Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition.

Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.

Estimation of Muscle Forces of Lower Limbs Based on CNN-LSTM Neural Network and Wearable Sensor System.

Estimation of vivo muscle forces during human motion is important for understanding human motion control mechanisms and joint mechanics. This paper combined the advantages of the convolutional neural network (CNN) and long-short-term memory (LSTM) and proposed a novel muscle force estimation method based on CNN-LSTM. A wearable sensor system was also developed to collect the angles and angular velocities of the hip, knee, and ankle joints in the sagittal plane during walking, and the collected kinematic data were used as the input for the neural network model. In this paper, the muscle forces calculated using OpenSim based on the Static Optimization (SO) method were used as the standard value to train the neural network model. Four lower limb muscles of the left leg, including gluteus maximus (GM), rectus femoris (RF), gastrocnemius (GAST), and soleus (SOL), were selected as the studying objects in this paper. The experiment results showed that compared to the standard CNN and the standard LSTM, the CNN-LSTM performed better in muscle forces estimation under slow (1.2 m/s), medium (1.5 m/s), and fast walking speeds (1.8 m/s). The average correlation coefficients between true and estimated values of four muscle forces under slow, medium, and fast walking speeds were 0.9801, 0.9829, and 0.9809, respectively. The average correlation coefficients had smaller fluctuations under different walking speeds, which indicated that the model had good robustness. The external testing experiment showed that the CNN-LSTM also had good generalization. The model performed well when the estimated object was not included in the training sample. This article proposed a convenient method for estimating muscle forces, which could provide theoretical assistance for the quantitative analysis of human motion and muscle injury. The method has established the relationship between joint kinematic signals and muscle forces during walking based on a neural network model; compared to the SO method to calculate muscle forces in OpenSim, it is more convenient and efficient in clinical analysis or engineering applications.

A Novel Gait Phase Recognition Method Based on DPF-LSTM-CNN Using Wearable Inertial Sensors.

Gait phase recognition is of great importance in the development of rehabilitation devices. The advantages of Long Short-Term Memory (LSTM) and Convolutional Neural Network (CNN) are combined (LSTM-CNN) in this paper, then a gait phase recognition method based on LSTM-CNN neural network model is proposed. In the LSTM-CNN model, the LSTM layer is used to process temporal sequences and the CNN layer is used to extract features A wireless sensor system including six inertial measurement units (IMU) fixed on the six positions of the lower limbs was developed. The difference in the gait recognition performance of the LSTM-CNN model was estimated using different groups of input data collected by seven different IMU grouping methods. Four phases in a complete gait were considered in this paper including the supporting phase with the right hill strike (SU-RHS), left leg swimming phase (SW-L), the supporting phase with the left hill strike (SU-LHS), and right leg swimming phase (SW-R). The results show that the best performance of the model in gait recognition appeared based on the group of data from all the six IMUs, with the recognition precision and macro-F1 unto 95.03% and 95.29%, respectively. At the same time, the best phase recognition accuracy for SU-RHS and SW-R appeared and up to 96.49% and 95.64%, respectively. The results also showed the best phase recognition accuracy (97.22%) for SW-L was acquired based on the group of data from four IMUs located at the left and right thighs and shanks. Comparably, the best phase recognition accuracy (97.86%) for SU-LHS was acquired based on the group of data from four IMUs located at left and right shanks and feet. Ulteriorly, a novel gait recognition method based on Data Pre-Filtering Long Short-Term Memory and Convolutional Neural Network (DPF-LSTM-CNN) model was proposed and its performance for gait phase recognition was evaluated. The experiment results showed that the recognition accuracy reached 97.21%, which was the highest compared to Deep convolutional neural networks (DCNN) and CNN-LSTM.

Analysis of Ankle Muscle Dynamics during the STS Process Based on Wearable Sensors.

Ankle joint moment is an important indicator for evaluating the stability of the human body during the sit-to-stand (STS) movement, so a method to analyze ankle joint moment is needed. In this study, a wearable sensor system that could derive surface-electromyography (sEMG) signals and kinematic signals on the lower limbs was developed for non-invasive estimation of ankle muscle dynamics during the STS movement. Based on the established ankle joint musculoskeletal information and sEMG signals, ankle joint moment during the STS movement was calculated. In addition, based on a four-segment STS dynamic model and kinematic signals, ankle joint moment during the STS movement was calculated using the inverse dynamics method. Ten healthy young people participated in the experiment, who wore a self-developed wearable sensor system and performed STS movements as an experimental task. The results showed that there was a high correlation (all R ≥ 0.88) between the results of the two methods for estimating ankle joint moment. The research in this paper can provide theoretical support for the development of an intelligent bionic joint actuator and clinical rehabilitation evaluation.

Synthesis of 1,3,5-trisubstituted pyrazoles via 1,3-dipolar cycloaddition of nitrile imines with ninhydrin-derived Morita-Baylis-Hillman carbonates.

An effective synthetic method for 1,3,5-trisubstituted pyrazoles via 1,3-dipolar cycloaddition reaction has been developed. This reaction could smoothly proceed between ninhydrin-derived Morita-Baylis-Hillman carbonates and nitrilimines to provide a wide scope of differently substituted pyrazoles in high yields (up to 95%). In addition, the reaction mechanism was also proposed to explain its regioselectivity.

High-efficiency photocatalytic H2-evolution in water/seawater over a novel noble metal free Ni3C/Mn0.5Cd0.5S Schottky junction.

Solar-powered seawater production of clean hydrogen fuel is highly prospective. In this work, Ni3C/Mn0.5Cd0.5S (NCMCS) Schottky junctions with excellent visible-light correspondence and photogenerated carrier separation properties are constructed using electrostatic attraction. The material achieves a hydrogen evolution rate of 6472.9 µmol h-1 g-1 in simulated seawater, which is 11 times higher than that of a single Mn0.5Cd0.5S (MCS). More attractively, the composite exhibits excellent hydrogen evolution rates in natural river water, groundwater and tap water, with significantly enhanced practical applicability. The underlying hydrogen evolution mechanism was extrapolated from a combination of experimental and theoretical calculations. The present work provides a low-cost and efficient hydrogen evolution photocatalyst for practical application, which can help promote the efficient conversion of solar-hydrogen energy.

Design and Optimization of an Adaptive Knee Joint Orthosis for Biomimetic Motion Rehabilitation Assistance.

In this paper, an adaptive knee joint orthosis with a variable rotation center for biomimetic motion rehabilitation assistance suitable for patients with knee joint movement dysfunction is designed. Based on the kinematic information of knee joint motion obtained by a motion capture system, a Revolute-Prismatic-Revolute (RPR) model is established to simulate the biomimetic motion of the knee joint, then a corresponding implementation for repetitively driving the flexion-extension motion of the knee joint, mainly assembled by a double-cam meshing mechanism, is designed. The pitch curve of each cam is calculated based on the screw theory. During the design process, size optimization is used to reduce the weight of the equipment, resulting in a reduction from 1.96 kg to 1.16 kg, achieving the goal of lightweight equipment. Finally, a prototype of the designed orthosis with the desired biomimetic rotation function is prepared and verified. The result shows that the rotation center of the prototype can achieve biomimetic motion coincident with the rotation center of an active knee joint, which can successfully provide rehabilitation assistance for the knee joint flexion-extension motion.

Biomechanical Evaluation of 2 Endoscopic Spine Surgery Methods for Treating Lumbar Disc Herniation: A Finite Element Study.

OBJECTIVE: This study aimed to evaluate the effects of 2 endoscopic spine surgeries on the biomechanical properties of normal and osteoporotic spines. METHODS: Based on computed tomography images of a healthy adult volunteer, 6 finite element models were created. After validating the normal intact model, a concentrated force of 400 N and a moment of 7.5 Nm were exerted on the upper surface of L3 to simulate 6 physiological activities of the spine. Five types of indices were used to assess the biomechanical properties of the 6 models, range of motion (ROM), maximum displacement value, intervertebral disc stress, maximum stress value, and articular protrusion stress, and by combining them with finite element stress cloud. RESULTS: In normal and osteoporotic spines, there was no meaningful change in ROM or disc stress in the 2 surgical models for the 6 motion states. Model N1 (osteoporotic percutaneous transforaminal endoscopic discectomy model) showed a decrease in maximum displacement value of 20.28% in right lateral bending. Model M2 (unilateral biportal endoscopic model) increased maximum displacement values of 16.88% and 17.82% during left and right lateral bending, respectively. The maximum stress value of L4-5 increased by 11.72% for model M2 during left rotation. In addition, using the same surgical approach, ROM, maximum displacement values, disc stress, and maximum stress values were more significant in the osteoporotic model than in the normal model. CONCLUSION: In both normal and osteoporotic spines, both surgical approaches were less disruptive to the physiologic structure of the spine. Furthermore, using the same endoscopic spine surgery, normal spine biomechanical properties are superior to osteoporotic spines.

Effects of high quality nursing in patients with lung cancer undergoing chemotherapy and related influence on self-care ability and pulmonary function.

OBJECTIVE: To explore the effects of high quality nursing in patients with lung cancer undergoing chemotherapy and related influence on self-care ability and pulmonary function. METHODS: 108 patients with lung cancer were grouped as the control group (54 cases, received routine nursing) and the observation group (54 cases, received high quality nursing including health education, psychological nursing, diet intervention, pain nursing and complication nursing). The psychology, self-care ability, pulmonary function, quality of life and complications before and after the intervention were compared. RESULTS: After 2 months of intervention, peak expiratory flow (PEF), percentage of forced vital capacity (FVC%) and the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of the two groups were all largely increased, and the observation group had even higher indexes than the control group (all P<0.05). Compared with before intervention, Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) scores of the two groups both decreased after 2 months of intervention, and the observation group had lower score than the control group. The score of Exercise of Self-care Agency (ESCA) Scale and the quality of life questionnaire-C30 formulated by the European Organization for research and treatment of cancer (EORTC QLQ-C30) in the two groups were both elevated after the intervention and the observation group had higher scores than the control group (all P<0.05). The observation group had much lower total incidence of adverse reactions than the control group during chemotherapy (P<0.05). CONCLUSION: High quality nursing for patients with lung cancer undergoing chemotherapy effectively alleviates the bad mood and improves the quality of life and lung function, which is worthy of clinical application.

Ultra performance liquid chromatography-tandem mass spectrometry assay for the quantification of RNA and DNA methylation.

Previous studies have reported that nucleic acid methylation is a critical element in cardiovascular disease, and most studies mainly focused on sequencing and biochemical research. Here we developed an Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/ MS) method for the quantification analysis of the dissociative epigenetic modified nucleosides (5mdC, 5mrC, m6A) in Myocardial Infarction (MI) SD rats from different periods (1 week, 4 weeks, 8 weeks) after the surgery. The samples for analysis were obtained from heart tissue and blood of the rats. All the quantification results are compared with the sham-operated group. Total RNA and DNA were isolated by enzymatic hydrolytic methods before the UPLC-MS/MS analysis. The statistical analysis demonstrates the dynamic changes of modified nucleosides in MI rats, and it showed good specificity, accuracy, stability and less samples were needed in the method. In this paper, we discovered that the concentration of 5mdC, 5mrC, m6A from heart tissue significantly increased at 8 weeks after the surgery. Furthermore, UPLC-MS/MS helps us observe the similar change of the concentration of those 3 methylated biomarkers in peripheral blood after 8 weeks. The result shows that the dynamic process of those 3 methylated biomarkers in peripheral blood is related to the content of methylated biomarkers from the heart tissue. Based on the scientific evidence available, we proved that the methylation of genetic materials in peripheral blood is similar to myocardial infarction tissue. The relation between them indicates that peripheral blood could be a promising alternative to the heart tissue which monitor the level of methylation and MI diagnosis-aided.

Quantum chemistry investigation on the reaction mechanism of the elemental mercury, chlorine, bromine and ozone system.

Ab initio calculations were performed to study the quantum chemistry reactions mechanisms among Hg(0), elemental halogen and O3. The geometry of reactions, transition states (TS), intermediates (M) and products were optimized using the MP2 method at the SDD basis function level for Hg, and using 6-311++G (3df, 3pd) for other species. Molecular energies were calculated at QCISD (T) level with zero point energy. Activation energies were calculated along with pre-exponential factors . The reaction rate constants within 298-1800 K were calculated according to transition state theory (TST). The influences of O3 on the reaction of Hg(0) with halogen are discussed. Hg(0) can be oxidized to Hg(1+) by halogen and O3, and halogen and O3 can be arranged in decreasing order as: Br2 > BrO > O3 > Br > Cl, BrCl > HBr > HCl, Br2 > Cl2 according to reaction rate constants. When O3 is presented, Br2, HBr, BrCl, Cl2 and HCl react with O3 and are initially converted to BrO and ClO. O3 is unfavorable for oxidation of Hg(0) by Br2. The mixture of HBr and O3 has better oxidizing Hg(0) performance than HBr and O3. Cl is less effective than Br for oxidation of Hg(0).

Novel numerical characterization of protein sequences based on individual amino acid and its application.

The hydrophobicity and hydrophilicity of amino acids play a very important role in protein folding and its interaction with the environment and other molecules, as well as its catalytic mechanism. Based on the two physicochemical indexes, a 2D graphical representation of protein sequences is introduced; meanwhile, a new numerical characteristic has been proposed to compute the distance of different sequences for analysis of sequence similarity/dissimilarity on the basis of this graphical representation. Furthermore, we apply the new distance in the similarities/dissimilarities of ND5 proteins of nine species and predict the four major classes based on the dataset containing 639 domains. The results show that the method is simple and effective.

Cu(2+) inhibition of glycine-activated currents in rat sacral dorsal commissural neurons.

The effect of Cu(2+) on glycine (Gly) response was examined in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin perforated patch clamp recording configuration under voltage-clamp conditions. Cu(2+), in the concentration range 10-1000 microM, reversibly inhibited chloride current activated by 30 microM Gly at a holding potential of -40 mV with an IC(50) of 88.4 microM. Cu(2+) shifted the Gly concentration response curve to the right in a parallel manner, which indicated that Cu(2+) decreased the apparent affinity of the receptor for Gly. Cu(2+) suppression of Gly-activated current was independent of membrane potential between -60 and +60 mV and did not involve a shift in the reversal potential of the current. Furthermore, Cu(2+) antagonized the inhibitory action of Zn(2+) in a concentration-dependent manner, suggesting a common site or mechanism of action of Cu(2+) and Zn(2+) on Gly receptors. The results show that Cu(2+) is a potent inhibitor of Gly receptor-mediated responses in rat spinal neurons.

Postnatal changes in the overall postsynaptic currents evoked in CA1 pyramidal neurons of the rat hippocampus.

Evoked fast postsynaptic currents (fPSCs) during the postnatal development of rats (postnatal day 6-70, P6-P70) were systematically examined in hippocampal CA1 pyramidal neurons using whole-cell recordings with biocytin-filled electrodes. Focal stimulation of the stratum radiatum in the CA1 region elicited fPSCs in 80% of the neurons P6-7, 90% of P9-10, and 100% of > or =P11. In neurons P6-7, the fPSCs were exclusively inward and had multiple (on average 5.6) peaks. The fPSCs increased in amplitude with the growth of dendritic arborization, but decreased in the number of peaks. A distinct outward fPSC following the inward fPSC emerged in neurons > or =P11 and was abolished by bicuculline (50 microM). Bicuculline increased the amplitude and duration of the initial inward fPSC (fEPSC) in all age groups and characteristically recruited the polysynaptic second component of fEPSCs in neurons P11-P21. No spontaneous periodic inward current was detected in any age group after blocking GABAA receptors. The coapplication of DL-2-amino-5-phosphonopentanoic acid (AP5, 100 microM) with bicuculline did not eliminate the polysynaptic second component, but the second component was only elicited in slices in which the CA3 region was kept intact. Moreover, the bicuculline- and AP5-resistant second component was due to the burst activity of CA3 pyramidal neurons, which were excited through excitatory recurrents of the Schaffer collaterals. Plausible physiological functions of the generation of the second component in vivo were discussed.

Cu2+ suppresses GABA(A) receptor-mediated responses in rat sacral dorsal commissural neurons.

The effect of copper ions (Cu(2+)) on gamma-aminobutyric acid (GABA)-induced responses in acutely dissociated neurons from the rat sacral dorsal commissural nucleus (SDCN) was investigated using a nystatin-perforated patch recording configuration under voltage clamp conditions. The application of Cu(2+) to SDCN neurons reversibly suppressed the GABA (10 microM)-activated Cl(-) current (I(GABA)) in a concentration-dependent manner (1-1000 microM; IC(50) = 24.5 microM). In the presence of Cu(2+) (30 microM), the concentration-response curve of GABA was shifted rightward without reducing I(GABA) recorded under the maximally effective concentration of GABA, thus indicating a dependence of Cu(2+) action on GABA concentration. Inhibition of GABA (10 microM) responses by 30 microM Cu(2+) was essentially voltage independent and was not accompanied by a shift in the reversal potential of the currents. Cu(2+) antagonized the suppressive effect of Zn(2+) in a concentration-dependent manner, suggesting competition between Cu(2+) and Zn(2+) for similar binding sites. These data demonstrate that Cu(2+) is a potent inhibitor of GABA(A) receptor-mediated responses, implying a possible modulatory effect of Cu(2+) on GABAergic synaptic transmission in the mammalian SDCN.

Beta-alanine acts on glycine receptors in the rat sacral dorsal commissural neurons.

Whole-cell current responses to bath application of beta-alanine (beta-ALA) were investigated in neurons acutely dissociated from the rat sacra! dorsal commissural nucleus (SDCN) using the nystatin perforated patch recording configuration under voltage-clamp conditions. beta-ALA activated inward currents in a concentration-dependent manner over the range of 10-3000 microM with an EC50 of 80.8 microM. The reversal potential of beta-ALA-activated currents (I beta-ALA) was close to the Cl- equilibrium potential. Strychnine and the chloride channel blocker picrotoxin suppressed the I beta-ALA in a concentration-dependent manner with the IC50 values of 0.19 microM and 343.6 microM, respectively. At the concentration of 3 microM, strychnine was sufficient to completely block 100 microM beta-ALA response, whereas it did not show a suppression of GABA response. In contrast, bicuculline, a potent GABAA receptor antagonist, at concentrations up to 10 microM, a dose that could block the GABA response completely, had little or no effect on I beta-ALA. Furthermore, the I beta-ALA was not affected by a preceding GABA response, but rather cross-desensitized with that evoked by glycine. The results indicate that beta-ALA activates the strychnine-sensitive glycine receptors in the SDCN neurons, and suggest that beta-ALA may act as a functional neurotransmitter in the mammalian SDCN.

Suppression of kainate-evoked AMPA receptor mediated responses by lanthanum in rat sacral dorsal commissural neurons.

The effect of lanthanum (La) on kainate (KA) responses in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) was investigated using the nystatin-perforated patch-recording configuration under voltage-clamp conditions. The responses to KA were mediated by activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in SDCN neurons. La(3+) reversibly inhibited KA (100 microM) activated currents (I(KA)) in a concentration-dependent manner over the range from 30 microM to 30 mM, with IC(50) values of 0.64 +/- 0.06 mM at a holding potential (V(H)) of -40 mV. Our further study indicated that the effects of La(3+) on I(KA) were voltage independent. Moreover, the inhibition was not use dependent and was not overcome by increasing the concentration of agonist. These findings indicate that La(3+) is an efficacious inhibitor of AMPA receptor mediated responses which may contribute to its cytotoxic effect.