Mechanical regulation of bone remodeling

Bone remodeling is a lifelong process that gives rise to a mature, dynamic bone structure via a balance between bone formation by osteoblasts and resorption by osteoclasts. These opposite processes allow the accommodation of bones to dynamic mechanical forces, altering bone mass in response to changing conditions. Mechanical forces are indispensable for bone homeostasis;skeletal formation, resorption, and adaptation are dependent on mechanical signals, and loss of mechanical stimulation can therefore significantly weaken the bone structure, causing disuse osteoporosis and increasing the risk of fracture. The exact mechanisms by which the body senses and transduces mechanical forces to regulate bone remodeling have long been an active area of study among researchers and clinicians. Such research will lead to a deeper understanding of bone disorders and identify new strategies for skeletal rejuvenation. Here, we will discuss the mechanical properties, mechanosensitive cell populations, and mechanotransducive signaling pathways of the skeletal system.

Nb2C MXene-Functionalized Scaffolds Enables Osteosarcoma Phototherapy and Angiogenesis/Osteogenesis of Bone Defects

Early surgical resection and chemotherapy of bone cancer are commonly used in the treatment of bone tumor,but it is still highly challenging to prevent recurrence and fill the bone defect caused by the resection site.In this work,we report a rational integration of photonic-responsive two-dimensional(2D)ultrathin niobium carbide(Nb2C)MXene nanosheets(NSs)into the 3D-printed bone-mimetic scaffolds(NBGS)for osteosarcoma treatment.The integrated 2D Nb2C-MXene NSs feature specific photonic response in the second near-infrared(NIR-II)biowindow with high tissue-penetrating depth,making it highly efficient in killing bone cancer cells.Importantly,Nb-based species released by the biodegradation of Nb2C MXene can obviously promote the neogenesis and migration of blood vessels in the defect site,which can transport more oxygen,vitamins and energy around the bone defect for the reparative process,and gather more immune cells around the defect site to accelerate the degradation of NBGS.The degradation of NBGS provides sufficient space for the bone remodeling.Besides,calcium and phosphate released during the degradation of the scaffold can promote the mineralization of new bone tissue.The intrinsic multifunctionality of killing bone tumor cell and promoting angiogenesis and bone regeneration makes the engineered Nb2C MXeneintegrated composite scaffolds a distinctive implanting biomaterial on the efficient treatment of bone tumor.

Exosomes-the enigmatic regulators of bone homeostasis

Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells.Recent studies have revealed a close relationship between exosomes and bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.

Toll-like receptor 9 defciency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation

Toll-like receptors(TLRs)play pivotal roles in inflammation and provide important links between the immune and skeletal systems.Although the activation of TLRs may affect osteoclast differentiation and bone metabolism,whether and how TLRs are required for normal bone remodeling remains to be fully explored.In the current study,we show for the first time that TLR9^(-/-)mice exhibit a low bone mass and low-grade systemic chronic inflammation,which is characterized by the expansion of CD4^(+)T cells and increased levels of inflammatory cytokines,including TNFα,RANKL,and IL1β.The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss.Importantly,TLR9 deletion alters the gut microbiota,and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9^(-/-)mice.Furthermore,through single-cell RNA sequencing,we identified myeloid-biased hematopoiesis in the bone marrow of TLR9^(-/-)mice and determined that the increase in myelopoiesis,likely caused by the adaptation of hematopoietic stem cells to systemic inflammation,also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9^(-/-)mice.Thus,our study provides novel evidence that TLR9 signaling connects the gut microbiota,immune system,and bone and is critical in maintaining the homeostasis of inflammation,hematopoiesis,and bone metabolism under normal conditions.

The RhHB1/RhLOX4 module affects the dehydration tolerance of rose flowers(Rosa hybrida)by fine-tuning jasmonic acid levels

Phytohormones are key factors in plant responsiveness to abiotic and biotic stresses,and maintaining hormone homeostasis is critically important during stress responses.Cut rose(Rosa hybrida)flowers experience dehydration stress during postharvest handling,and jasmonic acid(JA)levels change as a result of this stress.However,how JA is involved in dehydration tolerance remains unclear.We investigated the functions of the JA-and dehydration-induced RhHB1 gene,which encodes a homeodomain-leucine zipper Iγ-clade transcription factor,in rose flowers.Silencing RhHB1 decreased petal dehydration tolerance and resulted in a persistent increase in JA-Ile content and reduced dehydration tolerance.An elevated JA-Ile level had a detrimental effect on rose petal dehydration tolerance.RhHB1 was shown to lower the transient induction of JA-Ile accumulation in response to dehydration.In addition to transcriptomic data,we obtained evidence that RhHB1 suppresses the expression of the lipoxygenase 4(RhLOX4)gene by directly binding to its promoter both in vivo and in vitro.We propose that increased JA-Ile levels weaken the capacity for osmotic adjustment in petal cells,resulting in reduced dehydration tolerance.In conclusion,a JA feedback loop mediated by an RhHB1/RhLOX4 regulatory module provides dehydration tolerance by fine-tuning bioactive JA levels in dehydrated flowers.

Correction to:Nb2C MXene‑Functionalized Scaffolds Enables Osteosarcoma Phototherapy and Angiogenesis/Osteogenesis of Bone Defects

The original version of this article unfortunately contain some mistakes in figure.The authors found that the curves in Fig.1f,g were missing.The corrected version of Fig.1 is given below:Fig.1 Fabrication and characterization of ultrathin 2D Nb2C MXene NSs.a,b SEM images of Nb2AlC ceramics with corresponding element mapping(Nb,Al and C).c,d SEM images of multilayered Nb2C MXene and the corresponding element mapping(Nb,Al and C).

Unsupervised Feature Selection Using Structured Self-Representation

Unsupervised feature selection has become an important and challenging problem faced with vast amounts of unlabeled and high-dimension data in machine learning. We propose a novel unsupervised feature selection method using Structured Self-Representation( SSR) by simultaneously taking into account the selfrepresentation property and local geometrical structure of features. Concretely,according to the inherent selfrepresentation property of features,the most representative features can be selected. Mean while,to obtain more accurate results,we explore local geometrical structure to constrain the representation coefficients to be close to each other if the features are close to each other. Furthermore,an efficient algorithm is presented for optimizing the objective function. Finally,experiments on the synthetic dataset and six benchmark real-world datasets,including biomedical data,letter recognition digit data and face image data,demonstrate the encouraging performance of the proposed algorithm compared with state-of-the-art algorithms.

Mitochondrial dysfunction:mechanisms and advances in therapy

Mitochondria,with their intricate networks of functions and information processing,are pivotal in both health regulation and disease progression.Particularly,mitochondrial dysfunctions are identified in many common pathologies,including cardiovascular diseases,neurodegeneration,metabolic syndrome,and cancer.However,the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases.Nonetheless,these complexities do not prevent mitochondria from being among the most important therapeutic targets.In recent years,strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials.Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria,has shown promise in preclinical trials of various diseases.Mitochondrial components,including mtDNA,mitochondria-located microRNA,and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries.Here,we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases.We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies,as well as the clinical translational situation of related pharmacology agents.Finally,this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

Enhanced osteochondral regeneration with a 3D-Printed biomimetic scaffold featuring a calcified interfacial layer

The integrative regeneration of both articular cartilage and subchondral bone remains an unmet clinical need due to the difficulties of mimicking spatial complexity in native osteochondral tissues for artificial implants.Layer-by-layer fabrication strategies,such as 3D printing,have emerged as a promising technology replicating the stratified zonal architecture and varying microstructures and mechanical properties.However,the dynamic and circulating physiological environments,such as mass transportation or cell migration,usually distort the pre-confined biological properties in the layered implants,leading to undistinguished spatial variations and subsequently inefficient regenerations.This study introduced a biomimetic calcified interfacial layer into the scaffold as a compact barrier between a cartilage layer and a subchondral bone layer to facilitate osteogenic-chondrogenic repair.The calcified interfacial layer consisting of compact polycaprolactone(PCL),nano-hydroxyapatite,and tasquinimod(TA)can physically and biologically separate the cartilage layer(TA-mixed,chondrocytes-load gelatin methacrylate)from the subchondral bond layer(porous PCL).This introduction preserved the as-designed independent biological environment in each layer for both cartilage and bone regeneration,successfully inhibiting vascular invasion into the cartilage layer and preventing hyaluronic cartilage calcification owing to devascularization of TA.The improved integrative regeneration of cartilage and subchondral bone was validated through gross examination,micro-computed tomography(micro-CT),and histological and immunohistochemical analyses based on an in vivo rat model.Moreover,gene and protein expression studies identified a key role of Caveolin(CAV-1)in promoting angiogenesis through the Wnt/β-catenin pathway and indicated that TA in the calcified layer blocked angiogenesis by inhibiting CAV-1.

Hyperuricemia and its related diseases:mechanisms and advances in therapy

Hyperuricemia,characterized by elevated levels of serum uric acid(SUA),is linked to a spectrum of commodities such as gout,cardiovascular diseases,renal disorders,metabolic syndrome,and diabetes,etc.Significantly impairing the quality of life for those affected,the prevalence of hyperuricemia is an upward trend globally,especially in most developed countries.UA possesses a multifaceted role,such as antioxidant,pro-oxidative,pro-inflammatory,nitric oxide modulating,anti-aging,and immune effects,which are significant in both physiological and pathological contexts.The equilibrium of circulating urate levels hinges on the interplay between production and excretion,a delicate balance orchestrated by urate transporter functions across various epithelial tissues and cell types.While existing research has identified hyperuricemia involvement in numerous biological processes and signaling pathways,the precise mechanisms connecting elevated UA levels to disease etiology remain to be fully elucidated.In addition,the influence of genetic susceptibilities and environmental determinants on hyperuricemia calls for a detailed and nuanced examination.This review compiles data from global epidemiological studies and clinical practices,exploring the physiological processes and the genetic foundations of urate transporters in depth.Furthermore,we uncover the complex mechanisms by which the UA induced inflammation influences metabolic processes in individuals with hyperuricemia and the association with its relative disease,offering a foundation for innovative therapeutic approaches and advanced pharmacological strategies.

Glucagon-like peptide-1 receptor: mechanisms and advances in therapy

The glucagon-like peptide-1(GLP-1)receptor,known as GLP-1R,is a vital component of the G protein-coupled receptor(GPCR)family and is found primarily on the surfaces of various cell types within the human body.This receptor specifically interacts with GLP-1,a key hormone that plays an integral role in regulating blood glucose levels,lipid metabolism,and several other crucial biological functions.In recent years,GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms,significant therapeutic efficacy,and broad development prospects.This article thoroughly traces the developmental milestones of GLP-1 drugs,from their initial discovery to their clinical application,detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties.Additionally,this paper explores the potential applications of GLP-1 receptor agonists(GLP-1RAs)in fields such as neuroprotection,anti-infection measures,the reduction of various types of inflammation,and the enhancement of cardiovascular function.It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous,cardiovascular,musculoskeletal,and digestive systems.This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms.The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases,such as obesity,cardiovascular diseases,non-alcoholic fatty liver disease(NAFLD),neurodegenerative diseases,musculoskeletal inflammation,and various forms of cancer.The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions,showcasing their significant potential in the medical field.

Mitochondrial heterogeneity in diseases

As key organelles involved in cellular metabolism,mitochondria frequently undergo adaptive changes in morphology,components and functions in response to various environmental stresses and cellular demands.Previous studies of mitochondria research have gradually evolved,from focusing on morphological change analysis to systematic multiomics,thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell.The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity.Moreover,mitochondrial heterogeneity has been reported to influence a variety of physiological processes,including tissue homeostasis,tissue repair,immunoregulation,and tumor progression.Here,we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states,involving variant features of mitochondrial DNA,RNA,protein and lipid components.Then,the mechanisms that contribute to mitochondrial heterogeneity are also summarized,such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components.Additionally,multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells.Finally,we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage,reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions.The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.

Research on axial bearing capacity of rectangular concrete-filled steel tubular columns based on artificial neural networks

Design of rectangular concrete-filled steel tubular （CFT） columns has been a big concern owing to their complex constraint mechanism. Generally, most existing methods are based on simplified mechanical model with limited experimental data, which is not reliable under many conditions, e.g., columns using high strength materials. Artificial neural network （ANN） models have shown the effectiveness to solve complex problems in many areas of civil engineering in recent years. In this paper, ANN models were employed to predict the axial bearing capacity of rectangular CFT columns based on the experimental data. 305 experimental data from articles were collected, and 275 experimental samples were chosen to train the ANN models while 30 experimental samples were used for testing. Based on the comparison among different models, artificial neural network modell （ANN1） and artificial neural network model2 （ANN2） with a 20- neuron hidden layer were chosen as the fit prediction models. ANN1 has five inputs： the length （D） and width （B） of cross section, the thickness of steel （t）, the yield strength of steel （fy）, the cylinder strength of concrete （fc＇）- ANN2 has ten inputs： D, B, t, fy, f′, the length to width ratio （D/B）, the length to thickness ratio （D/t）, the width to thickness ratio （B/t）, restraint coefficient （ξ）, the steel ratio （α）. The axial beating capacity is the output data for both models.The outputs from ANN1 and ANN2 were verified and compared with those from EC4, ACI, GJB4142 and AISC360-10. The results show that the implemented models have good prediction and generalization capacity. Parametric study was conducted using ANN1 and ANN2 which indicates that effect law of basic parameters of columns on the axial bearing capacity of rectangular CFT columns differs from design codes.The results also provide convincing design reference to rectangular CFT columns.

Ischaemic stroke etiological classification system: the agreement analysis of CISS, SPARKLE and TOAST

Background and purpose The ideal stroke classification system needs to have validity,high reliability and applicability among different stroke research settings.The Chinese Ischemic Stroke Subclassification(CISS)and the Subtypes of Ischemic Stroke Classification System(SPARKLE)have emerged recently but have not been tested using agreement analysis.As a result,the objective of this study is to investigate the level of agreement among stroke subtype classifications using CISS,SPARKLE and Trial of Org 10172 in Acute Stroke Treatment(TOAST).We also analyse the inter-rater reliability of CISS.Methods The data include 623 inpatients who have had an ischaemic stroke,accrued from Beijing Tiantan Hospital between 1 October 2015 and 19 April 2016.According to the diagnostic standards of the three subtype classification systems,299 inpatients who satisfied the requirements of our study were independently classified with etiological subtypes,and we compared the three subclassifications.Results There was substantial overall agreement among the three classification systems:CISS versus SPARKLE(kappa value=0.684,p<0.001),CISS versus TOAST(kappa value=0.615,p<0.001)and SPARKLE versus TOAST(kappa value=0.675,p<0.001).The inter-rater reliability of CISS was excellent(kappa value=0.857,p<0.001).Furthermore,among the three subtype classification systems,the variance analysis results of the etiological subtypes were not uniform.Conclusion There were generally substantial agreements among three ischaemic stroke etiological classification systems.CISS is a valid and reliable classification system,with which different stroke research centres can apply and compare data.

An Epigenetic Role for Disrupted Paternal Gene Expression in Postzygotic Seed Abortion in Arabidopsis Interspecific Hybrids

Interspecific hybrids often increase the levels of heterozygosity and hybrid vigor, but some interspecific hybrid seeds are aborted shortly after fertilization. The mechanism behind this postzygotic seed abortion is poorly understood. Here, we report genome-wide analysis of allelic expression changes in developing siliques and seeds in three F1 interspecific crosses between Arabidopsis thaliana （Col, Ler, or C24） and Arabidopsis arenosa. The majority of maternally expressed genes （MEGs） were shared among all three F1 interspecific crosses, whereas ~90% of 272 paternally expressed genes （PEGs） were found only in one or two F1 crosses, suggesting a role for disrupted paternal gene expression in seed abortion that varies in different crosses. Consistent with this notion, 12 PEGs in the infertile interspecific hybrids matched MEGs in fertile intraspecific hybrids. This disruption of PEGs in the interspecific hybrids was consistent with the upregulation of the genes in the paternal-excess interploidy cross （2X6） between a diploid mother and a hexaploid father, leading to the seed abortion. Moreover, a subset of PEGs in the interspecific crosses were also upregulated in the intraspecific hybrid metlXWT or meaXWT, in which the mutant of MET1 （DNA METHYL TRANSFERASE1） or MEDEA, a Polycomb Repressive Complex2 gene, was used as the maternal parent. These data suggest that maternal epigenetic factors and paternal gene expression play important roles in the postzygotic seed abortion in interspecific hybrids or neo-allopolyploids.

Intercellular mitochondrial transfer as a means of tissue revitalization

As the crucial powerhouse for cell metabolism and tissue survival,the mitochondrion frequently undergoes morphological or positional changes when responding to various stresses and energy demands.In addition to intracellular changes,mitochondria can also be transferred intercellularly.Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction,the intercellular mitochondrial transfer also occurs under physiological conditions.In this review,the phenomenon of mitochondrial transfer is described according to its function under both physiological and pathological conditions,including tissue homeostasis,damaged tissue repair,tumor progression,and immunoregulation.Then,the mechanisms that contribute to this process are summarized,such as the trigger factors and transfer routes.Furthermore,various perspectives are explored to better understand the mysteries of cell-cell mitochondrial trafficking.In addition,potential therapeutic strategies for mitochondria-targeted application to rescue tissue damage and degeneration,as well as the inhibition of tumor progression,are discussed.

Primary hypertrophic osteoarthropathy:an update

Digital clubbing,which has been recognized as a sign of systemic disease,is one of the most ancient diseases.However,the pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood.The study of a clinically indistinguishable idiopathic form(primary hypertrophic osteoarthropathy,PHO)provides an opportunity to understand the pathogenesis of hypertrophic osteoarthropathy.Current advances in the study of PHO are discussed.The impaired metabolism of prostaglandin E2(PGE2)plays a central role in its pathogenesis.

In Vitro Comparative Effect of Three Novel Borate Bioglasses on the Behaviors of Osteoblastic MC3T3-E1 Cells

Most related investigations focused on the effects of borate glass on cell proliferation/biocompatibility in vitro or bone repair in vivo; however, very few researches were carried out on other cell behaviors. Three novel borate bioglasses were designed as scaffolds for bone regeneration in this wok. Comparative effects of three bioglasses on the behaviors of osteoblastic MC3T3-E1 cells were evaluated. Excellent cytocompatibility of these novel borate bioglasses were approved in this work. Meanwhile, the promotion on cell proliferation, protein secretion and migration with minor cell apoptosis were also discussed in details, which contributed to the potential clinical application as a new biomaterial for orthopedics.

Regulation of rose petal dehydration tolerance and senescence by RhNAP transcription factor via the modulation of cytokinin catabolism

Petals and leaves share common evolutionary origins but have different phenotypic characteristics,such as the absence of stomata in the petals of most angiosperm species.Plant NAC transcription factor,NAP,is involved in ABA responses and regulates senescence-associated genes,and especially those that affect stomatal movement.However,the regulatory mechanisms and significance of NAP action in senescing astomatous petals is unclear.A major limiting factor is failure of flower opening and accelerated senescence.Our goal is to understand the finely regulatory mechanism of dehydration tolerance and aging in rose flowers.We functionally characterized RhNAP,an AtNAP-like transcription factor gene that is induced by dehydration and aging in astomatous rose petals.Cytokinins(CKs)are known to delay petal senescence and we found that a cytokinin oxidase/dehydrogenase gene 6(RhCKX6)shares similar expression patterns with RhNAP.Silencing of RhNAP or RhCKX6 expression in rose petals by virus induced gene silencing markedly reduced petal dehydration tolerance and delayed petal senescence.Endogenous CK levels in RhNAP-or RhCKX6-silenced petals were significantly higher than those of the control.Moreover,RhCKX6 expression was reduced in RhNAP-silenced petals.This suggests that the expression of RhCKX6 is regulated by RhNAP.Yeast one-hybrid experiments and electrophoresis mobility shift assays showed that RhNAP binds to the RhCKX6 promoter in heterologous in vivo system and in vitro,respectively.Furthermore,the expression of putative signal transduction and downstream genes of ABA-signaling pathways were also reduced due to the repression of PP2C homolog genes by RhNAP in rose petals.Taken together,our study indicates that the RhNAP/RhCKX6 interaction represents a regulatory step enhancing dehydration tolerance in young rose petals and accelerating senescence in mature petals in a stomata-independent manner.