Exosomes are emerging as important elements that participate in intercellular communication and tumor microenvironment modulation, but the exact mechanisms by which tumor exosomes facilitate the ...generation of the immunosuppressive microenvironment remain unclear. Here we investigated the effects of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We also performed microRNA sequencing analysis of GDEs to identify the microRNA that mediated macrophage polarization. The microRNA-associated intracellular signaling pathway in macrophages was further investigated. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly induced M2 macrophage polarization, which subsequently promoted glioma proliferation, migration and invasion in vitro and in vivo. MicroRNA sequencing analysis identified miR-1246 as the most enriched microRNA in H-GDEs. Moreover, miR-1246 was enriched in the CSF of GBM patients and decreased after tumor resection. Further investigation determined that miR-1246 mediated H-GDE-induced M2 macrophage polarization by targeting TERF2IP to activate the STAT3 signaling pathway and inhibit the NF-κB signaling pathway. Our study elucidated a mechanism by which hypoxia and glioma influence M2 macrophage polarization via exosomes, which could facilitate the formation of the immunosuppressive microenvironment. Moreover, our results suggested that miR-1246 in the CSF of GBM patients may be a novel biomarker for GBM diagnosis and that treatment targeting microRNA-1246 may contribute to antitumor immunotherapy.
While immunosuppressive environments mediated by myeloid-derived suppressor cells (MDSCs) have been well documented in glioma patients, the mechanisms of MDSC development and activation have not been ...clearly defined. Here, we elucidated a role for glioma-derived exosomes (GDEs) in potentiating an MDSC pathway. We isolated normoxia-stimulated and hypoxia-stimulated GDEs and studied their MDSC induction abilities in vivo and in vitro. Analyses of spleen and bone marrow MDSC proportions (flow cytometry) and reactive oxygen species (ROS), arginase activity, nitric oxide (NO), T-cell proliferation and immunosuppressive cytokine (IL-10 and TGF-β, ELISA) levels were used to assess MDSC expansion and functional capacity. We also performed microRNA (miRNA) sequencing analysis of two types of GDEs to find miRNAs that potentially mediate the development and activation of MDSCs. GDE miRNA intracellular signaling in MDSCs was also studied. Hypoxia promoted the secretion of GDEs, and mouse MDSCs could uptake GDEs. Hypoxia-stimulated GDEs had a stronger ability to induce MDSCs than N-GDEs. The hypoxia-inducible expression of miR-10a and miR-21 in GDEs mediated GDE-induced MDSC expansion and activation by targeting RAR-related orphan receptor alpha (RORA) and phosphatase and tensin homolog (PTEN). Mice inoculated with miR-10a or miR-21 knockout glioma cells generated fewer MDSCs than those inoculated with normal glioma cells. These data elucidated a mechanism by which glioma cells influence the differentiation and activation of MDSCs via exosomes and demonstrated how local glioma hypoxia affects the entirety of tumor immune environments.
Exosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the ...immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.
The scanner is an important unit of the Coherent Doppler wind Lidar (CDWL) for long range detection. In the compact telescope system, a prism wedge rotating around the optical axis is often added to ...realize conical scanning of the laser beam. For the focused CDWL, the prism wedge can produce astigmatism in the measuring light, which will change the energy distribution in the detection space. Based on the geometric optics technique, the relation between the wedge parameters and the beam propagation status is analyzed in this paper. A modified range weighting function is also constructed by using the collection efficiency mode. A CDWL with 100 m focused distance was employed in the wind measurement experiments. Compared the measurement data from the CDWL with the anemometer at 50 m and 100 m height at the wind tower, the result indicates that the CDWL detection data is closer to the wind field at 50 m height, which is consistent with theoretical analysis. The optimized wedge parameters and the modified range weighting function are helpful for the further development of the miniaturized and lightweight CDWL.
Clear evidence shows that tumors could secrete microRNAs (miRNAs) via exosomes to modulate the tumor microenvironment (TME). However, the mechanisms sorting specific miRNAs into exosomes are still ...unclear. In order to study the biological function and characterization of exosomal miRNAs, we performed whole-transcriptome sequencing in 59 patients' whole-course cerebrospinal fluid (CSF) small extracellular vesicles (sEV) and matched glioma tissue samples. The results demonstrate that miRNAs could be divided into exosome-enriched miRNAs (ExomiRNAs) and intracellular-retained miRNAs (CLmiRNAs), and exosome-enriched miRNAs generally play a dual role. Among them, miR-1298-5p was enriched in CSF exosomes and suppressed glioma progression in vitro and vivo experiments. Interestingly, exosomal miR-1298-5p could promote the immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) to facilitate glioma. Therefore, we found miR-1298-5p had different effects on glioma cells and MDSCs. Mechanically, downstream signaling pathway analyses showed that miR-1298-5p plays distinct roles in glioma cells and MDSCs via targeting SETD7 and MSH2, respectively. Moreover, reverse verification was performed on the intracellular-retained miRNA miR-9-5p. Thus, we confirmed that tumor-suppressive miRNAs in glioma cells could be eliminated through exosomes and target tumor-associated immune cells to induce tumor-promoting phenotypes. Glioma could get double benefit from it. These findings uncover the mechanisms that glioma selectively sorts miRNAs into exosomes and modulates tumor immunity.
Hypoxia is an important feature of the tumor microenvironment and is associated with glioma progression and patient outcome. Exosomes have been implicated in the intercellular communication in the ...tumor microenvironment. However, the effects of hypoxic glioma exosomes on glioma migration and invasion and the underlying mechanisms remain poorly understood. In this study, we found that exosomes derived from hypoxic glioma cells (H-GDEs) promoted normoxic glioma migration and invasion in vitro and in vivo. Given that exosomes can regulate recipient cell functions by delivering microRNAs, we further revealed miR-1246 and miR-10b-5p were upregulated significantly in H-GDEs and delivered to normoxic glioma cells by H-GDEs. Moreover, we determined the clinical relevance of miR-1246 and miR-10b-5p in glioma patients. Subsequent investigations indicated that miR-1246 and miR-10b-5p markedly induced glioma migration and invasion in vitro and in vivo. Finally, we demonstrated that miR-1246 and miR-10b-5p induced glioma migration and invasion by directly targeting FRK and TFAP2A respectively. In conclusion, our findings suggest that the hypoxic microenvironment stimulates glioma to generate miR-1246- and miR-10b-5p-rich exosomes that are delivered to normoxic glioma cells to promote their migration and invasion; treatment targeting miR-1246 and miR-10b-5p may impair the motility of gliomas, providing a novel direction for the development of antitumor therapy.
The synthetic filament winder drives the filament through the traverse mechanism with rotary wings so that it can complete the transverse reciprocating motion when it is continuously wound and ...achieve the spiral distribution on the cylindrical package. When the existing traverse mechanism leads the filament, the filament is easy to oscillate and breaks away from the control of the rotary blade during the reversing process at both ends of the package, which directly affects its forming on the package. In this study, firstly, the filament leading process is analyzed from the filament leading principle of the traverse mechanism with rotary wings and the key points of the profile are identified. Secondly, we applied parameter constraints of key points and developed a blade profile that can not only meet the demand of filament reversing but also improve the above abnormal phenomena by curve-fitting, so that the blade can continuously and stably lead and control the filament during the reversing process. Finally, through the actual winding experiment, we contrasted the state of the filament leading process of the original blades with the improved blades, and verified the improvement effect. This study provides a design basis and optimization reference for realizing a smooth and stable relay between the filament and blades.
The purpose of this study was to investigate the associations of physical activity trajectories with maternal fatigue. Pregnant women provided objectively assessed physical activity data by Pregnancy ...Physical Activity Questionnaire four times. Fatigue scale-14 was used to assess fatigue during pregnancy. Growth mixture modelling characterized physical activity trajectories across pregnancy. The generalized estimating equations was used to analyze the relationship between different physical activity profiles and fatigue in pregnant women. A total of 626 pregnant women were included in analysis in a teaching hospital in Nantong city. Fatigue (total, mental and physical) was not different between two groups based on total energy expenditure of PA (constantly high vs. constantly low). The pregnant women in "constantly high household PA" group had the higher fatigue compared to "constantly low household PA" (P < 0.05) and "constantly medium household PA" (P < 0.05). The pregnant women in "constantly high sport PA" group had lower fatigue compared to "constantly low sport PA" (P < 0.05). Household PA and sport PA were still an independent influencing factor for fatigue after controlling for confounding variables. Specifically, we observed that higher household PA and lower sport PA were associated with higher fatigue during pregnancy.
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