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Previous data have suggested that the nuclear translocation of annexin 1 (ANXA1) is involved in neuronal apoptosis after ischemic stroke. As the mechanism and function of ANXA1 nuclear migration remain unclear, it is important to clarify how ANXA1 performs its role as an apoptosis ‘regulator’ in the nucleus. Here we report that importazole (IPZ), an importin β (Imp β )-specific inhibitor, decreased ANXA1 nuclear accumulation and reduced the rate of neuronal death induced by nuclear ANXA1 migration after oxygen-glucose deprivation–reoxygenation (OGD/R). Notably, ANXA1 interacted with the Bid (BH3-interacting-domain death agonist) promoter directly; however; this interaction could be partially blocked by the p53 inhibitor pifithrin- α (PFT- α ). Accordingly, ANXA1 was shown to interact with p53 in the nucleus and this interaction was enhanced following OGD/R. A luciferase reporter assay revealed that ANXA1 was involved in the regulation of p53-mediated transcriptional activation after OGD/R. Consistent with this finding, the nuclear translocation of ANXA1 after OGD/R upregulated the expression of Bid, which was impeded by IPZ, ANXA1 shRNA, or PFT- α . Finally, cell-survival testing demonstrated that silencing ANXA1 could improve the rate of cell survival and decrease the expression of both cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. These data suggested that Imp β -dependent nuclear ANXA1 migration participates in the OGD/R-dependent induction of neuronal apoptosis. ANXA1 interacts with p53 and promotes p53 transcriptional activity, which in turn regulates Bid expression. Silencing ANXA1 decreases the expression of Bid and suppresses caspase-3 pathway activation, thus improving cell survival after OGD/R. This study provides a novel mechanism whereby ANXA1 regulates apoptosis, suggesting the potential for a previously unidentified treatment strategy in minimizing apoptosis after OGD/R.

Annexin A1 (ANXA1) is a protein known to have multiple roles in the regulation of inflammatory responses. In this study, we find that after oxygen glucose deprivation/reoxygenation (ODG/R) injury, activated PKC phosphorylated ANXA1 at the serine 27 residue (p27S-ANXA1), and promoted the translocation of p27S-ANXA1 to the nucleus of BV-2 microglial cells. This in turn induced BV-2 microglial cells to produce large amounts of pro-inflammatory cytokines. The phenomenon could be mimicked by either transfecting a mutant form of ANXA1 with its serine 27 residue converted to aspartic acid, S27D, or by using the PKC agonist, phorbol 12-myristate 13-acetate (PMA) in these microglial cells. In contrast, transfecting cells with an ANXA1 S27A mutant (serine 27 converted to alanine) or treating the cells with the PKC antagonist, GF103209X (GF) reversed this effet. Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines.

Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular mechanism. In rat hippocampal slices, OGD/R treatment enhanced the ANXA1 expression in neuron, the formyl peptide receptor (FPRs) expression in microglia, and the microglial activation in the CA1 region (cornu ammonis 1). These effects were reversed by the FPRs antagonist Boc1. The cell membrane currents amplitude of BV-2 microglia (the microglial like cell-line) was increased when treated with Ac2-26, the N-terminal peptide of ANXA1. Ac2-26 treatment enhanced BV-2 microglial migration whereas Boc1 treatment inhibited the migration. In BV-2 microglia, both the expression of the CK2 target phosphorylated α-E-catenin and the binding of casein kinase II (CK2) with α-E-catenin were elevated by Ac2-26, these effects were counteracted by the CK2 inhibitor TBB and small interfering (si) RNA directed against transcripts of CK2 and FPRs. Moreover, both TBB and siRNA-mediated inhibition of CK2 blocked Ac2-26-mediated BV-2 microglia migration. Our findings indicate that ANXA1 promotes microglial activation and migration during OGD/R via FPRs, and CK2 target α-E-catenin phosphorylation is involved in this process.

Recently, fluorescence imaging microscopy has undergone through revolutionary advancement in spatial resolution, improving from submicron meter resolution to nanometer resolution that rivals those of electron microscopes. The key enabling elements of the innovative super-resolution fluorescence microscopy are the photoswitchable fluorophores. In this thesis, a diverse set of photoswitchable rhodamine fluorophores have been synthesized by varying the intra- and inter-molecular substitution on the spiro carbon. The desired photoswitching property enabled nanostructural determination, and indeed nanostructures in biological cells were successfully resolved beyond the limit of optical diffraction. While analogous to photochromism, thermochromism of synthesized rhodamine derivatives was also studied and employed as a means to encode information into optical fibers. Interestingly, when an orthogonal pair of a photochromic dye and a thermochromic dye was used, orthogonal stimuli of light and heat impart information encoding simultaneously and independently, thus realizing multiplexing in data encoding and transmission. To understand the unusual structures of photoswitches and thermoswitches, we developed a general procedure to grow single crystals and used X-ray crystallography to study their structure-property relationships.

Aims/Introduction Non‐alcoholic fatty liver disease (NAFLD) is becoming more and more prevalent in type 2 diabetes mellitus. Evidence connecting NAFLD to diabetic retinopathy (DR) is increasing, but the results vary. Thus, we undertook a meta‐analysis to explore the effect of NAFLD on diabetic retinopathy in patients with type 2 diabetes mellitus. Materials and Methods PubMed, Embase, Cochrane and Scopus database were searched for until September 30, 2019. Original studies analyzing the association between NAFLD and diabetic retinopathy in the type 2 diabetic population were included. This meta‐analysis was processed by RevMan 5.3 software. Subgroup analyses based on countries were carried out. The pooled odds ratios and 95% confidence intervals were used to evaluate the association between NAFLD and diabetic retinopathy incidence. The I2 test was used to assess heterogeneity of studies. Results We retrieved 414 articles, and nine studies involving 7,170 patients were included in the final analysis. The pooled effects estimate suggested that NAFLD was not associated with the risk of diabetic retinopathy in patients with type 2 diabetes mellitus. Subgroup analysis suggested that in China, Korea and Iran, patients with type 2 diabetes mellitus with NAFLD had a decreased risk for diabetic retinopathy compared with the non‐NAFLD individuals. However, in Italy and India, patients with type 2 diabetes mellitus with NAFLD had an increased risk for diabetic retinopathy compared with the non‐NAFLD individuals. In addition, no relevance between NAFLD and diabetic retinopathy was found in America. Conclusions On the whole, there was no association between NAFLD and diabetic retinopathy in individuals with type 2 diabetes mellitus. However, subgroup analysis showed that a difference of country may have an influence on the result. It showed that on the whole, NAFLD was not associated with the risk of DR in T2DM patients. However, subgroup analysis suggested that the difference of country may have an influence on the result.

Background Long non-coding RNAs (lncRNAs) have been associated with non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms of their specific roles in mediating aerobic glycolysis have been poorly explored. Methods Next-generation RNA sequencing assay was performed to identify the differentially expressed RNAs between NSCLC tissues with high 18 F-fluorodeoxyglucose (FDG) uptake and their adjacent normal lung tissues. LINC01123 expression in NSCLC tissues was measured by real-time PCR and in situ hybridization (ISH) assay. The biological role of LINC01123 in cell growth and aerobic glycolysis capability was determined by performing functional experiments in vitro and in vivo. Further, the transcription of LINC01123 was explored by bioinformatics analysis, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay. RNA immunoprecipitation (RIP) and luciferase analyses were used to confirm the predicted competitive endogenous RNA (ceRNA) mechanisms between LINC01123 and c-Myc. Results Three hundred sixty-four differentially expressed genes were identified in RNA-seq assay, and LINC01123 was one of the most overexpressed lncRNAs. Further validation in expanded NSCLC cohorts confirmed that LINC01123 was upregulated in 92 paired NSCLC tissues and associated with poor survival. Functional assays showed that LINC01123 promoted NSCLC cell proliferation and aerobic glycolysis. Mechanistic investigations revealed that LINC01123 was a direct transcriptional target of c-Myc. Meanwhile, LINC01123 increased c-Myc mRNA expression by sponging miR-199a-5p. In addition, rescue experiments showed that LINC01123 functioned as an oncogene depending on miR-199a-5p and c-Myc. Conclusion Since LINC01123 is upregulated in NSCLC, correlates with prognosis, and controls proliferation and aerobic glycolysis by a positive feedback loop with c-Myc, it is expected to be a potential biomarker and therapeutic target for NSCLC.

In recent years, with increasing passenger travel demand, high-speed railways have developed rapidly. The stop planning and timetabling problems are the core contents of high-speed railway transport planning and have important practical significance for improving efficiency of passenger travel and railway operation Dong et al. (2020). This study proposes a collaborative optimization approach that can be divided into two phases. In the first phase, a mixed-integer nonlinear programming model is constructed to obtain a stop plan by minimizing the total passenger travel time. The constraints of passenger origin-destination (OD) demand, train capacity, and stop frequency are considered in the first phase. In the second phase, the train timetable is optimized after the stop plan is obtained. A multiobjective mixed-integer linear optimization model is formulated by minimizing the total train travel time and the deviation between the expected and actual departure times from the origin station for all trains. Multiple types of trains and more refined headways are considered in the timetabling model. Finally, the approach is applied to China’s high-speed railway, and the GUROBI optimizer is used to solve the models in the above two stages. By analyzing the results, the total passenger travel time and train travel time decreased by 2.81% and 3.34% respectively. The proposed method generates a more efficient solution for the railway system.

Background Disease resistance phenotypes are associated with immune regulatory functions and immune tolerance and have implications for both the livestock industry and human health. Microbiota plays an essential role in regulating immunity and autoimmunity in the host organism, but the influence of host-microbiota interactions on disease resistance phenotypes remains unclear. Here, multiomics analysis was performed to identify potential regulatory mechanisms of disease resistance at both the microbiome and host levels in two pig breeds. Results Acute colitis models were established in Min pigs and Yorkshire pigs, and control and diseased individuals were compared. Compared with Yorkshire pigs under the same nutritional and management conditions, Min pigs exhibited strong disease resistance, as indicated by a low disease activity index (DAI) and a low histological activity index (HAI). Microbiota sequencing analysis showed that potentially harmful microbes Desulfovibrio , Bacteroides and Streptococcus were enriched in diseased individuals of the two breeds. Notably, potentially beneficial microbes, such as Lactobacillus , Clostridia and Eubacterium , and several genera belonging to Ruminococcaceae and Christensenellaceae were enriched in diseased Min pigs and were found to be positively associated with the microbial metabolites related to intestinal barrier function. Specifically, the concentrations of indole derivatives and short-chain fatty acids were increased in diseased Min pigs, suggesting beneficial action in protecting intestinal barrier. In addition, lower concentrations of bile acid metabolites and short-chain fatty acids were observed in diseased Yorkshire pigs, which were associated with increased potentially harmful microbes, such as Bilophila and Alistipes . Concerning enrichment of the immune response, the increase in CD4 + T cells in the lamina propria improved supervision of the host immunity response in diseased Min pigs, contributing to the maintenance of Th2-type immune superiority and immune tolerance patterns and control of excessive inflammation with the help of potentially beneficial microbes. In diseased Yorkshire pigs, more terms belonging to biological processes of immunity were enriched, including Toll-like receptors signalling, NF-κB signalling and Th1 and Th17-type immune responses, along with the increases of potentially harmful microbes and damaged intestinal barrier. Conclusions Cumulatively, the results for the two pig breeds highlight that host-microbiota crosstalk promotes a disease resistance phenotype in three ways: by maintaining partial PRR nonactivation, maintaining Th2-type immune superiority and immunological tolerance patterns and recovering gut barrier function to protect against colonic diseases. D5q-JhKXudhwStCYyhwkJ_ Video abstract.

With the advancement of machine-learning and deep-learning technologies, the estimation of the state of charge (SOC) of lithium-ion batteries is gradually shifting from traditional methodologies to a new generation of digital and AI-driven data-centric approaches. This paper provides a comprehensive review of the three main steps involved in various machine-learning-based SOC estimation methods. It delves into the aspects of data collection and preparation, model selection and training, as well as model evaluation and optimization, offering a thorough analysis, synthesis, and summary. The aim is to lower the research barrier for professionals in the field and contribute to the advancement of intelligent SOC estimation in the battery domain.

Hepatocellular carcinoma is considered to be the fifth most rampant type of cancer in the whole world and has a high death rate. The hypoxic microenvironment is one of the typical features of tumor tissues and has an important impact on the activity of multiple signaling pathways. It is of great significance to study the effects of hypoxia on the pathophysiological processes and molecular mechanisms of HCC. Signalling pathways associated with SHP2 were analysed using bioinformatics. Detection of relevant protein expression using Western blotting. Tube formation assay was used in evalution of the angiogenic potential. The concentrations of MDA and SOD were measured by ELISA. The cell migration and invasion ability were measured with a scratch wound assay and transwell assay in SMMC-7721, HepG2 and Huh-7 cells. The effect of hypoxia on the growth of hepatocellular carcinoma was examined using subcutaneous graft tumors and HE staining experiments in nude mice. Bioinformatics analysis of SHP2 negatively correlates with the PI3K signalling pathway. Hypoxia promotes the concentration of MDA and inhibited the concentration of SOD. Hypoxia may up-regulate NOX2, NOX4 and p-PI3K and down-regulate the treatment of p-SHP2. Compared with NC group, the expression of SHP2 and p-SHP2 was inhibited in SHP2 KD group and the expression of p-PI3K, HIF1α, COX2, FOXM1, β-catenin and MMP9 was promoted. However, the differences of the expression of p-PI3K, HIF1α, COX2, FOXM1, β-catenin and MMP9 between the two groups were abolished after the addition of PI3K inhibitor. The angiogenesis, migration and invasion abilities were significantly increased in SHP2 KD group compared with NC group. Similarly, after the addition of PI3K inhibitor, the difference of these abilities between the two groups was eliminated. Hypoxia can promote the growth of hepatocellular carcinoma. Hypoxia can activate the oxidative stress-mediated SHP2/PI3K signaling pathway to promote angiogenesis, migration, and invasion in hepatocellular carcinoma, thus advancing the development of hepatocellular carcinoma.