Neural Correlates of Color-Selective Metacontrast in Human Early Retinotopic Areas

Metacontrast is a visual illusion in which the visibility of a target stimulus is virtually lost when immediately followed by a nonoverlapping mask stimulus. For a colored target, metacontrast is color-selective, with target visibility markedly reduced when the mask and target are the same color, but only slightly reduced when the colors differ. This study investigated neural correlates of color-selective metacontrast for cone-opponent red and green stimuli in the human V1, V2, and V3 using functional magnetic resonance imaging. Neural activity was suppressed when the target was rendered less visible by the same-colored mask, and the suppression was localized in the cortical region retinotopically representing the target, correlating with the perceptual topography of visibility/invisibility rather than the physical topography of the stimulus. Retinotopy-based group analysis found that activity suppression was statistically significant for V2 and V3 and that its localization to the target region was statistically significant for V2. These results suggest that retinotopic color representations in early visual areas, especially in V2, are closely linked to the visibility of color

Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells

Background. Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach. Methods. We performed a cell proliferation/death-based drug screening using 10560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays. Results. Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y-box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis. Conclusion. In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects

Vulnerability to shear stress caused by altered peri-endothelial matrix is a key feature of Moyamoya disease

Abstract Moyamoya disease (MMD) is characterized by progressive bilateral stenotic changes in the terminal portion of the internal carotid arteries. Although RNF213 was identified as a susceptibility gene for MMD, the exact pathogenesis remains unknown. Immunohistochemical analysis of autopsy specimens from a patient with MMD revealed marked accumulation of hyaluronan and chondroitin sulfate (CS) in the thickened intima of occlusive lesions of MMD. Hyaluronan synthase 2 was strongly expressed in endothelial progenitor cells in the thickened intima. Furthermore, MMD lesions showed minimal staining for CS and hyaluronan in the endothelium, in contrast to control endothelium showing positive staining for both. Glycosaminoglycans of endothelial cells derived from MMD and control induced pluripotent stem cells demonstrated a decreased amount of CS, especially sulfated CS, in MMD. A computational fluid dynamics model showed highest wall shear stress values in the terminal portion of the internal carotid artery, which is the predisposing region in MMD. Because the peri-endothelial extracellular matrix plays an important role in protection, cell adhesion and migration, an altered peri-endothelial matrix in MMD may contribute to endothelial vulnerability to wall shear stress. Invading endothelial progenitor cells repairing endothelial injury would produce excessive hyaluronan and CS in the intima, and cause vascular stenosis