全文获取类型
收费全文 | 422篇 |
免费 | 34篇 |
出版年
2023年 | 6篇 |
2022年 | 5篇 |
2021年 | 21篇 |
2020年 | 13篇 |
2019年 | 20篇 |
2018年 | 14篇 |
2017年 | 8篇 |
2016年 | 11篇 |
2015年 | 30篇 |
2014年 | 27篇 |
2013年 | 28篇 |
2012年 | 39篇 |
2011年 | 35篇 |
2010年 | 13篇 |
2009年 | 16篇 |
2008年 | 19篇 |
2007年 | 26篇 |
2006年 | 16篇 |
2005年 | 12篇 |
2004年 | 9篇 |
2003年 | 15篇 |
2002年 | 12篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 7篇 |
1998年 | 6篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 4篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1976年 | 2篇 |
1972年 | 2篇 |
1969年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有456条查询结果,搜索用时 203 毫秒
41.
Sarrazin S Bonnaffé D Lubineau A Lortat-Jacob H 《The Journal of biological chemistry》2005,280(45):37558-37564
Cell-associated heparan sulfate (HS) is endowed with the remarkable ability to bind numerous proteins. As such, it represents a unique system that integrates signaling from circulating ligands with cellular receptors. This polysaccharide is extraordinary complex, and examples that define the structure-function relationship of HS are limited. In particular, it remains difficult to understand the structures by which HS interact with proteins. Among them, interferon-gamma (IFNgamma), a dimeric cytokine, binds to a complex oligosaccharide motif encompassing a N-acetylated glucosamine-rich domain and two highly sulfated sequences, each of which binds to one IFNgamma monomer. Based on this template, we have synthesized a set of glycoconjugate mimetics and evaluated their ability to interact with IFNgamma. One of these molecules, composed of two authentic N-sulfated octasaccharides linked to each other through a 50-Angstroms-long spacer termed 2O(10), displays high affinity for the cytokine and inhibits IFNgamma-HS binding with an IC(50) of 35-40 nm. Interestingly, this molecule also inhibits the binding of IFNgamma to its cellular receptor. Thus, in addition to its ability to delocalize the cytokine from cell surface-associated HS, this compound has direct anti-IFNgamma activity. Altogether, our results represent the first synthetic HS-like molecule that targets a cytokine, strongly validating the HS structural determinants for IFNgamma recognition, providing a new strategy to inhibit IFNgamma in a number of diseases in which the cytokine has been identified as a target, and reinforcing the view that it is possible to create"tailor-made"sequences based on the HS template to isolate therapeutic activities. 相似文献
42.
Lipid oxidation and autophagy in yeast 总被引:1,自引:0,他引:1
Kissová I Deffieu M Samokhvalov V Velours G Bessoule JJ Manon S Camougrand N 《Free radical biology & medicine》2006,41(11):1655-1661
Autophagy, a process involved in the degradation and the recycling of long-lived proteins and organelles to survive nitrogen starvation, is generally non-selective. However, recent data suggest that selective forms of autophagy exist, that are able to specifically target several organelles, including mitochondria. Conversely, mitochondrial alterations could trigger autophagy. Such a selective form of autophagy might be involved in the elimination of damaged mitochondria. We reported previously that, mitochondria were early targets of rapamycin-induced autophagy. Here we report that rapamycin-induced autophagy is accompanied by the early production of reactive oxygen species and by the early oxidation of mitochondrial lipid. Inhibition of these oxidative effects by resveratrol largely impaired autophagy of both cytosolic proteins and mitochondria, and delayed subsequent cell death. These results support a role of mitochondrial oxidation events in the activation of autophagy. 相似文献
43.
Co- and terpolyesters based on isosorbide and succinic acid for coating applications: synthesis and characterization 总被引:1,自引:0,他引:1
Noordover BA van Staalduinen VG Duchateau R Koning CE van Benthem RA Mak M Heise A Frissen AE van Haveren J 《Biomacromolecules》2006,7(12):3406-3416
Co- and terpolyesters based on succinic acid and isosorbide in combination with other renewable monomers such as 2,3-butanediol, 1,3-propanediol, and citric acid were synthesized and characterized. Linear polyesters were obtained via melt polycondensation of nonactivated dicarboxylic acids with OH functional monomers. Polymer end functionality (i.e., hydroxyl or carboxylic acid) was controlled by adjusting the monomer stoichiometry. The glass transition temperatures of the resulting polyesters could be effectively adjusted by varying the polymer composition and molar mass. By adding polyfunctional monomers such as trimethylolpropane or citric acid, polyesters with enhanced functionality were obtained. These biobased polyesters displayed functionalities and Tg values in the appropriate range for (powder) coating applications. The polyesters were cross-linked using conventional curing agents. Coatings from branched polyesters--hydroxyl as well as acid functional--showed significantly improved mechanical and chemical resistance compared to those formulated from linear polymers. These renewable polyesters proved to be suitable materials for coating applications with respect to solvent resistance, impact resistance, and hardness. 相似文献
44.
Laura A.E. HughesCarolina A.J. Khalid-de Bakker Kim M. SmitsPiet A. van den Brandt Daisy JonkersNita Ahuja James G. HermanMatty P. Weijenberg Manon van Engeland 《生物化学与生物物理学报:癌评论》2012,1825(1):77-85
In recent years, attention has focused on the biology and potential clinical importance of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). While it is generally well accepted that etiologically and clinically distinct subgroups exist in this disease, a precise definition of CIMP remains to be established. Here, we summarize existing literature that documents the prevalence of CIMP in CRC, with particular attention to the various methods and definitions used to classify a tumor as CIMP positive. Through a systematic review on both case-series and population based studies, we examined only original research articles reporting on sporadic CRC and/or adenomas in unselected cases. Forty-eight papers published between January 1999 and August 2011 met the inclusion criteria. We describe the use of multiple gene panels, marker threshold values, and laboratory techniques which results in a wide range in the prevalence of CIMP. Because there is no universal standard or consensus on quantifying the phenotype, establishing its true prevalence is a challenge. This bottleneck is becoming increasingly evident as molecular pathological epidemiology continues to offer possibilities for clear answers regarding environmental risk factors and disease trends. For the first time, large, unselected series of cases are available for analysis, but comparing populations and pooling data will remain a challenge unless a universal definition of CIMP and a consensus on analysis can be reached, and the primary cause of CIMP identified. 相似文献
45.
Berlivet S Moussette S Ouimet M Verlaan DJ Koka V Al Tuwaijri A Kwan T Sinnett D Pastinen T Naumova AK 《Human genetics》2012,131(7):1161-1171
46.
William C. Lamanna Roger Lawrence Stéphane Sarrazin Carlos Lameda-Diaz Philip L. S. M. Gordts Kelley W. Moremen Jeffrey D. Esko 《The Journal of biological chemistry》2012,287(43):36283-36290
Inherited defects in the ability to catabolize glycosaminoglycans result in lysosomal storage disorders known as mucopolysaccharidoses (MPS), causing severe pathology, particularly in the brain. Enzyme replacement therapy has been used to treat mucopolysaccharidoses; however, neuropathology has remained refractory to this approach. To test directly whether substrate reduction might be feasible for treating MPS disease, we developed a genetic model for substrate reduction therapy by crossing MPS IIIa mice with animals partially deficient in heparan sulfate biosynthesis due to heterozygosity in Ext1 and Ext2, genes that encode the copolymerase required for heparan sulfate chain assembly. Reduction of heparan sulfate by 30–50% using this genetic strategy ameliorated the amount of disease-specific biomarker and pathology in multiple tissues, including the brain. In addition, we were able to demonstrate that substrate reduction therapy can improve the efficacy of enzyme replacement therapy in cell culture and in mice. These results provide proof of principle that targeted inhibition of heparan sulfate biosynthetic enzymes together with enzyme replacement might prove beneficial for treating mucopolysaccharidoses. 相似文献
47.
48.
49.
Hughes LA Khalid-de Bakker CA Smits KM van den Brandt PA Jonkers D Ahuja N Herman JG Weijenberg MP van Engeland M 《Biochimica et biophysica acta》2012,1825(1):77-85
In recent years, attention has focused on the biology and potential clinical importance of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). While it is generally well accepted that etiologically and clinically distinct subgroups exist in this disease, a precise definition of CIMP remains to be established. Here, we summarize existing literature that documents the prevalence of CIMP in CRC, with particular attention to the various methods and definitions used to classify a tumor as CIMP positive. Through a systematic review on both case-series and population based studies, we examined only original research articles reporting on sporadic CRC and/or adenomas in unselected cases. Forty-eight papers published between January 1999 and August 2011 met the inclusion criteria. We describe the use of multiple gene panels, marker threshold values, and laboratory techniques which results in a wide range in the prevalence of CIMP. Because there is no universal standard or consensus on quantifying the phenotype, establishing its true prevalence is a challenge. This bottleneck is becoming increasingly evident as molecular pathological epidemiology continues to offer possibilities for clear answers regarding environmental risk factors and disease trends. For the first time, large, unselected series of cases are available for analysis, but comparing populations and pooling data will remain a challenge unless a universal definition of CIMP and a consensus on analysis can be reached, and the primary cause of CIMP identified. 相似文献
50.
Dubois L Ohm Kyvik K Girard M Tatone-Tokuda F Pérusse D Hjelmborg J Skytthe A Rasmussen F Wright MJ Lichtenstein P Martin NG 《PloS one》2012,7(2):e30153