Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD begins with steatosis and advances to nonalcoholic steatohepatitis (NASH) and cirrhosis. The ...molecular mechanisms involved in NAFLD progression are not understood. Based on recent studies showing dysregulation of epidermal growth factor receptor (EGFR) in animal models of liver injury, we sought to determine if inhibition of EGFR mitigates liver fibrosis and HSC activation in NAFLD. We utilized the high fat diet (HFD)-induced murine model of liver injury to study the role of EGFR in NAFLD. The lipid accumulation, oxidative stress, hepatic stellate cell (HSC) activation and matrix deposition were examined in the liver tissues. We also evaluated the EGFR signaling pathway, ROS activation and pro-fibrogenic phenotype in oxidized low density lipoproteins (ox-LDL) challenged cultured HSCs. We demonstrate that EGFR was phosphorylated in liver tissues of HFD murine model of NAFLD. Inhibition of EGFR prevented diet-induced lipid accumulation, oxidative stress, and HSC activation and matrix deposition. In cultured HSCs, we show that ox-LDL caused rapid activation of the EGFR signaling pathway and induce the production of reactive oxygen species. EGFR also mediated HSC activation and promoted a pro-fibrogenic phenotype. In conclusion, our data demonstrate that EGFR plays an important role in NAFLD and is an attractive target for NAFLD therapy.
•EGFR plays a detrimental role in the pathogenesis of HFD-induced liver damage.•EGFR mediates HFD-induced liver damage via elaboration of ROS and oxidative stress.•Inhibition of EGFR prevented HSC activation.•EGFR inhibitor can prevent the liver fibrosis in HFD mice.
For the efficient optimization of a multistage depressed collector (MDC), an axis-adjustable MDC optimized using the genetic algorithm (GA) is presented in this article. The optimization processes ...are realized with a reasonable balance between the collector recovery efficiency and electron reflux rate by modifying the fitness function of GA. Through the proposed method, the best recovery efficiency 88.5% and 0.72% electron reflux rate of MDC are obtained, and a three-stage symmetric collector has been designed with the GA optimization and fabricated, for a 0.22-THz TWT. The experimental results are in well agreement with that of simulations, which indicates that the methods we propose would be beneficial to the design of high efficiency of TWT.
The urban agglomerations in the Yellow River Basin are important carriers for China’s high-quality development. It is an inevitable trend to promote sustainable development and people’s well-being in ...the urban agglomerations of the Yellow River Basin. A case study of 70 cities of seven urban agglomerations in the Yellow River Basin from 2011 to 2017 is presented. The two-stage super-efficiency network slacks-based measure (Super-NSBM) model considering undesirable outputs is adopted to measure the ecological well-being performance (EWP), and the spatial correlation analysis method is used to analyze the spatio-temporal evolution characteristics of the EWP. The results show that the average EWP of the seven urban agglomerations in the Yellow River Basin was less than 1, showing a trend of firstly rising and then slowly decreasing. The average EWP presents the distribution pattern of the highest in the middle reaches, followed by the upper reaches, and the lowest in the lower reaches of the Yellow River Basin, respectively. The average ecological economic efficiency in the first stage of urban agglomerations of the Yellow River Basin was greater than the average economic well-being efficiency in the second stage. The average EWP in the Yellow River Basin shows local spatial heterogeneity during the study period. Policy measures are proposed to promote the improvement of the EWP of urban agglomerations in the Yellow River Basin. This study can provide reference for the policy formulation of high-quality green development and sustainable construction of urban agglomeration in the Yellow River Basin.
In this article, an improved predictive torque control (PTC) for permanent magnet synchronous motor (PMSM) based on weighting factor elimination and fast voltage vector selection is proposed to ...improve the problems of tedious tuning of weighting factor and heavy computation burden in the conventional PTC. First, a universal scheme, which can be applicable to both surface-mounted PMSM (SPMSM) and interior PMSM (IPMSM), is proposed to convert the control of electromagnetic torque and stator flux amplitude to the control of stator flux vectors. Since the units of stator flux vectors are the same, the weighting factor in the cost function can be eliminated. Second, the control of stator flux vectors is further converted to the control of stator voltage vectors. On this basis, a fast voltage vector selection scheme based on a graphical analysis method is proposed to pick out the one nearest to the reference stator voltage vector among all the candidate voltage vectors in the finite control set (FCS) directly. Therefore, the computation burden of the proposed PTC strategy can be reduced greatly owing to the elimination of the online rolling optimization. The feasibility and effectiveness of the proposed strategy are verified by simulations and experiments.
Myc is a key driver of colorectal cancer initiation and progression, but remains a difficult drug target. In this study, we show that mTOR inhibition potently suppresses intestinal polyp formation, ...regresses established polyps, and prolongs lifespan of APC
mice. Everolimus in diet strongly reduces p-4EBP1, p-S6, and Myc levels, and induces apoptosis of cells with activated β-catenin (p-S552) in the polyps on day 3. The cell death is accompanied by ER stress, activation of the extrinsic apoptotic pathway, innate immune cell recruitment, and followed by T-cell infiltration on day 14 persisting for months thereafter. These effects are absent in normal intestinal crypts with physiologic levels of Myc and a high rate of proliferation. Using normal human colonic epithelial cells, EIF4E S209A knockin and BID knockout mice, we found that local inflammation and antitumor efficacy of Everolimus requires Myc-dependent induction of ER stress and apoptosis. These findings demonstrate mTOR and deregulated Myc as a selective vulnerability of mutant APC-driven intestinal tumorigenesis, whose inhibition disrupts metabolic and immune adaptation and reactivates immune surveillance necessary for long-term tumor control.
Background
Gastric cancer continues to be a significant global healthcare challenge, and its burden remains substantial. The development of gastric cancer (GC) is closely linked to chronic atrophic ...gastritis (CAG), yet there is a scarcity of research exploring the underlying mechanisms of CAG-induced carcinogenesis.
Methods
In this study, we conducted a comprehensive investigation into the oncogenes involved in CAG using both bulk transcriptome and single-cell transcriptome data. Our approach employed hdWGCNA to identify pathogenic genes specific to CAG, with non-atrophic gastritis (NAG) serving as the control group. Additionally, we compared CAG with GC, using normal gastric tissue as the control group in the single-cell transcriptome analysis. By intersecting the identified pathogenic genes, we pinpointed key network molecules through protein interaction network analysis. To further refine the gene selection, we applied LASSO, SVM-RFE, and RF techniques, which resulted in a set of cancer-related genes (CRGs) associated with CAG. To identify CRGs potentially linked to gastric cancer progression, we performed a univariate COX regression analysis on the gene set. Subsequently, we explored the relationship between CRGs and immune infiltration, drug sensitivity, and clinical characteristics in gastric cancer patients. We employed GSVA to investigate how CRGs regulated signaling pathways in gastric cancer cells, while an analysis of cell communication shed light on the impact of CRGs on signal transmission within the gastric cancer tumor microenvironment. Lastly, we analyzed changes in metabolic pathways throughout the progression of gastric cancer.
Results
Using hdWGCNA, we have identified a total of 143 pathogenic genes that were shared by CAG and GC. To further investigate the underlying mechanisms, we conducted protein interaction network analysis and employed machine learning screening techniques. As a result, we have identified 15 oncogenes that are specifically associated with chronic atrophic gastritis. By performing ROC reanalysis and prognostic analysis, we have determined that GADD45B is the most significant gene involved in the carcinogenesis of CAG. Immunohistochemical staining and differential analysis have revealed that GADD45B expression was low in GC tissues while high in normal gastric tissues. Moreover, based on prognostic analysis, high expression of GADD45B has been correlated with poor prognosis in GC patients. Additionally, an analysis of immune infiltration has shown a relationship between GADD45B and the infiltration of various immune cells. By correlating GADD45B with clinical characteristics, we have found that it primarily affects the depth of invasion in GC. Through cell communication analysis, we have discovered that the CD99 signaling pathway network and the CDH signaling pathway network are the main communication pathways that significantly alter the microenvironment of gastric tissue during the development of chronic atrophic gastritis. Specifically, GADD45B-low GC cells were predominantly involved in the network communication of the CDH signaling pathway, while GADD45B-high GC cells played a crucial role in both signaling pathways. Furthermore, we have identified several metabolic pathways, including D-Glutamine and D-glutamate metabolism and N-Glycan biosynthesis, among others, that played important roles in the occurrence and progression of GC, in addition to the six other metabolic pathways. In summary, our study highlighted the discovery of 143 pathogenic genes shared by CAG and GC, with a specific focus on 15 oncogenes associated with CAG. We have identified GADD45B as the most important gene in the carcinogenesis of CAG, which exhibited differential expression in GC tissues compared to normal gastric tissues. Moreover, GADD45B expression was correlated with patient prognosis and is associated with immune cell infiltration. Our findings also emphasized the impact of the CD99 and CDH signaling pathway networks on the microenvironment of gastric tissue during the development of CAG. Additionally, we have identified key metabolic pathways involved in GC progression.
Conclusion
GADD45B, an oncogene implicated in chronic atrophic gastritis, played a critical role in GC development. Decreased expression of GADD45B was associated with the onset of GC. Moreover, GADD45B expression levels were closely tied to poor prognosis in GC patients, influencing the infiltration patterns of various cells within the tumor microenvironment, as well as impacting the metabolic pathways involved in GC progression.
•Ochratoxin A(OTA) induces aerobic glycolysis of GES-1 cells.•OTA increases the glycolytic-associated enzymes (HK2, PFK1, LDHA) in GES-1 cells.•OTA promotes the phosphorylation and nuclear ...translocation of PKM2.•OTA reduces the TCA-cycle-associated enzymes (IDH1 and ODGH) in GES-1 cells.
Ochratoxin A (OTA) is a ubiquitous mycotoxin with potential nephrotoxic, hepatotoxic and immunotoxic effects. We previously demonstrated that OTA could cause mitochondrial function disturbance in GES-1 cells in vitro, which lead to the presumption that the glucose metabolism of GES-1 cells will be altered by OTA. Therefore in the present study, we explored the toxicity of OTA on glucose metabolism of GES-1 cells and the molecular mechanism. We found that OTA could induce aerobic glycolysis, evidenced shown by increase of glucose consumption, lactate production and cellular ATP concentration. We further detected expressions of GLUT1 and glycolytic enzymes including HK2, PFK1, PKM2 and LDHA as well as tricarboxylic acid (TCA) cycle-associated enzymes including IDH1, OGDH and CS. The results showed that expression of GLUT1 as well as the activities and expressions of HK2, PFK1 and LDHA were significantly increased while IDH1 and OGDH were reduced by OTA. As to PKM2, western blot showed that OTA could elevated the phospho-PKM2 Ser37 protein level and induce the nuclear accumulation of PKM2, which was further supported by immunofluorescence analyses, in addition, pyruvate kinase activity was reduced by OTA. In conclusion, these findings suggest that OTA exposure induces the metabolic shift from oxidative phosphorylation to aerobic glycolysis via regulating the activities and expressions of glycolysis and TCA-cycle associated molecules in GES-1 cells.
Based on the first-principles calculations of density functional theory (DFT), the crystal structure, molecular structure, electronic properties, and optical absorption properties of methyl ...urotropine perchlorate under hydrostatic compression in the range of 0 ~ 100 GPa were calculated. The results show that the crystal structure of methyl urotropine perchlorate undergoes two structural transformations under hydrostatic compression. The H1A-H1B bond breaks at 25 GPa, generating two new covalent bonds N3-H1A and O1-H1B. The covalent bonds of O2A-C1 and Cl1-H3A are formed at 85 GPa. The compression ratio of lattice constants (
a
,
b
,
c
) and unit cell volume change abruptly at 25 GPa and 85 GPa, respectively. The conclusion that new bonds are formed under high pressure is further demonstrated by analyzing the partial density of states (PDOS) of N3, H1A, O1, H1B, O2A, C1, Cl1, and H3A atoms. The absorption spectrum showed that the absorption peak of methyl urotropine perchlorate gradually enhanced with the increase of pressure and the highest absorption peak shifted to high frequency.
Highlights
The structure of methyl urotropine perchlorate was optimized, and its lattice constants (a, b, c, and V) and compression ratios at different pressures were calculated.
Methyl urotropine perchlorate undergoes two structural transitions at pressurization to 25 GPa and 85 GPa, with the breaking of old bonds and the formation of new bonds.
The DOS of methyl urotropine perchlorate was analyzed, further confirming the structural transformation by high pressure.
The effect of high pressure on optical absorption properties was investigated.
Nanomaterials with natural enzyme-mimicking characteristics have aroused extensive attention in various fields owing to their economical price, ease of large-scale production, and environmental ...resistance. Previous investigations have demonstrated that composition, size, shape, and surface modification play important roles in the enzymelike activity of nanomaterials; however, a fundamental understanding of the crystal facet effect, which determines surface energy or surface reactivity, has rarely been reported. Herein, fluorite cubic CeO2 nanocrystals with controllably exposed {111}, {100}, or {110} facets are fabricated as proof-of-concept candidates to study the facet effect on the peroxidase-mimetic activity. Both experiments and theoretical results show that {110}-dominated CeO2 nanorods (CeO2 NR) possess the highest peroxidase-mimetic activity due to the richest defects on their surfaces, which are beneficial to capture metal atoms to further enrich their artificial enzymatic functionality for cascade catalysis. For instance, the introduction of atomically dispersed Au on CeO2 NR surfaces not only enhances the peroxidase activity but also endows the obtained catalyst with glucose oxidase (GO x )-mimicking activity, which realizes enzyme-free cascade reactions for glucose colorimetric detection. This work not only provides an understanding for crystal facet engineering of nanomaterials to enhance the catalytic activity but also opens up a new way for the design of biomimetic nanomaterials with multiple functions.
For developing countries, an adequate domestic water supply is conventionally assessed based on the proportion of communities that are covered by improved water sources. However, it is difficult to ...evaluate water poverty accurately, as it is multidimensional. For this reason, this paper used the Water Poverty Index (WPI) to measure water poverty in rural communities of arid areas in China. This study also uses the Least Square Error (LSE) model to analyze the influencing factors of water poverty. Based on the WPI and LSE, the results showed that the rural communities of Sheshu, Fanyao, Dongcao, Qiaodi, and Gouershang (listed in order of priority of need for intervention) are in a water poverty situation. In rural communities with high water poverty, the suggested priority order for the study was environment, capacity, use, resources, and access, with the environmental factor needing to be improved. The results are useful for prioritizing areas and identifying the extent of the need for policy intervention on different scales. The research findings are intended to complement the evaluation of water poverty and to provide a strategy for regional water resources management to relieve water poverty.
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