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Sensing nutrient levels and coordinating metabolism are requisites for all living organisms. In eukaryotes, heterotrimeric adenosine monophosphate-activated protein kinase/sucrose nonfermenting 1 (...

Myasthenia gravis (MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. T follicular helper (Tfh) cells have been implicated in many autoimmune diseases. However, whether and how Tfh cells are involved in MG remain unclear. Here, we established and studied a widely-used and approved animal model of human MG, the rat model with acetylcholine receptor alpha (AChRα) subunit (R-AChR(97–116))-induced experimental autoimmune myasthenia gravis (EAMG). This model presented mild body-weight loss 10 days after the first immunization (representing the early stage of disease) and more obvious clinical manifestations and body-weight loss 7 days after the second immunization (representing the late stage of disease). AChR-specific pre-Tfh cells and mature Tfh cells were detected in these two stages, respectively. In co-cultures of Tfh cells and B cells, the number of IgG2b-secreting B cells and the level of anti-AChR antibodies in the supernatant were higher in the cultures containing EAMG-derived Tfh cells. In immunohistochemistry and immunofluorescence assays, a substantial number of CD4(+)/Bcl-6(+) T cells and a greater number of larger germinal centers were observed in lymph node tissues resected from EAMG rats. Based on these results, we hypothesize that an AChR-specific Tfh cell-mediated humoral immune response contributes to the development of EAMG.

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most malignant form of glioma and represents 81% of malignant brain and central nervous system (CNS) tumors. Like most cancers, GBM causes metabolic recombination to promote cell survival, proliferation, and invasion of cancer cells. In this study, we propose a method for constructing the metabolic subpathway activity score matrix to accurately identify abnormal targets of GBM metabolism. By integrating gene expression data from different sequencing methods, our method identified 25 metabolic subpathways that were significantly abnormal in the GBM patient population, and most of these subpathways have been reported to have an effect on GBM. Through the analysis of 25 GBM-related metabolic subpathways, we found that (S)-2,3-Epoxysqualene, which was at the central region of the sterol biosynthesis subpathway, may have a greater impact on the entire pathway, suggesting a potential high association with GBM. Analysis of CCK8 cell activity indicated that (S)-2,3-Epoxysqualene can indeed inhibit the activity of U87-MG cells. By flow cytometry, we demonstrated that (S)-2,3-Epoxysqualene not only arrested the U87-MG cell cycle in the G0/G1 phase but also induced cell apoptosis. These results confirm the reliability of our proposed metabolic subpathway identification method and suggest that (S)-2,3-Epoxysqualene has potential therapeutic value for GBM. In order to make the method more broadly applicable, we have developed an R system package crmSubpathway to perform disease-related metabolic subpathway identification and it is freely available on the GitHub (https://github.com/hanjunwei-lab/crmSubpathway).

Osteopontin (OPN) is a multifunctional extracellular matrix phosphoprotein that has a specific and complicated structure, and contributes to numerous physiological and pathological activities. The mechanism of OPN in many diseases has been confirmed; however, the role of OPN in myasthenia gravis (MG) remains unclear. In this study, we recombined rat OPN protein in vitro, and assessed how OPN affects the development of autoimmunity using an experimental autoimmune myasthenia gravis (EAMG) rat model. The results showed that the concentration of OPN in serum was up-regulated. Both mRNA and protein levels in splenocytes increased in the EAMG model. OPN treatment in vitro strongly promoted the differentiation of Th1 cells, and inhibited the differentiation of Treg cells. Intraperitoneal injection of OPN revealed the early incidence of EAMG, and more serious disease. This effect was accompanied by an increased percentage of Th1 cells. In conclusion, OPN likely exacerbates the pathogenesis of EAMG by promoting the differentiation of Th1 cells and inhibiting the differentiation of Treg cells.

The mechanical performances of sandwiched morphing skin used for morphing aircraft are principally determined by the cellular substructure undertaking morphing stress. In this paper, in order to guide the design of sandwiched morphing skins utilized in different morphing applications, several optimal topologies of cellular-based structures are calculated, and the mechanical properties of them are evaluated. Initially, the topology optimization technique is utilized to minimize stiffness in the direction of deformation. This is followed by establishing 3D models through post-processing. Then the experiments and finite element analyses are performed to evaluate the designs and compare them with conventional regular honeycomb structure as well as zero Poisson’s ratio structure. Among them, a novel load transmitting block is designed for transferring shear load using axial movement. The simulated and experimental results show the superiority of optimized topologies. Also, the consistency of them guarantees the reliability of finite element model. Based on it, this research investigates the mechanical performances of periodic cellular structures and the influence depending on the number of cells. The results of the effective transverse modulus, the effective shear modulus, the out-of-plane displacement and the twist angle give support for the development of sandwiched morphing skins in real applications.

Microcapsules of neem extract (MNE) were observed using an optical microscope (OM) and scanning electron microscope (SEM). The antifungal activity of the extract was evaluated by an agar diffusion assay. The MNE were induced into the wood material by a full-cell process. The diameters of the microcapsules were measured by OM, and the distribution of microcapsules in wood was observed by SEM. Wood blocks of Populus tomentosa were treated with the MNE, neem extract (NE), and an acid mixture of melamine formaldehyde resin (MF) and sodium dodecyl sulfate (AMS); their antifungal properties against Penicillium citrinum, Trichoderma virens, and Aspergillus niger were visually assessed. The microcapsules prepared by MF, 1% sodium dodecyl sulfate (SDS), and 10% NH4Cl showed regular shape and good dispersion. The agar diffusion assay showed that the neem extract had significant inhibition against all tested fungi, and the optimum concentration of NE was 10%. The diameters of the microcapsules were normally distributed in a range of 0.4 μm to 4 μm, and the microcapsules were unevenly distributed in the vessels and surface of Populus tomentosa. Wood specimens treated with MNE observed complete inhibition to all studied fungi, and the mark grades of specimens treated with MNE against three fungi all reached 5 (no growth of fungi).

Metformin, the most widely used medicine for type 2 diabetes, displays anti-inflammatory functions via activating AMP-activated protein kinase (AMPK). Circulating autoantibodies and disequilibrium of helper T cells and regulatory T cells are pathological hallmarks of myasthenia gravis (MG). Rectify the imbalance of different T cell populations has become an important therapeutic strategy to treat MG. In this study, we assessed the effect of metformin on the development of autoimmunity using an experimental autoimmune myasthenia gravis (EAMG) rat model. We first provided evidence that oral administration of metformin attenuated the onset of EAMG. This effect was accompanied by a substantial decrease of circulating auto-antibody levels with no effect on blood glucose level. While metformin treatment in vitro showed little effect on inducible Treg, metformin strongly inhibited Th17 cell differentiation through the increase of reactive oxygen species and AMPK. Furthermore, an attenuation of antigen-induced IgG2b antibody production by two different doses of metformin was also observed in the AChR-specific recall response. In conclusion, the above results indicate that metformin may have therapeutic value for the clinical treatment of MG.