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Flying wing aircraft has many encouraging advantages, but there still were many unsteady aerodynamic uncertainty of the structures. Dynamic stability is a most significant analysis object. This paper wants to propose the flutter characteristic of a real flying wing aircraft. Firstly, an efficient finite element modelling method was taken to find basic dynamic features of the presented aircraft with effective mode analysis. Typical dynamic characteristics including bending and twisting modes of the structure were analyzed to propose possible dynamic stability of the aircraft. Secondly, a frequency domain fluid-structure interaction method was proposed to solve flutter analysis problem of the aircraft. With different heights and Ma number, flutter features of the aircraft were presented. It was seen from the computational results that dynamic stability analysis is necessary for the flying wing aircraft with proper flight velocity and height. The present dynamic modelling method and flutter computation process can give an effect reference for the design of flying wing aircraft. Also it can provide useful suggestions for existing flying wing aircraft structures.

Fucosylation is one of the most important glycan terminal modifications that affects multiple biological activities of proteins. 2-Fluorofucose (2FF), its specific inhibitor, has recently been reported to reveal numerous biological effects by blocking fucosylation both in vitro and in vivo. The current study aimed to evaluate the effect of 2FF on hydrogen peroxide (H2O2)-induced oxidative damage in vitro. In our study, treatment with H2O2 increased the level of fucosylation, and 2FF improved the cell viability in H2O2-treated HepG2 cells. Our study also showed that 2FF significantly decreased the overproduction of reactive oxygen species (ROS) induced by H2O2 and the activities of catalase, glutathione and Mn-superoxide dismutase were remarkably increased by 2FF pretreatment. Furthermore, 2FF attenuated H2O2-induced early mitochondria dysfunction. The second part of the study revealed that 2FF enhanced antioxidant capacity by affecting Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Being pretreated with 2FF significantly increased the nuclear translocation of Nrf2 and simultaneously promoted the expression of downstream proteins, such as HO-1 and NQO1. Moreover, 2FF remarkably suppressed the expression of inflammation-associated proteins. Taken together, these data suggest that 2FF might have a potential therapeutic effect for oxidative stress.

The V-tail configuration has excellent stealth performance and has been using widely in the aerodynamic shape design of advanced aircraft. Many recent studies have focused on numerical simulation about V-tail configuration flight performance. The relative wind tunnel tests still need to be developed. This challenge is a focused aspect in such research. In the present experimental study, the role of flight control law was investigated in order to keep the test model in the target attitude and height. An effective design method of a full model of the aircraft with twin V-tails is proposed based on CFD evaluation. This model was manufactured based on the design of a two degrees of freedom support system via a Chinese wind tunnel. A longitudinal flight control law was proposed and simulated. Wind tunnel tests were employed to find the effectiveness of the model design and the control law. It is seen from the results that the proposed experimental method via a full model of the aircraft with twin V-tails and a novel longitudinal flight control law is effective. These test results can provide appliable contributions on the development of the support system for wind tunnel experiments. The proposed model design and test methods can be useful for applications in the aeroelastic wind tunnel tests of the full model aircrafts.

Human trophoblast cell apoptosis may induce miscarriage. Trophoblast cells are sensitive to environmental BaP-7,8-dihydrodiol-9,10-epoxide (BPDE). However, how BPDE induces human trophoblast cell apoptosis is still largely elusive. In this work, we used BPDE-treated human trophoblast cells and villous tissues collected from recurrent miscarriage and health control groups to explore the underlying mechanism of BPDE-induced human trophoblast cell apoptosis. Continued with our recent work, we found that lncRNA HZ01 (lnc-HZ01) could induce human trophoblast cell apoptosis. In mechanism, lnc-HZ01 up-regulated p53 expression level by suppressing its MDM2-mediated proteasomal degradation. Meanwhile, we found that p53 acted as lnc-HZ01 transcription factor and promoted lnc-HZ01 transcription. Thus, lnc-HZ01 and p53 composed a positive feedback loop in human trophoblast cells. In normal trophoblast cells, relatively low levels of lnc-HZ01 and p53 suppressed p53/caspase-3 apoptosis pathway, giving normal pregnancy. Upon BPDE exposure, BPDE up-regulated the expression levels of lnc-HZ01 and p53, triggered this positive feedback loop, activated the p53/caspase-3 apoptosis pathway, and then induced miscarriage. Collectively, we discovered new mechanism by which lnc-HZ01 regulated BPDE-induced human trophoblast cell apoptosis, providing scientific basis for the diagnosis and treatment of unexplained recurrent miscarriage.

Few-layer black phosphorus (BP) has recently emerged as a promising two-dimensional (2D) material for electronic and optoelectronic devices because of its high mobility and tunable band gap. However, BP is known to quickly degrade and oxidize in ambient conditions by breaking of the P-P bonds. As a result, there is a growing need to encapsulate BP that avoids oxygen and water while retaining the high electric performance of the devices. Here, we demonstrate a hydrophobic polymer encapsulation technique with improved thermal conductivity for high current density, which preserves the electrical properties of BP back-gate transistors compared to the commonly used Al2O3 encapsulation with improved mobility and minimal traps. The on-off ratio increases by more than an order of magnitude at room temperature and more than 4 orders of magnitude at cryogenic temperatures. High field transport shows the first systematic study on unprecedented breakdown characteristics up to -5.5 V for the 0.16 μm transistors with a high current of 1.2 mA/μm at 20 K. These discoveries open up a new way to achieve high-performance 2D semiconductors with significantly improved breakdown voltage, on-off ratios, and stability under ambient conditions for practical applications in electronic and optoelectronic devices.

Key points Abnormal mitochondrial morphology and function in cardiomyocytes are frequently observed under persistent Gq protein-coupled receptor (Gq PCR) stimulation. Cardiac signalling mechanisms for regulating mitochondrial morphology and function under pathophysiological conditions in the heart are still poorly understood. We demonstrate that a downstream kinase of Gq PCR, protein kinase D (PKD) induces mitochondrial fragmentation via phosphorylation of dynamin-like protein 1 (DLP1), a mitochondrial fission protein. The fragmented mitochondria enhance reactive oxygen species generation and permeability transition pore opening in mitochondria, which initiate apoptotic signalling activation. This study identifies a novel PKD-specific substrate in cardiac mitochondria and uncovers the role of PKD on cardiac mitochondria, with special emphasis on the molecular mechanism(s) underlying mitochondrial injury with abnormal mitochondrial morphology under persistent Gq PCR stimulation. These findings provide new insights into the molecular basis of cardiac mitochondrial physiology and pathophysiology, linking Gq PCR signalling with the regulation of mitochondrial morphology and function. Abstract Regulation of mitochondrial morphology is crucial for the maintenance of physiological functions in many cell types including cardiomyocytes. Small and fragmented mitochondria are frequently observed in pathological conditions, but it is still unclear which cardiac signalling pathway is responsible for regulating the abnormal mitochondrial morphology in cardiomyocytes. Here we demonstrate that a downstream kinase of Gq protein-coupled receptor (Gq PCR) signalling, protein kinase D (PKD), mediates pathophysiological modifications in mitochondrial morphology and function, which consequently contribute to the activation of apoptotic signalling. We show that Gq PCR stimulation induced by α1 -adrenergic stimulation mediates mitochondrial fragmentation in a fission- and PKD-dependent manner in H9c2 cardiac myoblasts and rat neonatal cardiomyocytes. Upon Gq PCR stimulation, PKD translocates from the cytoplasm to the outer mitochondrial membrane (OMM) and phosphorylates a mitochondrial fission protein, dynamin-like protein 1 (DLP1), at S637. PKD-dependent phosphorylation of DLP1 initiates DLP1 association with the OMM, which then enhances mitochondrial fragmentation, mitochondrial superoxide generation, mitochondrial permeability transition pore opening and apoptotic signalling. Finally, we demonstrate that DLP1 phosphorylation at S637 by PKD occurs in vivo using ventricular tissues from transgenic mice with cardiac-specific overexpression of constitutively active Gαq protein. In conclusion, Gq PCR-PKD signalling induces mitochondrial fragmentation and dysfunction via PKD-dependent DLP1 phosphorylation in cardiomyocytes. This study is the first to identify a novel PKD-specific substrate, DLP1 in mitochondria, as well as the functional role of PKD in cardiac mitochondria. Elucidation of these molecular mechanisms by which PKD-dependent enhanced fission mediates cardiac mitochondrial injury will provide novel insight into the relationship among mitochondrial form, function and Gq PCR signalling.

In this paper, the adaptive observer-based tracking problem for multi-agent system with uncertain dynamics is considered. The communication topology among the agents is assumed to be directed and connected. To track the active leader, a distributed adaptive consensus protocol based on the relative output information with its neighboring agents is proposed for each following agent. To deal with uncertain dynamics, an adaptive learning law is included in the proposed protocol. Furthermore, to implement the protocol in a fully distributed fashion, distributed adaptive laws are adopted to adjust the coupling weights. By using Lyapunov method, the multi-agent system can be proved to achieve consensus via the proposed protocols. The established convergence condition is in term of linear matrix inequalities, by which the control protocol can be constructed effectively. Simulation results show the effectiveness of the proposed method for multi-agent systems with uncertain dynamics.

In this paper, the observer-based consensus problem for nonlinear multi-agent systems is considered. The dynamics of each agent is given in general form of Lipschitz nonlinear system, and the communication topology among the agents is assumed to be undirected and connected. The leader-following case and leaderless case are discussed. In the former, it is assumed that the leader’s input is possibly nonzero and time-varying and only a subset of the following agents can access the state information of the leader. To track the active leader, a distributed adaptive consensus protocol, based on the relative-output information with its neighbouring agents, is proposed for each following agent. It is shown that under suitable conditions, all the following agents can track the leader under the designed adaptive controllers and observers. Following that, the leaderless case is probed. Finally, a numerical example is given to illustrate our obtained result.

Photothermal therapy is a promising approach for antitumor application although regrettably restricted by available photothermal agents. Physical entrapment of organic near-infrared dyes into nanosystems was extensively studied to reverse the dilemma. However, problems still remained, such as drug bursting and leakage. We developed here an amphiphilic prodrug conjugate by chemically modifying indocyanine green derivative (ICG-COOH) and paclitaxel (PTX) to hyaluronic acid (HA) backbone for integration of photothermal-chemotherapy and specific tumor imaging. The prepared ICG-HA-PTX conjugates could self-assemble into nanomicelles to improve the stability and reduce systemic toxicity of the therapeutic agents. The high local concentration of ICG-COOH in nanomicelles resulted in fluorescence self-quenching, leading to no fluorescence signal being detected in circulation. When the nanomicelles reached the tumor site via electron paramagnetic resonance effect and HA-mediated active targeting, the overexpressed esterase in tumor cells ruptured the ester linkage between drugs and HA, achieving tumor-targeted therapy and specific imaging. A series of in vitro and in vivo experiments demonstrated that the easily prepared ICG- HA-PTX nanomicelles with high stability, smart release behavio r, and excellent tumor targeting ability showed formidable synergy in tumor inhibition, which provided new thoughts in developing an organic near-infrared-dye-based multifunctional delivery system for tumor theranostics.

Salusin-α is an endogenous bioactive peptide and likely to prevent atherosclerosis. But its protective effect against atherosclerosis in vivo remains poorly understood. The aim of the present study was to determine the potential effects of salusin-α on atherosclerosis and its associated metabolic disorders in high fat diet (HFD)-fed low density lipoprotein receptor deficient (LDLr-/-) mice, and also explore the possible underlying mechanisms involved. Our data showed that after 12 weeks treatment, salusin-α ameliorated HFD-induced weight gain, hyperlipidemia, and serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Salusin-α suppressed HFD-induced hepatic steatosis and regulated gene expression of fatty acid synthase, acetyl coenzyme A carboxylase-α, peroxisome proliferator-activated receptor-α, camitine palmitoyltransferase-1α and CYP7A1 in liver. Salusin-α reduced atherosclerotic plaque area and macrophage foam cell formation. Salusin-α prevented hepatic and aortic inflammation as evidenced by the reduced macrophage recruitment and mRNA expression of IL-6 and TNF-α in both liver and aorta. Salusin-α also reduced hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in liver and suppressing reactive oxygen species generation and protein expressions of NADPH-oxidase (NOX) 2 and NOX4 in both liver and aorta. Our present data suggest that salusin-α could reduce hepatic steatosis and atherosclerosis via its pleiotropic effects, including amelioration of lipid profiles, regulation of some key molecules involved in lipid metabolism in liver, anti-oxidative effect and anti-inflammatory action.

In this paper, the consensus problem of descriptor multi-agent systems is considered. Each agent’s dynamics is given in the general form of a continuous-time linear descriptor system, and the communication topology among the agents is assumed to be directed in fixed topology case and balanced in switching topology case, respectively. Three kinds of distributed observer-based consensus protocols are proposed to solve the descriptor multi-agent consensus problem. Multi-step algorithms are provided to design the gain matrices and coupling constants involved in the protocols. The design approach is based on the generalized Riccati equation, and Lyapunov stability theory. Some sufficient consensus conditions are established to guarantee that the descriptor multi-agent system achieves consensus under the directed fixed topology and balanced switching topology. Furthermore, the state variable feedback consensus problem and the observer-based consensus problem with a desired decay rate are discussed. Finally, a simulation example is provided to illustrate the obtained results.

This paper considers the leader-following tracking problem of second-order nonlinear multi-agent systems with a reference leader. It is assumed that all following agents can only access the relative position information with its neighbors, the position and velocity information of the leader is only accessed by a subset of the following agents, and the leader?s bounded reference input cannot be available by any following agents. To track the active leader, a distributed discontinuous observer-based consensus protocol is proposed for each following agent, whose observer is used to estimate the agent?s unmeasured velocity. Under connected undirected interaction topology, the proposed protocol can be used to solve the second-order nonlinear multi-agent consensus problem. While the reference input of the leader is known, the proposed protocol can solve the consensus problem under a class of directed switching interaction topologies. Furthermore, to make the designed approach in fully distributed fashion, the distributed adaptive laws are provided to design the protocol coupling parameters. Finally, a numerical example is presented to illustrate our obtained result.

The aim of this study was to evaluate the potential effects of 2,3,4′,5-tetrahydroxystilbene-2-O-β-d-glucoside (TSG) on the development of atherosclerotic plaque in ApoE−/−mice, and explore the mechanisms involved. Our data showed that after 8 weeks of treatment, TSG ameliorated serum levels of total cholesterol, triglyceride, and low density lipoprotein cholesterol, and increased serum levels of high density lipoprotein cholesterol in ApoE−/−mice. TSG suppressed hepatic steatosis, the formation of atherosclerotic lesions, and the formation of macrophage foam cells in ApoE−/−mice. Moreover, TSG improved the expressions of hepatic SR-BI, ABCG5, and CYP7A1, and up-regulated the protein expressions of aortic ABCA1 and ABCG1. An in-vitro study showed that TSG promoted macrophage cholesterol efflux and increased the protein expressions of ABCA1 and ABCG1. Our findings provide evidence for a positive role of TSG in preventing atherosclerosis by promoting reverse cholesterol transport. These effects may be achieved by stimulating cholesterol efflux through ABCA1 and ABCG1, promoting SR-BI-mediated cholesterol uptake in the liver, increasing secretion of cholesterol into bile by ABCG5, and improving cholesterol metabolism by the CYP7A1 pathway. In addition, antioxidative and anti-inflammatory effects of TSG may also contribute to its inhibitory effects on atherosclerosis. Further study is needed to investigate whether other potential mechanisms are involved in TSG-mediated atheroprotection.

2,3,4',5-tetrahydroxystilbene 2-O-β-D-glucoside (TSG), a resveratrol analog with glucoside, is purified from a traditional Chinese herbal medicine polygonum multiflorum. It has been extensively studied in last decade and known to exert strong anti-inflammatory, anti-oxidative, anti-apoptotic, and free radical scavenging activities, and therefore has been listed as a potential agent for disease therapies. Recent studies extend well-beyond effects of TSG on the injury of neurons, cardiomyocytes and endothelial cells, and report important functions of TSG in a lot of pathophysiological conditions. For example, TSG has been shown to prevent the production of pro-inflammatory cytokines in microglia and macrophages in vitro, and ameliorate pro-inflammatory responses in animal models with neurodegeneration, atherosclerosis, and rat paw or ear oedema. TSG can prevent the proliferation of vascular smooth cells, gastrointestinal dysfunctions, platelet aggregation, osteoblastic injury, diabetic nephropathy and melanogenesis. TSG is also indicated to facilitate long-term potentiation and learning and memory in both normal and pathological conditions. These effects to some extent enrich the understanding about the role of TSG in disease prevention and therapy. However, to date, we still have no outlined knowledges about the pharmacological effects of TSG, though the role of TSG in aging and Alzheimer's disease has been reviewed in recent years. Here, we summarize the current pharmacological developments of TSG as well as its possible mechanisms in disease prevention and therapy, aiming to push the understanding about the protective role of TSG as well as its preclinical assessment of novel applications.

In this paper, we focus on the consensus problem for leaderless and leader–followers multi-agent systems with periodically intermittent control. The dynamics of each agent in the system is a linear system, and the interconnection topology among the agents is assumed to be switching. We assume that each agent can only share the outputs with its neighbours. Therefore, a class of distributed intermittent observer-based consensus protocols are proposed for each agent. First, in order to solve this problem, a parameter-dependent common Lyapunov function is constructed. Using this function, we prove that all agents can access a prescribed value, under the designed intermittent controller and observer, if there are suitable conditions on communication. Second, based on the investigation of the leader-following consensus problem, we design a new distributed intermittent observer-based protocol for each following agent. Finally, we provide an illustrative example to verify the effectiveness of the proposed approach.

To investigate the effect of 2,3,4',5-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component extracted from the root of Polygonum multiflorum, on angiotensin II (Ang II)-induced proliferation of cultured rat vascular smooth muscle cells (VSMCs) and to identify the potential mechanism.Cell proliferation and cell cycle were determined by cell counting, 5-bromo-2'-deoxyuridine incorporation assay, proliferating cell nuclear antigen protein expression and flow cytometry. Levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), mitogenic extracellular kinase 1/2 (MEK1/2) and Src in VSMCs were measured by Western blot. The expression of c-fos, c-jun and c-myc mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR). Intracellular reactive oxygen species (ROS) was measured by fluorescence assay.TSG significantly inhibited Ang II-induced VSMCs proliferation and arrested cells in the G /S checkpoint (P0.05 or P0.01). TSG decreased the levels of phosphorylated ERK1/2, MEK1/2 and Src in VSMCs (P0.05 or P0.01). TSG also suppressed c-fos, c-jun and c-myc mRNA expression0.05 or P0.01). In addition, the intracellular ROS was reduced by TSG (P0.01).TSG inhibited Ang II-induced VSMCs proliferation. Its antiproliferative effect might be associated with down-regulation of intracellular ROS, followed by the suppression of the Src-MEK1/2-ERK1/2 signal pathway, and hence, blocking cell cycle progression.

This paper investigates the leader-following consensus problem of discrete-time multi-agent systems. The dynamics of the leader and all following agents adopt the same general form of a linear model that can be of any order. The interconnection topology among the agents is assumed to be switching and undirected. To track the active leader, two kinds of distributed observer-based consensus protocols are proposed for each following agent, whose distributed observers are used to estimate the leader's state and the tracking error based on the relative outputs of neighboring agents, respectively. In light of the modified discrete-time algebraic Riccati equality and Lyapunov method, we prove that the discrete-time leader-following consensus problem can be solved by proposing the distributed observer-based consensus protocol under switching topologies. Finally, a numerical example is given to illustrate the obtained result.

The proliferation of vascular smooth muscle cells (VSMCs) induced by injury to the intima of arteries is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. 2,3,4',5-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component extracted from Polygonum multiflorum, has been found to have an antiatherosclerotic effect. The aim of this study was to investigate the effects of TSG on platelet derived growth factor (PDGF)-BB induced VSMCs proliferation and to explore the possible mechanisms of such effects. Pretreatment of VSMCs with TSG significantly inhibited PDGF-BB-induced cell proliferation in a concentration-dependent but not time-dependent manner. In addition, flow cytometry analysis of the DNA content revealed blocking of the PDGF-BB-inducible cell cycle progression by TSG. On the contrary, an inhibitory effect of TSG on VSMCs proliferation and expression of cell cycle regulators were markedly attenuated by addition of an nitric oxide (NO) synthase inhibitor, a soluble guanylate cyclase inhibitor and a cyclic GMP (cGMP)-dependent protein kinase (PKG) inhibitor: N(G)-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4] oxadiazolo [4,3-α] quinoxalin-1-one (ODQ) and KT5823, respectively. It was also demonstrated that TSG enhanced NO and cGMP formation through up-regulating endothelial NO synthase expression in VSMCs. The findings indicate that TSG inhibited VSMCs proliferation induced by PDGF-BB may involve the NO/cGMP/PKG signal pathway.

1. 2,3,4',5-Tetrahydroxystilbene-2-O-β-d-glucoside (TSG) has been shown to have an anti-atherosclerotic effect. Vascular smooth muscle cell (VSMC) proliferation contributes to the pathobiology of atherosclerosis. The aim of the present study was to investigate the effects of TSG on platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation and to explore the molecular mechanisms underlying the effects. 2. Cultured rat VSMC were pretreated with TSG (l-50 μmol/L) for 1 h, followed by exposure to PDGF-BB (10 ng/mL) for 24 h, after which cell proliferation and cell cycle stages were examined. The expression of protein cell cycle regulators, including retinoblastoma (Rb), cyclin D1/E, cyclin-dependent kinase (CDK) 2/4, CDK inhibitors p21 and p27 and proliferative cell nuclear antigen (PCNA), was examined. Activation of extracellular signal-regulated kinase (ERK) 1/2 was evaluated to elucidate the possible upstream mechanism by which TSG affects cell cycle regulators. 3. The results showed that TSG dose-dependently inhibited PDGF-BB-induced VSMC proliferation, possibly by blocking the progression of the cell cycle from the G(1) to S phase. In addition, TSG significantly inhibited PDGF-BB-induced phosphorylation of Rb and the expression of cyclin D1, CDK4, cyclin E, CDK2 and PCNA. In addition, TSG suppressed PDGF-BB-induced downregulation of p27 and upregulation of p21, as well as PDGF-BB-induced activation of ERK1/2. 4. Together, the findings of the present study provide the first evidence that TSG can inhibit PDGF-BB-stimulated VSMC proliferation via cell cycle arrest in association with modulation of the expression of cell cycle regulators, which may be mediated, at least in part, by suppression of ERK1/2 activation.

Transition metal dichalcogenides (TMDCs) are emerging two-dimensional materials for their potential in next-generation electronics. One of the big challenges is to realize a large single-crystal TMDCs film with high mobility, which is critical for channel materials. Herein, we report an optimized atmospheric pressure chemical vapor deposition method for growing large single-crystal monolayer MoS2 on molten glass substrate with domain size up to 563 μm. Better interface quality can be achieved using high-κ dielectrics with respect to the conventional thermal SiO2. Mobility up to 24 cm2 V−1 s−1 at room temperature and 84 cm2 V−1 s−1 at 20 K can be obtained. This low-cost growth of high-quality, large single-crystal size of two dimensional materials provides a pathway for high-performance two dimensional electronic devices.

Maspin, a non-inhibitory member of serine protease family, acts as an effective tumor suppressor by inhibiting cell inhesion and mobility. We found that exogenous wild-type rMaspin had a low effect on tumor growth in vivo. However, when the peptide Arg-Gly-Asp-hexahistidine (RGD-6His) was introduced into rMaspin, the modified rMaspin showed significant inhibitory activity in angiogenic assays and tumor-bearing animal models. Overall, our data suggested that both the RGD and hexahistidine fragments contributed to improve the fusion protein activity and polyhistidine peptide could be considered as flexible linker to separate RGD and Maspin moieties to avoid function interference. Besides, it is an efficient tag to achieve purified recombinant proteins. Furthermore, rMaspin fusing with RGD and hexahistidine could be a viable anticancer candidate.

The Ca2+ influx into mitochondrial matrix is primarily mediated via the mitochondrial calcium uniporter (MCU). Basal tyrosine phosphorylation (P-Y) of MCU was shown in mass spectroscopy of human ti...

Regulation of mitochondrial morphology and dynamics is crucial for the maintenance of various cellular functions in cardiomyocytes. Abnormal mitochondrial morphologies concomitant with mitochondrial dysfunction are frequently observed both in human heart failure (HF) and in animal HF models. However, it is still unclear which cardiac signaling pathways regulate mitochondrial morphology and function under pathophysiological conditions. Recent reports suggest that Gq-protein coupled receptor (GqPCR) signaling pathways are critical for the development and progression of HF. Therefore, we hypothesize that GqPCR stimulation induces mitochondrial fragmentation and dysfunction, which initiates cardiomyocyte death. We found that protein kinase D (PKD) activated by GqPCR signaling was translocated to outer mitochondrial membrane (OMM) observed by Western blot analysis of cytosolic and mitochondria-enriched fractionated proteins and by live cell imaging of fluorescence resonance energy transfer (FRET). We also found that GqPCR-mediated PKD activation induced mitochondrial fragmentation, leading to increased reactive oxygen species (ROS) generation as well as increased mitochondrial permeability transition pore (mPTP) opening, which initiates apoptotic signaling activation and cardiomyocyte death. These morphological and functional changes in cardiac mitochondria were mediated via PKD-dependent phosphorylation of mitochondrial fission protein, Dynamin-Like Protein 1 (DLP1) at S637. Moreover, pretreatment with a novel potent PKD inhibitor CRT0066101 effectively inhibited GqPCR-mediated PKD translocation to OMM, DLP1 phosphorylation at S637, mitochondrial fragmentation, ROS generation and mPTP activation. In conclusion, we demonstrate that GqPCR stimulation induces mitochondrial fragmentation and dysfunction through PKD-dependent phosphorylation of DLP1 at S637, which likely contributes to cardiomyocyte injury. Thus, small-molecule PKD inhibitor may become a novel and potent therapeutic for preventing cardiac cell injury and death during HF.

Previous studies showed that prostacyclin inhibited fibrosis. However, both receptors of prostacyclin, prostacyclin receptor (IP) and peroxisome proliferator-activated receptor (PPAR), are abundant in cardiac fibroblasts. Here we investigated which receptor was vital in the anti-fibrosis effect of prostacyclin. In addition, the possible mechanism involved in protective effects of prostacyclin against cardiac fibrosis was also studied. We found that beraprost, a prostacyclin analogue, inhibited angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast proliferation in a concentration-dependent and time-dependent manner. Beraprost also suppressed Ang II-induced collagen I mRNA expression and protein synthesis in cardiac fibroblasts. After IP expression was knocked down by siRNA, Ang II-induced proliferation and collagen I synthesis could no longer be rescued by beraprost. However, treating cells with different specific inhibitors of PPAR subtypes prior to beraprost and Ang II stimulation, all of the above attenuating effects of beraprost were still available. Moreover, beraprost significantly blocked transforming growth factor β (TGF β) expression as well as Smad2 phosphorylation and reduced Smad-DNA binding activity. Beraprost also increased phosphorylation of cAMP response element binding protein (CREB) at Ser133 in the nucleus. Co-immunoprecipitation analysis revealed that beraprost increased CREB but decreased Smad2 binding to CREB-binding protein (CBP) in nucleus. In conclusion, beraprost inhibits cardiac fibroblast proliferation by activating IP and suppressing TGF β-Smad signal pathway.

In this paper, the leader-following consensus problem of high order multi-agent systems with time-varying communication delays and noises is considered. The interconnection topology among the agents is assumed to be switching and undirected. The dynamics of each agent and the leader is a linear system. To track the active leader, a neighbor-based control of each following agent is designed in using local information. The control design technique is based on algebraic graph theory, Riccati inequality and Lyapunov inequality. By using Lyapunov-Razumikhim and stochastic analysis methods, we prove that the closed loop tracking control system is stochastically stable in mean square and the estimation errors converge to zero in mean square as well. Finally, a numerical example is given to illustrate the obtained result. DOI: http://dx.doi.org/10.11591/telkomnika.v10i6.1429 Full Text: PDF

To develop a novel Escherichia coli cell surface display system by using C-terminally truncated NCgl1221 as the anchoring protein, which greatly enriched or optimized the bacterial displayed systems.We amplified the sequence of C-terminally truncated NCgl1221 and beta-amylase, and constructed the fusion expression vector. Then we transformed the recombinant plasmids PET-NA and PET-28a into Rosetta (DE3) pLysS. The fusion protein expression was induced by IPTG and identified by SDS-PAGE and Western blot analysis. The IPTG induced strains were immunostained and investigated by fluorescence microscope and flow cytometry to detect the displayed beta-amylase. Finally, we analyzed the activity of beta-amylase and starch hydrolization in order to determine whether the displayed beta-amylase has the activity or not.The fusion protein was successfully expressed in E. coli, and the active beta-amylase was displayed on the cell surface by fusing it to the C terminus of the anchor. The recombinant strain displaying beta-amylase can utilize soluble starch in the medium.A novel E. coli surface display system by using C-terminally truncated NCgl1221 as the anchor motif was successfully developed. The active enzyme with a molecular size of 56 kDa was displayed on E. coli by this system, which provided the basis for the application of the system in whole-cell biocatalyst or biosorbent.

This paper considers the problem of Hinfin control of a class of Hopfield neural network systems with time-varying delays and Markovian jumping parameters. The delays are assumed to be bounded. The jumping parameters considered here are generated from a continuous-time discrete-state homogenous Markov process, which are governed by a Markov process with discrete and finite state space. Our purpose is to design state feedback controllers that guarantee the systems are stochastic stability with a prescribed performance. Based on the Lyapunov method and stochastic analysis approach, a sufficient condition for the solvability of the problems are derived in term of linear matrix inequalities, which can be easily checked by resorting to available software packages. A numerical example is exploited to demonstrate the effectiveness of the proposed results.