Empagliflozin attenuates doxorubicin-impaired cardiac contractility by suppressing reactive oxygen species in isolated myocytes.

In animal studies, sodium-glucose co-transporter-2 inhibitors-such as empagliflozin-have been shown to improve heart failure and impaired cardiac contractility induced by anthracyclines-including doxorubicin-although the therapeutic mechanism remains unclear. Moreover, abnormalities in Ca2+ handling within ventricular myocytes are the predominant feature of heart failure. Accordingly, this study aimed to investigate whether empagliflozin can alleviate Ca2+ handling disorders induced by acute doxorubicin exposure and elucidate the underlying mechanisms. To this end, ventricular myocytes were isolated from C57BL/6 mice. Contraction function, Ca2+ handling, and mitochondrial reactive oxygen species (ROS) generation were then evaluated using IonOptix or confocal microscopy. Ca2+ handling proteins were detected by western blotting. Results show that incubation with 1 µmol/L of doxorubicin for 120-min impaired cardiac contractility in isolated myocytes, which was significantly alleviated by pretreatment with 1 µmol/L of empagliflozin. Doxorubicin also markedly induced Ca2+ handling disorders, including decreased Ca2+ transients, prolonged Ca2+ transient decay time, enhanced frequency of Ca2+ sparks, and decreased Ca2+ content in the sarcoplasmic reticulum. These dysregulations were improved by pretreatment with empagliflozin. Moreover, empagliflozin effectively inhibited doxorubicin-induced mitochondrial ROS production in isolated myocytes and rescued doxorubicin-induced oxidation of Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) and CaMKII-dependent phosphorylation of RyR2. Similarly, preincubation with 10 µmol/L Mito-TEMPO mimicked the protective effects of empagliflozin. Collectively, Empagliflozin ameliorated the doxorubicin-induced contraction malfunction and Ca2+-handling disorders. These findings suggest that empagliflozin alleviates Ca2+-handling disorders by improving ROS production in the mitochondria and alleviating the enhanced oxidative CaMKII signaling pathway induced by doxorubicin.

Visualization and mapping of the right phrenic nerve by intracardiac echocardiography during atrial fibrillation ablation.

OBJECTIVE: This study aimed to evaluate the feasibility of real-time visualization and mapping of the right phrenic nerve (RPN) by using intracardiac echocardiography (ICE) during atrial fibrillation (AF) ablation. BACKGROUND: RPN injury is a complication associated with the ablation of AF. Multiple approaches are currently being used to prevent and detect RPN injuries. However, none of these approaches can directly visualize the RPN in real-time during the ablation procedure. METHODS AND RESULTS: The RPN was detected using ICE. The RPN and its adjacent structures were analysed. The relationship between the RPN's distance from the superior vena cava (SVC) and its pacing capture threshold was quantified. The safety of SVC isolation guided by the ICE-visualized RPN was evaluated. Thirty-eight people were enrolled in this study. The RPN was visualized by ICE in 92% of patients. It ran through the space between the SVC and the mediastinal pleura and had a 'straw'-like appearance upon ICE imaging. The course of the RPN was close to the SVC (minimum 1.0 ± 0.4 mm) and the right superior pulmonary vein (minimum 14.1 ± 7.3 mm). There was a positive linear correlation between the RPN's capture threshold and its distance from the SVC (Spearman's correlation coefficient = 0.728, < 0.001). SVC isolation was guided by the RPN; none of the patients developed an RPN injury. CONCLUSIONS: RPN can be visualized by ICE in most patients, thus providing a novel approach for the real-time detection of RPN during AF ablation.

Empagliflozin Ameliorates Ouabain-Induced Na+ and Ca2+ Dysregulations in Ventricular Myocytes in an Na+-Dependent Manner.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents that have improved clinical outcomes in patients with heart failure; however, their therapeutic mechanisms remain elusive. Although contradictory results have been reported, it has been proposed that improving Na+ homeostasis may be the underlying mechanism of action of SGLT2 inhibitors in heart failure treatment. This study explored whether empagliflozin ameliorates Na+ and Ca2+ handling disorders induced by ouabain in an Na+-dependent manner. METHODS: Isolated ventricular myocytes of mice were incubated with ouabain to establish a cellular model of Na+ overload. Effects of empagliflozin on Na+ and Ca2+ handling were evaluated using an ionOptix system and a confocal microscope. Distinct cytosolic Na+ levels were established by incubating different ouabain concentrations (10, 50, and 100 µmol/L). RESULTS: In the absence of ouabain, 1 µmol/L empagliflozin had a negligible impact on Na+ and Ca2+ handling in ventricular myocytes. Ouabain (50 µmol/L) significantly enhanced cytosolic Na+ levels and dysregulated Ca2+ handling, including an increased Ca2+ transient amplitude, elevated Ca2+ content in the sarcoplasmic reticulum, and enhanced spontaneous Ca2+ release normalized by treatment with 1 µmol/L empagliflozin within 10 min. All Na+ and Ca2+ handling abnormalities induced by ouabain were reversed by 1 µmol/L empagliflozin. The efficacy of empagliflozin was more potent at higher cytosolic Na+ levels. Pretreatment with the Na+/H+ exchanger (NHE) inhibitor (1 µmol/L cariporide) abolished the effects of empagliflozin. CONCLUSION: Empagliflozin ameliorates ouabain-induced Na+ and Ca2+ handling disorders in a cytosolic Na+-dependent manner, potentially by inhibiting the NHE.

Outcome of cancer patients after atrial fibrillation ablation: Insights from the China-AF registry.

BACKGROUND: Cancer has become significant comorbidity in patients with atrial fibrillation (AF). However, little is known about the efficacy and safety of AF ablation, the first-line rhythm control strategy, in patients with cancer. This study aims to evaluate the incidence and risk of AF recurrence and safety endpoints in patients with cancer compared to the non-cancer group after ablation. METHODS: From August 2011 to December 2020, we consecutively enrolled cancer patients in the China-AF cohort. We used propensity score matching (1:3) to select the control group and assessed the risk of AF recurrence and adverse events after ablation in cancer patients using a multivariable Fine and Gray competing risk model. RESULTS: A total of 203 patients with cancer were enrolled and 21 of them were active cancer, with a median follow-up of 12.3 months. The cumulative incidence of AF recurrence was comparable between patients with and without cancer (43.8% vs. 51.1%; p = .88). No difference in the risk of AF recurrence, thromboembolism, major bleeding, and mortality was observed after adjusting confounders. Active cancer was not associated with an increased risk of AF recurrence compared to the stable disease (SHR = 1.32; 95% CI 0.72-2.43; p = .46). Cancer was associated with a low risk of cardiovascular hospitalization (SHR, 0.54; 95% CI, 0.36-0.81; p = .01). Subgroup analysis found that hematological malignancy was associated with a high risk of AF recurrence (SHR, 5.68; 95% CI, 3.00-10.8; p < .001). CONCLUSIONS: This study suggests that catheter ablation could be feasible for rhythm control of AF patients with concomitant cancer.

Advanced inter-spacecraft offset frequency setting strategy for the Taiji program based on a two-stage optimization algorithm.

For space-based gravitational wave (GW) detection, the continuity of detection data acquisition is crucial to the inversion of wave sources and the realization of scientific goals. To control the inter-spacecraft beat-note frequency in an appropriate range for continuous gravitational wave detection and to reduce the upper bound of the beat-note frequency for improving the detection capability, a two-stage optimization algorithm is proposed to solve the offset frequency setting strategy in the Taiji program. The optimization objectives are the maximum offset frequency duration and minimum upper bound of the beat-note frequency. Considering all feasible phase-locked schemes, Doppler frequency shift, and the bandwidth of the phasemeter, a series of offset frequency setting strategies satisfying the conditions was obtained. The solution results show that the upper bound can be reduced to 16 MHz and, in this case, the offset frequency changes nine times with a minimum and maximum offset frequency duration of 90 days and 713 days, respectively. If the Doppler frequency shift is constrained, the minimum upper bound can be reduced to 14 MHz. When the minimum duration is increased, the minimum upper bound is increased. These results show that, by varying the offset frequency a limited number of times, the data continuity requirements of the Taiji program can be satisfied, and the phasemeter development difficulty and detection capability can be balanced, and may provide a reference for the phasemeter design, the setting of phase-locking schemes, and inter-spacecraft offset frequency in the Taiji program.

Association of shift work and dietary inflammatory potential with all-cause death among us hypertensive population: national health and nutrition examination study, 2005-2010.

BACKGROUND & AIMS: The individual effect of working schedule on survival in the hypertensive population has not been adequately studied. Shiftworkers are also prone to unhealthy lifestyles like pro-inflammatory diet. Therefore, we assessed the effect of shift work and its joint association with dietary inflammatory potential on mortality risk among the large US nationally representative sample of adult hypertensive population. METHODS: Data were from a nationally representative prospective cohort among US hypertensive population (n = 3680; weighted population, 54,192,988). The participants were linked to the 2019 public-access linked mortality archives. The working schedule were self-reported using the Occupation Questionnaire Section. Dietary inflammatory index (DII) scores were equally calculated using the 24-hour dietary recall (24 h) interviews. Multivariable Cox proportional hazards regression models were used to estimate hazard ratio and 95% confidence intervals (95%CI) for survival of hypertension individuals by work schedule and dietary inflammatory potential. The joint effect of work schedule and dietary inflammatory potential was then examined. RESULTS: Among the 3680 hypertension individuals (39.89% female [n = 1479] and 71.42% white [n = 1707]; weighted mean [SE] age, 47.35 [0.32] years), 592 individuals reported shift work status. 474 (10.76%) reported shift work status with pro-inflammatory dietary pattern (DII scores > 0). 118 (3.06%) reported shift work status with anti-inflammatory dietary pattern (DII scores < 0). 646 (19.64%) reported a non-shift working schedule with anti-inflammatory dietary pattern, while 2442 (66.54%) reported non-shift working schedule with pro-inflammatory dietary pattern. After a median follow-up of 11.67 years (140 months), 317 deaths (cardiovascular diseases (CVD), 65; cancer, 104) were registered. Cox regression analysis showed that shift work was associated with higher risk of all-cause mortality (hazard ratio [HR], 1.48; 95% CI, 1.07-2.06) compared with non-shift workers. In the joint analysis, shift work status combined with pro-inflammatory dietary pattern was associated with the highest all-cause mortality risk. Moreover, adopting the anti-inflammatory diet significantly attenuates the deleterious effect of shift work on mortality risk. CONCLUSIONS: In this large representative sample of adults with hypertension in the U.S., the combination of shift work status with pro-inflammatory dietary pattern was highly prevalent and was associated with the highest risks of death from all causes.

Autonomous State Estimation and Observability Analysis for the Taiji Formation Using High-Precision Optical Sensors.

In certain observation periods of navigation missions for the Taiji formation, ground observation stations are unable to observe the spacecraft, while the state of the spacecraft can be estimated through the utilization of dynamic equations simulated on prior knowledge. However, this method cannot accurately track the spacecraft. In this paper, we focus on appropriately selecting the available onboard measurement to estimate the state of the spacecraft of the Taiji formation. We design two schemes to explore the performance of the state estimation based on the interspacecraft interferometry measurements and the measurements obtained from the Sun sensor and the radial velocity sensor. The observability of the system is numerically analyzed using the singular value decomposition method. Furthermore, we analyze error covariance propagation using the cubature Kalman filter. The results show that using high-precision interspacecraft angle measurement can improve significantly the observability of the system. The absolute position and velocity of the spacecraft can be estimated respectively with an accuracy of about 3.1 km and 0.14 m/s in the first scheme, where the prior information of the precision of the position and velocity is respectively 100 km and 1 m/s. When the measurement from the radial velocity sensor is used in the second scheme, the estimation accuracy of the velocity can be improved about 18 times better than that in the first scheme.

Weighted Sparseness-Based Anomaly Detection for Hyperspectral Imagery.

Anomaly detection of hyperspectral remote sensing data has recently become more attractive in hyperspectral image processing. The low-rank and sparse matrix decomposition-based anomaly detection algorithm (LRaSMD) exhibits poor detection performance in complex scenes with multiple background edges and noise. Therefore, this study proposes a weighted sparse hyperspectral anomaly detection method. First, using the idea of matrix decomposition in mathematics, the original hyperspectral data matrix is reconstructed into three sub-matrices with low rank, small sparsity and representing noise, respectively. Second, to suppress the noise interference in the complex background, we employed the low-rank, background image as a reference, built a local spectral and spatial dictionary through the sliding window strategy, reconstructed the HSI pixels of the original data, and extracted the sparse coefficient. We proposed the sparse coefficient divergence evaluation index (SCDI) as a weighting factor to weight the sparse anomaly map to obtain a significant anomaly map to suppress the background edge, noise, and other residues caused by decomposition, and enhance the abnormal target. Finally, abnormal pixels are segmented based on the adaptive threshold. The experimental results demonstrate that, on a real-scene hyperspectral dataset with a complicated background, the proposed method outperforms the existing representative algorithms in terms of detection performance.

Enhanced Detection Precision of the Taiji Program by Frequency Setting Strategy Based on a Hierarchical Optimization Algorithm.

For space-based gravitational wave detection, a laser interferometric measurement system composed of a three-spacecraft formation offers the most rewarding bandwidth of astrophysical sources. There are no oscillators available that are stable enough so that each spacecraft could use its own reference frequency. The conversion between reference frequencies and their distribution between all spacecrafts for the synchronization of the different metrology systems is the job of the inter-spacecraft frequency setting strategy, which is important for continuously acquiring scientific data and suppressing measurement noise. We propose a hierarchical optimization algorithm to solve the frequency setting strategy. The optimization objectives are minimum total readout displacement noise and maximum beat-note frequency feasible range. Multiple feasible parameter combinations were obtained for the Taiji program. These optimized parameters include lower and upper bounds of the beat note, sampling frequency, pilot tone signal frequency, ultrastable clock frequencies, and modulation depth. Among the 20 Pareto optimal solutions, the minimum total readout displacement noise was 4.12 pm/Hz, and the maximum feasible beat-note frequency range was 23 MHz. By adjusting the upper bound of beat-note frequency and laser power transmitted by the telescope, we explored the effects of these parameters on the minimum total readout displacement noise and optimal local laser power in greater depth. Our results may serve as a reference for the optimal design of laser interferometry system instrument parameters and may ultimately improve the detection performance and continuous detection time of the Taiji program.

Sex Differences and Temporal Trends in Hospitalization for Catheter Ablation of Nonvalvular Atrial Fibrillation: A Single-Center Experience for 15 Years.

Background: There exist sex differences in the clinical profile, management, and outcome of atrial fibrillation (AF). Catheter ablation of AF has become a first-line therapy and has markedly made headway over the recent decades. Little is known about sex differences and temporal trends in hospitalization for catheter ablation of AF in the real-world setting. Methods: We retrospectively retrieved medical records of patients at Beijing Anzhen Hospital between January 2005 and December 2019. The patients undergoing catheter ablation of AF were enrolled. Demographical and clinical data were compared between sexes. The temporal trends of sex differences were evaluated. Results: We identified 13502 male patients (66.8%) and 6713 female patients (33.2%). The number of patients undergoing AF ablation had remarkably increased over time, but no sex differences were observed (p=0.17). The median age of women was five years older than that of men (p < 0.001). The median time of in-hospital stay for the women decreased from 11 days to 4 days and for the men from 9 to 4 days. In-hospital mortality was 0.03% and 0.01% for women and men, respectively, with no significant difference between sexes. The women were more likely to have a comorbid diagnosis of hypertension and heart failure than men (p < 0.001). The CHA2DS2-VA score was higher in women than in men (1.64 vs. 1.28, p < 0.001). The temporal trend in the score increased in women from 1.17 to 1.81 (p < 0.001) and in men from 0.91 to 1.41 (p < 0.001). The percentage of patients with CHA2DS2-VA score ≥2 was higher in women than in men (49.8% vs. 35.8%, p < 0.001), and the temporal trend of this sex gap was nearly doubled (8.0% in 2005-2007 vs. 15.5% in 2017-2019, p=0.03). Conclusions: Safety of catheter ablation for AF was comparable in both sexes. In contrast, the women showed a higher CHA2DS2-VA score than men. The percentage of patients with CHA2DS2-VA score ≥2 increased more quickly in women than in men. Furthermore, sex-specific research is warranted to reduce this sex disparity.

Inter-spacecraft offset frequency setting strategy in the Taiji program.

For controlling the beat frequency of heterodyne interferometry so that the Taiji program can detect gravitational waves in space, an offset frequency setting strategy based on a linear programming algorithm is proposed. Considering factors such as Doppler frequency shift, phase-locking scheme, laser relative intensity noise, and phase detector bandwidth, inter-spacecraft offset frequency setting results suitable for the Taiji program are obtained. During the six years of running the detection process, the use of frequency bounds in the range of [5 MHz, 25 MHz] showed that offset frequencies will remain unchanged for a maximum of 1931 days. If the upper and lower bounds are adjusted, and the relative motion between spacecraft is further constrained, the offset frequencies do not need to change during the time of the mission. These results may provide insights into selecting the phase detector and designing operation parameters such as orbit and laser modulation frequency in the Taiji program.

Analgesic effect of nobiletin against neuropathic pain induced by the chronic constriction injury of the sciatic nerve in mice.

Neuropathic pain is chronic pain resulting from central or peripheral nerve damage that remains difficult to treat. Current evidence suggests that nobiletin, isolated from Citrus reticulata Blanco, possesses analgesic and neuroprotective effects. However, its effect on neuropathic pain has not been reported. This study evaluated the analgesic effect of nobiletin on neuropathic pain induced by chronic constriction injury (CCI) in mice. In vivo, mice were intragastrically administered with nobiletin (30, 60, 120 mg/kg) for eight consecutive days, respectively. Our study indicated that nobiletin ameliorated mechanical allodynia, cold allodynia and thermal hyperalgesia on CCI mice at doses that do not induce significant sedation. Moreover, nobiletin could ameliorate axonal and myelin injury of the sciatic nerve and further restore abnormal sciatic nerve electrical activity on CCI mice. In vitro studies indicated that nobiletin could suppress the proteins and mRNA expression of the IRF5/P2X4R/BDNF signalling pathway in fibronectin-induced BV2 cells. Overall, our results indicated that nobiletin might exert an analgesic effect on CCI-induced neuropathic pain in mice by inhibiting the IRF5/P2X4R/BDNF signalling pathway in spinal microglia. This study provided a novel potential therapeutic drug for neuropathic pain and new insights into the pharmacological action of nobiletin.

P53 suppresses the progression of hepatocellular carcinoma via miR-15a by decreasing OGT expression and EZH2 stabilization.

Existing literature has highlighted the tumour suppressive capacity of microRNA-15a (miR-15a); however, its role in hepatocellular carcinoma (HCC) remains relatively unknown. This study aimed to investigate the role of miR-15a in HCC and the associated underlying mechanism. Initially, RT-qPCR was performed to detect the expression of miR-15a in HCC tissues and cells. Bioinformatics analysis, Pearson correlation coefficient, dual-luciferase reporter assay, and molecular approaches were all conducted to ascertain the interaction between miR-15a and O-linked N-acetylglucosamine (GlcNAc) transferase (OGT). PUGNAc treatment and cycloheximide (CHX) assay were performed to evaluate O-GlcNAc and the stabilization of the enhancer of zeste homolog 2 (EZH2). Finally, gain- and loss-of-function studies were employed to elucidate the role of P53 and the miR-15a/OGT/EZH2 axis in the progression of HCC, followed by in vivo experiments based on tumour-bearing nude mice. Our results demonstrated that the miR-15a expression was decreased in the HCC tissues and cells. P53 upregulated miR-15a expression, which inhibited the proliferation, migration and invasion of HCC cells, while inducing apoptosis and triggering a G0/G1 cell cycle phase arrest. OGT stabilized EZH2 via catalysing O-GlcNAc, which reversed the effect of P53 and miR-15a. The results of our in vivo study provided evidence demonstrating that P53 could suppress the development of HCC via the miR-15a/OGT/EZH2 axis. P53 was found to inhibit the OGT expression by promoting the expression of miR-15a, which destabilized EZH2 and suppressed the development of HCC. The key findings of our study highlight a promising novel therapeutic strategy for the treatment of HCC.

Sex differences in the association between green tea consumption and hypertension in elderly Chinese adults.

BACKGROUND: Green tea has been one of the most popular beverages in China since ancient times. Mixed results concerning the effect of green tea consumption on the incidence of hypertension have been published over the past decades. However, no previous studies have focused on longevous individuals in China and the sex differences in the association between habitual green tea intake and hypertension. METHODS: The data extracted from the database of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2018 were used for a secondary analysis. Logistic regression models were employed to examine the odds ratio (OR) of daily green tea consumption on the incidence of hypertension by sex. RESULTS: A total of 9277 individuals were included in the analysis (39.8% were men). The included individuals had a mean age of 80.9 and 84.8 years for those who drank green tea daily and those who had never, respectively (p <  0.001). The incidence of hypertension varied at baseline according to green tea drinking habit and sex. For women who had a habitual green tea intake or had never drunk green tea, the incidence of hypertension was 47.3 and 43.9%, respectively (p = 0.241), whereas it was 51.6 and 39.7% for men (p <  0.001). After adjusting for potential confounders, a 38% increase in the risk of hypertension was observed in men who consumed green tea daily (OR, 1.38; 95% CI, 1.15-1.67; p <  0.001). CONCLUSIONS: Chinese longevous men had a 38% higher risk of developing hypertension when drinking green tea daily. However, no effect of green tea consumption on the incidence of hypertension in women was found. More attention should be paid to the lifestyle of longevous individuals for health promotion, and a sex-specific approach to deliver care for very elderly people is warranted.

MicroRNA-181a exerts anti-inflammatory effects via inhibition of the ERK pathway in mice with intervertebral disc degeneration.

Enzymatic decomposition of extracellular matrix and possibly local inflammation may cause intervertebral disc degeneration (IDD). MicroRNAs have been reported to correlate with the development of IDD. In this experiment, we aim at finding out the role of miR-181a in the inflammation of IDD and the underlying mechanism. The targeting relationship between miR-181a and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was verified. Following the establishment of IDD mouse models, disc height index (DHI) and the change of DHI (%DHI) were measured. The functional role of miR-181a in IDD was determined using ectopic expression and depletion and reporter assay experiments. Expression of miR-181a, TRAIL, extracellular signal-regulated kinase (ERK) pathway-related genes and inflammatory factors was evaluated. Also, the expression of collagen I and collagen II was observed. miR-181a directly targeted TRAIL. IDD mice exhibited significant degeneration of the intervertebral disc. miR-181a was downregulated while TRAIL was upregulated in mice with IDD. miR-181a upregulation and the ERK pathway inhibition could reduce expression of TRAIL, ERK pathway-related genes, inflammatory factors, and collagen I, but promote collagen II expression. Our results reveal that upregulation of miR-181a protects against inflammatory response by inactivating the ERK pathway via suppression of TRAIL in IDD mice. These results point to miR-181a as a potential therapeutic target for the clinical management of IDD.

Quercetin suppresses migration and invasion by targeting miR-146a/GATA6 axis in fibroblast-like synoviocytes of rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a systematic autoimmune disease which may lead to joint dysfunction and disability. Aberrant migration and invasion of fibroblast-like synoviocytes (FLSs) is one of the most predominant etiopathogenesis of RA. Quercetin is a bioflavonoid which is implicated in the development of RA, yet its role in regulating the migration and invasion of FLSs is still elusive. The aim of this study is to investigate the impact of quercetin treatment on migration and invasion of FLSs and the underlying mechanism.Methods: Capacity of migration and invasion of FLSs were assessed using transwell assay. Immunofluorescence assay was used to determine the expression of F-actin. The RNA levels of miR-146a and GATA transcription factor 6 (GATA6) were measured using quantitative real-time PCR. Western blot was used to examine the protein level of GATA6. The correlation between miR-146a and GATA6 was validated using luciferase reporter assay.Results: Transwell assay revealed that the migration and invasion of FLSs were significantly inhibited after quercetin treatment, which was also proved by decreased expression of F-actin. The RNA level of miR-146a was decreased in RA tissues and was negatively related to the expression of GATA transcription factor 6 (GATA6). Quercetin treatment elevated the RNA level of miR-146a, but suppressed the expression of GATA6 in FLSs. Further luciferase reporter assay validated that GATA6 is a downstream target of miR-146a. Besides, miR-146a inhibited the migration and invasion of FLSs, and further GATA6 over-expression abrogated the miR-146a-induced inhibition. In addition, specific anti-miR-146a inhibitor abolished quercetin-mediated suppression of migration and invasion of FLSs.Conclusion: Our study suggested that quercetin suppresses the migration and invasion of FLSs via regulating the miR-146a/GATA6 axis.

UAV Autonomous Tracking and Landing Based on Deep Reinforcement Learning Strategy.

Unmanned aerial vehicle (UAV) autonomous tracking and landing is playing an increasingly important role in military and civil applications. In particular, machine learning has been successfully introduced to robotics-related tasks. A novel UAV autonomous tracking and landing approach based on a deep reinforcement learning strategy is presented in this paper, with the aim of dealing with the UAV motion control problem in an unpredictable and harsh environment. Instead of building a prior model and inferring the landing actions based on heuristic rules, a model-free method based on a partially observable Markov decision process (POMDP) is proposed. In the POMDP model, the UAV automatically learns the landing maneuver by an end-to-end neural network, which combines the Deep Deterministic Policy Gradients (DDPG) algorithm and heuristic rules. A Modular Open Robots Simulation Engine (MORSE)-based reinforcement learning framework is designed and validated with a continuous UAV tracking and landing task on a randomly moving platform in high sensor noise and intermittent measurements. The simulation results show that when the moving platform is moving in different trajectories, the average landing success rate of the proposed algorithm is about 10% higher than that of the Proportional-Integral-Derivative (PID) method. As an indirect result, a state-of-the-art deep reinforcement learning-based UAV control method is validated, where the UAV can learn the optimal strategy of a continuously autonomous landing and perform properly in a simulation environment.

Study on the stabilization mechanisms of wet-milled cepharanthine nanosuspensions using systematical characterization.

Objectives: Stability issues are inevitable problems that are encountered in nanosuspension (NS) technology developments and in the industrial application of pharmaceuticals. This study aims to assess the stability of wet-milled cepharanthine NSs and elucidate the stabilization mechanisms of different stabilizers.Methods: The aggregation state was examined via scanning electron microscopy, laser diffraction, and rheometry. The zeta potential, stabilizer adsorption, surface tension, and drug-stabilizer interactions were employed to elucidate the stabilization mechanisms.Results: The results suggest that croscarmellose sodium (CCS), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), or polyvinyl pyrrolidone VA64 (PVP VA64) alone was able to prevent nanoparticle aggregation for at least 30 days. Attempts to evaluate the stability mechanisms of different stabilization systems revealed that CCS improved the steric-kinetic stabilization of the NSs, attributed to its high viscosity, swelling capacity, and physical barrier effects. In contrast, the excellent physical stability of TPGS systems was mainly due to the reduced surface tension and higher crystallinity. PVP VA64 can adsorb onto the surfaces of nanoparticles and stabilize the NS via steric forces.Conclusion: This study demonstrated the complex effects of CCS, TPGS, and PVP VA64 on cepharanthine NS stability and presented an approach for the rational design of stable NSs.

FOXC1 up-regulates the expression of toll-like receptors in myocardial ischaemia.

Myocardial ischaemia (MI) remains a major cause of death and disability worldwide. Accumulating evidence suggests a significant role for innate immunity, in which the family of toll-like receptors (TLRs) acts as an essential player. We previously reported and reviewed the changes of Tlr expression in models of MI. However, the underlying mechanisms regulating Tlr expression in MI remain unclear. The present study first screened transcription factors (TFs) that potentially regulate Tlr gene transcription based on in silico analyses followed by experimental verification, using both in vivo and in vitro models. Forkhead box C1 (FOXC1) was identified as a putative TF, which was highly responsive to MI. Next, by focusing on two representative TLR subtypes, an intracellular subtype TLR3 and a cell-surface subtype TLR4, the regulation of FOXC1 on Tlr expression was investigated. The overexpression or knockdown of FoxC1 was observed to up- or down-regulate Tlr3/4 mRNA and protein levels, respectively. A dual-luciferase assay showed that FOXC1 trans-activated Tlr3/4 promoter, and a ChIP assay showed direct binding of FOXC1 to Tlr3/4 promoter. Last, a functional study of FOXC1 was performed, which revealed the pro-inflammatory effects of FOXC1 and its destructive effects on infarct size and heart function in a mouse model of MI. The present study for the first time identified FOXC1 as a novel regulator of Tlr expression and described its function in MI.

Interleukin enhancement binding factor 3 inhibits cardiac hypertrophy by targeting asymmetric dimethylarginine-nitric oxide.

Persistent cardiac hypertrophy eventually leads to deterioration of heart function and changes to normal morphology. Decreased nitric oxide (NO) production plays a critical role in modulating cardiac hypertrophy. Interleukin enhancement binding factor 3 (ILF3), a member of the double-stranded RNA-binding protein family, is known to regulate the transcription and stability of mRNA. Therefore, the major aim of the present study was to determine the role of ILF3 in reduction of NO production in cardiac hypertrophy. Cardiac hypertrophy models of neonatal rat cardiomyocytes (NRCMs) and adult rats were induced by angiotensin II (Ang II) in this study. First, it was found that ILF3 expression, NO production, and nitric oxide synthase (NOS) activity was decreased in cultured cardiomyocytes and adult rats treated with Ang II, compared with NRCMs treated with vehicle and rats treated with saline infusion, respectively. These effects induced by Ang II were significantly exacerbated by specific ILF3 knockdown. Moreover, the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, was increased significantly in the Ang II-induced hypertrophic NRCMs and adult rats. Additionally, decreased protein expression and mRNA level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) were observed. Furthermore, specific ILF3 knockdown further aggravated these effects, but didn't reduce the expression level of NOS isoforms. In conclusion, our data show that ADMA accumulation-mediated decrease in NO production plays an important role in cardiomyocyte remodeling, which may be associated with ILF3-mediated DDAH1 reduction.