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Background Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC. Method The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP–ADO pathway amplified by HCC–macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts. Results Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP–adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance. Conclusion In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP–adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC. Graphical Abstract

Backgrounds Mitochondria plays a critical role in the development and pathogenesis of nonalcoholic fatty liver disease (NAFLD). Neohesperidin (NHP) could lower blood glucose and prevent obesity in mice. However, the direct effect of NHP on hepatic steatosis has not been reported. Methods Mice were fed with either a chow diet or HFD with or without oral gavage of NHP for 12 weeks. A variety of biochemical and histological indicators were examined. In vitro cell culture model was utilized to demonstrate underlying molecular mechanism of the effect induced by NHP treatment. Results NHP increases mitochondrial biogenesis, improves hepatic steatosis and systematic insulin resistance in high fat diet (HFD) fed mice. NHP elevates hepatic mitochondrial biogenesis and fatty acid oxidation by increasing PGC-1α expression. Mechanistically, the activation of AMP-activated protein kinase (AMPK) is involved in NHP induced PGC-1α expression. Conclusions PGC-1α-mediated mitochondrial biogenesis plays a vital role in the mitigation of hepatic steatosis treated by NHP. Our result suggests that NHP is a good candidate to be dietary supplement for the auxiliary treatment of NAFLD.

A recent publication highlights the importance of high yes-associated protein (YAP) expressing cells in liver regeneration following partial hepatectomy. Although the names of the cell populations described in these articles [hybrid periportal hepatocytes (HybHP) or epithelial-mesenchymal transition (EMT)-reprogrammed hepatocytes] are not identical, they all express high levels of YAP. We hypothesize that the HybHP and EMT-reprogrammed hepatocytes might be a similar cell population. Hippo signaling is the primary pathway that regulates YAP activity. According to the contribution of these two types of cells to liver regeneration and the high YAP expression, Hippo-YAP signaling activation may be a common regulatory pathway experienced by cells undergoing dedifferentiation and reactivating proliferative activity during liver regeneration. Although no evidence has shown that HybHP cells contribute to hepatocellular carcinoma in mouse models, we can not rule out the possibility that these highly regenerative cells can further develop into tumor cells when they acquire mutations caused by viral infection or other risk factors like alcohol. The detailed mechanistic insight of the regulation of YAP expression and activity in HybHP (or other types of cells contributing to liver regeneration) is unknown. We hypothesize that liver regeneration under various conditions will eventually lead to divergent consequences, likely due to the duration of YAP activation regulated by Hippo-large tumor suppressor 1 and 2 pathway in a context- and cell type-dependent manner.

After years of in-depth research on immune checkpoints, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPIs) has been shown to be effective in primary liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The clinical development of novel ICPIs continues at a rapid pace, with more than 200 clinical trials of immunotherapeutic agents registered as of July 2021 for the treatment of liver cancer. In this review, we discussed the immune tolerance mechanism of liver cancer and the biological basis of immune checkpoints, focusing on the current status of ICPIs' development and clinical application. In addition, ICPIs combined with local resection, radiofrequency ablation, chemoembolization, and other molecular targeted drug therapies have shown better efficacy. Combined therapy based on multidisciplinary cooperation is the future direction of treatment in liver cancer.

Background Flavonoids are reported to modulate the composition of gut microbiota, which play an important role in preventing obesity and associated metabolic diseases. In this study, we investigated the effect of Total Flavonoids of Quzhou Fructus Aurantii Extract (TFQ) on gut microbial community in mice fed with a high-fat diet (HFD). Methods C57BL/6J mice were fed with either a chow diet or HFD with or without oral gavage of TFQ (300 mg/kg/day) for 12 weeks. Results Our data indicate TFQ significantly reduced obesity, inflammatio,n and liver steatosis. TFQ elevates the expression of tight junction proteins and reduces metabolic endotoxemia. In addition, TFQ treatment reverses HFD-induced gut dysbiosis, as indicated by the reduction of Firmicutes to Bacteroidetes ratio, the increase of genera Akkermansia and Alistipes, and the decrease of genera Dubosiella, Faecalibaculum, and Lactobacillus. Conclusion These findings support a prebiotic role of TFQ as a dietary supplement for the intervention of gut dysbiosis and obesity-related metabolic disorders.

With the rapid development of social and economic growth of the Internet, online shopping has become an indispensable part of people’s lives, college students has become a main force in online shopping. Although online shopping has gradually matured, there are still many problems, and the problems are worth discussing. Based on the social background of big data, based on the questionnaire survey on the online shopping consumption of students of the International College of Zhengzhou University, this article uses the basic statistical analysis methods, correspondence analysis, and SPSS software and EXCEL software. Use Logistic regression method to analyze students’ online shopping consumption. Combined with the status of students’ online shopping, find out the differences of students’ online shopping behaviors, analyze the psychological characteristics of online shopping consumption, in order to correctly guide students’ consumption concepts. Then logistic regression analysis was used to find out the key factors that influence students’ online shopping frequency. Finally, based on the previous analysis conclusions, the school, e-commerce, and the government propose corresponding countermeasures.

With rapidly increased construction of nuclear power plants worldwide to reduce energy shortage and subsequent environment contamination, routine use of radiotherapy and radiodiagnosis equipment in the clinical medicine, the research on the health effect of radiation exposure has become a very important area to explore. Traditional Chinese Medicine (TCM) may be an ideal candidate therapy as it usually produces fewer side effects even with long-term administration. In this paper, we reviewed current therapeutic approaches to prevent radiation-induced brain neuropathological and functional changes. Neuroprotective effects of TCM in different brain injury models have been briefly summarized. We then reviewed the neuroprotective and radioprotective effect of TCM in different radiation exposure models and discussed the potential molecular mechanism(s) of the neuroprotective and radioprotective effect of TCM. The conclusions and future research directions were made in the last part of the paper.

The radioprotective effect of herb epimedium (or yin yang huo) extract (5 g/kg, oral administration daily for 4 weeks) on neurogenesis and cognition after acute radiation exposure with 5.5 Gy was evaluated in Balb/c mice by behavioral tests and immunohistochemical study. The results indicated that epimedium extract could improve animal weight loss, locomotor activity and spatial learning and memory which are similar to pre-irradiation intraperitoneal injection (100 mg/kg) of amifostine phosphate, a well- known radioprotective drug. Immunohistochemical study showed that epimedium extract prevented the loss of proliferation cells, newly generated neurons, and interneurons in the hilus, in particular, the subgranular zone of the dentate gyrus. It suggests that herb epimedium may be a promising radio-neuro-protective drug to prevent radiation-induced neuropsychological disorders.

We need to achieve real-time parameter control and process a large number of complex numerical calculations in the research of satellite mobile communications fading channel. MATLAB has powerful numerical calculation functions and graphing display characteristics, VC++ has powerful functions to make program interface and can achieve port operation, real-time processing. MATLAB and VC++ mixed programming combines the advantages of both languages and provides strong technical support to the research of satellite mobile communications fading channel. This paper introduces the calculation model of satellite mobile communications fading channel and presents the process of mixed programming. The complex calculation of fading channel is completed and the results are presented.

Through the research and analysis of Shanghai Port Container transportation capacity, we can see that the construction of underground container transport system is important to transfer Shanghai into an international hub. Combined the functional orientation of the concept program of underground container lines with the underground characteristics of the container transport system, a system of evaluation target has been set up. Sorted the concept lines by using AHP-Fuzzy comprehensive evaluation, the result can reflect the actual situation of concept lines objectively, and can also provide optimizational service for the concept program of underground container line.

In this paper, in order to analyze the capability of squeezed branch pile under different work condition and the cooperation mechanism between the pile and soil, non-liner numerical simulation was carried out using ANSYS. In the finite element model, the elastic-perfectly plastic Drucker-Prager material was assumed for soil. Contact interface elements were placed between the pile and soil. It showed that the squeezed branches took lots of the load, and the ratio it took was related to the load and the elastic modulus of soil; the plastic section of the soil was run-through from bottom to the top; the horizontal displacement of the top soil was moved to the pile, but the horizontal displacement of the soil of the bottom was moved away from the pile; the squeezed branch will break away from the soil above the squeezed branch when the load was at a certain value.

Simulation of sound wave propagation at the inlet of a jet engine is difficult due to the complex geometries of the propagation channel, so many simplifications are needed. A more realistic model is introduced in this paper to do the simulation. Dispersion-relation-preserving finite schemes are used in this paper where structured grids are designed by conformal mapping; the advanced perfectly matched layer absorbing boundary conditions are used to prescribe the input sound wave at the fan face of inlet. The advantages of the methods used in this paper are shown by two different cases.

To study the combustion characteristics of the polyethylene (PE) particle and coal powder at blast temperature of the blast furnace, the contents of CO and CO2 of off-gas during the combustion of PE particle and coal powder at the 1 200 °C and 1 250 °C were measured using carbon monoxide and carbon dioxide infrared analyzer, and then the corresponding combustion ratio was calculated. The results showed that when the temperature is high, the combustion speed of PE and coal powder is high and the corresponding combustion ratio is high. Whereas, the combustion speed and ratio of PE are much higher than those of coal powder.

Circulating cell-endothelial cell interaction in sepsis is a rate-determining factor in organ dysfunction, and interventions targeting this process have a potential therapeutic value. In this project, we examined whether curcumin, an active ingredient of turmeric and an anti-inflammatory agent, could disrupt interactions between circulating blood cells and endothelium and improve survival in a murine model of sepsis.Mice were subjected to cecal ligation and puncture (CLP) to induce sepsis vs. sham surgery. We studied leukocyte and platelet adhesion in cerebral microcirculation using intravital fluorescent video microscopy technique, blood-brain barrier (BBB) dysfunction using Evans Blue (EB) leakage method, P-selectin expression using dual radiolabeling technique, and survival in mice subjected to Sham, CLP, and CLP with curcumin pre-treatment (CLP + curcumin).Curcumin significantly attenuated leukocyte and platelet adhesion in cerebral microcirculation, EB leakage in the brain tissue, and improved survival in mice with CLP. P-selectin expression in mice with CLP + curcumin was significantly attenuated compared with CLP in various microcirculatory beds, including brain. Reduction in platelet adhesion was predominantly via modulation of endothelium by curcumin.Curcumin pre-treatment modulates leukocyte and platelet adhesion and BBB dysfunction in mice with CLP via P-selectin expression and improves survival in mice with CLP.