Novel Role of Endothelial CD45 in Regulating Endothelial-to-Mesenchymal Transition in Atherosclerosis.

Background: Protein-tyrosine-phosphatase CD45 is exclusively expressed in all nucleated cells of the hematopoietic system but is rarely expressed in endothelial cells. Interestingly, our recent study indicated that activation of the endogenous CD45 promoter in human endothelial colony forming cells (ECFCs) induced expression of multiple EndoMT marker genes. However, the detailed molecular mechanisms underlying CD45 that drive EndoMT and the therapeutic potential of manipulation of CD45 expression in atherosclerosis are entirely unknown. Method: We generated a tamoxifen-inducible EC-specific CD45 deficient mouse strain (EC-iCD45KO) in an ApoE-deficient (ApoE-/-) background and fed with a Western diet (C57BL/6) for atherosclerosis and molecular analyses. We isolated and enriched mouse aortic endothelial cells with CD31 beads to perform single-cell RNA sequencing. Biomedical, cellular, and molecular approaches were utilized to investigate the role of endothelial CD45-specific deletion in the prevention of EndoMT in ApoE-/- model of atherosclerosis. Results: Single-cell RNA sequencing revealed that loss of endothelial CD45 inhibits EndoMT marker expression and transforming growth factor-ß signaling in atherosclerotic mice. which is associated with the reductions of lesions in the ApoE-/- mouse model. Mechanistically, the loss of endothelial cell CD45 results in increased KLF2 expression, which inhibits transforming growth factor-ß signaling and EndoMT. Consistently, endothelial CD45 deficient mice showed reduced lesion development, plaque macrophages, and expression of cell adhesion molecules when compared to ApoE-/- controls. Conclusions: These findings demonstrate that the loss of endothelial CD45 protects against EndoMT-driven atherosclerosis, promoting KLF2 expression while inhibiting TGFß signaling and EndoMT markers. Thus, targeting endothelial CD45 may be a novel therapeutic strategy for EndoMT and atherosclerosis.

Targeting Liver Epsins Ameliorates Dyslipidemia in Atherosclerosis.

Rationale: Low density cholesterol receptor (LDLR) in the liver is critical for the clearance of low-density lipoprotein cholesterol (LDL-C) in the blood. In atherogenic conditions, proprotein convertase subtilisin/kexin 9 (PCSK9) secreted by the liver, in a nonenzymatic fashion, binds to LDLR on the surface of hepatocytes, preventing its recycling and enhancing its degradation in lysosomes, resulting in reduced LDL-C clearance. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution of circulating LDL-C to atherosclerosis, we hypothesize that liver epsins promote atherosclerosis by controlling LDLR endocytosis and degradation. Objective: We will determine the role of liver epsins in promoting PCSK9-mediated LDLR degradation and hindering LDL-C clearance to propel atherosclerosis. Methods and Results: We generated double knockout mice in which both paralogs of epsins, namely, epsin-1 and epsin-2, are specifically deleted in the liver (Liver-DKO) on an ApoE -/- background. We discovered that western diet (WD)-induced atherogenesis was greatly inhibited, along with diminished blood cholesterol and triglyceride levels. Mechanistically, using scRNA-seq analysis on cells isolated from the livers of ApoE-/- and ApoE-/- /Liver-DKO mice on WD, we found lipogenic Alb hi hepatocytes to glycogenic HNF4α hi hepatocytes transition in ApoE-/- /Liver-DKO. Subsequently, gene ontology analysis of hepatocyte-derived data revealed elevated pathways involved in LDL particle clearance and very-low-density lipoprotein (VLDL) particle clearance under WD treatment in ApoE-/- /Liver-DKO, which was coupled with diminished plasma LDL-C levels. Further analysis using the MEBOCOST algorithm revealed enhanced communication score between LDLR and cholesterol, suggesting elevated LDL-C clearance in the ApoE-/- Liver-DKO mice. In addition, we showed that loss of epsins in the liver upregulates of LDLR protein level. We further showed that epsins bind LDLR via the ubiquitin-interacting motif (UIM), and PCSK9-triggered LDLR degradation was abolished by depletion of epsins, preventing atheroma progression. Finally, our therapeutic strategy, which involved targeting liver epsins with nanoparticle-encapsulated siRNAs, was highly efficacious at inhibiting dyslipidemia and impeding atherosclerosis. Conclusions: Liver epsins promote atherogenesis by mediating PCSK9-triggered degradation of LDLR, thus raising the circulating LDL-C levels. Targeting epsins in the liver may serve as a novel therapeutic strategy to treat atherosclerosis by suppression of PCSK9-mediated LDLR degradation.

Epsins oversee smooth muscle cell reprograming by influencing master regulators KLF4 and OCT4.

Smooth muscle cells in major arteries play a crucial role in regulating coronary artery disease. Conversion of smooth muscle cells into other adverse cell types in the artery propels the pathogenesis of the disease. Curtailing artery plaque buildup by modulating smooth muscle cell reprograming presents us a new opportunity to thwart coronary artery disease. Here, our report how Epsins, a family of endocytic adaptor proteins oversee the smooth muscle cell reprograming by influencing master regulators OCT4 and KLF4. Using single-cell RNA sequencing, we characterized the phenotype of modulated smooth muscle cells in mouse atherosclerotic plaque and found that smooth muscle cells lacking epsins undergo profound reprogramming into not only beneficial myofibroblasts but also endothelial cells for injury repair of diseased endothelium. Our work lays concrete groundwork to explore an uncharted territory as we show that depleting Epsins bolsters smooth muscle cells reprograming to endothelial cells by augmenting OCT4 activity but restrain them from reprograming to harmful foam cells by destabilizing KLF4, a master regulator of adverse reprograming of smooth muscle cells. Moreover, the expression of Epsins in smooth muscle cells positively correlates with the severity of both human and mouse coronary artery disease. Integrating our scRNA-seq data with human Genome-Wide Association Studies (GWAS) identifies pivotal roles Epsins play in smooth muscle cells in the pathological process leading to coronary artery disease. Our findings reveal a previously unexplored direction for smooth muscle cell phenotypic modulation in the development and progression of coronary artery disease and unveil Epsins and their downstream new targets as promising novel therapeutic targets for mitigating metabolic disorders.

Residual plastic film decreases crop yield and water use efficiency through direct negative effects on soil physicochemical properties and root growth.

Film mulching has been extensively used to improve agricultural production in arid regions of China. However, without sufficient mulch film recovery, large amounts of residual film accumulated in the farmland, which would affect crop yield and water use efficiency (WUE). In order to comprehensively analyze the effects of residual film on crop yield and WUE, and clarify its influencing mechanism, present study adopted a meta-analysis to systematically evaluate the impacts of residual film on soil physicochemical properties, crop root growth, yield, and WUE. The results showed that residual film significantly increased soil bulk density and the soil moisture content in 0-20 cm soil layer, but decreased soil porosity, soil organic matter, soil total nitrogen content, and soil moisture content in >20 cm soil layer, especially when residual film amount was >400 kg ha-1. Residual film significantly reduced crop root dry weight, root length, root diameter, root volume and root surface area. Generally, crop yield and WUE decreased with the increase of residual film amount; and crop yield was reduced by about 14.00 % when the residual film amount increased by 1000 kg ha-1. In average, crop yield and WUE under film residual condition were significantly decreased by 13.46 % and 9.21 %, respectively. The negative effects of residual film on root growth, yield and WUE were greater for cash crops (cotton, tomato and potato) than for cereal crops (wheat, maize). The structural equation model indicated that residual film generated indirect negative effects on crop yield and WUE by directly affecting soil physicochemical properties and crop root growth, with the standard path coefficients of -0.302 and - 0.217, respectively. The results would provide a theoretical basis for reducing residual film pollution on farmland and promoting the green and sustainable development of agriculture.

Elucidating the crosstalk between endothelial-to-mesenchymal transition (EndoMT) and endothelial autophagy in the pathogenesis of atherosclerosis.

Atherosclerosis, a chronic systemic inflammatory condition, is implicated in most cardiovascular ischemic events. The pathophysiology of atherosclerosis involves various cell types and associated processes, including endothelial cell activation, monocyte recruitment, smooth muscle cell migration, involvement of macrophages and foam cells, and instability of the extracellular matrix. The process of endothelial-to-mesenchymal transition (EndoMT) has recently emerged as a pivotal process in mediating vascular inflammation associated with atherosclerosis. This transition occurs gradually, with a significant portion of endothelial cells adopting an intermediate state, characterized by a partial loss of endothelial-specific gene expression and the acquisition of "mesenchymal" traits. Consequently, this shift disrupts endothelial cell junctions, increases vascular permeability, and exacerbates inflammation, creating a self-perpetuating cycle that drives atherosclerotic progression. While endothelial cell dysfunction initiates the development of atherosclerosis, autophagy, a cellular catabolic process designed to safeguard cells by recycling intracellular molecules, is believed to exert a significant role in plaque development. Identifying the pathological mechanisms and molecular mediators of EndoMT underpinning endothelial autophagy, may be of clinical relevance. Here, we offer new insights into the underlying biology of atherosclerosis and present potential molecular mechanisms of atherosclerotic resistance and highlight potential therapeutic targets.

Cholinergic signaling via the α7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation.

BACKGROUND: The involvement of the autonomic nervous system in the regulation of inflammation is an emerging concept with significant potential for clinical applications. Recent studies demonstrate that stimulating the vagus nerve activates the cholinergic anti-inflammatory pathway that inhibits pro-inflammatory cytokines and controls inflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-κB signaling, which results in suppression of pro-inflammatory cytokine production. However, the role of the α7nAChR in the regulation of other aspects of the immune response, including the recruitment of monocytes/macrophages to the site of inflammation remained poorly understood. RESULTS: We observed an increased mortality in α7nAChR-deficient mice (compared with wild-type controls) in mice with endotoxemia, which was paralleled with a significant reduction in the number of monocyte-derived macrophages in the lungs. Corroborating these results, fluorescently labeled α7nAChR-deficient monocytes adoptively transferred to WT mice showed significantly diminished recruitment to the inflamed tissue. α7nAChR deficiency did not affect monocyte 2D transmigration across an endothelial monolayer, but it significantly decreased the migration of macrophages in a 3D fibrin matrix. In vitro analysis of major adhesive receptors (L-selectin, ß1 and ß2 integrins) and chemokine receptors (CCR2 and CCR5) revealed reduced expression of integrin αM and αX on α7nAChR-deficient macrophages. Decreased expression of αMß2 was confirmed on fluorescently labeled, adoptively transferred α7nAChR-deficient macrophages in the lungs of endotoxemic mice, indicating a potential mechanism for α7nAChR-mediated migration. CONCLUSIONS: We demonstrate a novel role for the α7nAChR in mediating macrophage recruitment to inflamed tissue, which indicates an important new aspect of the cholinergic regulation of immune responses and inflammation.

Construction and external validation of a nomogram model for predicting the risk of esophageal stricture after endoscopic submucosal dissection: a multicenter case-control study.

Esophageal stricture is a common complication after endoscopic submucosal dissection (ESD) for superficial esophageal cancer and precancerous lesions, we intend to investigate the independent risk factors of esophageal stricture after ESD by adding the data of included living habits, established a nomogram model to predict the risk of esophageal stricture, and verified it by external data. The clinical data and living habits of patients with early esophageal cancer and precancerous lesions who underwent ESD in the Affiliated Hospital of North Sichuan Medical College and Langzhong People's Hospital from March 2017 to August 2021 were retrospectively collected. The data collected from the two hospitals were used as the development group (n = 256) and the validation group (n = 105), respectively. Univariate and multivariate logistic regression analyses were used to determine independent risk factors for esophageal stricture after ESD and establish a nomogram model for the development group. The prediction performance of the nomogram model is internally and externally verified by calculating C-Index and plotting the receiver operating characteristic curve (ROC) and calibration curve, respectively. The results showed that Age, drinking water temperature, neutrophil-lymphocyte ratio, the extent of esophageal mucosal defect, longitudinal diameter of resected mucosa, and depth of tissue invasion (P < 0.05) were independent risk factors for esophageal stricture after ESD. The C-Index of the development group and validation group was 0.925 and 0.861, respectively. The ROC curve and area under the curve (AUC) of the two groups suggested that the discrimination and prediction performance of the model were good. The two groups of calibration curves are consistent and almost overlap with the ideal calibration curve, indicating that the predicted results of this model are in good agreement with the actual observed results. In conclusion, this nomogram model has a high accuracy for predicting the risk of esophageal stricture after ESD, providing a theoretical basis for reducing or avoiding esophageal stricture and guiding clinical practice.

Targeting Epsins to Inhibit Fibroblast Growth Factor Signaling While Potentiating Transforming Growth Factor-ß Signaling Constrains Endothelial-to-Mesenchymal Transition in Atherosclerosis.

BACKGROUND: Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, the underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) in atherosclerosis and assessed the efficacy of a therapeutic peptide in a preclinical model of this disease. METHODS: Using single-cell RNA sequencing combined with molecular, cellular, and biochemical analyses, we investigated the role of epsins in stimulating EndoMT using knockout in Apoe-/- and lineage tracing/proprotein convertase subtilisin/kexin type 9 serine protease mutant viral-induced atherosclerotic mouse models. The therapeutic efficacy of a synthetic peptide targeting atherosclerotic plaques was then assessed in Apoe-/- mice. RESULTS: Single-cell RNA sequencing and lineage tracing revealed that epsins 1 and 2 promote EndoMT and that the loss of endothelial epsins inhibits EndoMT marker expression and transforming growth factor-ß signaling in vitro and in atherosclerotic mice, which is associated with smaller lesions in the Apoe-/- mouse model. Mechanistically, the loss of endothelial cell epsins results in increased fibroblast growth factor receptor-1 expression, which inhibits transforming growth factor-ß signaling and EndoMT. Epsins directly bind ubiquitinated fibroblast growth factor receptor-1 through their ubiquitin-interacting motif, which results in endocytosis and degradation of this receptor complex. Consequently, administration of a synthetic ubiquitin-interacting motif-containing peptide atheroma ubiquitin-interacting motif peptide inhibitor significantly attenuates EndoMT and progression of atherosclerosis. CONCLUSIONS: We conclude that epsins potentiate EndoMT during atherogenesis by increasing transforming growth factor-ß signaling through fibroblast growth factor receptor-1 internalization and degradation. Inhibition of EndoMT by reducing epsin-fibroblast growth factor receptor-1 interaction with a therapeutic peptide may represent a novel treatment strategy for atherosclerosis.

Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression.

BACKGROUND: Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically target macrophage Epsins with specially designed S2P-conjugated lipid nanoparticles, which encapsulate small-interfering RNAs to suppress Epsins. METHODS: We used single-cell RNA sequencing with our newly developed algorithm MEBOCOST (Metabolite-mediated Cell Communication Modeling by Single Cell Transcriptome) to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells. Biomedical, cellular, and molecular approaches were utilized to investigate the role of macrophage Epsins in regulating lipid metabolism and transport. We performed this study using myeloid-specific Epsin double knockout (LysM-DKO) mice and mice with a genetic reduction of ABCG1 (ATP-binding cassette subfamily G member 1; LysM-DKO-ABCG1fl/+). The nanoparticles targeting lesional macrophages were developed to encapsulate interfering RNAs to treat atherosclerosis. RESULTS: We revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages. Inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing lesional macrophage-specific nanoparticle delivery of Epsin small-interfering RNAs, we showed that silencing of macrophage Epsins diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, we demonstrated that Epsins bound to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promoted ABCG1 degradation via lysosomes and hampered ABCG1-mediated cholesterol efflux and reverse cholesterol transport. In a LysM-DKO-ABCG1fl/+ mouse model, enhanced cholesterol efflux and reverse transport due to Epsin deficiency was suppressed by the reduction of ABCG1. CONCLUSIONS: Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux.

Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases.

Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases. Therefore, promoting lymphangiogenesis represents a promising therapeutic approach. This brief review summarizes the most recent findings related to the modulation of lymphatic function to treat metabolic and cardiovascular diseases such as obesity, myocardial infarction, atherosclerosis, and hypertension. We also discuss experimental and therapeutic approaches to enforce lymphatic growth and remodeling as well as efforts to define the molecular and cellular mechanisms underlying these processes.

Kinesio taping for ankle sprain in youth athlete: A protocol for systematic review and meta-analysis.

BACKGROUND: Ankle sprain is considered a major problem that may hinder youth athletes' athletic development because it will lead to ongoing dysfunction, reoccurrence of ankle sprain, chronic ankle instability, and posttraumatic osteoarthritis. Kinesio taping (KT) is a therapeutic taping technique that has been widely used in the treatment of various ankle issues including sprained ankles and in the prevention of ankle sprains. It can not only provide the injured ankle with support during the rehabilitation phase, but also enhance the ankle stability during activity. However, the available evidence regarding its effectiveness in the treatment and prevention of ankle sprain is inconsistent. Therefore, a systematic review will help clinicians and coaches better understand the application of KT in clinical and training practices. This study is to systematically review the literature on the use of KT to improve outcomes including ankle function, proprioception, and pain and to evaluate the effectiveness of KT in the treatment and prevention of ankle sprain injuries. METHODS: A comprehensive electronic search of the literature will be undertaken in the following databases: PubMed, CINAHL, SPORTDiscus, Cochrane library, Web of Science and Scopus from 1979 to August 2022. The Physiotherapy Evidence Database scale will be used to assess the methodological quality of all included studies and RevMan 5.3 (Copenhagen, The Nordic Cochrane Centre) for the data analysis. RESULTS: This study will provide a standardized evaluation and comparison for effects of KT on the treatment and prevention of ankle sprains in youth athletes. CONCLUSION: This review will provide the evidence of the effectiveness of KT used in the treatment and prevention of ankle sprain in youth athletes. This review will also provide directions and recommendations for future research and clinical practices targeting treatment and prevention of ankle sprains in youth athletes.

Defective efferocytosis of vascular cells in heart disease.

The efficient phagocytic clearance of dying cells and apoptotic cells is one of the processes that is essential for the maintenance of physiologic tissue function and homeostasis, which is termed "efferocytosis." Under normal conditions, "find me" and "eat me" signals are released by apoptotic cells to stimulate the engulfment and efferocytosis of apoptotic cells. In contrast, abnormal efferocytosis is related to chronic and non-resolving inflammatory diseases such as atherosclerosis. In the initial steps of atherosclerotic lesion development, monocyte-derived macrophages display efficient efferocytosis that restricts plaque progression; however, this capacity is reduced in more advanced lesions. Macrophage reprogramming as a result of the accumulation of apoptotic cells and augmented inflammation accounts for this diminishment of efferocytosis. Furthermore, defective efferocytosis plays an important role in necrotic core formation, which triggers plaque rupture and acute thrombotic cardiovascular events. Recent publications have focused on the essential role of macrophage efferocytosis in cardiac pathophysiology and have pointed toward new therapeutic strategies to modulate macrophage efferocytosis for cardiac tissue repair. In this review, we discuss the molecular and cellular mechanisms that regulate efferocytosis in vascular cells, including macrophages and other phagocytic cells and detail how efferocytosis-related molecules contribute to the maintenance of vascular hemostasis and how defective efferocytosis leads to the formation and progression of atherosclerotic plaques.

The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease.

Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, valve diseases, fibrosis, and pulmonary arterial hypertension (PAH). Therefore, a deeper understanding of the cellular and molecular mechanisms underlying EndoMT in CVD should provide urgently needed insights into reversing this condition. This review summarizes a 30-year span of relevant literature, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD.

Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses.

Diabetes mellitus is a worldwide health problem that usually comes with severe complications. There is no cure for diabetes yet and the threat of these complications is what keeps researchers investigating mechanisms and treatments for diabetes mellitus. Due to advancements in genomics, epigenomics, proteomics, and single-cell multiomics research, considerable progress has been made toward understanding the mechanisms of diabetes mellitus. In addition, investigation of the association between diabetes and other physiological systems revealed potentially novel pathways and targets involved in the initiation and progress of diabetes. This review focuses on current advancements in studying the mechanisms of diabetes by using genomic, epigenomic, proteomic, and single-cell multiomic analysis methods. It will also focus on recent findings pertaining to the relationship between diabetes and other biological processes, and new findings on the contribution of diabetes to several pathological conditions.

Non-alcoholic Steatohepatitis Pathogenesis, Diagnosis, and Treatment.

There has been a rise in the prevalence of non-alcohol fatty liver disease (NAFLD) due to the popularity of western diets and sedentary lifestyles. One quarter of NAFLD patients is diagnosed with non-alcoholic steatohepatitis (NASH), with histological evidence not only of fat accumulation in hepatocytes but also of liver cell injury and death due to long-term inflammation. Severe NASH patients have increased risks of cirrhosis and liver cancer. In this review, we discuss the pathogenesis and current methods of diagnosis for NASH, and current status of drug development for this life-threatening liver disease.

Epsins Negatively Regulate Aortic Endothelial Cell Function by Augmenting Inflammatory Signaling.

Background: The endothelial epsin 1 and 2 endocytic adaptor proteins play an important role in atherosclerosis by regulating the degradation of the calcium release channel inositol 1,4,5-trisphosphate receptor type 1 (IP3R1). In this study, we sought to identify additional targets responsible for epsin-mediated atherosclerotic endothelial cell activation and inflammation in vitro and in vivo. Methods: Atherosclerotic ApoE-/- mice and ApoE-/- mice with an endothelial cell-specific deletion of epsin 1 on a global epsin 2 knock-out background (EC-iDKO/ApoE-/-), and aortic endothelial cells isolated from these mice, were used to examine inflammatory signaling in the endothelium. Results: Inflammatory signaling was significantly abrogated by both acute (tumor necrosis factor-α (TNFα) or lipopolysaccharide (LPS)) and chronic (oxidized low-density lipoprotein (oxLDL)) stimuli in EC-iDKO/ApoE-/- mice and murine aortic endothelial cells (MAECs) isolated from epsin-deficient animals when compared to ApoE-/- controls. Mechanistically, the epsin ubiquitin interacting motif (UIM) bound to Toll-like receptors (TLR) 2 and 4 to potentiate inflammatory signaling and deletion of the epsin UIM mitigated this interaction. Conclusions: The epsin endocytic adaptor proteins potentiate endothelial cell activation in acute and chronic models of atherogenesis. These studies further implicate epsins as therapeutic targets for the treatment of inflammation of the endothelium associated with atherosclerosis.

Restoration of Noradrenergic Function in Parkinson's Disease Model Mice.

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson's disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine ß-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

Smart configuration of cobalt hexacyanoferrate assembled on carbon fiber cloths for fast aqueous flexible sodium ion pseudocapacitor.

Aqueous rechargeable batteries (ARBs) have the advantages of low cost, high safety and sustainable environmental friendliness. However, the key challenge for ARBs is the narrow electrochemical stability window of the water, undoubtedly leading to the low output voltage, the underachieved capacity and a low energy density. Prussian blues and their analogues have attracted great research interest for energy storage due to the advantages of facile synthesis, versatile categories and tunable three dimensional frameworks. Herein a flexible integrated potassium cobalt hexacyano ferrates (Co-HCF) on carbon fiber clothes (CFCs) were designed through a feasible route combining the controllable electrochemical deposition and the efficient co-precipitation process. The Co-HCF@CFCs demonstrate an excellent sodium ion storage with a high reversible capacity of 91 mAh g-1 at 1 A g-1 and 55 mAh g-1 at 10 A g-1 in aqueous electrolytes. The long cycling stability at the high current demonstrate the excellent structure stability of the Co-HCF@CFCs. Analysis on the rate Cyclic voltammograms (CV) profiles reveal the fast electrochemical kinetics with the capacitive controlled process, while galvanostatic intermittent titration technique (GITT) tests fast diffusion coefficient related with the sodium ions intercalation/deintercalation in the Co-HCF@CFCs. In addition, the flexible Co-CHF@CFCs also demonstrate excellent performance for quasi-solid-state ARBs even at the high bending angles. The high quality Co-HCF@CFCs with advantage of high rate capability and excellent reversible capacity make them a promising candidate for high performance ARBs.

Frontline Science: The expression of integrin αD ß2 (CD11d/CD18) on neutrophils orchestrates the defense mechanism against endotoxemia and sepsis.

Neutrophil-macrophage interplay is a fine-tuning mechanism that regulates the innate immune response during infection and inflammation. Cell surface receptors play an essential role in neutrophil and macrophage functions. The same receptor can provide different outcomes within diverse leukocyte subsets in different inflammatory conditions. Understanding the variety of responses mediated by one receptor is critical for the development of anti-inflammatory treatments. In this study, we evaluated the role of a leukocyte adhesive receptor, integrin αD ß2 , in the development of acute inflammation. αD ß2 is mostly expressed on macrophages and contributes to the development of chronic inflammation. In contrast, we found that αD -knockout dramatically increases mortality in the cecal ligation and puncture sepsis model and LPS-induced endotoxemia. This pathologic outcome of αD -deficient mice is associated with a reduced number of monocyte-derived macrophages and an increased number of neutrophils in their lungs. However, the tracking of adoptively transferred fluorescently labeled wild-type (WT) and αD-/- monocytes in WT mice during endotoxemia demonstrated only a moderate difference between the recruitment of these two subsets. Moreover, the rescue experiment, using i.v. injection of WT monocytes to αD -deficient mice followed by LPS challenge, showed only slightly reduced mortality. Surprisingly, the injection of WT neutrophils to the bloodstream of αD-/- mice markedly increased migration of monocyte-derived macrophage to lungs and dramatically improves survival. αD -deficient neutrophils demonstrate increased necrosis/pyroptosis. αD ß2 -mediated macrophage accumulation in the lungs promotes efferocytosis that reduced mortality. Hence, integrin αD ß2 implements a complex defense mechanism during endotoxemia, which is mediated by macrophages via a neutrophil-dependent pathway.