Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease

Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases.In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases

L Antigen Family Member 3 Serves as a Prognostic Biomarker for the Clinical Outcome and Immune Infiltration in Skin Cutaneous Melanoma

L Antigen Family Member 3 (LAGE3) is an important RNA modification-related protein. Whereas few studies have interrogated the LAGE3 protein, there is limited data on its role in tumors. Here, we analyzed and profiled the LAGE3 protein in skin cutaneous melanoma (CM) using TCGA, GTEx, or GEO databases. Our data showed an upregulation of LAGE3 in melanoma cell lines compared to normal skin cell lines. Besides, the Kaplan–Meier curves and Cox proportional hazard model revealed that LAGE3 was an independent survival indicator for CM, especially in metastatic CM. Moreover, LAGE3 was negatively associated with multiple immune cell infiltration levels in CM, especially CD8+ T cells in metastatic CM. Taken together, our study suggests that LAGE3 could be a potential prognostic biomarker and might be a potential target for the development of novel CM treatment strategies

Oxidation Resistance and Wetting Behavior of MgO-C Refractories: Effect of Carbon Content

Various carbon contents in the MgO-C refractory were studied with respect to the oxidation resistance and the wetting behavior with slag. The bulk density, apparent porosity, cold crushing strength, oxidation rate, and mass loss rate of the fired MgO-C refractories with various carbon contents were measured and compared. The wetting and penetration behavior of the cured MgO-C refractory with the molten slag were observed in-situ. The contact angle and the shape parameters of molten slag, including the apparent radius, height, and volume were compared. The results showed that the regenerated MgO effectively restrained the carbon oxidation in the MgO-C refractory, which was more evident at the low carbon content refractory. The contact angle between the MgO-C refractory and the molten slag increased as the carbon content increased. The increased contact angle decreased the penetration of the molten slag

Fabrication of ZrO2(MgO)/CaAl2O4+CaAl4O7 Bilayer Structure Used for Sulfur Sensor by Laser Cladding

The ZrO2(MgO)/CaAl2O4+CaAl4O7 bilayer structure used for sulfur sensor was fabricated by the laser powder cladding (LPC) method using the MgO partially stabilized zirconia (2.7 wt% MgO-PSZ) as the substrate and the CaAl2O4 + CaAl4O7 composites as the coating material. The microstructure, phase composition and ionic conductivity of this bilayer structure were investigated for better application in the sulfur determination. The results indicated that the structure of the coating was dense and well-distributed with a thickness of 100 μm. The ionic conductivity of the ZrO2(MgO)/CaAl2O4+CaAl4O7 bilayer structure was up to 2.06 × 10−3 S·cm−1 at 850 °C that met the required ionic conductivity of ionic conductor for solid electrolyte sulfur sensor. Furthermore, the sulfur sensor Mo|Cr+Cr2O3| ZrO2(MgO)| CaAl2O4+CaAl4O7|[S]Fe| Mo was assembled used this bilayer structure and tested in carbon-saturated liquid iron at 1773 K and 1823 K. The stability and reproducibility of the sulfur sensor were satisfactory and could be used for sulfur determination in the liquid iron

Effects of the Molding Method and Blank Size of Green Body on the Sintering Densification of Magnesia

The bulk density of sintered magnesia is significantly influenced by molding methodology and blank size of the green body during dry pressing. The entrapped air in the green body plays a critical role in determining the bulk density of magnesia samples. Herein, high-density magnesia samples, with different sizes, are prepared by using vacuum compaction molding and conventional compaction molding. The physical properties, such as bulk density and pore size distribution, and morphology or as-sintered magnesia samples were characterized by using Archimedes method, mercury porosimetry, and scanning electron microscopy (SEM). The results indicate that the bulk density of conventional compaction magnesia samples decreased below 3.40 g·cm−3 with the increase of thickness due to the presence of entrapped-air induced large pores and intergranular cracks. In addition, the large pores and intergranular cracks in conventionally-compacted samples are observed by SEM images. However, vacuum compaction of magnesia samples resulted in a bulk density of higher than 3.40 g·cm−3 for all thicknesses. Moreover, the defects in vacuum-compacted magnesia samples are mainly in the form of small circular pores