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NG2 glia, also known as oligodendrocyte precursor cells (OPCs), play an important role in proliferation and give rise to myelinating oligodendrocytes during early brain development. In contrast to other glial cell types, the most intriguing aspect of NG2 glia is their ability to directly sense synaptic inputs from neurons. However, whether this synaptic interaction is bidirectional or unidirectional, or its physiological relevance has not yet been clarified. Here, we report that NG2 glia form synaptic complexes with hippocampal interneurons and that selective photostimulation of NG2 glia (expressing channelrhodopsin-2) functionally drives GABA release and enhances inhibitory synaptic transmission onto proximal interneurons in a microcircuit. The mechanism involves GAD67 biosynthesis and VAMP-2 containing vesicular exocytosis. Further, behavioral assays demonstrate that NG2 glia photoactivation triggers anxiety-like behavior in vivo and contributes to chronic social defeat stress. Nerve/glial antigen 2 (NG2) glia can sense synaptic inputs from neurons. Here, the authors show NG2 glia form functional GABAergic synapses by regulating inhibitory synaptic transmission onto adjacent hippocampal interneurons, and activation of NG2 glia induces anxiety-like behaviour in a mouse model of chronic social defeat stress.

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA-binding protein that can regulate the translation of specific mRNAs. In this study, we developed an FXS human forebrain organoid model and observed that the loss of FMRP led to dysregulated neurogenesis, neuronal maturation and neuronal excitability. Bulk and single-cell gene expression analyses of FXS forebrain organoids revealed that the loss of FMRP altered gene expression in a cell-type-specific manner. The developmental deficits in FXS forebrain organoids could be rescued by inhibiting the phosphoinositide 3-kinase pathway but not the metabotropic glutamate pathway disrupted in the FXS mouse model. We identified a large number of human-specific mRNAs bound by FMRP. One of these human-specific FMRP targets, CHD2, contributed to the altered gene expression in FXS organoids. Collectively, our study revealed molecular, cellular and electrophysiological abnormalities associated with the loss of FMRP during human brain development. Using a human forebrain organoid model of fragile X syndrome, Kang et al. reveal a critical role of FMRP in human brain development and identify a large number of human-specific mRNAs that could be regulated by FMRP.

Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 ( Phf8 ) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects. We also show that mTOR signaling pathway is hyperactive in hippocampus in Phf8 knockout mouse. Mechanistically, we show that demethylation of H4K20me1 by Phf8 results in transcriptional suppression of RSK1 and homeostasis of mTOR signaling. Pharmacological suppression of mTOR signaling with rapamycin in Phf8 knockout mice recovers the weakened LTP and cognitive deficits. Together, our results indicate that loss of Phf8 in animals causes deficient learning and memory by epigenetic disruption of mTOR signaling, and provides a potential therapeutic drug target to treat XLID. Mutations in PHF8 gene are genetically associated with X-linked mental retardation. Here, Chen et al. show that Phf8 KO mouse have cognitive and synaptic plasticity impairment, and pharmacological inhibition of mTOR signaling can partially alleviate such defects.

T-2 toxin is produced by the Fusarium genus. Ingestion of food or feed contaminated by T-2 toxin will cause damage to kidney. Selenium (Se), an essential trace element, showed the significant protective effects against kidney and renal cell damage induced by toxic substances. To explore the protective effects and mechanisms of Se against T-2-induced renal lesions, forty-eight male Kunming mice were exposed to T-2 toxin (1.0 mg/kg) and/or Se (0.2 mg/kg) for 28 days. In this study, we found that Se alleviated T-2-induced nephrotoxicity, presenting as increasing the body weight and kidney coefficient, relieving the renal structure injury, decreasing the contents of renal function-related biomarkers, decreasing the levels of reactive oxygen species (ROS), and increasing the mitochondrial membrane potential in T-2 toxin-treated mice. In addition, inhibition of renal cell apoptosis by Se was associated with blocking the mitochondrial pathway in T-2 toxin-treated mice, presenting as decreasing the protein expression of cytochrome-c, activities of caspase-3/9, as well as regulating the protein and mRNA expressions of Bax and Bcl-2. These results documented that the alleviating effect of Se on T-2-induced nephrotoxicity is related to the inhibition of ROS-mediated renal apoptosis.

The communication between neurons and, in some cases, between neurons and non-neuronal cells, through neurotransmission plays a crucial role in various physiological and pathological processes. Despite its importance, the neuromodulatory transmission in most tissues and organs remains poorly understood due to the limitations of current tools for direct measurement of neuromodulatory transmitters. In order to study the functional roles of neuromodulatory transmitters in animal behaviors and brain disorders, new fluorescent sensors based on bacterial periplasmic binding proteins (PBPs) and G-protein coupled receptors have been developed, but their results have not been compared to or multiplexed with traditional methods such as electrophysiological recordings. In this study, a multiplexed method was developed to measure acetylcholine (ACh), norepinephrine (NE), and serotonin (5-HT) in cultured rat hippocampal slices using simultaneous whole-cell patch clamp recordings and genetically encoded fluorescence sensor imaging. The strengths and weaknesses of each technique were compared, and the results showed that both techniques did not interfere with each other. In general, genetically encoded sensors GRAB NE and GRAB 5 HT 1 . 0 showed better stability compared to electrophysiological recordings in detecting NE and 5-HT, while electrophysiological recordings had faster temporal kinetics in reporting ACh. Moreover, genetically encoded sensors mainly report the presynaptic neurotransmitter release while electrophysiological recordings provide more information of the activation of downstream receptors. In sum, this study demonstrates the use of combined techniques to measure neurotransmitter dynamics and highlights the potential for future multianalyte monitoring.

Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor. Despite the presence of tumor-infiltrating lymphocytes, many patients do not respond to PD-L1/PD-1 blockade therapy. Here they show that PD-L1 antibody armed with interferon-α (IFNα) improves tumor targeting and antigen presentation while countering innate or T-cell-drive PD-L1 upregulation, and overcomes resistance to checkpoint blockade therapy.

The incidence of cutaneous melanoma (CM) has been increasing annually worldwide. In this study, we identify that MrgprF, a MAS related GPR family member, is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region, and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome. We demonstrate that MrgprF forced expression inhibits tumor cell proliferation, migration, xenograft tumor growth, and metastasis. On the contrary, MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells, supporting the inhibitory role of MrgprF during tumor progression. Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase (PI3K) complex formation between p101 and p110γ subunits, the critical step for phosphatidylinositol-(3, 4)-P2 (PIP2) conversion to phosphatidylinositol-(3, 4, 5)-P3 (PIP3), and then reduces the activation of PI3K/Akt signaling. This effect can be reversed by Akt specific agonist SC79. In addition, AMG 706, a previously documented inhibitor for endothelial cell proliferation, is identified as a potential agonist for MrgprF, and can impede tumor growth both in vitro and in vivo. Taken together, our findings suggest that MrgprF, a novel tumor suppressor in cutaneous melanoma, may be useful as a therapeutic target in the future.

The physical phenomena of submerged arc welding (SAW) conducted with a 1.6 mm flux-cored wire were investigated using X-ray imaging technique. Three kinds of metal transfer modes were confirmed in this paper, namely the front flux wall-guided droplet transfer, back flux wall-guided droplet transfer, and repelled droplet transfer, of which the corresponding percentages were 47.65%, 45.29%, and 7.06%, respectively. Although the average sizes of the droplets for SAW and FCAW (flux-cored wire welding) were 2.0 mm and 1.9 mm with an average droplet transfer time of 90.3 ms, it required 36.4% more time for the droplet of SAW to finish one metal transfer than it did in FCAW. In addition, the volume of the cavity was not constant but repeated a cycle mode of “expansion and contraction” during the whole process. Thus, the dynamics of the cavity and viscous resistance caused by the flux collectively slowed down the velocity of the droplets from the wire to the weld pool in SAW. Compared with FCAW, a smoother weld without pits and pores was manufactured during the SAW process. Due to the compression effect of the flux, the 14.5 mm average weld width of SAW was 2.9 mm shorter than that of the FCAW. Furthermore, the thickness of slag with a porous structure in SAW was 2.7 times of that in FCAW, indicating that it could provide better protection to the weld of SAW.

Aluminum (Al) is an accumulative toxic metal. Excessive Al accumulation inhibits osteoblasts mineralization and induces osteoporosis. However, the inhibition mechanism of Al on the mineralization is not fully understood. Thus, in this study, the rat osteoblasts were cultured and exposed to 0 mmol L −1 (control group, CG) and 0.52 mmol L −1 aluminum trichloride (AlCl 3 , treatment group, TG) for 7, 14, and 21 days, respectively. We found that mineralized matrix nodules, the activity of bone alkaline phosphatase, the concentration of extracellular calcium, the mRNA expression of type-I collagen, the mRNA and protein expressions of osteopontin, osteocalcin, and bone sialoprotein were all decreased, while the concentration of extracellular phosphorus was increased in TG compared with CG with time prolonged. Taken together, these results indicated that AlCl 3 inhibited osteoblasts mineralization in vitro.

In underwater wet welding, the unstable welding process caused by the generation and rupture of bubbles and the chilling effect of water on the welding area result in low quality of welded joints, which makes it difficult to meet the practical application of marine engineering. To improve the process stability and joining quality, a mixture of welding flux with a water glass or epoxy resin was placed on the welding zone before underwater welding. In this paper, welds’ appearance, geometry statistics of welds’ formation, welding process stability, slag structure, microstructure, pores and mechanical properties were investigated. It was found that with the addition of water glass in the mixture, the penetration of weld was effectively increased, and the frequency of arc extinction was reduced. Though the porosity rose to a relatively high level, the joints’ comprehensive mechanical properties were not significantly improved. Notably, the applied epoxy resin completely isolated the surrounding water from the welding area, which greatly improved process stability. Furthermore, it benefited from the microstructure filled with massive acicular ferrite, the average elongation and room temperature impact toughness increased by 178.4%, and 69.1% compared with underwater wet welding, respectively, and the bending angle of the joint reaches to 180°.