The Mulibrey (Muscle–liver–brain–eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FINmajor (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

MiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC.

BackgroundDuchenne muscular dystrophy (DMD) is an X-linked lethal genetic disorder for which there is no effective treatment. Previous studies have shown that stem cell transplantation into mdx mice can promote muscle regeneration and improve muscle function, however, the specific molecular mechanisms remain unclear. DMD suffers varying degrees of hypoxic damage during disease progression. This study aimed to investigate whether induced pluripotent stem cells (iPSCs) have protective effects against hypoxia-induced skeletal muscle injury.ResultsIn this study, we co-cultured iPSCs with C2C12 myoblasts using a Transwell nested system and placed them in a DG250 anaerobic workstation for oxygen deprivation for 24 h. We found that iPSCs reduced the levels of lactate dehydrogenase and reactive oxygen species and downregulated the mRNA and protein levels of BAX/BCL2 and LC3II/LC3I in hypoxia-induced C2C12 myoblasts. Meanwhile, iPSCs decreased the mRNA and protein levels of atrogin-1 and MuRF-1 and increased myotube width. Furthermore, iPSCs downregulated the phosphorylation of AMPKα and ULK1 in C2C12 myotubes exposed to hypoxic damage.ConclusionsOur study showed that iPSCs enhanced the resistance of C2C12 myoblasts to hypoxia and inhibited apoptosis and autophagy in the presence of oxidative stress. Further, iPSCs improved hypoxia-induced autophagy and atrophy of C2C12 myotubes through the AMPK/ULK1 pathway. This study may provide a new theoretical basis for the treatment of muscular dystrophy in stem cells.

The discovery of magnetic order in atomically-thin van der Waals materials has strengthened the alliance between spintronics and two-dimensional materials. An important use of magnetic two-dimensional materials in spintronic devices, which has not yet been demonstrated, would be for coherent spin injection via the spin-pumping effect. Here, we report spin pumping from Cr2Ge2Te6 into Pt or W and detection of the spin current by inverse spin Hall effect. The magnetization dynamics of the hybrid Cr2Ge2Te6/Pt system are measured, and a magnetic damping constant of ~ 4–10 × 10−4 is obtained for thick Cr2Ge2Te6 flakes, a record low for ferromagnetic van der Waals materials. Moreover, a high interface spin transmission efficiency (a spin mixing conductance of 2.4 × 1019/m2) is directly extracted, which is instrumental in delivering spin-related quantities such as spin angular momentum and spin-orbit torque across an interface of the van der Waals system. The low magnetic damping that promotes efficient spin current generation together with high interfacial spin transmission efficiency suggests promising applications for integrating Cr2Ge2Te6 into low-temperature two-dimensional spintronic devices as the source of coherent spin or magnon current.

Neurotoxicity of organophosphate compounds (OPs) can catastrophically cause nervous system injury by inhibiting acetylcholinesterase (AChE) expression. Although artificial systems have been developed for indirect neuroprotection, they are limited to dissociating P-O bonds for eliminating OPs. However, these systems have failed to overcome the deactivation of AChE. Herein, we report our finding that Al3+ is engineered onto the nodes of metal–organic framework to synthesize MOF-808-Al with enhanced Lewis acidity. The resultant MOF-808-Al efficiently mimics the catalytic behavior of AChE and has a self-defense ability to break the activity inhibition by OPs. Mechanism investigations elucidate that Al3+ Lewis acid sites with a strong polarization effect unite the highly electronegative –OH groups to form the enzyme-like catalytic center, resulting in superior substrate activation and nucleophilic attack ability with a 2.7-fold activity improvement. The multifunctional MOF-808-Al, which has satisfactory biosafety, is efficient in reducing neurotoxic effects and preventing neuronal tissue damage.