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Optic nerve injury (ONI) induces retinal ganglion cell (RGC) death and optic nerve atrophy that lead to visual loss. Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and has an important role in stress-induced RGC apoptosis. In this study, we found that ONI-induced p38 activation and RGC loss were suppressed in ASK1-deficient mice. Sequential in vivo retinal imaging revealed that post-ONI treatment with a p38 inhibitor into the eyeball was effective for RGC protection. ONI-induced monocyte chemotactic protein-1 production in RGCs and microglial accumulation around RGCs were suppressed in ASK1-deficient mice. In addition, the productions of tumor necrosis factor and inducible nitric oxide synthase in microglia were decreased when the ASK1-p38 pathway was blocked. These results suggest that ASK1 activation in both neural and glial cells is involved in neural cell death, and that pharmacological interruption of ASK1-p38 pathways could be beneficial in the treatment of ONI. [ABSTRACT FROM AUTHOR]

Background: Fractional flow reserve (FFR) is used to evaluate the need for percutaneous coronary intervention (PCI) in cases of moderate stenosis of the coronary artery. Recently, diagnostic imaging support with computational fluid dynamics (CFD) analysis has been garnering attention. This study defines the relationship between FFR conducted for cardiac catheterization and CFD analyses conducted using coronary computed tomography (CT) for moderate stenosis, in addition to considering whether wall pressure (WP) and wall shear stress (WSS) can be used to evaluate ischemia. Methods and Results: Cases in which FFR was measured via coronary CT and cardiac catheterization was performed within 3 months were collected retrospectively. In the CFD analysis, WP and WSS were calculated and compared with FFR. Three groups were created to compare results of CFD analysis and FFR values according to the location of the stenosis: the right coronary artery, the left anterior descending artery, and the left circumflex artery. There was a correlation between FFR and WSS according to CFD analysis for moderate stenosis of the coronary artery, with a cut-off value for treatment able to be calculated. Conclusions: The results of this study suggest that ischemia can be evaluated by conducting CFD analysis (WSS) using coronary CT., Competing Interests: There is no conflict of interest to disclose., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)

The quality of the present day fluoroscopic images is sufficiently high for use as exposure images depending on the environment where the fluoroscopic images are recorded. In some facilities which use fluoroscopic images as exposure images they are recorded with a radiological x-ray diagnostic device equipped with a fluoroscopic storage function. There are, however, cases where fluoroscopic images cannot be used as exposure images because the quality of the fluoroscopic image cannot be assured in the environment where the fluoroscopic images are recorded. This poses problems when stored fluoroscopic images are used in place of exposure images without any clearly established standard. In the present study, we establish that stored fluoroscopic images can be used as exposure images by using gray values obtained from profile curves. This study finds that replacement of stored fluoroscopic images with exposure images requires 20.1 or higher gray scale value differences between the background and signal, using a 20 cm thick acrylic phantom (here an adult abdomen as representing the human body) as the specific geometry. This suggests the conclusion that the gray value can be considered a useful index when using stored fluoroscopic images as exposure images., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Dock3, a new member of the guanine nucleotide exchange factor family, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes neurite outgrowth through the formation of a protein complex with Fyn and WAVE downstream of brain-derived neurotrophic factor (BDNF) signaling. Here, we report a novel Dock3-mediated BDNF pathway for neurite outgrowth. We show that Dock3 forms a complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling and induces neurite outgrowth via Rac1 activation in PC12 cells. We also show the importance of Dock3 phosphorylation in Rac1 activation and show two key events that are necessary for efficient Dock3 phosphorylation: membrane recruitment of Dock3 and interaction of Dock3 with Elmo. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the central nervous system where it stimulates actin polymerization by multiple pathways., (© 2012 The Authors Journal compilation © 2012 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.)

Dock3, a new member of the guanine nucleotide exchange factors, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes axonal outgrowth downstream of brain-derived neurotrophic factor (BDNF) signaling. We previously showed that Dock3 forms a complex with Fyn and WASP (Wiskott-Aldrich syndrome protein) family verprolin-homologous (WAVE) proteins at the plasma membrane, and subsequent Rac1 activation promotes actin polymerization. Here we show that Dock3 binds to and inactivates glycogen synthase kinase-3β (GSK-3β) at the plasma membrane, thereby increasing the nonphosphorylated active form of collapsin response mediator protein-2 (CRMP-2), which promotes axon branching and microtubule assembly. Exogenously applied BDNF induced the phosphorylation of GSK-3β and dephosphorylation of CRMP-2 in hippocampal neurons. Moreover, increased phosphorylation of GSK-3β was detected in the regenerating axons of transgenic mice overexpressing Dock3 after optic nerve injury. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the CNS, where it regulates cell polarity and promotes axonal outgrowth by stimulating dual pathways: actin polymerization and microtubule assembly.

Gangliosides, sialic acid-containing glycosphingolipids, have been considered to play roles as neurotrophic factors. Exogenous gangliosides added to the culture medium of neuronal cells or injected in artificially injured sites of nerve tissues actually showed neurotrophic factor-like effects such as neurite extension and alleviation of nerve tissue deterioration. In this study, neuroregeneration in the mutant mice lacking complex gangliosides was examined. To determine whether the nervous system maintains regenerative activity in the long-term absence of complex gangliosides, we analyzed hypoglossal nerve regeneration after axotomy in the mutant mice of GM2/GD2 synthase. These mice exhibited marked impairment of regenerative activity both in the number of surviving neurons and in the number of peroxidase-positive neurons. Moreover, reduced levels of gene expression of neurotrophic factors and their receptors including CNTF, p75 NTR, TrkB, and others in hypoglossal neurons were observed in real-time reverse transcription-polymerase chain reaction combined with laser capture microdissection, suggesting that these molecules are, at least partly, involved in the regeneration of lesioned nerves and that their expression levels are precisely controlled in the presence of intact expression of complex gangliosides.

GM2/GD2 synthase gene knockout mice lack all complex gangliosides, which are abundantly expressed in the nervous systems of vertebrates. In turn, they have increased precursor structures GM3 and GD3, probably replacing the roles of the depleted complex gangliosides. In this study, we found that 9-O-acetyl GD3 is also highly expressed as one of the major glycosphingolipids accumulating in the nervous tissues of the mutant mice. The identity of the novel component was confirmed by neuraminidase treatment, thin layer chromatography-immunostaining, two-dimensional thin layer chromatography with base treatment, and mass spectrometry. All candidate factors reported to be possible inducer of 9-O- acetylation, such as bitamine D binding protein, acetyl CoA transporter, or O-acetyl ganglioside synthase were not up-regulated. Tis21 which had been reported to be a 9-O-acetylation inducer was partially down-regulated in the null mutants, suggesting that Tis21 is not involved in the induction of 9-O-acetyl-GD3 and that accumulated high amount of GD3 might be the main factor for the dramatic increase of 9-O-acetyl GD3. The ability to acetylate exogenously added GD3 in the normal mouse astrocytes was examined, showing that the wild-type brain might be able to synthesize very low levels of 9-O-acetyl GD3. Increased 9-O-acetyl GD3, in addition to GM3 and GD3, may play an important role in the compensation for deleted complex gangliosides in the mutant mice.

alpha2,8-Sialyltransferase (alpha2,8S-T, GD3 synthase) has been reported to be involved in the enhanced cell proliferation of malignant tumors. Using a cloned cDNA of alpha2,8S-T, transfectant cells were established and the effects of the gene expression on the cell phenotypes were analyzed. In contrast with PC12 cells, in which we reported marked growth enhancement based on the transfection of alpha2,8S-T, Swiss3T3 cells showed no enhancement in either cell proliferation or phosphorylation of MAP kinases after the transfection of alpha2,8S-T when treated with platelet-derived growth factor. Correspondingly, the receptor for platelet-derived growth factor also showed no increased phosphorylation upon the factor stimulation. However, in the wound-healing scratching assay, the Swiss3T3 transfectant cells demonstrated increased mobility as the PC12 transfectant cells. These results suggest that the enhancing effects of alpha2,8S-T on the proliferation and mobility are differential depending on the cell types, and ganglioside-associating molecules in the individual cell types need to be investigated.