The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV c...The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.展开更多
With the growing emphasis on maternal and child oral health,the significance of managing oral health across preconception,pregnancy,and infancy stages has become increasingly apparent.Oral health challenges extend bey...With the growing emphasis on maternal and child oral health,the significance of managing oral health across preconception,pregnancy,and infancy stages has become increasingly apparent.Oral health challenges extend beyond affecting maternal wellbeing,exerting profound influences on fetal and neonatal oral development as well as immune system maturation.This expert consensus paper,developed using a modified Delphi method,reviews current research and provides recommendations on maternal and child oral health management.It underscores the critical role of comprehensive oral assessments prior to conception,diligent oral health management throughout pregnancy,and meticulous oral hygiene practices during infancy.Effective strategies should be seamlessly integrated across the life course,encompassing preconception oral assessments,systematic dental care during pregnancy,and routine infant oral hygiene.Collaborative efforts among pediatric dentists,maternal and child health workers,and obstetricians are crucial to improving outcomes and fostering clinical research,contributing to evidence-based health management strategies.展开更多
提出一种基于多重信号分类算法(multiple signal classification,MUSIC)和可控响应功率(steered power response,SRP)声源定位算法的变压器局部放电故障定位方法。首先利用MUSIC算法对变压器内高低压绕组匝间局部放电进行测向,测向结果...提出一种基于多重信号分类算法(multiple signal classification,MUSIC)和可控响应功率(steered power response,SRP)声源定位算法的变压器局部放电故障定位方法。首先利用MUSIC算法对变压器内高低压绕组匝间局部放电进行测向,测向结果考虑误差范围可有效缩小SRP算法的搜索空间。然后利用SRP算法在缩小后的搜索空间内对局部放电进行定位,SRP算法的定位精度随搜索空间的缩小有显著提高。在此基础上,应用研制的光纤超声传感器阵列,对变压器高低压绕组匝间局部放电进行的定位仿真和实验结果表明,相较于SRP算法,MUSIC-SRP算法的定位精度有极大提高,验证了该方法的有效性。展开更多
TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adu...TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.展开更多
Investigation of metal–organic frameworks(MOFs)for biomedical applications has attracted much attention in recent years.MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined s...Investigation of metal–organic frameworks(MOFs)for biomedical applications has attracted much attention in recent years.MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined structure,ultrahigh surface area and porosity,tunable pore size,and easy chemical functionalization.In this review,the unique properties of MOFs and their advantages as nanocarriers for drug delivery in biomedical applications were discussed in the first section.Then,state-ofthe-art strategies to functionalize MOFs with therapeutic agents were summarized,including surface adsorption,pore encapsulation,covalent binding,and functional molecules as building blocks.In the third section,the most recent biological applications of MOFs for intracellular delivery of drugs,proteins,and nucleic acids,especially aptamers,were presented.Finally,challenges and prospects were comprehensively discussed to provide context for future development of MOFs as efficient drug delivery systems.展开更多
Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic a...Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.展开更多
There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transfo...There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transforming growth factor-β(TGF-β)signalling in the cartilage and subchondral bone of the TMJ using a temporomandibular joint disorder(TMD) rat model, an ageing mouse model and a Camurati–Engelmann disease(CED) mouse model. In the three animal models, the subchondral bone phenotypes in the mandibular condyles were evaluated by μCT, and changes in TMJ condyles were examined by TRAP staining and immunohistochemical analysis of Osterix and p-Smad2/3. Condyle degradation was confirmed by Safranin O staining, the Mankin and OARSI scoring systems and type X collagen(Col X), p-Smad2/3 a and Osterix immunohistochemical analyses. We found apparent histological phenotypes of TMJ-OA in the TMD, ageing and CED animal models, with abnormal activation of TGF-βsignalling in the condylar cartilage and subchondral bone. Moreover, inhibition of TGF-β receptor I attenuated TMJ-OA progression in the TMD models. Therefore, aberrant activation of TGF-β signalling could be a key player in TMJ-OA development.展开更多
Once pulp necrosis or apical periodontitis occurs on immature teeth,the weak root and open root apex are challenging to clinicians.Berberine(BBR)is a potential medicine for bone disorders,therefore,we proposed to appl...Once pulp necrosis or apical periodontitis occurs on immature teeth,the weak root and open root apex are challenging to clinicians.Berberine(BBR)is a potential medicine for bone disorders,therefore,we proposed to apply BBR in root canals to enhance root repair in immature teeth.An in vivo model of immature teeth with apical periodontitis was established in rats,and root canals were filled with BBR,calcium hydroxide or sterilized saline for 3 weeks.The shape of the roots was analyzed by micro-computed tomography and histological staining.In vitro,BBR was introduced into stem cells from apical papilla(SCAPs).Osteogenic differentiation of stem cells from apical papilla was investigated by alkaline phosphatase activity,mineralization ability,and gene expression of osteogenic makers.The signaling pathway,which regulated the osteogenesis of SCAPs was evaluated by quantitative real time PCR,Western blot analysis,and immunofluorescence.In rats treated with BBR,more tissue was formed,with longer roots,thicker root walls,and smaller apex diameters.In addition,we found that BBR promoted SCAPs osteogenesis in a time-dependent and concentration-dependent manner.BBR induced the expression ofβ-catenin and enhancedβ-catenin entering into the nucleus,to up-regulate more runt-related nuclear factor 2 downstream.BBR enhanced root repair in immature teeth with apical periodontitis by activating the canonical Wnt/β-catenin pathway in SCAPs.展开更多
PTH-related peptide(PTHr P) improves the bone marrow micro-environment to activate the bone-remodelling, but the coordinated regulation of PTHr P and transforming growth factor-β(TGFβ) signalling in TMJ-OA remains i...PTH-related peptide(PTHr P) improves the bone marrow micro-environment to activate the bone-remodelling, but the coordinated regulation of PTHr P and transforming growth factor-β(TGFβ) signalling in TMJ-OA remains incompletely understood. We used disordered occlusion to establish model animals that recapitulate the ordinary clinical aetiology of TMJ-OA. Immunohistochemical and histological analyses revealed condylar fibrocartilage degeneration in model animals following disordered occlusion. TMJ-OA model animals administered intermittent PTHr P(i PTH) exhibited significantly decreased condylar cartilage degeneration. Micro-CT,histomorphometry, and Western Blot analyses disclosed that i PTH promoted subchondral bone formation in the TMJ-OA model animals. In addition, i PTH increased the number of osterix(OSX)-positive cells and osteocalcin(OCN)-positive cells in the subchondral bone marrow cavity. However, the number of osteoclasts was also increased by i PTH, indicating that subchondral bone volume increase was mainly due to the i PTH-mediated increase in the bone-formation ability of condylar subchondral bone.In vitro, PTHr P treatment increased condylar subchondral bone marrow-derived mesenchymal stem cell(SMSC) osteoblastic differentiation potential and upregulated the gene and protein expression of key regulators of osteogenesis. Furthermore, we found that PTHr P-PTH1R signalling inhibits TGFβ signalling during osteoblastic differentiation. Collectively, these data suggested that i PTH improves OA lesions by enhancing osteoblastic differentiation in subchondral bone and suppressing aberrant active TGFβsignalling. These findings indicated that PTHr P, which targets the TGFβ signalling pathway, may be an effective biological reagent to prevent and treat TMJ-OA in the clinic.展开更多
Homoeostasis depends on the close connection and intimate molecular exchange between extracellular, intracellular and intercellular networks. Intercellular communication is largely mediated by gap junctions(GJs), a ty...Homoeostasis depends on the close connection and intimate molecular exchange between extracellular, intracellular and intercellular networks. Intercellular communication is largely mediated by gap junctions(GJs), a type of specialized membrane contact composed of variable number of channels that enable direct communication between cells by allowing small molecules to pass directly into the cytoplasm of neighbouring cells. Although considerable evidence indicates that gap junctions contribute to the functions of many organs, such as the bone, intestine, kidney, heart, brain and nerve, less is known about their role in oral development and disease. In this review, the current progress in understanding the background of connexins and the functions of gap junctions in oral development and diseases is discussed. The homoeostasis of tooth and periodontal tissues, normal tooth and maxillofacial development, saliva secretion and the integrity of the oral mucosa depend on the proper function of gap junctions.Knowledge of this pattern of cell–cell communication is required for a better understanding of oral diseases. With the everincreasing understanding of connexins in oral diseases, therapeutic strategies could be developed to target these membrane channels in various oral diseases and maxillofacial dysplasia.展开更多
Osteoporosis is a common disease that affects patient quality of life,especially among the elderly population.Although inflammation contributes significantly to osteoporosis,the underlying mechanism is unclear.In this...Osteoporosis is a common disease that affects patient quality of life,especially among the elderly population.Although inflammation contributes significantly to osteoporosis,the underlying mechanism is unclear.In this study,we found that tumor necrosis factor(TNF)-a,an inflammatory environment mimic,inhibits osteogenesis of bone mesenchymal stem ceils(BMSCs),induces miR-146a and decreases Smad4.Moreover,overexpression of miR-146a inhibited the osteogenic ability of BMSCs,whereas blocking miR-146a partially rescued the osteogenesis deficiency under TNF-a treatment.Molecularly,miR-146a decreased Smad4 expression at the protein level by binding to an element located in the Smad43'-untranslated region,and restoration of Smad4 reversed the inhibitory effects of miR-146a on osteogenesis.Together,our results showed that the inflammatory environment mimic TNF-ol inhibits osteogenesis via upregulation of miR-146a and subsequent downregulation of Smad4,thus suggesting that therapeutic manipulation of miR-146a maybe a potential strategy to improve osteogenesis in the context of osteoporosis.展开更多
Apical periodontitis, dominated by dense inflammatory infiltrates and increased osteoclast activities, can lead to alveolar bone destruction and tooth loss. It is believed that miRNA participates in regulating various...Apical periodontitis, dominated by dense inflammatory infiltrates and increased osteoclast activities, can lead to alveolar bone destruction and tooth loss. It is believed that miRNA participates in regulating various biological processes, osteoclastogenesis included. This study aims to investigate the differential expression of miRNAs in rat apical periodontitis and explore their functional target genes. Microarray analysis was used to identify differentially expressed miRNAs in apical periodontitis. Bioinformatics technique was applied for predicting the target genes of differentially expressed miRNAs and their biological functions. The result provided us with an insight into the potential biological effects of the differentially expressed miRNAs and showed particular enrichment of target genes involved in the MAPK signaling pathways. These findings may highlight the intricate and specific roles of miRNA in inflammation and osteoclastogenesis, both of which are key aspects of apical periodontitis, thus contributing to the future investigation into the etiology, under- lying mechanism and treatment of apical periodontitis.展开更多
Bone remodelling keeps going through the lifespan of human by bone formation and bone resorption.In the craniofacial region,mandibles act as the main force for biting and chewing,and also become susceptible to a commo...Bone remodelling keeps going through the lifespan of human by bone formation and bone resorption.In the craniofacial region,mandibles act as the main force for biting and chewing,and also become susceptible to a common bone-loss disease,namely,apical periodontitis,once infected dental pulp is not treated timely,during which bone resorption occurs from the apical foramen to the apical bone area.Although conventional root canal treatment(RCT)can remove the most of the infection,chronical apical periodontitis due to incomplete removal of dental pulp and subsequent microleakage will become refractory and more challenging,and this process has scarcely been specifically studied as a bone remodelling issue in rat models.Therefore,to study chronical and refractory apical periodontitis owing to incomplete cleaning of infected dental pulp and microleackage in vivo,we establish a modified rat model of gradually progressive apical periodontitis by sealing residual necrotic dental pulp and introducing limited saliva,which simulates gradually progressive apical periodontitis,as observed in the clinical treatment of chronical and refractory apical periodontitis.We show that bone-loss is inevitable and progressive in this case of apical periodontitis,which confirms again that complete and sound root canal treatment is crucial to halt the progression of chronical and refractory apical periodontitis and promote bone formation.Interestingly,bone remodelling was enhanced at the initial stage of apical periodontitis in this model while reduced with a high osteoblast number afterwards,as shown by the time course study of the modified model.Suggesting that the pathological apical microenvironment reserve its hard tissue formation ability to some degree but in a disturbed manner.Hopefully,our findings can provide insights for future bone regenerative treatment for apical periodontitisassociated bone loss.展开更多
Dear Editor,Hepatitis B virus(HBV)infection remains a major cause of liver diseases worldwide,which affects approximately 250 million people globally(Yuen et al.2018).Individuals with chronic HBV infection are at high...Dear Editor,Hepatitis B virus(HBV)infection remains a major cause of liver diseases worldwide,which affects approximately 250 million people globally(Yuen et al.2018).Individuals with chronic HBV infection are at high risk of developing liver cirrhosis,and ultimately hepatocellular carcinoma(HCC).HBV is a Hepadnavirus DNA virus,which specifically infects and efficiently replicates in hepatocytes.It has been proposed for decades that HBV replicates preferentially in non-dividing quiescent hepatocytes(Ozer et al.1996).展开更多
Postmenopausal osteoporosis （PMO） is a prevalent metabolic bone disease characterized by bone loss and structural destruction, which increases the risk of fracture in postmenopausal women. Owing to the high morbidit...Postmenopausal osteoporosis （PMO） is a prevalent metabolic bone disease characterized by bone loss and structural destruction, which increases the risk of fracture in postmenopausal women. Owing to the high morbidity and serious complications of PMO, many efforts have been devoted to its prophylaxis and treatment. The intestinal microbiota is the complex community of microorganisms colonizing the gastrointestinal tract. Probiotics, which are dietary or medical supplements consisting of beneficial intestinal bacteria, work in concert with endogenous intestinal microorganisms to maintain host health. Recent studies have revealed that bone loss in PMO is closely related to host immunity, which is influenced by the intestinal microbiota. The curative effects of probiotics on metabolic bone diseases have also been demonstrated. The effects of the intestinal microbiota on bone metabolism suggest a promising target for PMO management. This review seeks to summarize the critical effects of the intestinal microbiota and probiotics on PMO, with a focus on the molecular mechanisms underlying the pathogenic relationship between bacteria and host, and to define the possible treatment options.展开更多
Brassinosteroid is an important hormone that interacts with auxin and gibberellin to regulate plant growth and development. However,there is currently a relative lack of information regarding brassinosteroid in apple....Brassinosteroid is an important hormone that interacts with auxin and gibberellin to regulate plant growth and development. However,there is currently a relative lack of information regarding brassinosteroid in apple. Previous study confirmed that exogenous brassinosteroid treatments increased growth and endogenous brassinosteroid, auxin, as well as gibberellin levels of apple nursery trees. Here we succeeded to find that exogenous brassinosteroid treatments upregulated the transcript expression of auxin biosynthesis, transport, and positive signal transduction genes as well as gibberellin biosynthesis genes. In contrast, the application of exogenous brassinosteroid downregulated the expression of genes encoding negative regulators of auxin and gibberellin signal transductions. Rapid responses of several brassinosteroid-,auxin-, and gibberellin-related genes to the brassinosteroid and brassinazole treatments inferred the crosstalk of BR and IAA or GA. Furthermore,the expression levels of cell growth-related genes were also enhanced by exogenous brassinosteroid. Auxin and gibberellin treatments also influenced growth of apple tree and enhanced the expression of brassinosteroid-and cell growth-related genes. These results indicate that the growth of apple tree is regulated by the interaction between brassinosteroid, auxin, and gibberellin. Our work opened new avenues for deep portfolio of apple tree growth and laid the foundation for future studies aimed at elucidating the mechanisms regulating hormone interactionsmediated growth in apple trees.展开更多
Composing web services is gained daily attention in Service Oriented Computing. It includes the dynamic discovery, interaction and coordination of agent-based semantic web services. The authors first follow Function O...Composing web services is gained daily attention in Service Oriented Computing. It includes the dynamic discovery, interaction and coordination of agent-based semantic web services. The authors first follow Function Ontology and Automated Mechanism Design for service agents aggregating. Then the problem is formulated but it is ineffective to solve it from the traditional global view. Because the complexity is NP-complete and it is dii^cult or even impossible to get some personal information. This paper provides a multi-agent negotiation idea in which each participant negotiates under the condition of its reservation payoff being satisfied. Numerical experiment is given and well evaluates the negotiation.展开更多
As the system becomes more intelligent and embedded,the operating environment is gradually changed from closed,static,and controllable to more open,dynamic,and difficult to control.As a result,the design of complex so...As the system becomes more intelligent and embedded,the operating environment is gradually changed from closed,static,and controllable to more open,dynamic,and difficult to control.As a result,the design of complex software systems is faced with many challenges arising from the uncertainty of the environment(UoE).On the one hand,ignoring the UoE to manually describe requirements is not only a tough job,but it can also hinder the discovery of potential requirements;on the other hand,it is a challenge to integrate the representation of and reasoning of UoE into the process of modeling complex systems.Based on the analysis of the characteristics of complex systems engineering,this paper takes solving the UoE caused by stakeholders prefer-ences and complex environment context as the entry point and designs a fuzzy con-trol decision-making framework.Specifically,the framework contributes to the spiral of complex systems while solving the UoE by constructing a closed-loop intelligent sys-tem based on automatic data flow between information space and physical space for environment sensing,uncertainty analysis,requirements mining,fuzzy reasoning,deci-sion execution as well as feedback optimization.Finally,the framework is validated with a concrete example of an adaptive treadmill system based on the support tools developed.展开更多
基金supported by the National Key R&D Program of China(No.2022YFA1303600 and No.2023YFC2306800)the National Natural Science Foundation of China(No.82372235 and No.82272315)the Sanming Project of Medicine in Shenzhen(No.SZSM202311032).
文摘The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.
基金supported by grants from the National Natural Science Foundation of China(82270958)the Major Science and Technology Projects in Yunnan Province(202302AA310038)the National Key Clinical Specialty Development Project of Pediatric Dentistry Division of China(20230610)。
文摘With the growing emphasis on maternal and child oral health,the significance of managing oral health across preconception,pregnancy,and infancy stages has become increasingly apparent.Oral health challenges extend beyond affecting maternal wellbeing,exerting profound influences on fetal and neonatal oral development as well as immune system maturation.This expert consensus paper,developed using a modified Delphi method,reviews current research and provides recommendations on maternal and child oral health management.It underscores the critical role of comprehensive oral assessments prior to conception,diligent oral health management throughout pregnancy,and meticulous oral hygiene practices during infancy.Effective strategies should be seamlessly integrated across the life course,encompassing preconception oral assessments,systematic dental care during pregnancy,and routine infant oral hygiene.Collaborative efforts among pediatric dentists,maternal and child health workers,and obstetricians are crucial to improving outcomes and fostering clinical research,contributing to evidence-based health management strategies.
文摘提出一种基于多重信号分类算法(multiple signal classification,MUSIC)和可控响应功率(steered power response,SRP)声源定位算法的变压器局部放电故障定位方法。首先利用MUSIC算法对变压器内高低压绕组匝间局部放电进行测向,测向结果考虑误差范围可有效缩小SRP算法的搜索空间。然后利用SRP算法在缩小后的搜索空间内对局部放电进行定位,SRP算法的定位精度随搜索空间的缩小有显著提高。在此基础上,应用研制的光纤超声传感器阵列,对变压器高低压绕组匝间局部放电进行的定位仿真和实验结果表明,相较于SRP算法,MUSIC-SRP算法的定位精度有极大提高,验证了该方法的有效性。
基金supported by U.S. National Institutes of Health grants (AR063943 and DK057501 to X.C. AR064833 to J.L.C.)+3 种基金the National Natural Science Foundation of China (81771099 to X.X.)the Key Project for Frontier Research of Science and Technology Department of Sichuan Province (2016JY0006 to X.Z.)Sichuan Province Science and Technology Innovation Team Program (2017TD0016 to Q.Y.).X.X.supported by the visiting scholar fellowship from West China Hospital of Stomatology, Sichuan University
文摘TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.
基金supported by the National Natural Science Foundation of China(Grant No.21827811)Research and development plan of key areas in Hunan Province(Grant No.2019SK2201)Innovation science and technology plan of Hunan Province(Grant No.2017XK2103).
文摘Investigation of metal–organic frameworks(MOFs)for biomedical applications has attracted much attention in recent years.MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined structure,ultrahigh surface area and porosity,tunable pore size,and easy chemical functionalization.In this review,the unique properties of MOFs and their advantages as nanocarriers for drug delivery in biomedical applications were discussed in the first section.Then,state-ofthe-art strategies to functionalize MOFs with therapeutic agents were summarized,including surface adsorption,pore encapsulation,covalent binding,and functional molecules as building blocks.In the third section,the most recent biological applications of MOFs for intracellular delivery of drugs,proteins,and nucleic acids,especially aptamers,were presented.Finally,challenges and prospects were comprehensively discussed to provide context for future development of MOFs as efficient drug delivery systems.
基金supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers AR071432 and AR063943
文摘Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.
基金supported by 2016JQ0054 and NSFC grants 81470711 to L.Z.National Key Research and Development Program of China 2016YFC1102700 to X.Z.
文摘There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transforming growth factor-β(TGF-β)signalling in the cartilage and subchondral bone of the TMJ using a temporomandibular joint disorder(TMD) rat model, an ageing mouse model and a Camurati–Engelmann disease(CED) mouse model. In the three animal models, the subchondral bone phenotypes in the mandibular condyles were evaluated by μCT, and changes in TMJ condyles were examined by TRAP staining and immunohistochemical analysis of Osterix and p-Smad2/3. Condyle degradation was confirmed by Safranin O staining, the Mankin and OARSI scoring systems and type X collagen(Col X), p-Smad2/3 a and Osterix immunohistochemical analyses. We found apparent histological phenotypes of TMJ-OA in the TMD, ageing and CED animal models, with abnormal activation of TGF-βsignalling in the condylar cartilage and subchondral bone. Moreover, inhibition of TGF-β receptor I attenuated TMJ-OA progression in the TMD models. Therefore, aberrant activation of TGF-β signalling could be a key player in TMJ-OA development.
文摘Once pulp necrosis or apical periodontitis occurs on immature teeth,the weak root and open root apex are challenging to clinicians.Berberine(BBR)is a potential medicine for bone disorders,therefore,we proposed to apply BBR in root canals to enhance root repair in immature teeth.An in vivo model of immature teeth with apical periodontitis was established in rats,and root canals were filled with BBR,calcium hydroxide or sterilized saline for 3 weeks.The shape of the roots was analyzed by micro-computed tomography and histological staining.In vitro,BBR was introduced into stem cells from apical papilla(SCAPs).Osteogenic differentiation of stem cells from apical papilla was investigated by alkaline phosphatase activity,mineralization ability,and gene expression of osteogenic makers.The signaling pathway,which regulated the osteogenesis of SCAPs was evaluated by quantitative real time PCR,Western blot analysis,and immunofluorescence.In rats treated with BBR,more tissue was formed,with longer roots,thicker root walls,and smaller apex diameters.In addition,we found that BBR promoted SCAPs osteogenesis in a time-dependent and concentration-dependent manner.BBR induced the expression ofβ-catenin and enhancedβ-catenin entering into the nucleus,to up-regulate more runt-related nuclear factor 2 downstream.BBR enhanced root repair in immature teeth with apical periodontitis by activating the canonical Wnt/β-catenin pathway in SCAPs.
基金NSFC grant(82170921,81771033)the Department of Science and Technology of Sichuan Province(2016JQ0054)to L.Z.The Yunnan Provincial Department of Science and Technology-Kunming Medical University granted a basic research joint special fund project(202001AY070001-151)to J.Z.
文摘PTH-related peptide(PTHr P) improves the bone marrow micro-environment to activate the bone-remodelling, but the coordinated regulation of PTHr P and transforming growth factor-β(TGFβ) signalling in TMJ-OA remains incompletely understood. We used disordered occlusion to establish model animals that recapitulate the ordinary clinical aetiology of TMJ-OA. Immunohistochemical and histological analyses revealed condylar fibrocartilage degeneration in model animals following disordered occlusion. TMJ-OA model animals administered intermittent PTHr P(i PTH) exhibited significantly decreased condylar cartilage degeneration. Micro-CT,histomorphometry, and Western Blot analyses disclosed that i PTH promoted subchondral bone formation in the TMJ-OA model animals. In addition, i PTH increased the number of osterix(OSX)-positive cells and osteocalcin(OCN)-positive cells in the subchondral bone marrow cavity. However, the number of osteoclasts was also increased by i PTH, indicating that subchondral bone volume increase was mainly due to the i PTH-mediated increase in the bone-formation ability of condylar subchondral bone.In vitro, PTHr P treatment increased condylar subchondral bone marrow-derived mesenchymal stem cell(SMSC) osteoblastic differentiation potential and upregulated the gene and protein expression of key regulators of osteogenesis. Furthermore, we found that PTHr P-PTH1R signalling inhibits TGFβ signalling during osteoblastic differentiation. Collectively, these data suggested that i PTH improves OA lesions by enhancing osteoblastic differentiation in subchondral bone and suppressing aberrant active TGFβsignalling. These findings indicated that PTHr P, which targets the TGFβ signalling pathway, may be an effective biological reagent to prevent and treat TMJ-OA in the clinic.
基金supported by the National Natural Science Foundation of China(81600840,81771047 to J.X.)。
文摘Homoeostasis depends on the close connection and intimate molecular exchange between extracellular, intracellular and intercellular networks. Intercellular communication is largely mediated by gap junctions(GJs), a type of specialized membrane contact composed of variable number of channels that enable direct communication between cells by allowing small molecules to pass directly into the cytoplasm of neighbouring cells. Although considerable evidence indicates that gap junctions contribute to the functions of many organs, such as the bone, intestine, kidney, heart, brain and nerve, less is known about their role in oral development and disease. In this review, the current progress in understanding the background of connexins and the functions of gap junctions in oral development and diseases is discussed. The homoeostasis of tooth and periodontal tissues, normal tooth and maxillofacial development, saliva secretion and the integrity of the oral mucosa depend on the proper function of gap junctions.Knowledge of this pattern of cell–cell communication is required for a better understanding of oral diseases. With the everincreasing understanding of connexins in oral diseases, therapeutic strategies could be developed to target these membrane channels in various oral diseases and maxillofacial dysplasia.
基金supported by the National Natural Science Foundation of China(81570803)Guangzhou Foundation for Science and Technology Planning Project,China(201704030083)+1 种基金Science and Technology Planning Project of Guangdong Province,China(2017A050501013)the Fundamental Research Funds for the Central Universities(17ykjc21)
文摘Osteoporosis is a common disease that affects patient quality of life,especially among the elderly population.Although inflammation contributes significantly to osteoporosis,the underlying mechanism is unclear.In this study,we found that tumor necrosis factor(TNF)-a,an inflammatory environment mimic,inhibits osteogenesis of bone mesenchymal stem ceils(BMSCs),induces miR-146a and decreases Smad4.Moreover,overexpression of miR-146a inhibited the osteogenic ability of BMSCs,whereas blocking miR-146a partially rescued the osteogenesis deficiency under TNF-a treatment.Molecularly,miR-146a decreased Smad4 expression at the protein level by binding to an element located in the Smad43'-untranslated region,and restoration of Smad4 reversed the inhibitory effects of miR-146a on osteogenesis.Together,our results showed that the inflammatory environment mimic TNF-ol inhibits osteogenesis via upregulation of miR-146a and subsequent downregulation of Smad4,thus suggesting that therapeutic manipulation of miR-146a maybe a potential strategy to improve osteogenesis in the context of osteoporosis.
基金supported by JCPT2011-9 and SKLODSCU 20130012 to XDZNSFC grant 81200760 and SKLODSCU 20130014 to LWZ
文摘Apical periodontitis, dominated by dense inflammatory infiltrates and increased osteoclast activities, can lead to alveolar bone destruction and tooth loss. It is believed that miRNA participates in regulating various biological processes, osteoclastogenesis included. This study aims to investigate the differential expression of miRNAs in rat apical periodontitis and explore their functional target genes. Microarray analysis was used to identify differentially expressed miRNAs in apical periodontitis. Bioinformatics technique was applied for predicting the target genes of differentially expressed miRNAs and their biological functions. The result provided us with an insight into the potential biological effects of the differentially expressed miRNAs and showed particular enrichment of target genes involved in the MAPK signaling pathways. These findings may highlight the intricate and specific roles of miRNA in inflammation and osteoclastogenesis, both of which are key aspects of apical periodontitis, thus contributing to the future investigation into the etiology, under- lying mechanism and treatment of apical periodontitis.
基金supported by the National Natural Science Foundation of China(Grant No.81371136)to X.Z.National Natural Science Foundation of China(Grant No.81771033)to L.Z
文摘Bone remodelling keeps going through the lifespan of human by bone formation and bone resorption.In the craniofacial region,mandibles act as the main force for biting and chewing,and also become susceptible to a common bone-loss disease,namely,apical periodontitis,once infected dental pulp is not treated timely,during which bone resorption occurs from the apical foramen to the apical bone area.Although conventional root canal treatment(RCT)can remove the most of the infection,chronical apical periodontitis due to incomplete removal of dental pulp and subsequent microleakage will become refractory and more challenging,and this process has scarcely been specifically studied as a bone remodelling issue in rat models.Therefore,to study chronical and refractory apical periodontitis owing to incomplete cleaning of infected dental pulp and microleackage in vivo,we establish a modified rat model of gradually progressive apical periodontitis by sealing residual necrotic dental pulp and introducing limited saliva,which simulates gradually progressive apical periodontitis,as observed in the clinical treatment of chronical and refractory apical periodontitis.We show that bone-loss is inevitable and progressive in this case of apical periodontitis,which confirms again that complete and sound root canal treatment is crucial to halt the progression of chronical and refractory apical periodontitis and promote bone formation.Interestingly,bone remodelling was enhanced at the initial stage of apical periodontitis in this model while reduced with a high osteoblast number afterwards,as shown by the time course study of the modified model.Suggesting that the pathological apical microenvironment reserve its hard tissue formation ability to some degree but in a disturbed manner.Hopefully,our findings can provide insights for future bone regenerative treatment for apical periodontitisassociated bone loss.
基金This work was supported by the National S&T Major Project for Infectious Diseases of China(Nos.2017ZX10202202,2017ZX10202203)Beijing Natural Science Foundation(7182079).
文摘Dear Editor,Hepatitis B virus(HBV)infection remains a major cause of liver diseases worldwide,which affects approximately 250 million people globally(Yuen et al.2018).Individuals with chronic HBV infection are at high risk of developing liver cirrhosis,and ultimately hepatocellular carcinoma(HCC).HBV is a Hepadnavirus DNA virus,which specifically infects and efficiently replicates in hepatocytes.It has been proposed for decades that HBV replicates preferentially in non-dividing quiescent hepatocytes(Ozer et al.1996).
基金supported by the National Natural Science Foundation of China(grant numbers 81430011,81470711,and 81670978)the Brilliant Young Investigator Award,Sichuan University(grant number 2015SCU04A16)
文摘Postmenopausal osteoporosis （PMO） is a prevalent metabolic bone disease characterized by bone loss and structural destruction, which increases the risk of fracture in postmenopausal women. Owing to the high morbidity and serious complications of PMO, many efforts have been devoted to its prophylaxis and treatment. The intestinal microbiota is the complex community of microorganisms colonizing the gastrointestinal tract. Probiotics, which are dietary or medical supplements consisting of beneficial intestinal bacteria, work in concert with endogenous intestinal microorganisms to maintain host health. Recent studies have revealed that bone loss in PMO is closely related to host immunity, which is influenced by the intestinal microbiota. The curative effects of probiotics on metabolic bone diseases have also been demonstrated. The effects of the intestinal microbiota on bone metabolism suggest a promising target for PMO management. This review seeks to summarize the critical effects of the intestinal microbiota and probiotics on PMO, with a focus on the molecular mechanisms underlying the pathogenic relationship between bacteria and host, and to define the possible treatment options.
基金sponsored by the Chinese Postdoctoral Science Foundation (2015K3080215822)the Ecological Adaptability Selection of Apple Superior Stock and Scion Combinations in the Loess Plateau (A2990215082)+5 种基金the Screening and Interaction Molecular Mechanism of Apple Stock and Scion Combinations (K3380217027)the National Apple Industry Technology System of the Agriculture Ministry of China (CARS-27)the National Spark Plan Program (2014GA850002)the Science and Technology Innovative Engineering Project in Shaanxi Province of China (2015NY114)the Innovation Project of Science and Technology of Shaanxi Province (2016TZC-N-11-6)the Key Research Project of Shaanxi Province (2017ZDXM-NY-019)
文摘Brassinosteroid is an important hormone that interacts with auxin and gibberellin to regulate plant growth and development. However,there is currently a relative lack of information regarding brassinosteroid in apple. Previous study confirmed that exogenous brassinosteroid treatments increased growth and endogenous brassinosteroid, auxin, as well as gibberellin levels of apple nursery trees. Here we succeeded to find that exogenous brassinosteroid treatments upregulated the transcript expression of auxin biosynthesis, transport, and positive signal transduction genes as well as gibberellin biosynthesis genes. In contrast, the application of exogenous brassinosteroid downregulated the expression of genes encoding negative regulators of auxin and gibberellin signal transductions. Rapid responses of several brassinosteroid-,auxin-, and gibberellin-related genes to the brassinosteroid and brassinazole treatments inferred the crosstalk of BR and IAA or GA. Furthermore,the expression levels of cell growth-related genes were also enhanced by exogenous brassinosteroid. Auxin and gibberellin treatments also influenced growth of apple tree and enhanced the expression of brassinosteroid-and cell growth-related genes. These results indicate that the growth of apple tree is regulated by the interaction between brassinosteroid, auxin, and gibberellin. Our work opened new avenues for deep portfolio of apple tree growth and laid the foundation for future studies aimed at elucidating the mechanisms regulating hormone interactionsmediated growth in apple trees.
基金This research is supported by the National Natural Science Fund for Distinguished Young Scholars of China under Grant No.60625204the Key Project of National Natural Science Foundation of China under Grant No.60736015+1 种基金the National 863 Hight-Tech Project of China under Grant No.2006AA01Z155the Knowledge Innovation Program of the Chinese Academy of Sciences
文摘Composing web services is gained daily attention in Service Oriented Computing. It includes the dynamic discovery, interaction and coordination of agent-based semantic web services. The authors first follow Function Ontology and Automated Mechanism Design for service agents aggregating. Then the problem is formulated but it is ineffective to solve it from the traditional global view. Because the complexity is NP-complete and it is dii^cult or even impossible to get some personal information. This paper provides a multi-agent negotiation idea in which each participant negotiates under the condition of its reservation payoff being satisfied. Numerical experiment is given and well evaluates the negotiation.
文摘As the system becomes more intelligent and embedded,the operating environment is gradually changed from closed,static,and controllable to more open,dynamic,and difficult to control.As a result,the design of complex software systems is faced with many challenges arising from the uncertainty of the environment(UoE).On the one hand,ignoring the UoE to manually describe requirements is not only a tough job,but it can also hinder the discovery of potential requirements;on the other hand,it is a challenge to integrate the representation of and reasoning of UoE into the process of modeling complex systems.Based on the analysis of the characteristics of complex systems engineering,this paper takes solving the UoE caused by stakeholders prefer-ences and complex environment context as the entry point and designs a fuzzy con-trol decision-making framework.Specifically,the framework contributes to the spiral of complex systems while solving the UoE by constructing a closed-loop intelligent sys-tem based on automatic data flow between information space and physical space for environment sensing,uncertainty analysis,requirements mining,fuzzy reasoning,deci-sion execution as well as feedback optimization.Finally,the framework is validated with a concrete example of an adaptive treadmill system based on the support tools developed.
