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Summary: MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2. A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS.

Abstract Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.

In this study, we explored the effect of an active afterheater on the growth of gallium oxide single crystals using the EFG method. We analyzed the temperature distribution of the crystal under the growing process through multiphysics simulations of the models with and without an active afterheater and investigated the morphology of crystals by applying each model to real experimental growths. The afterheater is a component in the growing furnace that activates radiant heat transfer, and its performance depends on its location, size, material, and shape. The simulation results showed that the afterheater applied in this study was found to be effective in obtaining good temperature distribution in the reactor. Through experimental crystal growth corresponding to the simulation approaches, it was confirmed that an appropriate afterheater reduces thermal stress at the growth front and provides a thermal annealing effect on the post-grown crystals during the growing process to improve crystal quality.

Exposure to excessive lipopolysaccharide (LPS) by the gut microbiota disturbance causes ulcerative colitis and memory impairment. Therefore, we isolated anti-inflammatory Lactobacillus johnsonii CJLJ103 (LJ) from human fecal microbiota as an inhibitor for Escherichia coli growth and LPS production and investigated anti-colitic and memory impairment-ameliorating effects in mice. Oral administration of LJ inhibited 2,3,6-trinitrobenzenesulfonic acid (TNBS)-induced colon shortening, colonic myeloperoxidase activity, and NF-κB activation in mice. Furthermore, LJ inhibited TNBS-induced TNF and IL-1β expression in the colon but increased TNBS-suppressed expression of IL-10 and tight-junction proteins. Treatment with LJ inhibited fecal LPS levels and proteobacteria/bacteroidetes ratio in mice with TNBS-induced colitis. Furthermore, LJ ameliorated LPS-induced memory impairment in mice. LJ also suppressed LPS-induced NF-κB activation in the hippocampus and increased LPS-suppressed brain-derived neurotrophic factor expression. These findings suggest that LJ, a member of human gut microbiota, may ameliorate colitis and memory impairment, thereby acting as a useful probiotic.

In the present study, we isolated Bifidobacterium longum CH57, which suppresses macrophage activation, from human gut microbiota and Lactobacillus brevis CH23, which inhibit Th17 cell differentiation, from kimchi, and investigated anti-inflammatory effects of CH23, CH57, and their probiotic mixture (PM) in mice with TNBS-induced colitis. CH57 inhibited NF-κB activation in LPS-stimulated macrophages. Oral administration of CH57 in mice attenuated TNBS-induced colitis and TNF-α expression. CH23 inhibited IL-17 and RORγt expression in splenic T cells. Oral administration of CH23 in mice inhibited TNBS-induced colon shortening, myeloperoxidase activity, and Th17 cell differentiation and induced TNBS-suppressed Treg differentiation. PM increased TNBS-suppressed claudin, occludin, and ZO-1 expression and Treg differentiation, while CH57 inhibited Th17 cell differentiation and RORγt and IL-17 expression. PM inhibited TNBS-induced macrophage activation. Moreover, CH23 and CH57 synergistically inhibited macrophage activation and Th17 cell differentiation in vitro. The PM may synergistically ameliorate colitis by inhibiting macrophage activation and restoring Th17/Treg balance.