Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization

Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury.Strikingly,hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs(HSEVs)exhibit increased therapeutic potency.We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair.SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation.HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation.HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro.Micro RNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that mi R-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1.Reducing mi R-146a-5p expression in HSEVs partially attenuated macrophage polarization.Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting mi R-146a-5p,which alters macrophage polarization.This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Helmholtz Decomposition of Vector Fields Using an Optimal Preconditioned Conjugate Gradient Algorithm

In this article, we study numerically a Helmholtz decomposition methodology, based on a formulation of the mathematical model as a saddle-point problem. We use a preconditioned conjugate gradient algorithm, applied to an associated operator equation of elliptic type, to solve the problem. To solve the elliptic partial differential equations, we use a second order mixed finite element approximation for discretization. We show, using 2-D synthetic vector fields, that this approach, yields very accurate solutions at a low computational cost compared to traditional methods with the same order of approximation.

PRECONDITIONED GAUSS-SEIDEL TYPE ITERATIVE METHOD FOR SOLVING LINEAR SYSTEMS

The preconditioned Gauss-Seidel type iterative method for solving linear systems, with the proper choice of the preconditioner, is presented. Convergence of the preconditioned method applied to Z-matrices is discussed. Also the optimal parameter is presented. Numerical results show that the proper choice of the preconditioner can lead to effective by the preconditioned Gauss-Seidel type iterative methods for solving linear systems.

High-efciency improved symmetric successive over-relaxation preconditioned conjugate gradient method for solving large-scale finite element linear equations

Fast solving large-scale linear equations in the finite element analysis is a classical subject in computational mechanics. It is a key technique in computer aided engineering （CAE） and computer aided manufacturing （CAM）. This paper presents a high-efficiency improved symmetric successive over-relaxation （ISSOR） preconditioned conjugate gradient （PCG） method, which maintains lelism consistent with the original form. Ideally, the by 50% as compared with the original algorithm. the convergence and inherent paralcomputation can It is suitable for be reduced nearly high-performance computing with its inherent basic high-efficiency operations. By comparing with the numerical results, it is shown that the proposed method has the best performance.

Researches on preconditioned wire arrayZpinches in Xi’an Jiaotong University

The dynamics of wire array Z pinches are greatly affected by the initial state of the wires,which can be preconditioned by a prepulse current.Recent advances in experimental research on preconditioned wire array Z pinches at Xi’an Jiaotong University are presented in this paper.Single-wire explosion experiments were carried out to check the state of the preconditioning and to obtain the current parameters needed for wire gasification.Double-wire explosion experiments were conducted to investigate the temporal evolution of the density distribution of the two gasified wires.Based on the results of these experiments,a double-pulse Z-pinch facility,Qin-1,in which a 10 kA prepulse current was coupled with the 0.8 MA main current was designed and constructed.Wire arrays of different wire materials,including silver and tungsten,can be preconditioned by the prepulse current to a gaseous state.Implosion of the two preconditioned aluminum wires exhibited no ablation and little trailing mass.

IMPROVED PRECONDITIONED CONJUGATE GRADIENT METHOD AND ITS APPLICATION IN F.E.A.FOR ENGINEERING

In this paper two theorems with theoretical and practical significance are given in respect to the preconditioned conjugate gradient method (PCCG). The theorems discuss respectively the qualitative property of the iterative solution and the construction principle of the iterative matrix. The authors put forward a new incompletely LU factorizing technique for non-M-matrix and the method of constructing the iterative matrix. This improved PCCG is used to calculate the ill-conditioned problems and large-scale three-dimensional finite element problems, and simultaneously contrasted with other methods. The abnormal phenomenon is analyzed when PCCG is used to solve the system of ill-conditioned equations, ft is shown that the method proposed in this paper is quite effective in solving the system of large-scale finite element equations and the system of ill-conditioned equations.

Formulation of a Preconditioned Algorithm for the Conjugate Gradient Squared Method in Accordance with Its Logical Structure

In this paper, we propose an improved preconditioned algorithm for the conjugate gradient squared method (improved PCGS) for the solution of linear equations. Further, the logical structures underlying the formation of this preconditioned algorithm are demonstrated via a number of theorems. This improved PCGS algorithm retains some mathematical properties that are associated with the CGS derivation from the bi-conjugate gradient method under a non-preconditioned system. A series of numerical comparisons with the conventional PCGS illustrate the enhanced effectiveness of our improved scheme with a variety of preconditioners. This logical structure underlying the formation of the improved PCGS brings a spillover effect from various bi-Lanczos-type algorithms with minimal residual operations, because these algorithms were constructed by adopting the idea behind the derivation of CGS. These bi-Lanczos-type algorithms are very important because they are often adopted to solve the systems of linear equations that arise from large-scale numerical simulations.

CONVERGENCE OF PRECONDITIONED GAUSS-SEIDEL ITERATIVE METHODS

Let the linear system Ax=b where the coefficient matrix A=(aij)∈Rm,n is an L-ma-trix(that is,aij】0 （?） i and aij≤0 （?） i≠j),A=I-L-U,I is the identity matrix,-L and-U are,respectively,strictly lower and strictly upper triangular parts of A.In[1]theauthors considered two preconditioned linear systems?x=（?） and ?x=（?）

The AOR Iterative Method for Preconditioned Linear Systems

The preconditioned methods for solving linear system are discussed. The convergence rate of accelerated overrelaxation (AOR) method can be enlarged by using the preconditioned method when the classical AOR method converges, and the preconditioned method is invalid when the classical iterative method does not converge. The results in corresponding references are improved and perfected.

A Preconditioned Multigrid Method for Efficient Simulation of Three-dimensional Compressible and Incompressible Flows

To develop an efficient and robust aerodynamic analysis method for numerical optimization designs of wing and complex configuration, a combination of matrix preconditioning and multigrid method is presented and investigated. The time derivatives of three-dimensional Navier-Stokes equations are preconditioned by Choi-Merkle preconditioning matrix that is originally designed for two-dimensional low Mach number viscous flows. An extension to three-dimensional viscous flow is implemented, and a method improving the convergence for transonic flow is proposed. The space discretizaition is performed by employing a finite-volume cell-centered scheme and using a central difference. The time marching is based on an explicit Rtmge-Kutta scheme proposed by Jameson. An efficient FAS multigrid method is used to accelerate the convergence to steady-state solutions. Viscous flows over ONERA M6 wing and M100 wing are numerically simulated with Mach numbers ranging from 0.010 to 0.839. The inviscid flow over the DLR-F4 wing-body configuration is also calculated to preliminarily examine the performance of the presented method for complex configuration. The computed results are compared with the experimental data and good agreement is achieved. It is shown that the presented method is efficient and robust for both compressible and incompressible flows and is very attractive for aerodynamic optimization designs of wing and complex configuration.

Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxininteracting protein-mediated hypoxia-inducible factor-1αpathway

BACKGROUND Extracellular vesicles(EVs)derived from hypoxia-preconditioned(HP)mesenchymal stem cells(MSCs)have better cardioprotective effects against myocardial infarction(MI)in the early stage than EVs isolated from normoxic(NC)-MSCs.However,the cardioprotective mechanisms of HP-EVs are not fully understood.AIM To explore the cardioprotective mechanism of EVs derived from HP MSCs.METHODS We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs(ADSCs)following hypoxia in vitro or MI in vivo,in order to improve the survival of cardiomyocytes(CMs)and restore cardiac function.The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays.MicroRNA(miRNA)sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs.The molecular mechanism of EVs in mediating thioredoxin-interacting protein(TXNIP)was verified by the dual-luciferase reporter assay.Co-immunoprecipitation,western blotting,and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha(HIF-1α)ubiquitination and degradation via the chromosomal region maintenance-1(CRM-1)-dependent nuclear transport pathway.RESULTS HP-EVs derived from MSCs reduced both infarct size(necrosis area)and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo.Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP,an oxidative stress-associated protein.We showed miRNA224-5p,the most upregulated miRNA in HP-EVs,directly combined the 3’untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury.Our results demonstrated that MI triggered TXNIP-mediated HIF-1αubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs,which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI.CONCLUSION The anti-apoptotic effects of HP-EVs in alleviating MI and the hypoxic conditions of CMs until reperfusion therapy may partly result from EV miR-224-5p targeting TXNIP.

Neurophenotyping of Zebrafish Larvae that Are Preconditioned with Anesthetic Agent

Anesthetics evoke a stress-response, upregulating heat shock genes. This neuroprotective response to proteotoxic stress represents preconditioning, a process by which neuronal tissue, previously exposed to anesthetics, is protected against future insult. It presumes a sub-lethal injury, affecting protein unfolding. Our hypothesis is: preconditioning evokes molecular events that result in downstream changes that offer a selective advantage in terms of neuronal function. We focused on the neurobehavioral aspects which we neurophenotyped. Larval zebrafish were exposed to trifluoroethanol (TFE), an anesthetic mimetic, and tested for both individual and group behavioral markers of neuronal function. In bright/dark tests, we observed that TFE-exposed larvae spent more time in the dark area (typically an adult-like response) than control larvae. The response of TFE larvae to noise startle was directly opposite to that of controls. TFE larvae swam towards the source of the startle (into the bright zone), whereas control larvae swam away from the source of the startle (into the dark), typical of fear-response. The larvae also exhibited several differences in social behaviors, including synchronized schooling and shoaling behaviors. The TFE-group showed a greater number of synchronized events versus controls. The TFE-group also exhibited more shoaling events compared with controls. While the long-term effects have yet to be determined, these results shed light on the mechanism of anesthetic preconditioning. These complex zebrafish behaviors normally develop with age and therefore represent, in the TFE-exposed group, a pattern of accelerated maturation of neuronal function, which is the neurophenotype attributed to preconditioning.

A Preconditioned Gridless Method for Solving Euler Equations at Low Mach Numbers

A preconditioned gridless method is developed for solving the Euler equations at low Mach numbers.The preconditioned system in a conservation form is obtained by multiplying apreconditioning matrix of the type of Weiss and Smith to the time derivative of the Euler equations,which are discretized using agridless technique wherein the physical domain is distributed by clouds of points.The implementation of the preconditioned gridless method is mainly based on the frame of the traditional gridless method without preconditioning,which may fail to converge for low Mach number simulations.Therefore,the modifications corresponding to the affected terms of preconditioning are mainly addressed.The numerical results show that the preconditioned gridless method still functions for compressible transonic flow simulations and additionally,for nearly incompressible flow simulations at low Mach numbers as well.The paper ends with the nearly incompressible flow over a multi-element airfoil,which demonstrates the ability of the method presented for treating flows over complicated geometries.

Preconditioned method in parallel computation

The grid equations in decomposed domain by parallel computation are soled, and a method of local orthogonalization to solve the large-scaled numerical computation is presented. It constructs preconditioned iteration matrix by the combination of predigesting LU decomposition and local orthogonalization, and the convergence of solution is proved. Indicated from the example, this algorithm can increase the rate of computation efficiently and it is quite stable.

Umbilical cord-derived mesenchymal stem cells preconditioned with isorhamnetin:potential therapy for burn wounds

BACKGROUND Impaired wound healing can be associated with different pathological states.Burn wounds are the most common and detrimental injuries and remain a major health issue worldwide.Mesenchymal stem cells(MSCs)possess the ability to regenerate tissues by secreting factors involved in promoting cell migration,proliferation and differentiation,while suppressing immune reactions.Preconditioning of MSCs with small molecules having cytoprotective properties can enhance the potential of these cells for their use in cell-based therapeutics.AIM To enhance the therapeutic potential of MSCs by preconditioning them with isorhamnetin for second degree burn wounds in rats.METHODS Human umbilical cord MSCs(hU-MSCs)were isolated and characterized by surface markers,CD105,vimentin and CD90.For preconditioning,hU-MSCs were treated with isorhamnetin after selection of the optimized concentration(5μmol/L)by cytotoxicity analysis.The migration potential of these MSCs was analyzed by the in vitro scratch assay.The healing potential of normal,and preconditioned hU-MSCs was compared by transplanting these MSCs in a rat model of a second degree burn wound.Normal,and preconditioned MSCs(IH+MSCs)were transplanted after 72 h of burn injury and observed for 2 wk.Histological and gene expression analyses were performed on day 7 and 14 after cell transplantation to determine complete wound healing.RESULTS The scratch assay analysis showed a significant reduction in the scratch area in the case of IH+MSCs compared to the normal untreated MSCs at 24 h,while complete closure of the scratch area was observed at 48 h.Histological analysis showed reduced inflammation,completely remodeled epidermis and dermis without scar formation and regeneration of hair follicles in the group that received IH+MSCs.Gene expression analysis was time dependent and more pronounced in the case of IH+MSCs.Interleukin(IL)-1β,IL-6 and Bcl-2 associated X genes showed significant downregulation,while transforming growth factorβ,vascular endothelial growth factor,Bcl-2 and matrix metallopeptidase 9 showed significant upregulation compared to the burn wound,showing increased angiogenesis and reduced inflammation and apoptosis.CONCLUSION Preconditioning of hU-MSCs with isorhamnetin decreases wound progression by reducing inflammation,and improving tissue architecture and wound healing.The study outcome is expected to lead to an improved cell-based therapeutic approach for burn wounds.

A Note on Parameterized Preconditioned Method for Singular Saddle Point Problems

Recently, some authors (Li, Yang and Wu, 2014) studied the parameterized preconditioned HSS (PPHSS) method for solving saddle point problems. In this short note, we further discuss the PPHSS method for solving singular saddle point problems. We prove the semi-convergence of the PPHSS method under some conditions. Numerical experiments are given to illustrate the efficiency of the method with appropriate parameters.

Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis

Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

Secretive derived from hypoxia preconditioned mesenchymal stem cells promote cartilage regeneration and mitigate joint inflammation via extracellular vesicles

Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great potential to enhance MSCs paracrine therapeutic effect. In our study, the paracrine effects of secretome derived from MSCs preconditioned in normoxia and hypoxia was compared through both in vitro functional assays and an in vivo rat osteochondral defect model. Specifically, the paracrine effect of total EVs were compared to that of soluble factors to characterize the predominant active components in the hypoxic secretome. We demonstrated that hypoxia conditioned medium, as well as the corresponding EVs, at a relatively low dosage, were efficient in promoting the repair of critical-sized osteochondral defects and mitigated the joint inflammation in a rat osteochondral defect model, relative to their normoxia counterpart. In vitro functional test shows enhancement through chondrocyte proliferation, migration, and matrix deposition, while inhibit IL-1β-induced chondrocytes senescence, inflammation, matrix degradation, and pro-inflammatory macrophage activity. Multiple functional proteins, as well as a change in EVs’ size profile, with enrichment of specific EV-miRNAs were detected with hypoxia preconditioning, implicating complex molecular pathways involved in hypoxia pre-conditioned MSCs secretome generated cartilage regeneration.

THE RESTRICTIVELY PRECONDITIONED CONJUGATE GRADIENT METHODS ON NORMAL RESIDUAL FOR BLOCK TWO-BY-TWO LINEAR SYSTEMS

The restrictively preconditioned conjugate gradient （RPCG） method is further developed to solve large sparse system of linear equations of a block two-by-two structure. The basic idea of this new approach is that we apply the RPCG method to the normal-residual equation of the block two-by-two linear system and construct each required approximate matrix by making use of the incomplete orthogonal factorization of the involved matrix blocks. Numerical experiments show that the new method, called the restrictively preconditioned conjugate gradient on normal residual （RPCGNR）, is more robust and effective than either the known RPCG method or the standard conjugate gradient on normal residual （CGNR） method when being used for solving the large sparse saddle point problems.

ASSESSMENT OF A CENTRAL DIFFERENCE FINITE VOLUME SCHEME FOR MODELING OF CAVITATING FLOWS USING PRECONDITIONED MULTIPHASE EULER EQUATIONS

A numerical treatment for the prediction of cavitating flows is presented and assessed. The algorithm uses the preconditioned multiphase Euler equations with appropriate mass transfer terms. A central difference finite volume scheme with suitable dissipation terms to account for density jumps across the cavity interface is shown to yield an effective method for solving the multiphase Euler equations. The Euler equations are utilized herein for the cavitation modeling, because some certain characteristics of cavitating flows can be obtained using the solution of this system of equations with relative low computational effort. In addition, the Euler equations are appropriate for the assessment of the numerical method used, because of the sensitivity of the solution to the numerical instabilities. For this reason, a sensitivity study is conducted to evaluate the effects of various parameters, such as numerical dissipation coefficients and grid size, on the accuracy and performance of the solution. The computations are performed for steady cavitating flows around the NACA 0012 and NACA 66 （MOD） hydrofoils and also an axisymmetric hemispherical fore-body under different conditions and the results are compared with the available numerical and experimental data. The solution procedure presented is shown to be accurate and efficient for predicting steady sheet- and super-cavitation for 2D/axisymmetric geometries.