A high-resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration

Articular cartilage damage is a universal health problem.Despite recent progress,chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration.Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions,but the characteristics and intermediate molecular mechanisms remain unclear.In this study,we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation.We performed various assays,such as single-cell RNA sequencing(scRNA-seq),live-cell metabolic assays,and assays for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq),to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages.Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation,whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling.Using the chemical inhibitor BTB06584,we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss.Notably,this two-stage transition was also validated in human chondrocytes.An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers.Overall,this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.

Single cell analysis reveals inhibition of angiogenesis attenuates the progression of heterotopic ossification in Mkx^(−/−)mice

Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.

Composite Converter Combined APFC with Switched-capacitor Converter

To reduce switch numbers and voltage stress in semiconductor devices,this paper proposes a novel single-phase converter combined Active Power Factor Correction(APFC)with switched-capacitor converter.In addition,dynamic voltage regulation and voltage gain are improved by integrating the boost converter and switching capacitor cells.The interstage bulk capacitor is no longer needed.An average current control with redistribution of voltage in cells is proposed to obtain voltage lift ability of the switching capacitor cells and maintain a high-power factor.To study and verify the proposed converter preliminarily,theoretical analysis and simulation are presented in the paper.Furthermore,a 50o W prototype with two different configurations is built for experimental verification.The proposed converter can reach 95.62%of maximum efficiency,0.99 of power factor,and 3.55%of THD with 600 V output voltage,simultaneously.

Seamless and early gap healing of osteochondral defects by autologous mosaicplasty combined with bioactive supramolecular nanofiber-enabled gelatin methacryloyl(BSN-GelMA)hydrogel

Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice.Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regeneration without uneven surface,graft necrosis and sclerosis.However,poor gap integration is a serious concern,which eventually leads to deterioration of joint function.To deal with such complications,this study has developed a strategy to effectively enhance integration of the gap region following mosaicplasty by applying injectable bioactive supramolecular nanofiber-enabled gelatin methacryloyl(GelMA)hydrogel(BSN-GelMA).A rabbit osteochondral defect model demonstrated that BSN-GelMA achieved seamless osteochondral healing in the gap region between plugs of osteochondral defects following mosaicplasty,as early as six weeks.Moreover,the International Cartilage Repair Society score,histology score,glycosaminoglycan content,subchondral bone volume,and collagen II expression were observed to be the highest in the gap region of BSN-GelMA treated group.This improved outcome was due to bio-interactive materials,which acted as tissue fillers to bridge the gap,prevent cartilage degeneration,and promote graft survival and migration of bone marrow mesenchymal stem cells by releasing bioactive supramolecular nanofibers from the GelMA hydrogel.This study provides a powerful and applicable approach to improve gap integration after autologous mosaicplasty.It is also a promising off-the-shelf bioactive material for cell-free in situ tissue regeneration.

Epidemiological Characteristics of Human Brucellosis-China,2016−2019

Introduction:Brucellosis is an important zoonotic infectious disease with its main mode of transmission from livestock to humans.The study analyzed epidemiological characteristics of human brucellosis from 2016 to 2019 in China,aiming to understand progress of the National Program of Brucellosis Prevention and Control.Methods:The research obtained data on human brucellosis cases reported through China’s National Notifiable Disease Reporting System(NNDRS)from January 1,2016 to December 31,2019 and described brucellosis epidemiological patterns by region,seasonality,age,sex,and occupation.Results:The number of cases reported nationwide in China decreased from 47,139(3.4/100,000)in 2016 to 37,947(2.7/100,000)in 2018,and then increased to 44,036(3.2/100,000)in 2019,with an average annual incidence of 3.0/100,000 during the four study years.Brucellosis in Xinjiang declined from 35.6/100,000 in 2016 to 16.3/100,000 in 2019-an average annual decrease of 22.9%.Brucellosis in Inner Mongolia increased from 23.8/100,000 in 2016 to 54.4/100,000 in 2019-an average increase of 31.8%per year and accounting for 22%of all reported cases.Northern China reported 95.2%of cases during this period and still had an incidence of 7.2/100,000 and 87.0%of counties being affected by brucellosis in 2019.In this region in 2019,males aged 45-64 years old had an incidence of over 15.9/100,000,compared with over 7.0/100,000 among females aged 45-64 years old.Conclusions:Although there was progress in prevention and control of human brucellosis in some provincial-level administrative divisions(PLADs)in 2016 through 2019,progress was limited nationwide and there was an overall resurgence of brucellosis in 2019.The resurgence was primarily in Inner Mongolia.An One Health approach should be strengthened to ensure successful and sustainable brucellosis prevention and control in China.

Epidemiological Survey of First Human Brucellosis Outbreak Caused by the Sika Deer(Cervus nippon)—Guizhou Province,China,2019

Summary What is already known on this topic?Brucellosis is a zoonotic infectious disease caused by Brucella spp.The main source of infection in human brucellosis is sick animals,mainly including sheep,goat,and cattle,but sika deer(Cervus nippon)can also cause human brucellosis.The first human brucellosis case in Guizhou Province was reported in 2009,and no brucellosis outbreak was reported caused by sika deer ever before.

Investigation of Brucellosis Caused by Raw Goat Milk—Fujian Province,China,April–June,2019

Summary What is already known about this topic?Brucellosis is one of the most important zoonotic diseases in China.Goat milk and dairy products are essential pathways for foodborne transmission of brucellosis.Pasteurization can completely kill Brucella spp.in milk,and milk-borne transmission is mainly related to unhealthy dietary hygiene habits and insufficient epidemic control among animals.