Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis

Osteoarthritis(OA)is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA.These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium.In this study,we found that phosphoglycerate mutase 5(PGAM5)significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models.To address the role of PGAM5 in macrophages in OA,we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo.Mechanistically,we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways,whereas inhibited M2 polarization via STAT6-PPARγpathway in murine bone marrow-derived macrophages.Furthermore,we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2(DVL2)which resulted in the inhibition ofβ-catenin and repolarization of M2 macrophages into M1 macrophages.Conditional knockout of both PGAM5 andβ-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice.Motivated by these findings,we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection,which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis.Collectively,these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.

Impact of surface roughness,surface charge,and temperature on sandstone wettability alteration by nanoparticles

The wettability of rocks affects the balance between capillary and viscous forces during multiphase flow through porous media,which in turn determines the fluid displacement process governing the recovery of oil from subsurface formations.In this work,the mechanism of wettability reversal of aged synthetic sandstones by metal oxide nanoparticles(SiO_(2) and Al_(2)O_(3))was investigated with particular focus on the impact of surface roughness,zeta potential,and temperature.The synthetic surfaces were prepared from powders of Berea sandstone with known grain size ranges and their average roughness and roughness ratio were obtained from the 3D surface reconstruction of their microscope images.Each surface was subsequently aged in Permian crude oil to alter its wettability.For surfaces with larger grain sizes and lower surface roughness ratios,the lower capillary pressure allowed stronger oil/surface interactions,leading to enhanced oil-wetness.The wettability alteration effects of nanoparticles were then examined through real-time top view imaging and dynamic front view contact angle experiments.The negatively charged SiO_(2) nanoparticles rapidly reversed the sandstone wettability,indicating their potential applicability as wettability alteration agents.By contrast,the positively charged Al_(2)O_(3) counterpart caused no wettability reversal.The mechanism of wettability alteration was further studied by microscale interaction analyses and nanoscale transmission electron microscopy.Because nanoparticles were only a few nanometers large,the microscale roughness had a negligible effect on the wettability reversal.Instead,the combined effect of van der Waals dispersion forces and surface-charge-induced electrostatic forces were recognized as the two key factors affecting the wettability of sandstone particles.Such interactions may be curbed at elevated temperatures due to a decrease in the zeta potential and colloidal stability of the particles.

Adaptive nonlinear Kalman filters based on credibility theory with noise correlation

To solve the divergence problem and overcome the difficulty in guaranteeing filtering accuracy during estimation of the process noise covariance or the measurement noise covariance with traditional new information-based nonlinear filtering methods,we design a new method for estimating noise statistical characteristics of nonlinear systems based on the credibility Kalman Filter(KF)theory considering noise correlation.This method first extends credibility to the Unscented Kalman Filter(UKF)and Extended Kalman Filter(EKF)based on the credibility theory.Further,an optimization model for nonlinear credibility under noise related conditions is established considering noise correlation.A combination of filtering smoothing and credibility iteration formula is used to improve the real-time performance of the nonlinear adaptive credibility KF algorithm,further expanding its application scenarios,and the derivation process of the formula theory is provided.Finally,the performance of the nonlinear credibility filtering algorithm is simulated and analyzed from multiple perspectives,and a comparative analysis conducted on specific experimental data.The simulation and experimental results show that the proposed credibility EKF and credibility UKF algorithms can estimate the noise covariance more accurately and effectively with lower average estimation time than traditional methods,indicating that the proposed algorithm has stable estimation performance and good real-time performance.

Nano-calcium silicate mineralized fish scale scaffolds for enhancing tendon-bone healing

Tendon-bone healing is essential for an effective rotator cuff tendon repair surgery,however,this remains a significant challenge due to the lack of biomaterials with high strength and bioactivity.Inspired by the high-performance exoskeleton of natural organisms,we set out to apply natural fish scale(FS)modified by calcium silicate nanoparticles(CS NPs)as a new biomaterial(CS-FS)to overcome the challenge.Benefit from its“Bouligand”microstructure,such FS-based scaffold maintained excellent tensile strength(125.05 MPa)and toughness(14.16 MJ/m^(3)),which are 1.93 and 2.72 times that of natural tendon respectively,allowing it to well meet the requirements for rotator cuff tendon repair.Additionally,CS-FS showed diverse bioactivities by stimulating the differentiation and phenotypic maintenance of multiple types of cells participated into the composition of tendon-bone junction,(e.g.bone marrow mesenchymal stem cells(BMSCs),chondrocyte,and tendon stem/progenitor cells(TSPCs)).In both rat and rabbit rotator cuff tear(RCT)models,CS-FS played a key role in the tendon-bone interface regeneration and biomechanical function,which may be achieved by activating BMP-2/Smad/Runx2 pathway in BMSCs.Therefore,natural fish scale-based biomaterials are the promising candidate for clinical tendon repair due to their outstanding strength and bioactivity.