Modified mRNA as a Treatment for Myocardial Infarction.

Myocardial infarction (MI) is a severe disease with high mortality worldwide. However, regenerative approaches remain limited and with poor efficacy. The major difficulty during MI is the substantial loss of cardiomyocytes (CMs) with limited capacity to regenerate. As a result, for decades, researchers have been engaged in developing useful therapies for myocardial regeneration. Gene therapy is an emerging approach for promoting myocardial regeneration. Modified mRNA (modRNA) is a highly potential delivery vector for gene transfer with its properties of efficiency, non-immunogenicity, transiency, and relative safety. Here, we discuss the optimization of modRNA-based therapy, including gene modification and delivery vectors of modRNA. Moreover, the effective of modRNA in animal MI treatment is also discussed. We conclude that modRNA-based therapy with appropriate therapeutical genes can potentially treat MI by directly promoting proliferation and differentiation, inhibiting apoptosis of CMs, as well as enhancing paracrine effects in terms of promoting angiogenesis and inhibiting fibrosis in heart milieu. Finally, we summarize the current challenges of modRNA-based cardiac treatment and look forward to the future direction of such treatment for MI. Further advanced clinical trials incorporating more MI patients should be conducted in order for modRNA therapy to become practical and feasible in real-world treatment.

The Release of Cyclophilin A from Rapamycin-Stimulated Vascular Smooth Muscle Cells Mediated by Myosin II Activation: Involvement of Apoptosis but Not Autophagy.

INTRODUCTION: The exocytosis of cyclophilin A (CyPA) by a vesicular pathway in response to reactive oxygen species has been determined. However, other sources of extracellular CyPA remain obscure. OBJECTIVE: The aim of this study was to determine the role of autophagy in the secretion of CyPA. METHODS AND RESULTS: Rapamycin induced the activation of autophagy and release of CyPA from primary cultured rat aortic smooth muscle cells (RASMCs). However, inhibition of autophagy by knockdown of Atg7 or chloroquine did not affect the rapamycin-induced release of CyPA. With the exception of myosin II activity, rho-associated coiled-coil kinase (ROCK), actin remodelling, and synaptic vesicles were not implicated in the release of rapamycin-induced CyPA. Finally, we confirmed that rapamycin-induced extracellular CyPA originated from apoptotic RASMCs. Furthermore, the decreased activation of myosin II by blebbistatin blocked the release of CyPA from apoptotic RASMCs induced by rapamycin. CONCLUSIONS: Rapamycin induced the release of CyPA from apoptotic RASMCs but did not affect exocytosis through autophagosomes. ROCK, actin remodelling, and synaptic vesicles were not involved in the apoptosis-related release of CyPA. Myosin II activation modulated the apoptosis of vascular smooth muscle cells and the release of CyPA from rapamycin-induced apoptotic cell death.

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction.

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-ß-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.

Square-Root Unscented Information Filter and Its Application in SINS/DVL Integrated Navigation.

To address the problem of low accuracy for the regular filter algorithm in SINS/DVL integrated navigation, a square-root unscented information filter (SR-UIF) is presented in this paper. The proposed method: (1) adopts the state probability approximation instead of the Taylor model linearization in EKF algorithm to improve the accuracy of filtering estimation; (2) selects the most suitable parameter form at each filtering stage to simply the calculation complexity; (3) transforms the square root to ensure the symmetry and positive definiteness of the covariance matrix or information matrix, and then to enhance the stability of the filter. The simulation results indicate that the estimation accuracy of SR-UIF is higher than that of EKF, and similar to UKF; meanwhile the computational complexity of SR-UIF is lower than that of UKF.

A Model of Gravity Vector Measurement Noise for Estimating Accelerometer Bias in Gravity Disturbance Compensation.

Compensation of gravity disturbance can improve the precision of inertial navigation, but the effect of compensation will decrease due to the accelerometer bias, and estimation of the accelerometer bias is a crucial issue in gravity disturbance compensation. This paper first investigates the effect of accelerometer bias on gravity disturbance compensation, and the situation in which the accelerometer bias should be estimated is established. The accelerometer bias is estimated from the gravity vector measurement, and a model of measurement noise in gravity vector measurement is built. Based on this model, accelerometer bias is separated from the gravity vector measurement error by the method of least squares. Horizontal gravity disturbances are calculated through EGM2008 spherical harmonic model to build the simulation scene, and the simulation results indicate that precise estimations of the accelerometer bias can be obtained with the proposed method.

Strapdown Airborne Gravimetry Quality Assessment Method Based on Single Survey Line Data: A Study by SGA-WZ02 Gravimeter.

Quality assessment is an important part in the strapdown airborne gravimetry. Root mean square error (RMSE) evaluation method is a classical way to evaluate the gravimetry quality, but classical evaluation methods are preconditioned by extra flight or reference data. Thus, a method, which is able to largely conquer the premises of classical quality assessment methods and can be used in single survey line, has been developed in this paper. According to theoretical analysis, the method chooses the stability of two horizontal attitude angles, horizontal specific force and vertical specific force as the determinants of quality assessment method. The actual data, collected by SGA-WZ02 from 13 flights 21 lines in certain survey, was used to build the model and elaborate the method. To substantiate the performance of the quality assessment model, the model is applied in extra repeat line flights from two surveys. Compared with internal RMSE, standard deviation of assessment residuals are 0.23 mGal and 0.16 mGal in two surveys, which shows that the quality assessment method is reliable and stricter. The extra flights are not necessary by specially arranging the route of flights. The method, summarized from SGA-WZ02, is a feasible approach to assess gravimetry quality using single line data and is also suitable for other strapdown gravimeters.

Compensation of Horizontal Gravity Disturbances for High Precision Inertial Navigation.

Horizontal gravity disturbances are an important factor that affects the accuracy of inertial navigation systems in long-duration ship navigation. In this paper, from the perspective of the coordinate system and vector calculation, the effects of horizontal gravity disturbance on the initial alignment and navigation calculation are simultaneously analyzed. Horizontal gravity disturbances cause the navigation coordinate frame built in initial alignment to not be consistent with the navigation coordinate frame in which the navigation calculation is implemented. The mismatching of coordinate frame violates the vector calculation law, which will have an adverse effect on the precision of the inertial navigation system. To address this issue, two compensation methods suitable for two different navigation coordinate frames are proposed, one of the methods implements the compensation in velocity calculation, and the other does the compensation in attitude calculation. Finally, simulations and ship navigation experiments confirm the effectiveness of the proposed methods.

Improving the Strapdown Airborne Vector Gravimetry by a Backward Inertial Navigation Algorithm.

Strapdown airborne gravimetry is an efficient way to obtain gravity field data. A new method has been developed to improve the accuracy of airborne vector gravimetry. The method introduces a backward strapdown navigation algorithm into the strapdown gravimetry, which is the reverse process of forward algorithm. Compared with the forward algorithm, the backward algorithm has the same performance in the condition of no sensor error, but has different error characteristics in actual conditions. The differences of the two algorithms in the strapdown gravimetry data processing are presented by simulations, which show that the two algorithms have different performance in the horizontal attitude measurement and convergence of integrated navigation filter. On the basis of detailed analysis, the procedures of accuracy improvement method are presented. The result of this method is very promising when applying to an actual flight test carried out by a SGA-WZ02 strapdown gravimeter. After applying the proposed method, the repeatability of two gravity disturbance horizontal components were 1.83 mGal and 1.80 mGal under the resolution of 6 km, which validate the effectiveness of the method. Furthermore, the wavenumber correlation filter is also discussed as an alternative data fusion method.

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.

PURPOSE: Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). METHODS: Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. RESULTS: We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFß-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). CONCLUSIONS: Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.

New Matching Method for Accelerometers in Gravity Gradiometer.

The gravity gradiometer is widely used in mineral prospecting, including in the exploration of mineral, oil and gas deposits. The mismatch of accelerometers adversely affects the measuring precision of rotating accelerometer-based gravity gradiometers. Several strategies have been investigated to address the imbalance of accelerometers in gradiometers. These strategies, however, complicate gradiometer structures because feedback loops and re-designed accelerometers are needed in these strategies. In this paper, we present a novel matching method, which is based on a new configuration of accelerometers in a gravity gradiometer. In the new configuration, an angle was introduced between the measurement direction of the accelerometer and the spin direction. With the introduced angle, accelerometers could measure the centrifugal acceleration generated by the rotating disc. Matching was realized by updating the scale factors of the accelerometers with the help of centrifugal acceleration. Further simulation computations showed that after adopting the new matching method, signal-to-noise ratio improved from -41 dB to 22 dB. Compared with other matching methods, our method is more flexible and costs less. The matching accuracy of this new method is similar to that of other methods. Our method provides a new idea for matching methods in gravity gradiometer measurement.

A New Method for Land Vehicle Gravimetry Using SINS/VEL.

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Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of ß2-AR/PI3K/AKT signaling pathway.

Cardiomyocyte apoptosis contributes to ischemic cardiac injury and the development of heart failure. Higenamine is a key component of the Chinese herb aconite root that has been prescribed for treating symptoms of heart failure for thousands of years in the oriental Asian countries. It has been shown that higenamine has anti-apoptotic effects in a few cell types including cardiomyocytes. However, the pharmacological target and molecular mechanism of higenamine in the heart are still not fully illustrated. Herein, we report that higenamine protected myocyte apoptosis and ischemia/reperfusion (I/R) injury through selective activation of beta2-adrenergic receptor (ß2-AR). In particular, we show that higenamine significantly reduced I/R-induced myocardial infarction in mice. In both primary neonatal rat and adult mouse ventricular myocytes, we show higenamine inhibited cell apoptosis and also reduced biochemical markers of apoptosis such as cleaved caspase 3 and 9. More importantly, we show that the anti-apoptotic effects of higenamine in cardiomyocytes were completely abolished by ß2-AR but not ß1-AR antagonism. Furthermore, we confirmed that higenamine attenuated I/R-induced myocardial injury and reduced cleaved caspases in a ß2-AR dependent manner in intact mouse hearts. Higenamine stimulated AKT phosphorylation and required PI3K activation for the anti-apoptotic effect in cardiomyocytes. These findings together suggest that anti-apoptotic and cardiac protective effects of higenamine are mediated by the ß2-AR/PI3K/AKT cascade.

An SINS/GNSS Ground Vehicle Gravimetry Test Based on SGA-WZ02.

In March 2015, a ground vehicle gravimetry test was implemented in eastern Changsha to assess the repeatability and accuracy of ground vehicle SINS/GNSS gravimeter-SGA-WZ02. The gravity system developed by NUDT consisted of a Strapdown Inertial Navigation System (SINS), a Global Navigation Satellite System (GNSS) remote station on test vehicle, a GNSS static master station on the ground, and a data logging subsystem. A south-north profile of 35 km along the highway in eastern Changsha was chosen and four repeated available measure lines were obtained. The average speed of a vehicle is 40 km/h. To assess the external ground gravity disturbances, precise ground gravity data was built by CG-5 precise gravimeter as the reference. Under relative smooth conditions, internal accuracy among repeated lines shows an average agreement at the level of 1.86 mGal for half wavelengths about 1.1 km, and 1.22 mGal for 1.7 km. The root-mean-square (RMS) of difference between calculated gravity data and reference data is about 2.27 mGal/1.1 km, and 1.74 mGal/1.7 km. Not all of the noises caused by vehicle itself and experiments environments were eliminated in the primary results. By means of selecting reasonable filters and improving the GNSS observation conditions, further developments in ground vehicle gravimetry are promising.

Optimized Design of the SGA-WZ Strapdown Airborne Gravimeter Temperature Control System.

The temperature control system is one of the most important subsystems of the strapdown airborne gravimeter. Because the quartz flexible accelerometer based on springy support technology is the core sensor in the strapdown airborne gravimeter and the magnet steel in the electromagnetic force equilibrium circuits of the quartz flexible accelerometer is greatly affected by temperature, in order to guarantee the temperature control precision and minimize the effect of temperature on the gravimeter, the SGA-WZ temperature control system adopts a three-level control method. Based on the design experience of the SGA-WZ-01, the SGA-WZ-02 temperature control system came out with a further optimized design. In 1st level temperature control, thermoelectric cooler is used to conquer temperature change caused by hot weather. The experiments show that the optimized stability of 1st level temperature control is about 0.1 °C and the max cool down capability is about 10 °C. The temperature field is analyzed in the 2nd and 3rd level temperature control using the finite element analysis software ANSYS. The 2nd and 3rd level temperature control optimization scheme is based on the foundation of heat analysis. The experimental results show that static accuracy of SGA-WZ-02 reaches 0.21 mGal/24 h, with internal accuracy being 0.743 mGal/4.8 km and external accuracy being 0.37 mGal/4.8 km compared with the result of the GT-2A, whose internal precision is superior to 1 mGal/4.8 km and all of them are better than those in SGA-WZ-01.

A Flight Test of the Strapdown Airborne Gravimeter SGA-WZ in Greenland.

An airborne gravimeter is one of the most important tools for gravity data collection over large areas with mGal accuracy and a spatial resolution of several kilometers. In August 2012, a flight test was carried out to determine the feasibility and to assess the accuracy of the new Chinese SGA-WZ strapdown airborne gravimeter in Greenland, in an area with good gravity coverage from earlier marine and airborne surveys. An overview of this new system SGA-WZ is given, including system design, sensor performance and data processing. The processing of the SGA-WZ includes a 160 s length finite impulse response filter, corresponding to a spatial resolution of 6 km. For the primary repeated line, a mean r.m.s. deviation of the differences was less than 1.5 mGal, with the error estimate confirmed from ground truth data. This implies that the SGA-WZ could meet standard geophysical survey requirements at the 1 mGal level.

Experimental investigations on airborne gravimetry based on compressed sensing.

Gravity surveys are an important research topic in geophysics and geodynamics. This paper investigates a method for high accuracy large scale gravity anomaly data reconstruction. Based on the airborne gravimetry technology, a flight test was carried out in China with the strap-down airborne gravimeter (SGA-WZ) developed by the Laboratory of Inertial Technology of the National University of Defense Technology. Taking into account the sparsity of airborne gravimetry by the discrete Fourier transform (DFT), this paper proposes a method for gravity anomaly data reconstruction using the theory of compressed sensing (CS). The gravity anomaly data reconstruction is an ill-posed inverse problem, which can be transformed into a sparse optimization problem. This paper uses the zero-norm as the objective function and presents a greedy algorithm called Orthogonal Matching Pursuit (OMP) to solve the corresponding minimization problem. The test results have revealed that the compressed sampling rate is approximately 14%, the standard deviation of the reconstruction error by OMP is 0.03 mGal and the signal-to-noise ratio (SNR) is 56.48 dB. In contrast, the standard deviation of the reconstruction error by the existing nearest-interpolation method (NIPM) is 0.15 mGal and the SNR is 42.29 dB. These results have shown that the OMP algorithm can reconstruct the gravity anomaly data with higher accuracy and fewer measurements.

The inertial attitude augmentation for ambiguity resolution in SF/SE-GNSS attitude determination.

The Unaided Single Frequency/Single Epoch Global Navigation Satellite System (SF/SE GNSS) model is the most challenging scenario for ambiguity resolution in the GNSS attitude determination application. To improve the performance of SF/SE-GNSS ambiguity resolution without excessive cost, the Micro-Electro-Mechanical System Inertial Measurement Unit (MEMS-IMU) is a proper choice for the auxiliary sensor that carries out the inertial attitude augmentation. Firstly, based on the SF/SE-GNSS compass model, the Inertial Derived Baseline Vector (IDBV) is defined to connect the MEMS-IMU attitude measurement with the SF/SE-GNSS ambiguity search space, and the mechanism of inertial attitude augmentation is revealed from the perspective of geometry. Then, through the quantitative description of model strength by Ambiguity Dilution of Precision (ADOP), two ADOPs are specified for the unaided SF/SE-GNSS compass model and its inertial attitude augmentation counterparts, respectively, and a sufficient condition is proposed for augmenting the SF/SE-GNSS model strength with inertial attitude measurement. Finally, in the framework of an integer aperture estimator with fixed failure rate, the performance of SF/SE-GNSS ambiguity resolution with inertial attitude augmentation is analyzed when the model strength is varying from strong to weak. The simulation results show that, in the SF/SE-GNSS attitude determination application, MEMS-IMU can satisfy the requirements of ambiguity resolution with inertial attitude augmentation.

In Situ Polymerized Self-Healing Microcapsules as Multifunctional Fillers toward Phosphate Ceramic Coatings.

The protective efficacy of chemically bonded phosphate ceramic coatings (CBPC) is notably diminished owing to the presence of micropores and inadequate self-healing capacity in prolonged corrosive environments. Consequently, it is imperative to augment the corrosion and wear resistance of phosphate ceramic coatings while imbuing them with self-healing capabilities. In this work, a novel self-healing phosphate ceramic coating (MC-PTx@CBPC, x = 0.5, 1.0, 1.5) is designed by urea-formaldehyde (UF) in situ polymerization of nanoscale microcapsules encapsulated with 1H,1H,2H,2H-perfluorodecyltriethoxysilane (PFDTES) and evaluated in detail for corrosion and wear resistance. The corrosion inhibition efficiencies of all formulated MC-PTx@CBPC (x = 0.5, 1.0, 1.5) coatings exceed 90%, with the impedance modulus at the lowest frequency (|Z|f=0.01) showing enhancements of 1-2 orders of magnitude compared to pure CBPC. Moreover, the self-healing function becomes active during prolonged immersion. This can be primarily ascribed to the formation of a unique micronanostructure facilitated by nanoscale microcapsules and micrometer-sized alumina ceramics, bonded via the AlPO4 phase. This structure enhances both the hydrophobicity and the bonding strength of the coating. Specifically, following prolonged immersion, the encapsulated PFDTES is liberated from the microcapsules, undergoing hydrolysis and subsequent polymerization upon contact with the electrolyte to form a protective thin film. This film efficiently obstructs the ingress of corrosive agents. Furthermore, the special micronanostructure enhances the hardness of the coating and the releasing PFDTES can form a lubricating film at the interface of abrasion, thus reducing the wear rate and friction coefficient of the MC-PTx@CBPC (x = 0.5, 1.0, 1.5). Therefore, MC-PTx@CBPC (x = 0.5, 1.0, 1.5) possesses excellent corrosion protection, tribological properties, and self-healing capabilities, which provide thought-provoking ideas for phosphate ceramic coatings to protect metals in harsh environments.

Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia-reperfusion injury.

Phosphodiesterase 3A (PDE3A) is a major regulator of cAMP in cardiomyocytes. PDE3 inhibitors are used for acute treatment of congestive heart failure, but are associated with increased incidence of arrhythmias and sudden death with long-term use. We previously reported that chronic PDE3A downregulation or inhibition induced myocyte apoptosis in vitro. However, the cardiac protective effect of PDE3A has not been demonstrated in vivo in disease models. In this study, we examined the role of PDE3A in regulating myocardial function and survival in vivo using genetically engineered transgenic mice with myocardial overexpression of the PDE3A1 isozyme (TG). TG mice have reduced cardiac function characterized by reduced heart rate and ejection fraction (52.5±7.8% vs. 83.9±4.7%) as well as compensatory expansion of left ventricular diameter (4.19±0.19mm vs. 3.10±0.18mm). However, there was no maladaptive increase of fibrosis and apoptosis in TG hearts compared to wild type (WT) hearts, and the survival rates also remained the same. The diminution of cardiac contractile function is very likely attributed to a decrease in beta-adrenergic receptor (ß-AR) response in TG mice. Importantly, the myocardial infarct size (4.0±1.8% vs. 24.6±3.8%) and apoptotic cell number (1.3±1.0% vs. 5.6±1.5%) induced by ischemia/reperfusion (I/R) injury were significantly attenuated in TG mice. This was associated with decreased expression of inducible cAMP early repressor (ICER) and increased expression of anti-apoptotic protein BCL-2. To further verify the anti-apoptotic effects of PDE3A1, we performed in vitro apoptosis study in isolated adult TG and WT cardiomyocytes. We found that the apoptotic rates stimulated by hypoxia/reoxygenation or H2O2 were indeed significantly reduced in TG myocytes, and the differences between TG and WT myocytes were completely reversed in the presence of the PDE3 inhibitor milrinone. These together indicate that PDE3A1 negatively regulates ß-AR signaling and protects against I/R injury by inhibiting cardiomyocyte apoptosis.