1992年 | 38篇 |
1991年 | 40篇 |
1990年 | 20篇 |
1989年 | 26篇 |
1988年 | 31篇 |
1987年 | 14篇 |
1986年 | 19篇 |
1985年 | 12篇 |
1984年 | 14篇 |
1983年 | 16篇 |
1982年 | 16篇 |
1981年 | 15篇 |
1980年 | 6篇 |
1979年 | 8篇 |
1978年 | 10篇 |
1977年 | 3篇 |
1975年 | 4篇 |
1974年 | 8篇 |
1962年 | 3篇 |
排序方式: 共有8901条查询结果,搜索用时 15 毫秒
991.
Domínguez JM Fuertes A Orozco L del Monte-Millán M Delgado E Medina M 《The Journal of biological chemistry》2012,287(2):893-904
Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreases Tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory, and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compounds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissociation rate, although the drug retains its inhibitory activity with decreased potency and long residence time. In addition, tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of nonspecific reactivity. Results obtained with [(35)S]tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low protein turnover rate observed for the enzyme are particularly relevant from a pharmacological perspective and could have significant implications on its therapeutic potential. 相似文献
992.
993.
994.
Álvaro-Benito M Sainz-Polo MA González-Pérez D González B Plou FJ Fernández-Lobato M Sanz-Aparicio J 《The Journal of biological chemistry》2012,287(23):19674-19686
Schwanniomyces occidentalis β-fructofuranosidase (Ffase) is a GH32 dimeric enzyme that releases fructose from the nonreducing end of various oligosaccharides and essential storage fructans such as inulin. It also catalyzes the transfer of a fructosyl unit to an acceptor producing 6-kestose and 1-kestose, prebiotics that stimulate the growth of bacteria beneficial for human health. We report here the crystal structure of inactivated Ffase complexed with fructosylnystose and inulin, which shows the intricate net of interactions keeping the substrate tightly bound at the active site. Up to five subsites were observed, the sugar unit located at subsite +3 being recognized by interaction with the β-sandwich domain of the adjacent subunit within the dimer. This explains the high activity observed against long substrates, giving the first experimental evidence of the direct role of a GH32 β-sandwich domain in substrate binding. Crucial residues were mutated and their hydrolase/transferase (H/T) activities were fully characterized, showing the involvement of the Gln-228/Asn-254 pair in modulating the H/T ratio and the type β(2-1)/β(2-6) linkage formation. We generated Ffase mutants with new transferase activity; among them, Q228V gives almost specifically 6-kestose, whereas N254T produces a broader spectrum product including also neokestose. A model for the mechanism of the Ffase transfructosylation reaction is proposed. The results contribute to an understanding of the molecular basis regulating specificity among GH-J clan members, which represent an interesting target for rational design of enzymes, showing redesigned activities to produce tailor-made fructooligosaccharides. 相似文献
995.
Roselló-Lletí E Rivera M Cortés R Azorín I Sirera R Martínez-Dolz L Hove L Cinca J Lago F González-Juanatey JR Salvador A Portolés M 《Biochemical and biophysical research communications》2012,418(2):222-228
We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n=38) and DCM (n=27) patients, undergoing heart transplantation and control donors (n=6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p<0.05) and DCM (141%, p<0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p<0.05) and DCM (1.70-fold, p<0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p<0.0001), and it was increased in pathological hearts (p<0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p<0.05 and 131%, p<0.001) and DCM (56%, p<0.01 and 69%, p<0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p<0.001), perinucleolar chromatin (p<0.01) and dense fibrillar components (p<0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p<0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein. 相似文献
996.
Two new species are described, Borreria cerradoana and B. velascoana, from Bolivia and Brazil, and a new combination is made, B. spinosa var. minima. Through an identification key, all 28 species of Borreria for Bolivia are recorded, and comments on geographical distribution and habitat are provided. Borreria brachystemonoides, B. poaya, and B. tenera are confirmed as new records for the country. 相似文献
997.
998.
Ring1a/b polycomb proteins regulate the mesenchymal stem cell niche in continuously growing incisors
Lapthanasupkul P Feng J Mantesso A Takada-Horisawa Y Vidal M Koseki H Wang L An Z Miletich I Sharpe PT 《Developmental biology》2012,367(2):140-153
Rodent incisors are capable of growing continuously and the renewal of dental epithelium giving rise to enamel-forming ameloblasts and dental mesenchyme giving rise to dentin-forming odontoblasts and pulp cells is achieved by stem cells residing at their proximal ends. Although the dental epithelial stem cell niche (cervical loop) is well characterized, little is known about the dental mesenchymal stem cell niche. Ring1a/b are the core Polycomb repressive complex1 (PRC1) components that have recently also been found in a protein complex with BcoR (Bcl-6 interacting corepressor) and Fbxl10. During mouse incisor development, we found that genes encoding members of the PRC1 complex are strongly expressed in the incisor apical mesenchyme in an area that contains the cells with the highest proliferation rate in the tooth pulp, consistent with a location for transit amplifying cells. Analysis of Ring1a(-/-);Ring1b(cko/cko) mice showed that loss of Ring1a/b postnatally results in defective cervical loops and disturbances of enamel and dentin formation in continuously growing incisors. To further characterize the defect found in Ring1a(-/-);Ring1b(cko/cko) mice, we demonstrated that cell proliferation is dramatically reduced in the apical mesenchyme and cervical loop epithelium of Ring1a(-/-);Ring1b(cko/cko) incisors in comparison to Ring1a(-/-);Ring1b(fl/fl)cre- incisors. Fgf signaling and downstream targets that have been previously shown to be important in the maintenance of the dental epithelial stem cell compartment in the cervical loop are downregulated in Ring1a(-/-);Ring1b(cko/cko) incisors. In addition, expression of other genes of the PRC1 complex is also altered. We also identified an essential postnatal requirement for Ring1 proteins in molar root formation. These results show that the PRC1 complex regulates the transit amplifying cell compartment of the dental mesenchymal stem cell niche and cell differentiation in developing mouse incisors and is required for molar root formation. 相似文献
999.
Fernanda P. Werneck Tony Gamble Guarino R. Colli Miguel T. Rodrigues Jack W. Sites Jr 《Evolution; international journal of organic evolution》2012,66(10):3014-3034
The relative influence of Neogene geomorphological events and Quaternary climatic changes as causal mechanisms on Neotropical diversification remains largely speculative, as most divergence timing inferences are based on a single locus and have limited taxonomic or geographic sampling. To investigate these influences, we use a multilocus (two mitochondrial and 11 nuclear genes) range‐wide sampling of Phyllopezus pollicaris, a gecko complex widely distributed across the poorly studied South American ‘dry diagonal’ biomes. Our approach couples traditional and model‐based phylogeography with geospatial methods, and demonstrates Miocene diversification and limited influence of Pleistocene climatic fluctuations on P. pollicaris. Phylogeographic structure and distribution models highlight that persistence across multiple isolated regions shaped the diversification of this species complex. Approximate Bayesian computation supports hypotheses of allopatric and ecological/sympatric speciation between lineages that largely coincide with genetic clusters associated with Chaco, Cerrado, and Caatinga, standing for complex diversification between the ‘dry diagonal’ biomes. We recover extremely high genetic diversity and suggest that eight well‐supported clades may be valid species, with direct implications for taxonomy and conservation assessments. These patterns exemplify how low‐vagility species complexes, characterized by strong genetic structure and pre‐Pleistocene divergence histories, represent ideal radiations to investigate broad biogeographic histories of associated biomes. 相似文献
1000.