Establishment of machine learning-based tool for early detection of pulmonary embolism.

BACKGROUND AND OBJECTIVES: Pulmonary embolism (PE) is a complex disease with high mortality and morbidity rate, leading to increasing society burden. However, current diagnosis is solely based on symptoms and laboratory data despite its complex pathology, which easily leads to misdiagnosis and missed diagnosis by inexperienced doctors. Especially, CT pulmonary angiography, the gold standard method, is not widely available. In this study, we aim to establish a rapid and accurate screening model for pulmonary embolism using machine learning technology. Importantly, data required for disease prediction are easily accessed, including routine laboratory data and medical record information of patients. METHODS: We extracted features from patients' routine laboratory results and medical records, including blood routine, biochemical group, blood coagulation routine and other test results, as well as symptoms and medical history information. Samples with a feature loss rate greater than 0.8 were deleted from the original database. Data from 4723 cases were retained, 231 of which were positive for pulmonary embolism. 50 features were retained through the positive and negative statistical hypothesis testing which was used to build the predictive model. In order to avoid identification as majority-class samples caused by the imbalance of sample proportion, we used the method of Synthetic Minority Oversampling Technique (SMOTE) to increase the amount of information on minority samples. Five typical machine learning algorithms were used to model the screening of pulmonary embolism, including Support Vector Machines, Logistic Regression, Random Forest, XGBoost, and Back Propagation Neural Networks. To evaluate model performance, sensitivity, specificity and AUC curve were analyzed as the main evaluation indicators. Furthermore, a baseline model was established using the characteristics of the pulmonary embolism guidelines as a comparison model. RESULTS: We found that XGBoost showed better performance compared to other models, with the highest sensitivity and specificity (0.99 and 0.99, respectively). Moreover, it showed significant improvement in performance compared to the baseline model (sensitivity and specificity were 0.76 and 0.76 respectively). More important, our model showed low missed diagnosis rate (0.46) and high AUC value (0.992). Finally, the calculation time of our model is only about 0.05 s to obtain the possibility of pulmonary embolism. CONCLUSIONS: In this study, five machine learning classification models were established to assess the likelihood of patients suffering from pulmonary embolism, and the XGBoost model most significantly improved the precision, sensitivity, and AUC for pulmonary embolism screening. Collectively, we have established an AI-based model to accurately predict pulmonary embolism at early stage.

Omentin-1 enhances the inhibitory effect of endothelial progenitor cells on neointimal hyperplasia by inhibiting the p38 MAPK/CREB pathway.

AIMS: Endothelial progenitor cells (EPCs) play an important role in vascular repair. However, they are dysfunctional in the inflammatory microenvironment during restenosis. In this study, we investigated whether omentin-1, an anti-inflammatory factor, could reduce neointima formation after carotid artery injury (CAI) in rats by improving EPC functions that were damaged by inflammation and the underlying mechanisms. MAIN METHODS: EPCs were transfected with adenoviral vectors expressing human omentin-1 or green fluorescent protein (GFP). Then, the rats received 2 × 106 EPCs expressing omentin-1 or GFP by tail vein injection directly after CAI and again 24 h later. Hematoxylin-eosin staining and immunohistochemistry were used for analyzing neointimal hyperplasia. Besides, EPCs were treated with omentin-1 and TNF-α to examine the underlying mechanism. KEY FINDINGS: Our results showed that omentin-1 could significantly improve EPC functions, including proliferation, apoptosis and tube formation. Meanwhile, EPCs overexpressed with omentin-1 could significantly reduce neointimal hyperplasia and tumor necrosis factor-α (TNF-α) expression after CAI in rats. TNF-α could notably induce EPC dysfunction, which could be markedly reversed by omentin-1 through the inhibition of the p38 MAPK/CREB pathway. Furthermore, a p38 MAPK agonist (anisomycin) significantly abrogated the protective effects of omentin-1 on EPCs damaged by TNF-α. SIGNIFICANCE: Our results indicated that genetically modifying EPC with omentin-1 could be an alternative strategy for the treatment of restenosis.

Computed tomographic manifestations of celiac ganglia between hypertensive and non-hypertensive population.

The celiac ganglion (CG) is associated with the sympathetic nervous system (SNS) and plays an important role in the pathogenesis of hypertension. The characteristics of the CG in patients with hypertension remain unknown. The aim of our study was to explore the differences in celiac ganglia (CGs) characteristics between hypertensive and non-hypertensive populations using computed tomography (CT). CGs manifestations on multidetector row CT in 1003 patients with and without hypertension were retrospectively analyzed. The morphological characteristics and CT values of the left CGs were recorded. The CT values of the ipsilateral adrenal gland (AG) and crus of the diaphragm (CD) were also measured. The left CG was located between the left AG and CD, and most CGs were long strips. The frequency of visualization of the left CGs was higher in the hypertension group than in the non-hypertension group (p < .05). There were no significant differences in the maximum diameter, size, and shape ratio of the left CGs between the two groups (p > .05). Except for the left CG in the arterial phase, the CT values of the left CG and AG in the non-hypertensive group were higher than those in the hypertension group (p < .05). The venous phase enhancement of the left CG in the non-hypertension group was significantly higher than that in the hypertension group (p < .05). Our findings reveal that CGs have characteristic manifestations in the hypertensive population. As important targets of the SNS, CGs have the potential to regulate blood pressure.

Association between healthy lifestyle and the occurrence of cardiometabolic multimorbidity in hypertensive patients: a prospective cohort study of UK Biobank.

BACKGROUND: Cardiometabolic multimorbidity (CMM) is becoming increasingly common in patients with hypertension, and it is well established that healthy lifestyle plays a key role in the prevention of hypertension. However, the association between combined lifestyle factors and CMM in patients with hypertension is uncertain. METHODS: This prospective analysis included the data (obtained from the UK biobank) of participants with hypertension who did not have coronary heart disease (CHD), stroke, or diabetes. The outcome was the occurrence of CMM, defined as ≥ 1 disease of CHD, stroke, and diabetes that occurred in participants with hypertension. Four lifestyle factors (smoking, alcohol consumption, diet, and physical activity) were assessed using a weighted healthy lifestyle score, and participants were divided into four groups: the very unhealthy, unhealthy, healthy, and very healthy groups. The flexible parameter Royston-Parmar proportional hazard model was used to estimate hazard ratios (HRs) between lifestyles and CMM, as well as the difference in CMM-free life expectancy. RESULTS: During a median follow-up of 12.2 years, 9812 (18.4%) of the 53,397 hypertensive patients occurred CMM. Compared with the very unhealthy group, the very healthy group had a 41% reduction in the risk for CMM in hypertensive patients and a 32-50% reduction in the risk for specific cardiometabolic diseases such as CHD, stroke, and diabetes. For each lifestyle factor, non-smoking had the greatest protective effect against CMM (HR: 0.64, 95% confidence interval (CI) 0.60-0.68). A lifestyle combining multiple healthy factors extended CMM-free life expectancy (e.g., six years longer at age 45 years for participants in the very healthy group). CONCLUSIONS: Combined healthy lifestyle factors were associated with a lower risk for CMM in hypertensive patients. This suggests that combined healthy lifestyle should be supported to decrease disease burden.

Prophylactic exercise-derived circulating exosomal miR-125a-5p promotes endogenous revascularization after hindlimb ischemia by targeting endothelin converting enzyme 1.

Background: Prophylactic exercise improves clinical outcomes in patients experiencing severe ischemic diseases. Previous studies have shown that exercise could alter the amount or content of circulating exosomes. However, little is known about the role of precursory exercise-derived circulating exosomes (Exe-Exo) in ischemic diseases. We therefore aimed to explore the function and mechanism of Exe-Exo in endogenous revascularization and perfusion recovery in peripheral arterial disease. Methods and Results: We first determined that 4 weeks of precursory treadmill exercise improved perfusion recovery on days 7, 14 and 21 after unilateral femoral artery ligation (FAL) but had no effect immediately after ligation. Then, local muscle delivery of Exe-Exo promotes arteriogenesis, angiogenesis and perfusion recovery, which could be abolished by GW4869, a well-recognized pharmacological agent inhibiting exosome release. This suggests that Exe-Exo mediated exercise-induced revascularization. In vitro, Exe-Exo enhanced endothelial cell proliferation, migration and tube formation. In addition, we identified miR-125a-5p as a novel exerkine through exosomal miRNA sequencing and RT-qPCR validation. Inhibition of miR-125a-5p abrogated the beneficial effects of Exe-Exo both in vivo and in vitro. Mechanistically, these exercise-afforded benefits were attributed to the exosomal miR-125a-5p downregulation of ECE1 expression and the subsequent activation of the AKT/eNOS downstream signaling pathway. Specifically, skeletal muscle may be a major tissue source of exercise-induced exosomal miR-125a-5p via fluorescence in situ hybridization. Conclusions: Endogenous circulating exosomal miR-125a-5p promotes exercise-induced revascularization via targeting ECE1 and activating AKT/eNOS downstream signaling pathway. Identify exosomal miR-125a-5p as a novel exerkine, and highlight its potential therapeutic role in the prevention and treatment of peripheral arterial disease.

Accurate Location in Dynamic Traffic Environment Using Semantic Information and Probabilistic Data Association.

High-accurate and real-time localization is the fundamental and challenging task for autonomous driving in a dynamic traffic environment. This paper presents a coordinated positioning strategy that is composed of semantic information and probabilistic data association, which improves the accuracy of SLAM in dynamic traffic settings. First, the improved semantic segmentation network, building on Fast-SCNN, uses the Res2net module instead of the Bottleneck in the global feature extraction to further explore the multi-scale granular features. It achieves the balance between segmentation accuracy and inference speed, leading to consistent performance gains on the coordinated localization task of this paper. Second, a novel scene descriptor combining geometric, semantic, and distributional information is proposed. These descriptors are made up of significant features and their surroundings, which may be unique to a traffic scene, and are used to improve data association quality. Finally, a probabilistic data association is created to find the best estimate using a maximum measurement expectation model. This approach assigns semantic labels to landmarks observed in the environment and is used to correct false negatives in data association. We have evaluated our system with ORB-SLAM2 and DynaSLAM, the most advanced algorithms, to demonstrate its advantages. On the KITTI dataset, the results reveal that our approach outperforms other methods in dynamic traffic situations, especially in highly dynamic scenes, with sub-meter average accuracy.

Establishment of a GFP::LMNB1 knockin cell line (CSUi002-A-1) from a dystonia patient-specific iPSC by CRISPR/Cas9 editing.

LMNB1, as one of the major components of nuclear lamina, anchors heterochromatin and associates with transcription regulation. LMNB1 was previously demonstrated to be upregulated and nuclear-to-cytoplasmic mislocalized in DYT1 dystonia specific neurons. Here, we established a knockin cell line with GFP::LMNB1 fusion expression from a DYT1 patient derived iPSC line, by CRISPR/Cas9 editing. The generated iPSCs displayed GFP and LMNB1 co-localization, reminiscent of successful genomic editing. They remained pluripotent and normal karyotype, and possessed the potential to differentiate into three germ layers. This GFP::LMNB1 knockin iPSC will be used for studying the lamina-pathophysiology of DYT1 dystonia, and other nucleus-centered questions.

LINC00472 regulates vascular smooth muscle cell migration and proliferation via regulating miR-149-3p.

LncRNAs are one group of gene modulators functioning via several mechanisms in pathological and physiological conditions. We noted that LINC00472 expression level is elevated in atherosclerotic coronary tissues compared with normal coronary artery samples. LINC00472 is also upregulated in vascular smooth muscle cells (VSMCs) induced by TNF-α and PDGF-BB. Ectopic expression of LINC00472 induced VSMC migration and proliferation. The predicted binding sequence between miR-149-3p and LINC00472 was analyzed by LncBase Predicted. Overexpression of miR-149-3p decreases the luciferase activity of wild-type reporter plasmid, but not the mutant one. Ectopic expression of LINC00472 suppresses the expression of miR-149-3p in VSMCs. Furthermore, we demonstrated that miR-149-3p expression is decreased in atherosclerotic coronary tissues. MiR-149-3p was downregulated in VSMCs induced by TNF-α and PDGF-BB. Overexpression of LINC00472 induces VSMC migration and proliferation via regulating miR-149-3p. These data suggested that LINC00472 acts a critical role in the migration and proliferation of VSMCs partly via modulating miR-149-3p.

miRNA-22 as a Candidate Diagnostic Biomarker for Coronary Slow Flow.

BACKGROUND: Coronary slow flow (CSF) refers to the phenomenon of delayed distal flow in the absence of lesions detected on coronary angiography. Although the detection rate of CSF has been increasing in clinical practice, early diagnosis is difficult and the factors contributing to this condition remain unclear. Given the increasing demonstration of the roles of microRNAs (miRNAs) in disease and as diagnostic biomarkers, the aim of this study was to analyze the expression of serum miRNA-22 in patients with CSF detected using coronary angiography and its diagnostic efficacy. METHODS AND RESULTS: A retrospective analysis including 44 patients with CSF and 42 patients with normal coronary flow (control group) was conducted. Additionally, all included patients either did not have visually estimated coronary artery stenosis or had <50% stenosis. Plasma samples were collected from patients in these two groups, and the levels of miRNA-22 were detected. The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic efficiency of serum miRNA-22 in the context of CSF. RESULTS: The expression of serum miRNA-22 was significantly higher in the CSF patients than in the control subjects (P < 0.0001). The area under the ROC curve for miRNA-22 in diagnosing CSF was 0.8293 (95% confidence interval: 0.7313-0.9272), with a sensitivity of 75.0% and specificity of 88.1%. CONCLUSIONS: The expression of serum miRNA-22 in CSF is upregulated compared to that in subjects with normal coronary flow and shows relatively high clinical diagnostic efficiency, suggesting a new potential biomarker for the early diagnosis of CSF.

Plasma Choline as a Diagnostic Biomarker in Slow Coronary Flow.

AIM: The slow coronary flow (SCF) phenomenon was characterized by delayed perfusion of epicardial arteries, and no obvious coronary artery lesion in coronary angiography. The prognosis of patients with slow coronary flow was poor. However, there is lack of rapid, simple, and accurate method for SCF diagnosis. This study aimed to explore the utility of plasma choline as a diagnostic biomarker for SCF. METHODS: Patients with coronary artery stenosis <40% evaluated by the coronary angiogram method were recruited in this study and were grouped into normal coronary flow (NCF) and SCF by thrombolysis in myocardial infarction frame count (TFC). Plasma choline concentrations of patients with NCF and SCF were quantified by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry. Correlation analysis was performed between plasma choline concentration and TFC. Receiver operating characteristic (ROC) curve analysis with or without confounding factor adjustment was applied to predict the diagnostic power of plasma choline in SCF. RESULTS: Forty-four patients with SCF and 21 patients with NCF were included in this study. TFC in LAD, LCX, and RCA and mean TFC were significantly higher in patients with SCF in comparison with patients with NCF (32.67 ± 8.37 vs. 20.66 ± 3.41, P < 0.01). Plasma choline level was obviously higher in patients with SCF when compared with patients with NCF (754.65 ± 238.18 vs. 635.79 ± 108.25, P=0.007). Plasma choline level had significantly positive correlation with Mean TFC (r = 0.364, P=0.002). Receiver operating characteristic (ROC) analysis showed that choline with or without confounding factor adjustment had an AUC score of 0.65 and 0.77, respectively. CONCLUSIONS: TFC were closely related with plasma choline level, and plasma choline can be a suitable and stable diagnostic biomarker for SCF.

Overexpression of long noncoding RNA ANRIL inhibits phenotypic switching of vascular smooth muscle cells to prevent atherosclerotic plaque development in vivo.

BACKGROUND: Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. Long noncoding RNA ANRIL (lncRNA-ANRIL) is critical in vascular homeostasis. Metformin produces multiple beneficial effects in atherosclerosis. However, the underlying mechanisms need to be elucidated. METHODS AND RESULTS: Metformin increased lncRNA-ANRIL expression and AMPK activity in cultured VSMCs, and inhibited the phenotypic switching of VSMCs to the synthetic phenotype induced by platelet-derived growth factor (PDGF). Overexpression of lncRNA-ANRIL inhibited phenotypic switching and reversed the reduction of AMPK activity in PDGF-treated VSMCs. While, gene knockdown of lncRNA-ANRIL by adenovirus or silence of AMPKγ through siRNA abolished AMPK activation induced by metformin in VSMCs. RNA-immunoprecipitation analysis indicated that the affinity of lncRNA-ANRIL to AMPKγ subunit was increased by metformin. In vivo, administration of metformin increased the levels of lncRNA-ANRIL, suppressed VSMC phenotypic switching, and prevented the development of atherosclerotic plaque in Apoe-/- mice fed with western diet. These protective effects of metformin were abolished by infecting Apoe-/- mice with adenovirus expressing lncRNA-ANRIL shRNA. The levels of AMPK phosphorylation, AMPK activity, and lncRNA-ANRIL expression were decreased in human atherosclerotic lesions. CONCLUSION: Metformin activates AMPK to suppress the formation of atherosclerotic plaque through upregulation of lncRNA-ANRIL.

NFAT5 promotes arteriogenesis via MCP-1-dependent monocyte recruitment.

Studies have demonstrated that nuclear factor of activated T cells 5 (NFAT5) is not only a tonicity-responsive transcription factor but also activated by other stimuli, so we aim to investigate whether NFAT5 participates in collateral arteries formation in rats. We performed femoral artery ligature (FAL) in rats for hindlimb ischaemia model and found that NFAT5 was up-regulated in rat adductors with FAL compared with sham group. Knockdown of NFAT5 with locally injection of adenovirus-mediated NFAT5-shRNA in rats significantly inhibited hindlimb blood perfusion recovery and arteriogenesis. Moreover, NFAT5 knockdown decreased macrophages infiltration and monocyte chemotactic protein-1 (MCP-1) expression in rats adductors. In vitro, with interleukin-1ß (IL-1ß) stimulation and loss-of-function studies, we demonstrated that NFAT5 knockdown inhibits MCP-1 expression in endothelial cells and chemotaxis of THP-1 cells regulated by ERK1/2 pathway. More importantly, exogenous MCP-1 delivery could recover hindlimb blood perfusion, promote arteriogenesis and macrophages infiltration in rats after FAL, which were depressed by NFAT5 knockdown. Besides, NFAT5 knockdown also inhibited angiogenesis in gastrocnemius muscles in rats. Our results indicate that NFAT5 is a critical regulator of arteriogenesis and angiogenesis via MCP-1-dependent monocyte recruitment, suggesting that NFAT5 may represent an alternative therapeutic target for ischaemic diseases.

Self-Assembled VO2 Mesh Film-Based Resistance Switches with High Transparency and Abrupt ON/OFF Ratio.

Vanadium dioxide, a well-known phase transition material with abrupt resistance change during its transition temperature, is herein used to fabricate the transparent mesh film onto a glass slide through self-assembly mesh printing. A record high ON/OFF ratio up to 104 is achieved together with high visible transmittance of 86% compared to the normal glass slide with visible transmittance at 88%. The high transparent properties make the resistive switches applicable for next-generation electronics, such as see-through computing device and beyond. A simple and scalable mesh printing approach-integrated phase change material may provide a promising way to fabricate transparent resistance switches for next-generation electronics.

Circulating miR-182-5p and miR-5187-5p as biomarkers for the diagnosis of unprotected left main coronary artery disease.

BACKGROUND: Patients with unprotected left main coronary artery disease (uLMCAD) have high mortality rate due to sudden heart failure and acute myocardial infarction, for which reliable diagnostic biomarkers to detect this disease at an early stage are in urgent need. Circulating microRNAs (miRNAs) have emerged as a class of novel biomarkers for cardiovascular diseases. The purpose of this study was to investigate utility of miRNAs as biomarkers for early detection of uLMCAD. METHODS: High-throughput sequencing (NGS) was initially employed to compare circulating miRNA expression profiles in uLMCAD patients to that in patients without coronary artery disease (CAD) to identify candidate miRNA biomarkers. We further validated the expression of candidate miRNAs by quantitative polymerase chain reaction (qPCR) in a larger cohort. Receiver operating characteristic (ROC) analysis with multivariate logistic regression was used to evaluate the diagnostic power of candidate miRNAs individually and combined. RESULTS: MiR-182-5p, miR-199a-5p and miR-5187-5p were found significantly differentially expressed through NGS (fold changes =1.35, 1.65, 0.5, P values =0.018, 0.046, 0.030, respectively, n=5 for both uLMCAD group and non-CAD control group). In a larger cohort (n=27 for uLMCAD patient and n=38 for non-CAD controls), qPCR confirmed that expression of miR-182-5p was up-regulated (2.57-fold, P=0.011) and expression of miR-5187-5p was down-regulated (0.47-fold, P=0.018) in the plasma of uLMCAD patients. ROC analysis with multivariate logistic regression show that miR-182 and miR-5187 have an AUC score of 0.97 and 0.94 respectively, indicating high diagnostic power as biomarkers for uLMCAD. Interestingly, correlation analysis suggests that the expression of two miRNAs were independent to each other. CONCLUSIONS: These results suggested that circulating miR-182-5p and miR-5187-5p were suitable diagnostic biomarkers for uLMCAD, both potentially providing diagnostic information for discriminating uLMCAD patients from non-CAD population prior to invasive diagnostic coronary angiography (CAG).

Endothelial progenitor cell impairment mediated vasodilation dysfunction via diminishing nitric oxide production in postmenopausal females.

Vascular endothelial dysfunction is the major contributing factor to hypertension. Endothelial progenitor cells (EPCs) are essential for endogenous vascular endothelial renovation. The activity and number of circulating EPCs are preserved in prehypertensive premenopausal females according to our previous research. However, the changes of EPCs in prehypertensive postmenopausal females are poorly understood, and the mechanisms responsible for the loss of the gender protection advantage of cardiovascular disease remain unexplored. In order to determine the effects of EPCs in prehypertensive postmenopausal females, the number and activity of circulating EPCs were tested in the present study. Next, the function of EPCs secreting nitric oxide (NO), vascular endothelial growth factor (VEGF) and granulocyte­macrophage colony­stimulating factor (GM­CSF), as well as their concentration in the plasma, were measured. The association between flow­mediated dilation (FMD) and EPC secretion was also assessed. Attenuation of proliferation and migration of EPCs was observed in prehypertensive patients in comparison with normotensive subjects. In addition, a reduced NO production secreted by EPCs was detected in prehypertensive patients as compared with that in normotensive patients. There was no significant difference in EPC function between postmenopausal females and age­matched males. Finally, the association between FMD and NO production was validated. Collectively, these data indicated that impaired EPCs mediated vasodilation dysfunction via decreasing NO production. Therefore, EPC function enhancement and NO level augmentation are emerging as novel therapeutic strategies for prehypertension therapy.

Human tissue kallikrein-1 protects against the development of erectile dysfunction in a rat model of hyperhomocysteinemia.

The aim of this study was to investigate the mechanism by which a diet inducing high hyperhomocysteinemia (HHcy) leads to the deterioration of erectile function in rats and whether this is inhibited by expression of the human tissue kallikrein-1 (hKLK1) gene. We established a rat model of HHcy by feeding methionine (Met)-rich diets to male Sprague-Dawley (SD) rats. Male wild-type SD rats (WTRs) and transgenic rats harboring the hKLK1 gene (TGRs) were fed a normal diet until 10 weeks of age. Then, 30 WTRs were randomly divided into three groups as follows: the control (n = 10) group, the low-dose (4% Met, n = 10) group, and the high-dose (7% Met, n = 10) group. Another 10 age-matched TGRs were fed the high-dose diet and designated as the TGR+7% Met group. After 30 days, in all four groups, erectile function was measured and penile tissues were harvested to determine oxidative stress, endothelial cell content, and penis fibrosis. Compared with the 7% Met group, the TGR+7% Met group showed diminished HHcy-induced erectile dysfunction (ED), indicating the improvement caused by hKLK1. Regarding corpus cavernosum endothelial cells, hKLK1 preserved endothelial cell-cell junctions and endothelial cell content, and activated protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) signaling. Fibrosis assessment indicated that hKLK1 preserved normal penis structure by inhibiting apoptosis in the corpus cavernosum smooth muscle cells. Taken together, these findings showed that oxidative stress, impaired corpus cavernosum endothelial cells, and severe penis fibrosis were involved in the induction of ED by HHcy in rats, whereas hKLK1 preserved erectile function by inhibiting these pathophysiological changes.

Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K.

Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR-185-5p were differently expressed in plasma from patients with ACS by high-throughput RNA sequencing. The expressional levels of miR-185-5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT-PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR-185-5p. In HUVECs, miR-185-5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR-185-5p inhibitors performed the opposites. Further, the inhibitory effects of miR-185-5p up-regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus-mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain-function of miR-185-5p by agomir infusion down-regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR-185-5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR-185-5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.

MicroRNA-3619-5p suppresses bladder carcinoma progression by directly targeting ß-catenin and CDK2 and activating p21.

Current studies indicate that microRNAs (miRNAs) are widely decreased in various tumors and function as tumor suppressors by inhibiting cancer cell proliferation, survival, invasion, and migration. The potential application of using miRNAs to predict therapeutic responses to multiple types of cancer treatment holds high promise. In current study, we demonstrate that miR-3619-5p is downregulated in bladder cancer (BCa) tissues and cells. Exogenous overexpression of miR-3619-5p in BCa cells inhibits proliferation, migration, and invasion. Moreover, a nude mouse xenograft model shows that miR-3619-5p inhibits BCa cell growth. We also demonstrate that miR-3619-5p leads to the activation of p21 by targeting its promoter in BCa cells. Enforced miR-3619-5p expression consistently leads to the downregulation of ß-catenin and cyclin-dependent kinase 2 (CDK2) through predicted binding sites within the ß-catenin and CDK2 3'-untranslated regions (UTRs), respectively. Moreover, ß-catenin and CDK2 knockdown is able to mimic BCa cells growth and metastasis effects induced by overexpressing miR-3619-5p. We further confirm that miR-3619-5p inhibits Wnt-ß-catenin signal pathway and EMT progression in BCa cells. We also found that miR-3619-5p-induced growth arrest and metastasis inhibition are p21-dependent in BCa cells. Taken together, these results confirm that miR-3619-5p plays a tumor suppressive role in BCa by interfering with cell growth and metastasis and may serve as a potential therapeutic target in BCa treatment.

Cryptomelane-Type KMn8O16 as Potential Cathode Material - for Aqueous Zinc Ion Battery.

Aqueous battery has been gained much more interest for large-scale energy storage fields due to its excellent safety, high power density and low cost. Cryptomelane-type KMn8O16 confirmed by X-ray diffraction (XRD) was successfully synthesized by a modified hydrothermal method, followed by annealed at 400°C for 3 h. The morphology and microstructure of as-prepared KMn8O16 investigated by field-emission scanning electron microscopy (FE-SEM) with the energy spectrum analysis (EDS) and transmission electron microscopy (TEM) demonstrate that one-dimensional nano rods with the length of about 500 nm constitute the microspheres with the diameter about 0.5~2 µm. The cyclic voltammetry measurement displays that the abundant intercalation of zinc ions on the cathode takes place during the initial discharge process, indicating that cryptomelane-type KMn8O16 can be used as the potential cathode material for aqueous zinc ion batteries. The electrode shows a good cycling performance with a reversible capacity of up to 77.0 mAh/g even after 100 cycles and a small self-discharge phenomenon.

Upregulation of E­cadherin expression mediated by a novel dsRNA suppresses the growth and metastasis of bladder cancer cells by inhibiting ß-catenin/TCF target genes.

Low expression levels of E­cadherin are correlated with poor prognosis in patients with bladder cancer (BCa). A small activating RNA (saRNA) targeting a specific promoter region can activate gene expression. In the present study, two small double-stranded RNAs (dsRNAs) targeting the promoter region of human E­cadherin were designed and synthesized, and the regulatory role of saRNAs in E­cadherin expression was investigated. The results of reverse transcription-quantitative polymerase chain reaction and western blotting demonstrated that transfection of dsEcad­346 into the BCa cell lines T24 and 5637 significantly activated E­cadherin expression. Furthermore, transfection of dsEcad­346 and miR­373 induced cell cycle arrest in G0/G1 phase, promoted apoptosis and significantly inhibited migration and invasion of BCa cells. Results of immunofluorescence and western blotting indicated that ß-catenin was redistributed from the nucleus to the cell membrane following transfection of dsEcad­346 and miR­373. Additionally, the expression of ß-catenin/T-cell factor complex (TCF) target genes (c­MYC, matrix metallopeptidase 2, cyclin D1) was suppressed following transfection of BCa cells with saRNA. Silencing of E­cadherin expression blocked the inhibitory effect of dsEcad­346 and miR­373 on BCa cells. In conclusion, a novel designed dsEcad­346 can activate the expression of E­cadherin in BCa cells. saRNA-mediated activation of E­cadherin expression inhibited the growth and metastasis of BCa cells by promoting the redistribution of ß-catenin from nucleus to cell membrane and inhibiting the ß-catenin/TCF target genes.