Hyperlipidemia-induced MicroRNA155-5p improves β-cell Function by targeting Mafb

A high-fat diet increases intestinal permeability and promotes leakage of LPS into the circulation, where it primarily binds to lipoproteins and may promote GLP-1-mediated insulin secretion. Notably, patients with familial hypercholesterolemia have a reduced risk for T2DM. However, chronically elevated circulating LPS levels during HFD feeding also induce adipose tissue inflammation and obesity-induced insulin resistance. In macrophages, LPS and hyperlipidemia selectively induce miR-155-5p expression and trigger inflammatory activation. However, the role of miR-155-5p in obesity-related metabolic and cardiovascular diseases is poorly understood. Therefore, the aim of the current study was to determine whether miR-155-5p mediates the effects of hyperlipidemia on obesity and glucose homeostasis. Hyperlipidemia-associated endotoxemia increased deposition of oxLDL and induced miR-155-5p expression in pancreatic islets of Ldlr–/– mice. Mild oxidative modification of LDL led to increased endotoxin activity and increased miR-155-5p expression in pancreatic β-cells. In Mir155–/–Ldlr–/–mice, glucose and plasma glucagon levels were increased, whereas plasma insulin and GLP-1 levels were reduced compared with Mir155+/+Ldlr–/– mice. The α-to-β-cell ratio and the glucagon protein level were higher, whereas the insulin and GLP-1 protein content was reduced in islets from Mir155–/–Ldlr–/–mice. Treatment with low-dose LPS up-regulated islet miR-155-5p expression, increased insulin and GLP-1 plasma levels and lowered the glucose levels following intraperitoneal glucose injection in Ldlr–/– mice, and the effects of LPS on glucose metabolism were partially abolished by Mir155 knockout. Microarray analysis revealed inhibition of insulin, GLP-1, and IL-6 signaling pathways and upregulation of putative miR-155 targets, including Mafb, Sema5a, Med12l, Auh, and Stmn2 in islets from Mir155–/–Ldlr–/–mice. In murine β-cells, overexpression of miR-155-5p enriched Mafb mRNA in the RISC. Moreover, luciferase reporter assays showed that MafB suppressed Il6 expression by binding to the Il6 promoter region. In Ldlr–/–mice, blocking the interaction between miR-155-5p and MafB increased FBG levels and decreased the expression of Il6, the GLP-1 producing enzyme Pcsk1, and insulin production in islets. Probably due to elevated plasma GLP-1 levels, miR-155-5p limited the progression of obesity and adipose tissue inflammation, and reduced hyperlipidemia and atherosclerosis in HFD-fed Ldlr–/– mice. Taken together, hyperlipidemia-associated endotoxemia can improve glucose homeostasis by upregulating miR-155-5p expression in pancreatic β-cells. Targeting of MafB by miR-155-5p may limit β-to-α-cell reprogramming and promotes β-cell function likely through IL-6-induced GLP-1 production in α-cells. Hence, hyperlipidemia-induced miR-155-5p improves the adaptation of β-cells to insulin resistance. Increasing miR-155-5p levels in β-cell may be a valuable therapeutic strategy against diabetes and the MetS.Die Verfütterung eines „high fat“ Futters führt zu einer erhöhten Darmpermeabilität, die zu einer Steigerung der LPS Konzentration in der Zirkulation führt. Dort bindet LPS an Lipoproteine und stimuliert dadurch die GLP-1-vermittelte Sekretion von Insulin. Patienten mit familiären Hypercholesterinämie leiden seltener an T2DM. Die durch das „high fat“ Futter chronisch erhöhte LPS Konzentration in der Zirkulation induziert die Entzündung im adipösen Gewebe und die Adipositas-bedingte Insulinresistenz. LPS und Hyperlipidämie induzieren die Expression von miR-155-5p und rufen eine inflammatorische Aktivierung in Makrophagen hervor. Allerdings ist über die Rolle von miR-155-5p in mit Adipositas verbundenen metabolischen und kardiovaskulären Erkrankungen wenig bekannt. Das Ziel dieses Vorhabens ist die Effekte von miR-155-5p in Hyperlipidämie-vermittelter Adipositas und Glukose-Homöostase zu untersuchen. Die Hyperlipidämie-assoziierte Endotoxämie erhöhte die Akkumulation von oxLDL und die Expression von miR-155-5p in den Langerhans-Inseln von Ldlr–/– Mäusen. Während die Glukose- und Glukagon Plasmawerte verglichen mit den Werten in Mir155+/+Ldlr–/– Mäusen erhöht waren, wurde eine Reduktion der Insulin- und GLP-1 Plasmawerte in Mir155–/–Ldlr–/– Mäusen detektiert. Das Verhältnis von α-zu-β Zellen und die Glukagon-Proteinwerte waren erhöht, wohingegen die Insulin- und GLP-1 Proteinwerte in den Langerhans-Inseln der Mir155–/–Ldlr–/– Mäusen reduziert waren. Eine Behandlung mit niedrig dosiertem LPS erhöhte die Expression von miR-155-5p, steigerte die Insulin- und die GLP-1 Plasmawerte, reduzierte jedoch die Glukosewerte nach einer intraperitonealen Glukose-Injektion in Ldlr–/– Mäusen. Ferner ist die LPS-assoziierte Wirkung teilweise durch den Mir155 Knockout aufgehoben. In den Langerhans-Inseln derMir155–/–Ldlr–/– Mäusen zeigte die Microarray-Analyse eine Inhibierung von Insulin, GLP-1 und dem IL-6 Signalweg sowie eine Erhöhung vermeintlicher miR-155 Targets, wie z.B. Mafb, Sema5a, Med12l, Auh und Stmn2. Die Überexpression von miR-155-5p führte zur Anreicherung der Mafb mRNA im RISC. Die Luciferase Reporter-Assay zeigte, dass MafB die Expression von Il6 durch die Bindung an den Il6 Promoter supprimiert. In Ldlr–/– Mäusen führte die Hemmung der Interaktion zwischen miR-155-5p und MafB zu erhöhten FBG Werten und zu reduzierten Expressionen von Il6, GLP-1 produziertem Enzym Pcsk1 und zur verringerten Insulin Produktion in den Langerhans-Inseln. MiR-155-5p reduzierte die Adipositas und die Inflammation im adipösen Gewebe wahrscheinlich aufgrund der erhöhten GLP-1 Konzentration im Plasma. Nach Verfütterung des „high fat“ Futters inhibierte miR-155-5p die Hyperlipidämie und die Entwicklung der Atherosklerose in Ldlr–/– Mäusen. Zusammenfassend verbessert die Hyperlipidämie-assoziierte Endotoxämie die Glukose-Homöostase durch die gesteigerte Expression von miR-155-5p in den β-Zellen. Die Hemmung von MafB durch miR-155-5p reduzierte die β-α Zell Umprogrammierung und verbesserte die β-Zell Funktion durch eine IL-6-induzierte GLP-1 Produktion in den α-Zellen. Die Hyperlipidämie-vermittelte Induktion von miR-155-5p trägt zur Anpassung von β-Zellen an die Insulinresistenz bei. Die erhöhte Expression von miR-155-5p in den β-Zellen stellt einen vielversprechenden Ansatz in der Therapie des Diabetes und des MetS dar

Hyperlipidemia-induced MicroRNA155-5p improves β-cell Function by targeting Mafb

A high-fat diet increases intestinal permeability and promotes leakage of LPS into the circulation, where it primarily binds to lipoproteins and may promote GLP-1-mediated insulin secretion. Notably, patients with familial hypercholesterolemia have a reduced risk for T2DM. However, chronically elevated circulating LPS levels during HFD feeding also induce adipose tissue inflammation and obesity-induced insulin resistance. In macrophages, LPS and hyperlipidemia selectively induce miR-155-5p expression and trigger inflammatory activation. However, the role of miR-155-5p in obesity-related metabolic and cardiovascular diseases is poorly understood. Therefore, the aim of the current study was to determine whether miR-155-5p mediates the effects of hyperlipidemia on obesity and glucose homeostasis. Hyperlipidemia-associated endotoxemia increased deposition of oxLDL and induced miR-155-5p expression in pancreatic islets of Ldlr–/– mice. Mild oxidative modification of LDL led to increased endotoxin activity and increased miR-155-5p expression in pancreatic β-cells. In Mir155–/–Ldlr–/–mice, glucose and plasma glucagon levels were increased, whereas plasma insulin and GLP-1 levels were reduced compared with Mir155+/+Ldlr–/– mice. The α-to-β-cell ratio and the glucagon protein level were higher, whereas the insulin and GLP-1 protein content was reduced in islets from Mir155–/–Ldlr–/–mice. Treatment with low-dose LPS up-regulated islet miR-155-5p expression, increased insulin and GLP-1 plasma levels and lowered the glucose levels following intraperitoneal glucose injection in Ldlr–/– mice, and the effects of LPS on glucose metabolism were partially abolished by Mir155 knockout. Microarray analysis revealed inhibition of insulin, GLP-1, and IL-6 signaling pathways and upregulation of putative miR-155 targets, including Mafb, Sema5a, Med12l, Auh, and Stmn2 in islets from Mir155–/–Ldlr–/–mice. In murine β-cells, overexpression of miR-155-5p enriched Mafb mRNA in the RISC. Moreover, luciferase reporter assays showed that MafB suppressed Il6 expression by binding to the Il6 promoter region. In Ldlr–/–mice, blocking the interaction between miR-155-5p and MafB increased FBG levels and decreased the expression of Il6, the GLP-1 producing enzyme Pcsk1, and insulin production in islets. Probably due to elevated plasma GLP-1 levels, miR-155-5p limited the progression of obesity and adipose tissue inflammation, and reduced hyperlipidemia and atherosclerosis in HFD-fed Ldlr–/– mice. Taken together, hyperlipidemia-associated endotoxemia can improve glucose homeostasis by upregulating miR-155-5p expression in pancreatic β-cells. Targeting of MafB by miR-155-5p may limit β-to-α-cell reprogramming and promotes β-cell function likely through IL-6-induced GLP-1 production in α-cells. Hence, hyperlipidemia-induced miR-155-5p improves the adaptation of β-cells to insulin resistance. Increasing miR-155-5p levels in β-cell may be a valuable therapeutic strategy against diabetes and the MetS.Die Verfütterung eines „high fat“ Futters führt zu einer erhöhten Darmpermeabilität, die zu einer Steigerung der LPS Konzentration in der Zirkulation führt. Dort bindet LPS an Lipoproteine und stimuliert dadurch die GLP-1-vermittelte Sekretion von Insulin. Patienten mit familiären Hypercholesterinämie leiden seltener an T2DM. Die durch das „high fat“ Futter chronisch erhöhte LPS Konzentration in der Zirkulation induziert die Entzündung im adipösen Gewebe und die Adipositas-bedingte Insulinresistenz. LPS und Hyperlipidämie induzieren die Expression von miR-155-5p und rufen eine inflammatorische Aktivierung in Makrophagen hervor. Allerdings ist über die Rolle von miR-155-5p in mit Adipositas verbundenen metabolischen und kardiovaskulären Erkrankungen wenig bekannt. Das Ziel dieses Vorhabens ist die Effekte von miR-155-5p in Hyperlipidämie-vermittelter Adipositas und Glukose-Homöostase zu untersuchen. Die Hyperlipidämie-assoziierte Endotoxämie erhöhte die Akkumulation von oxLDL und die Expression von miR-155-5p in den Langerhans-Inseln von Ldlr–/– Mäusen. Während die Glukose- und Glukagon Plasmawerte verglichen mit den Werten in Mir155+/+Ldlr–/– Mäusen erhöht waren, wurde eine Reduktion der Insulin- und GLP-1 Plasmawerte in Mir155–/–Ldlr–/– Mäusen detektiert. Das Verhältnis von α-zu-β Zellen und die Glukagon-Proteinwerte waren erhöht, wohingegen die Insulin- und GLP-1 Proteinwerte in den Langerhans-Inseln der Mir155–/–Ldlr–/– Mäusen reduziert waren. Eine Behandlung mit niedrig dosiertem LPS erhöhte die Expression von miR-155-5p, steigerte die Insulin- und die GLP-1 Plasmawerte, reduzierte jedoch die Glukosewerte nach einer intraperitonealen Glukose-Injektion in Ldlr–/– Mäusen. Ferner ist die LPS-assoziierte Wirkung teilweise durch den Mir155 Knockout aufgehoben. In den Langerhans-Inseln derMir155–/–Ldlr–/– Mäusen zeigte die Microarray-Analyse eine Inhibierung von Insulin, GLP-1 und dem IL-6 Signalweg sowie eine Erhöhung vermeintlicher miR-155 Targets, wie z.B. Mafb, Sema5a, Med12l, Auh und Stmn2. Die Überexpression von miR-155-5p führte zur Anreicherung der Mafb mRNA im RISC. Die Luciferase Reporter-Assay zeigte, dass MafB die Expression von Il6 durch die Bindung an den Il6 Promoter supprimiert. In Ldlr–/– Mäusen führte die Hemmung der Interaktion zwischen miR-155-5p und MafB zu erhöhten FBG Werten und zu reduzierten Expressionen von Il6, GLP-1 produziertem Enzym Pcsk1 und zur verringerten Insulin Produktion in den Langerhans-Inseln. MiR-155-5p reduzierte die Adipositas und die Inflammation im adipösen Gewebe wahrscheinlich aufgrund der erhöhten GLP-1 Konzentration im Plasma. Nach Verfütterung des „high fat“ Futters inhibierte miR-155-5p die Hyperlipidämie und die Entwicklung der Atherosklerose in Ldlr–/– Mäusen. Zusammenfassend verbessert die Hyperlipidämie-assoziierte Endotoxämie die Glukose-Homöostase durch die gesteigerte Expression von miR-155-5p in den β-Zellen. Die Hemmung von MafB durch miR-155-5p reduzierte die β-α Zell Umprogrammierung und verbesserte die β-Zell Funktion durch eine IL-6-induzierte GLP-1 Produktion in den α-Zellen. Die Hyperlipidämie-vermittelte Induktion von miR-155-5p trägt zur Anpassung von β-Zellen an die Insulinresistenz bei. Die erhöhte Expression von miR-155-5p in den β-Zellen stellt einen vielversprechenden Ansatz in der Therapie des Diabetes und des MetS dar

The impact of land use/cover change on extreme temperatures on the Yangtze River Delta, China

The contribution from land use/cover change (LUCC) toward temperature in recent decades is of great concern across the globe. Although there have been many studies, most of them focus on the discussion of average temperature and lack a discussion of extreme temperatures. In this study, we first investigated the spatio-temporal changes in extreme temperatures in the Yangtze River Delta during 1980–2020 using the ensemble empirical mode decomposition (EEMD) method. Then, we explored the impact of LUCC on extreme temperatures using the observation minus reanalysis (OMR) method. Finally, the relationship between the normalized difference vegetation index (NDVI) and extreme temperatures was analyzed using the correlation analysis method. We found that: (1) extreme temperatures have a nonlinear variation characteristics on different time scales. Extremely high temperatures (EHT) clearly exhibited a monthly time scale (quasi-3-month), an interannual time scale (quasi-1-year, quasi-2-year, quasi-3-year and quasi-5-year), and an interdecadal time scale (quasi-10-year and quasi-35-year). Extremely low temperatures (ELT) also clearly exhibited a monthly time scale (quasi-3-month), an interannual scale (quasi-1-year, quasi-2-year, quasi-3-year and quasi-6-year), and an interdecadal scale (quasi-10-year and quasi-20-year). (2) EHT showed an east–middle–west staggered phase and ELT showed a southeast–northwest anti-phase characteristic in spatial distribution. (3) The contribution rates of LUCC on EHT and ELT are 53.6% and 92.4%, respectively, which are higher than for the average temperature (40%). (4) The monthly time scale response of the NDVI to extreme temperatures is more regionally concentrated and significant than that on the interannual time scale in spatial distribution. This paper makes up for the insufficiency of the impact of land use/cover changes on extreme temperature changes at multiple time scales and enriches our understanding of climate change

MC-MLP:Multiple Coordinate Frames in all-MLP Architecture for Vision

In deep learning, Multi-Layer Perceptrons (MLPs) have once again garnered attention from researchers. This paper introduces MC-MLP, a general MLP-like backbone for computer vision that is composed of a series of fully-connected (FC) layers. In MC-MLP, we propose that the same semantic information has varying levels of difficulty in learning, depending on the coordinate frame of features. To address this, we perform an orthogonal transform on the feature information, equivalent to changing the coordinate frame of features. Through this design, MC-MLP is equipped with multi-coordinate frame receptive fields and the ability to learn information across different coordinate frames. Experiments demonstrate that MC-MLP outperforms most MLPs in image classification tasks, achieving better performance at the same parameter level. The code will be available at: https://github.com/ZZM11/MC-MLP

Simple and Efficient Partial Graph Adversarial Attack: A New Perspective

As the study of graph neural networks becomes more intensive and comprehensive, their robustness and security have received great research interest. The existing global attack methods treat all nodes in the graph as their attack targets. Although existing methods have achieved excellent results, there is still considerable space for improvement. The key problem is that the current approaches rigidly follow the definition of global attacks. They ignore an important issue, i.e., different nodes have different robustness and are not equally resilient to attacks. From a global attacker's view, we should arrange the attack budget wisely, rather than wasting them on highly robust nodes. To this end, we propose a totally new method named partial graph attack (PGA), which selects the vulnerable nodes as attack targets. First, to select the vulnerable items, we propose a hierarchical target selection policy, which allows attackers to only focus on easy-to-attack nodes. Then, we propose a cost-effective anchor-picking policy to pick the most promising anchors for adding or removing edges, and a more aggressive iterative greedy-based attack method to perform more efficient attacks. Extensive experimental results demonstrate that PGA can achieve significant improvements in both attack effect and attack efficiency compared to other existing graph global attack methods

Controlling Factors of Microplastic Riverine Flux and Implications for Reliable Monitoring Strategy

Embargo until December 12, 2022A significant proportion of marine plastic debris and microplastics is assumed to be derived from river systems. In order to effectively manage plastic contamination of the marine environment, an accurate quantification of riverine flux of land-based plastics and microplastics is imperative. Rivers not only represent pathways to the ocean, but are also complex ecosystems that support many life processes and ecosystem services. Yet riverine microplastics research is still in its infancy, and many uncertainties still remain. Major barriers exist in two aspects. First, nonharmonized sampling methodologies make it problematic for compiling data across studies to better estimate riverine fluxes of microplastics globally; Second, the significant spatiotemporal variation of microplastics in rivers which was affected by the river characteristics, MPs properties, etc. also have important influence on the estimation of riverine MPs fluxes. In this study, we made a comprehensive review from the above two aspects based on published peer-reviewed studies and provide recommendations and suggestions for a reliable monitoring strategy of riverine MPs, which is beneficial to the further establish sampling methods for rivers in different geographical locations. Besides, methods for achieving a high level of comparability across studies in different geographical contexts are highlighted. Riverine microplastic flux monitoring is another important part of this manuscript. The influential factors and calculation methods of microplastic flux in rivers are also discussed in this paper.acceptedVersio

Macrophage MicroRNAs as Therapeutic Targets for Atherosclerosis, Metabolic Syndrome, and Cancer

Macrophages play a crucial role in the innate immune system and contribute to a broad spectrum of pathologies in chronic inflammatory diseases. MicroRNAs (miRNAs) have been demonstrated to play important roles in macrophage functions by regulating macrophage polarization, lipid metabolism and so on. Thus, miRNAs represent promising diagnostic and therapeutic targets in immune disorders. In this review, we will summarize the role of miRNAs in atherosclerosis, metabolic syndrome, and cancer by modulating macrophage phenotypes, which has been supported by in vivo evidence

Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4

MicroRNAs regulate the maladaptation of endothelial cells (ECs) to naturally occurring disturbed blood flow at arterial bifurcations resulting in arterial inflammation and atherosclerosis in response to hyperlipidemic stress. Here, we show that reduced endothelial expression of the RNAse Dicer, which generates almost all mature miRNAs, decreases monocyte adhesion, endothelial C-X-C motif chemokine 1 (CXCL1) expression, atherosclerosis and the lesional macrophage content in apolipoprotein E knockout mice (Apoe(-/-)) after exposure to a high-fat diet. Endothelial Dicer deficiency reduces the expression of unstable miRNAs, such as miR-103, and promotes Kruppel-like factor 4 (KLF4)-dependent gene expression in murine atherosclerotic arteries. MiR-103 mediated suppression of KLF4 increases monocyte adhesion to ECs by enhancing nuclear factor-kappa B-dependent CXCL1 expression. Inhibiting the interaction between miR-103 and KLF4 reduces atherosclerosis, lesional macrophage accumulation and endothelial CXCL1 expression. Overall, our study suggests that Dicer promotes endothelial maladaptation and atherosclerosis in part by miR103-mediated suppression of KLF4

A Node Influence Based Label Propagation Algorithm for Community Detection in Networks

Label propagation algorithm (LPA) is an extremely fast community detection method and is widely used in large scale networks. In spite of the advantages of LPA, the issue of its poor stability has not yet been well addressed. We propose a novel node influence based label propagation algorithm for community detection (NIBLPA), which improves the performance of LPA by improving the node orders of label updating and the mechanism of label choosing when more than one label is contained by the maximum number of nodes. NIBLPA can get more stable results than LPA since it avoids the complete randomness of LPA. The experimental results on both synthetic and real networks demonstrate that NIBLPA maintains the efficiency of the traditional LPA algorithm, and, at the same time, it has a superior performance to some representative methods