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In Duchenne muscular dystrophy (DMD), a lack of functional dystrophin leads to myofiber instability and progressive muscle damage that results in fibrosis. While fibrosis is primarily characterized by an accumulation of extracellular matrix (ECM) components, there are changes in ECM architecture during fibrosis that relate more closely to functional muscle stiffness. One of these architectural changes in dystrophic muscle is collagen cross-linking, which has been shown to increase the passive muscle stiffness in models of fibrosis including the mdx mouse, a model of DMD. We tested whether the intraperitoneal injections of beta-aminopropionitrile (BAPN), an inhibitor of the cross-linking enzyme lysyl oxidase, would reduce collagen cross-linking and passive stiffness in young and adult mdx mice compared to saline-injected controls. We found no significant differences between BAPN treated and saline treated mice in collagen cross-linking and stiffness parameters. However, we observed that while collagen cross-linking and passive stiffness scaled positively in dystrophic muscles, collagen fiber alignment scaled with passive stiffness distinctly between muscles. We also observed that the dystrophic diaphragm showed the most dramatic fibrosis in terms of collagen content, cross-linking, and stiffness. Overall, we show that while BAPN was not effective at reducing collagen cross-linking, the positive association between collagen cross-linking and stiffness in dystrophic muscles still show cross-linking as a viable target for reducing passive muscle stiffness in DMD or other fibrotic muscle conditions.

Fibro-adipogenic progenitors (FAPs) are essential in supporting regeneration in skeletal muscle, but in muscle pathologies FAPs the are main source of excess extracellular matrix (ECM) resulting in fibrosis. Fibrotic ECM has altered mechanical and architectural properties, but the feedback onto FAPs of stiffness or ECM properties is largely unknown. In this study, FAPs' sensitivity to their ECM substrate was assessed using collagen coated polyacrylamide to control substrate stiffness and collagen hydrogels to engineer concentration, crosslinking, fibril size, and alignment. FAPs on substrates of fibrotic stiffnesses had increased myofibroblast activation, depicted by αSMA expression, compared to substrates mimicking healthy muscle, which correlated strongly YAP nuclear localization. Surprisingly, fibrosis associated collagen crosslinking and larger fibril size inhibited myofibroblast activation, which was independent of YAP localization. Additionally, collagen crosslinking and larger fibril diameters were associated with decreased remodeling of the collagenous substrate as measured by second harmonic generation imaging. Inhibition of YAP activity through verteporfin reduced myofibroblast activation on stiff substrates but not substrates with altered architecture. This study is the first to demonstrate that fibrotic muscle stiffness can elicit FAP activation to myofibroblasts through YAP signaling. However, fibrotic collagen architecture actually inhibits myofibroblast activation through a YAP independent mechanism. These data expand knowledge of FAPs sensitivity to ECM and illuminate targets to block FAP's from driving progression of muscle fibrosis.

Objective To analyse trends and patterns in inpatient antibacterial use in China's tertiary and secondary hospitals between 2013 and 2021. Methods The analysis involved quarterly data from hospitals covered by China's Center for Antibacterial Surveillance. We obtained information on hospital characteristics (e.g. province, a de-identified hospital code, hospital level and inpatient days) and antibacterial characteristics (e.g. generic name, drug classification, dosage, administration route and usage volume). We quantified antibacterial use as the number of daily defined doses per 100 patient-days. The analysis took into account the World Health Organization's (WHO's) Access, Watch, Reserve classification of antibiotics. Findings Between 2013 and 2021, overall antibacterial use in inpatients decreased significantly from 48.8 to 38.0 daily defined doses per 100 patient-days (P < 0.001). In 2021, the variation between provinces was almost twofold: 29.1 daily defined doses per 100 patient-days in Qinghai versus 55.3 in Tibet. The most-used antibacterials in both tertiary and secondary hospitals throughout the study period were third-generation cephalosporins, which comprised around one third of total antibacterial use. Carbapenems entered the list of most-used antibacterial classifications in 2015. The most frequently used antibacterials in WHO's classification belonged to the Watch group: usage increased significantly from 61.3% (29.9/48.8) in 2013 to 64.1% (24.4/38.0) in 2021 (P < 0.001). Conclusion Antibacterial use in inpatients decreased significantly during the study period. However, the rising proportion of last-resort antibacterials used is concerning, as is the large gap between the proportion of antibacterials used belonging to the Access group and WHO's global target of no less than 60%. Objectif Analyser les tendances et schemas propres a l'utilisation des antibacteriens en milieu hospitalier dans les hopitaux secondaires et tertiaires en Chine, entre 2013 et 2021. Methodes L'analyse repose sur des donnees trimestrielles provenant d'hopitaux couverts par le Center for Antibacterial Surveillance chinois. Nous nous sommes procure des informations sur les caracteristiques des hopitaux (province, code hospitalier anonymise, niveau de l'etablissement et jours d'hospitalisation par exemple) et des antibacteriens (notamment le nom generique, la classe pharmacologique, le dosage, le mode d'administration et le volume utilise). Nous avons quantifie l'usage d'antibacteriens et le nombre de doses journalieres definies par 100 jours-patients. Lanalyse a pris en compte la classification AWaRe (Access, Watch et Reserve) de Organisation mondiale de la Sante. Resultats Entre 2013 et 2021, le recours global aux antibacteriens en milieu hospitalier a considerablement diminue, passant de 48,8 a 38,0 doses journalieres definies pour 100 jours-patients (P < 0,001). En 2021, les variations entre provinces etaient presque multipliees par deux: 29,1 doses journalieres definies pour 100 jours-patients dans le Qinghai, contre 55,3 au Tibet. Pendant toute la duree de l'etude, les antibacteriens d'usage le plus courant, tant dans les hopitaux secondaires que tertiaires, etaient les cephalosporines de troisieme generation, qui representaient pres d'un tiers de l'usage total d'antibacteriens. Les carbapenemes ont ete ajoutes a la liste des classes d'antibacteriens les plus utilisees en 2015. D'apres la classification de l'OMS, les antibacteriens les plus frequemment employes appartenaient a la categorie Watch: leur usage a sensiblement augmente, passant de 61,3% (29,9/48,8) en 2013 a 64,1% (24,4/38,0) en 2021 (P < 0,001). Conclusion Lemploi d'antibacteriens en milieu hospitalier a connu une forte baisse au cours de la periode d'etude. Cependant, le pourcentage d'utilisation croissant des antibacteriens de dernier recours est inquietant, tout comme l'important decalage entre le pourcentage d'antibacteriens utilises appartenant a la categorie Access et la cible mondiale de l'OMS, qui consiste a ne pas depasser les 60%. Objetivo Analizar las tendencias y patrones en el uso de antibacterianos en pacientes hospitalizados en hospitales de atencion terciaria y secundaria de China entre 2013 y 2021. Metodos El analisis incluyo datos trimestrales de hospitales cubiertos a traves del Center for Antibacterial Surveillance (Centro de Vigilancia Antibacteriana) de China. Se obtuvo informacion sobre las caracteristicas de los hospitales (por ejemplo, la provincia, un codigo de hospital anonimo, el nivel del hospital y los dias de hospitalizacion) y las caracteristicas de los antibacterianos (por ejemplo, el nombre generico, la clasificacion del farmaco, la dosis, la via de administracion y el volumen de uso). Se cuantifico el uso de antibacterianos como el numero de dosis diarias definidas por cada 100 pacientes-dia. El analisis tuvo en cuenta la clasificacion de antibioticos Access (Acceso), Watch (Vigilancia) y Reserve (Reserva) de la Organizacion Mundial de la Salud (OMS). Resultados Entre 2013 y 2021, el uso general de antibacterianos en pacientes hospitalizados disminuyo de manera significativa de 48,8 a 38,0 dosis diarias definidas por cada 100 pacientes-dia (p < 0,001). En 2021, la variacion entre provincias fue de casi el doble: 29,1 dosis diarias definidas por cada 100 pacientes-dia en Qinghai frente a 55,3 en Tibet. Los antibacterianos mas utilizados tanto en hospitales de atencion terciaria como secundaria durante todo el periodo de estudio fueron las cefalosporinas de tercera generacion, que representaron alrededor de un tercio del uso total de antibacterianos. Los carbapenemicos se incorporaron a la lista de antibacterianos mas utilizados en 2015. Los antibacterianos mas utilizados en la clasificacion de la OMS pertenecian al grupo Watch: el uso aumento a un ritmo significativo del 61,3 % (29,9/48,8) en 2013 al 64,1 % (24,4/38,0) en 2021 (p < 0,001). Conclusion El uso de antibacterianos en pacientes hospitalizados disminuyo en gran medida durante el periodo de estudio. Sin embargo, el aumento del porcentaje de antibacterianos de ultimo recurso utilizado es preocupante, al igual que la gran diferencia entre el porcentaje de antibacterianos utilizados pertenecientes al grupo Access y el objetivo global de la OMS de no menos del 60 %., Introduction The use of antibacterial drugs is a key driver of antibiotic resistance. (1) China is one of the largest producers and consumers of antibacterials worldwide and, in recent decades, [...]

Based on the quantum valley Hall effect analogy, this work proposes a phononic crystal plate with ligament-type beams to obtain the topological valley transmission of elastic waves. A pure Bragg degenerate state appears in the high-frequency region with a resonator introduced. By rotating the central scatterer and the beams, the mirror symmetry is broken to form a topological bandgap. Subsequently, this work finds that two selective edge states also appear beside the commonly non-trivial crossing edge states in the topological bandgap by calculating the projected band and eigenvalue spectrum of the supercell with different valley Hall phases phononic crystals. Their appearance is due to band separation of the topological edge states caused by an increase in the rotation angle. Both selective edge states can transmit topologically in specific paths. They will help further to broaden the width of the frequency band of topological transmission. Besides, an elastic wave splitter is designed and demonstrated numerically, which can form two channels and three channels in different frequency bands. With the topological selective edge state disappearing, a topological corner state exists in the edge bandgap. This work provides a theoretical reference for practical applications of broadband elastic wave topological transmission and elastic energy trapping. [ABSTRACT FROM AUTHOR]

Abstract In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines. However, there is still no effective strategy to regulate macrophages because of the difficulty and complexity of macrophage inflammatory phenotypic modulation and the insufficient therapeutic efficacy caused by the extracellular matrix (ECM) barrier. Here, AC73 and siUSP1 dual drug‐loaded lipid nanoparticle is designed to carry milk fat globule epidermal growth factor 8 (MFG‐E8) (named MUA/Y) to effectively inhibit macrophage proinflammatory signals and degrade the ECM barrier. MFG‐E8 is released in response to the high reactive oxygen species (ROS) environment in LF, transforming macrophages from a proinflammatory (M1) to an anti‐inflammatory (M2) phenotype and inducing macrophages to phagocytose collagen. Collagen ablation increases AC73 and siUSP1 accumulation in hepatic stellate cells (HSCs) and inhibits HSCs overactivation. Interestingly, complete resolution of liver inflammation, significant collagen degradation, and HSCs deactivation are observed in methionine choline deficiency (MCD) and CCl4 models after tail vein injection of MUA/Y. Overall, this work reveals a macrophage‐focused regulatory treatment strategy to eliminate LF progression at the source, providing a new perspective for the clinical treatment of advanced LF.

Absrtact: Mechanical alloying method was applied to synthesize Ni–Ti coatings on 316L stainless steel substrates. Effects of milling parameters on microstructures, microhardnesses, wear and corrosion resistances of the coatings were investigated. Formation mechanism of the coating was elucidated. The as-synthesized coatings possessed inner layers with composite lamellar structures and outer alloyed layers. The coating grew in certain milling time and then flaked with further milling, which was closely in relation to the particle ductility and the heat levels accumulated with the particle deformations and the ball frictions. The coating thickness and roughness were improved with the increase of rotational speed. The higher rotational speed promoted the plastic deformation, cold welding and hardening of the particles, which was conductive to the coating deposition in the initial milling process but advanced the peeling process in the shorter milling time. The coating microhardness was improved with its growth, which reached about 2 times of the substrate microhardeness. The wear resistance was improved because of the as-synthesized coatings, which were proportional to their surface microhardnesses. The corrosion resistances of the as-synthesized coatings increased with the suitable increase of milling time and then they decreased with further milling. The increase of the rotational speed favored the improvement of corrosion resistance. In general, the coating prepared at the rotational speed of 350 r/min for 13 h possessed both favorable microstructure and properties, which could protect the substrate from severely worn or corroded effectively.

Pulmonary fibrosis (PF) is an interstitial lung disease with complex pathological mechanism, and there is currently a lack of therapeutics that can heal it completely. Using gene therapy with drugs provides promising therapeutic strategies for synergistically reversing PF. However, improving the intracellular accumulation and transfection efficiency of therapeutic nucleic acids is still a critical issue that urgently needs to be addressed. Herein, we developed lipid nanoparticles (PEDPs) with high transfection efficiency coloaded with pDNA of nuclear factor erythroid 2-related factor 2 (pNrf2) and pirfenidone (PFD) for PF therapy. PEDPs can penetrate biological barriers, accumulate at the target, and exert therapeutic effects, eventually alleviating the oxidative stress imbalance in type II alveolar epithelial cells (AECs II) and inhibiting myofibroblast overactivation through the synergistic effects of Nrf2 combined with PFD, thus reversing PF. In addition, we systematically engineered various liposomes (LNPs), demonstrated that reducing the polyethylene glycol (PEG) proportion could significantly improve the uptake and transfection efficiency of the LNPs, and proposed a possible mechanism for this influence. This study clearly reveals that controlling the composition ratio of PEG in PEDPs can efficiently deliver therapeutics into AECs II, improve pNrf2 transfection, and synergize with PFD in a prospective strategy to reverse PF.