Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and downregulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.cancer stem cell | epithelial-to-mesenchymal transition | glioblastoma multiforme | glioblastoma | proneural-to-mesenchymal transition
[1] The existence of gas-phase ammonia (NH 3 ) in the atmosphere and its interaction with other trace chemical species could have a substantial impact on tropospheric chemistry and global climate change. China is a large agricultural country with an enormous animal population, tremendous nitrogen fertilizer consumption and, consequently, a large emission of NH 3 . Despite the importance of NH 3 in the global nitrogen (N) cycle, considerable inaccuracies and uncertainty exist regarding its emission in China. In this study, a comprehensive NH 3 emission inventory was compiled for China on a 1 km  1 km grid, which is suitable for input to atmospheric models. We attempted to estimate NH 3 emissions accurately by taking into consideration as many native experiment results as possible and parameterizing the emission factors (EFs) by the ambient temperature, soil acidity and other factors. The total NH 3 emission in China was approximately 9.8 Tg in 2006. The emission sources considered included livestock excreta (5.3 Tg), fertilizer application (3.2 Tg), agricultural soil (0.2 Tg), nitrogen-fixing plants (0.05 Tg), crop residue compost (0.3 Tg), biomass burning (0.1 Tg), urine from rural populations (0.2 Tg), chemical industry (0.2 Tg), waste disposal (0.1 Tg) and traffic (0.1 Tg). The regions with the highest emission rates are located in Central and Southwest China. Seasonally, the peak ammonia emissions occur in spring and summer.
Developing an understanding of structure-activity relationships and reaction mechanisms of catalytic processes is critical to the successful design of highly efficient catalysts. As a This is a previous version of the article published in
The receptor for advanced glycation end products, RAGE, is a member of the immunoglobulin superfamily of cell surface molecules differentially expressed on a range of cell types. Ligation of RAGE perturbs homeostatic mechanisms and, potentially, provides a basis for cellular dysfunction in pathologic situations in which its ligands accumulate. To understand factors underlying RAGE expression, we cloned the 5-flanking region of the RAGE gene and characterized putative regulatory motifs. Analysis of the putative promoter region revealed the presence of three potential NF-B-like and two SP1 binding sites. Transient transfection of vascular endothelial and smooth muscle cells using chimeric 5-deletion constructs linked to luciferase reporter revealed that the region ؊1543/؊587 contributed importantly to both basal and stimulated expression of the RAGE gene. This region of the RAGE gene contained three putative NF-B-like binding sites and was responsible for increased luciferase activity observed when endothelial or smooth muscle cells were stimulated with lipopolysaccharide. DNase I footprinting assays and electrophoretic mobility shift assay revealed that two of the three NF-B-like binding sites (1 and 2) were likely functional and responsive to stimuli. Upon simultaneous mutation of NF-B-like sites 1 and 2, both basal promoter expression and response to stimulation with LPS, as measured by relative luciferase activity, were significantly diminished. These results point to NF-Bdependent mechanisms regulating cellular expression of RAGE and suggest a means of linking RAGE to the inflammatory response.
RAGE1 (for receptor for advanced glycation end products), a member of the immunoglobulin superfamily of cell surface molecules, was initially identified and characterized as a cellular interaction site for advanced glycation end products or AGEs, ligands formed in diverse circumstances as a consequence of irreversible glycation/oxidation of proteins or lipids (1-6). AGE formation occurs during normal aging, and to an accelerated degree in hyperglycemic conditions such as diabetes mellitus. In renal failure, enhanced glycation of  2 -microglobulin occurs as a result of its markedly delayed clearance, one consequence of which, the formation of AGE- 2 -microglobulin, is likely linked to the inflammatory bone and joint destruction characteristic of dialysis-related amyloidosis (7-10). AGE formation is also favored in other settings associated with the accumulation of amyloid proteins, such as in components of intracellular neurofibrillary tangles (11-13), as well as in extracellular amyloid- peptide accumulations (14) characteristic of Alzheimer's disease. We hypothesized that expression of RAGE in a range of cells, including endothelial cells, vascular smooth muscle cells, mononuclear phagocytes, and certain neurons, as identified by immunohistochemistry and in situ hybridization studies (15, 16), places this molecule in prime position to mediate the pathogenic effects of AGEs.Analysis of RAGE in tissues has suggested ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.