Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis

Diabetic osteoporosis(DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1(HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

Recent advances in cell sheet technology for bone and cartilage regeneration: from preparation to application

Bone defects caused by trauma,tumour resection,infection and congenital deformities,together with articular cartilage defects and cartilage–subchondral bone complex defects caused by trauma and degenerative diseases,remain great challenges for clinicians.Novel strategies utilising cell sheet technology to enhance bone and cartilage regeneration are being developed.The cell sheet technology has shown great clinical potential in regenerative medicine due to its effective preservation of cell–cell connections and extracellular matrix and its scaffold-free nature.This review will first introduce several widely used cell sheet preparation systems,including traditional approaches and recent improvements,as well as their advantages and shortcomings.Recent advances in utilising cell sheet technology to regenerate bone or cartilage defects and bone–cartilage complex defects will be reviewed.The key challenges and future research directions for the application of cell sheet technology in bone and cartilage regeneration will also be discussed.

Engineering 3D approaches to model the dynamic microenvironments of cancer bone metastasis

Cancer metastasis to bone is a three-dimensional(3D), multistep, dynamic process that requires the sequential involvement of three microenvironments, namely, the primary tumour microenvironment, the circulation microenvironment and the bone microenvironment. Engineered 3D approaches allow for a vivid recapitulation of in vivo cancerous microenvironments in vitro, in which the biological behaviours of cancer cells can be assessed under different metastatic conditions. Therefore, modelling bone metastasis microenvironments with 3 D cultures is imperative for advancing cancer research and anti-cancer treatment strategies. In this review, multicellular tumour spheroids and bioreactors, tissue engineering constructs and scaffolds, microfluidic systems and 3D bioprinting technology are discussed to explore the progression of the 3D engineering approaches used to model the three microenvironments of bone metastasis. We aim to provide new insights into cancer biology and advance the translation of new therapies for bone metastasis.

Cytocompatibility with osteogenic cells and enhanced in vivo anti-infection potential of quaternized chitosan-loaded titania nanotubes

Infection is one of the major causes of failure of orthopedic implants. Our previous study demonstrated that nanotube modification of the implant surface, together with nanotubes loaded with quaternized chitosan （hydroxypropyltrimethyl ammonium chloride chitosan, HACC）, could effectively inhibit bacterial adherence and biofilm formation in vitro. Therefore, the aim of this study was to further investigate the in vitro cytocompatibility with osteogenic cells and the in vivo anti-infection activity of titanium implants with HACC-loaded nanotubes （NT-H）. The titanium implant （Ti）, nanotubes without polymer loading （NT）, and nanotubes loaded with chitosan （NT-C） were fabricated and served as controls. Firstly, we evaluated the cytocompatibility of these specimens with human bone marrow-derived mesenchymal stem cells in vitro. The observation of cell attachment, proliferation, spreading, and viability in vitro showed that NT-H has improved osteogenic activity compared with Ti and NT-C. A prophylaxis rat model with implantation in the femoral medullary cavity and inoculation with methiciUin-resistant Staphylococcus aureus was established and evaluated by radiographical, microbiological, and histopathological assessments. Our in vivo study demonstrated that NT-H coatings exhibited significant anti-infection capability compared with the Ti and NT-C groups. In conclusion, HACC-loaded nanotubes fabricated on a titanium substrate show good compatibility with osteogenic cells and enhanced anti-infection ability in vivo, providing a good foundation for clinical application to combat orthopedic implant-associated infections.

Irisin Attenuates Osteoarthritis by Inhibiting Apoptosis of Osteocytes Through Activating Erk Signaling Pathway

Osteoarthritis(OA)is an inflammatory disease involving the joints that is prevalent in the global aging population.The purpose of this study is to determine whether irisin can attenuate osteoarthritis(OA)progression in anterior cruciate ligament transection(ACLT)mice models and the mechanism of irisin therapy effect on OA by increase the resistance of apoptosis in MLO-Y4 cells induced by mechanical stretch in vitro.Methods For in vivo study,3-month-old male C57BL/6 J mice were randomized to three groups,sham-operated,anterior cruciate ligament transection(ACLT)-operated treated with vehicle,and ACLT-operated treated with irisin by intraperitoneal injection once a week.Cartilage erosion was observed by HE staining.Osteoarthritis Research Society International(OARSI)scores were evaluated according to the safranin O stai-ning.The microstructure of tibia cortical bone,trabecular bone,and subchondral bone was analyzed by micro-CT and the bone histomorphometry has been administrated including mineral apposition rate(MAR).Edu staining and cck-8 were used for the detection of the proliferation of MLO-Y4 cells.For mechanical stress,cells were seeded on the collagen-I coated chamber subjected with a peak biaxial stretch of 20%at 1 Hz for 16 hours to induce apoptosis.Flow cytometry was used for the detection of apoptosis and cell cycle.TUNNEL was used for staining the apoptotic cells and rt-PCR was applied for quantifying the expression of mRNA such as Bax,Bcl-2,SOST,c-myc,Opg.Western blot was utilized to confirm the mechanism of how irisin decrease the osteocyte apoptosis.Results In vivo,irisin can attenuate articular cartilage degeneration.Irisin maintains the proportion of hyaline cartilage and calcified cartilage and keep fewer cartilage erosions in ACLT-operated mice.For immunohistochemical(IHC)staining,irisin reduced the expression of caspase3,Bax and matrix metalloproteinase-13 in both cartilage and subchondral bone.Irisin-treated ACLT group shows higher Trabecular number(Tb.N)and bone volume fraction(BV/TV)compared to the vehicle-treated ACLT group.In vitro, irisin significantly increased the proliferation of MLO-Y4 cells detected by Edu and Ki67 staining,and irisin can protect the cells from both mechanical stretchinduced apoptosis detected by FITC-PI flow cytometry and maintain the cell activity by regulating the expression of Bax,Bcl-2,and c-myc.Transcriptome sequencing shows that irisin significantly activates the MAPK signaling pathway and we confirm the result by western blot:irisin effectively activates the Erk signaling pathway through phosphorylation and has a certain activation effect on p38 signaling pathway,no activation was observed for FAK signaling pathway.Conclusions Irisin can attenuate the progression of OA by decrease the apoptosis of osteocyte,which can improve the microarchitecture of subchondral bone.Erk pathway activation plays an important role in reducing the apoptosis of osteocyte.

Stem cells:two sides of the coin

Bone marrow derived mesenchymal stem cells(MSCs)have been widely used to promote the repair or regeneration of damaged tissues.In previous studies,we have developed several stem cells based strategies to promote the bone repair,which includes the BMP-2 gene medicine,construction of tissue engineering bone in bioreactor and clinical trial of enriched stem cell therapy.Among these studies,one challenge is to construct the tissue engineered bone at the large scale which face the problem of poor survivor of seeding cells in the scaffold interior.In our studies,the porousβ-TCP cylindrical scaffolds loading with MSCs were continuously perfused by a customized bioreactor(dynamic culture)at different flow rate or were immersed

A review of studies on the therapeutic effect of vagus nerve stimulation

BACKGROUND： Vagus nerve widely innervates in the human body, and it has diverse physiological functions. Many new physiological functions are gradually found. Studies on its action mechanism have been gradually deepened. Vagus nerve stimulation （VNS） has been used for treatment of epilepsy and depression in clinic. OBJECTIVE： To retrospectively investigate the therapeutic effects and mechanism of VNS. RETRIEVE STRATEGY： A computer-based online research in Pubmed with the key words of ＂vagus nerve stimulation＂ published between February 1990 and October 2006 in English were systemically reviewed. Totally 583 articles were collected and primarily selected. Inclusive criteria： the mechanism of therapeutic effects of VNS-related literatures. Exclusive criteria： repetitive study. LITERATURE EVALUATION： According to inclusive criteria, of the 57 articles, which met the inclusive criteria, 42 were associated with the therapeutic function of VNS, and 15 with the mechanism of these related functions. DATA SYNTHESIS： Vagus nerve has special nerve innervation and wide projection with extensive physiological effects. Till now, VNS has been used in the therapy of epilepsy and depression, and exact clinical effects have been obtained. Further studies have discovered other functions of VNS, such as the effect on the memory power, cognition, and perception to pain. Thus, the studies about VNS become diverse. Just because of the special physiological functions of vagus nerve, VNS can bring some adverse reactions such as foreign body sensation, hoarseness, trigeminal neuralgia, etc. The mechanism of therapeutic function of VNS is still under exploration. CONCLUSION： As a mature surgical technique, VNS has been widely used in the therapy of epilepsy, depression, inflammation, analgesia, relieving itching, etc. Although the mechanism is still unclear, it brings obvious clinical effects.

Cultivation Path of Compound Talents in Ophthalmic Diagnosis, Treatment, and Nursing Based on Artificial Intelligence

Artificial intelligence can effectively improve the efficiency and accuracy of medical diagnosis,clinical data analysis,medical image recognition,treatment plan decision-making,etc.It has broad application prospects in the ophthalmic diagnosis,treatment,and nursing industry.However,the application of artificial intelligence in the ophthalmic diagnosis and nursing industry in China started relatively late,and there are insufficient ophthalmic diagnosis and nursing personnel who are familiar with artificial intelligence technologies.In order to promote the modernization of ophthalmic medicine in China and accelerate the development of a high-quality and modern medical education system,it is necessary to train a new generation of compound ophthalmic medical talents who are skilled in artificial intelligence and develop an advanced talent training model that meets the needs of the ophthalmic profession and the society.Based on the application status and development prospects of artificial intelligence in the ophthalmology industry,this paper analyzes the current medical education model in ophthalmology,examines the path of cultivating compound talents in ophthalmic diagnosis,treatment,and nursing,as well as proposes suggestions for developing a high-quality and modern medical education system.

人类衰竭心脏中髓系细胞的全面描述

Heart failure(HF)remains a rising global epidemic worldwide[1,2].It is widely recognized that immune cells play important roles in the pathogenesis of HF.The hearts of HF patients are characterized by persistent low-grade inflammation,which has been linked to adverse ventricular remodeling as it promotes interstitial fibrosis and cardiomyocyte dysfunction and loss.

All-dielectric terahertz metasurface for linearly-polarized multichannel transmission and superposition states of spherical and vortex waves

Compared to pure vortex waves,the superposition state of spherical waves and vortex waves has enough degrees of freedom to upgrade applications in particle manipulation,information encryption,and large-capacity communications.Here,we propose a new scheme to achieve superposition states and multichannel transmission of vortex and spherical waves.Two transmissive all-silicon metasurfaces that enable mutual interference between linearly polarized(LP)waves in the terahertz region are demonstrated.Type A can achieve interference between x and y polarized waves,while type B can achieve interference between x(or y)and x(or y)polarized waves.The multichannel transmission and superposition states of topological charges of+3,+2,and+4 are designed and demonstrated from theoretical,simulative,and experimental perspectives at 1.1 THz.In addition,the objective fact that the focused superposition state must be observed close to the focal plane is also revealed.The measured results are in good agreement with the theoretical and simulative results.This work provides an idea for the design of ultrathin terahertz devices and could be applied in the fields of information encryption and highfrequency communications.

Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF-κB/MAPK signaling and protecting chondrocytes

The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction(q RT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium(CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection(ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB(NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases(MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages,promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.

A 3D-bioprinted scaffold with doxycycline-controlled BMP2-expressing cells for inducing bone regeneration and inhibiting bacterial infection

Large bone defects face a high risk of pathogen exposure due to open wounds,which leads to high infection rates and delayed bone union.To promote successful repair of infectious bone defects,fabrication of a scaffold with dual functions of osteo-induction and bacterial inhibition is required.This study describes creation of an engineered progenitor cell line(C3H10T1/2)capable of doxycycline(DOX)-mediated release of bone morphogenetic protein-2(BMP2).Three-dimensional bioprinting technology enabled creation of scaffolds,comprising polycaprolactone/mesoporous bioactive glass/DOX and bioink,containing these engineered cells.In vivo and in vitro experiments confirmed that the scaffold could actively secrete BMP2 to significantly promote osteoblast differentiation and induce ectopic bone formation.Additionally,the scaffold exhibited broad-spectrum antibacterial capacity,thereby ensuring the survival of embedded engineered cells when facing high risk of infection.These findings demonstrated the efficacy of this bioprinted scaffold to release BMP2 in a controlled manner and prevent the occurrence of infection;thus,showing its potential for repairing infectious bone defects.

Flexible and flame-retarding phosphorylated MXene/polypropylene composites for efficient electromagnetic interference shielding

Flame-retardant composites with high electromagnetic interference(EMI)shielding performance are desirable for electronic device packaging.Despite great potential of MXene for high EMI,it still remains a great challenge to develop high-performance flame-retardant polymer/MXene composites with excellent EMI shielding effectiveness because of the poor oxidative stability of MXene.Herein,phosphorylated MXene/polypropylene(PP)composites are prepared by coating phosphorylated MXene on PP fabric followed by spraying polyethylenimine(PEI)and hot-pressing.The phosphorylated MXene proves to be more durable against oxidation than pure MXene due to the protection effect of polyphosphates.Upon hot-pressing,melted PP fibers are fused together at their contact points and thus as-prepared composites are bi-continuous with two interpenetrating phases.The composites show significantly improved thermal stability and flame retardancy relative to pure PP,with a low total heat release(THR)of 3.7 kJ/g and a heat release rate(HRR)of 50.0 W/g,which are reduced by 78%and 87%,respectively.In addition,the composites exhibit a high electrical conductivity of~36,700 S/m and an EMI shielding performance of~90 d B over the whole frequency range of 8–12 GHz with a thickness of~400μm.The as-developed PP/MXene composites hold great promise for reliable protection of next-generation electronic devices working in complex environments.

Terahertz wavefront shaping with multi-channel polarization conversion based on all-dielectric metasurface

Polarization manipulation of electromagnetic wave or polarization multiplexed beam shaping based on metasurfaces has been reported in various frequency bands.However,it is difficult to shape the beam with multi-channel polarization conversion in a single metasurface.Here,we propose a new method for terahertz wavefront shaping with multi-channel polarization conversion via all-silicon metasurface,which is based on the linear shape birefringence effect in spatially interleaved anisotropic meta-atoms.By superimposing the eigen-and non-eigen-polarization responses of the two kinds of meta-atoms,we demonstrate the possibility for high-efficiency evolution of several typical polarization states with two independent channels for linearly polarized waves.The measured polarization conversion efficiency is higher than 70%in the range of 0.9–1.3 THz,with a peak value of 89.2%at 1.1 THz.In addition,when more other polarization states are incident,combined with the integration of sub-arrays,we can get more channels for both polarization conversion and beam shaping.Simulated and experimental results verify the feasibility of this method.The proposed method provides a new idea for the design of terahertz multi-functional metadevices.

Weak measurement of the magneto-optical spin Hall effect of light

The spin Hall effect of light(SHEL) is a photonic version of the spin Hall effect in electronic systems and has been studied for more than 10 years. However, the lack of effective methods for dynamic modulation of spin-dependent splitting may hinder its applications. By introducing additional spin-orbit coupling of photons or nonreciprocal phase shift(NRPS), the magneto-optical Kerr effect may be one of the methods to alleviate the situation. Here, we experimentally reveal an enhanced and tunable SHEL in magneto-optical oxide thin films under the transverse magneto-optical Kerr effect configuration for the first time, to the best of our knowledge, which can be regarded as the magneto-optical SHEL(MOSHEL). We study the magneto-optical response of the multilayer structure and select the optimal structural parameters by the magneto-optical transfer matrix method. With a transverse magnetic field along opposite directions, an obvious SHEL shift difference of H-polarized light caused by NRPS is observed via a weak measurement method. With optimal parameters, the maximum measured shift difference of the SHEL achieves about 70 μm. The demonstrated MOSHEL phenomenon may accelerate the application of the SHEL in the field of spin photonics devices and precision metrology.

Broadband and tunable terahertz absorption via photogenerated carriers in undoped silicon

Terahertz absorbers based on doped silicon have achieved broadband and high-efficiency absorption due to their high concentration of carriers.However,their tunable performance is obviously insufficient.Here,we propose a new scheme for active terahertz absorption based on undoped silicon with a metamaterial antireflection layer,which realizes both strong absorption and ultrahigh modulation depth.Benefiting from the weak absorption and high transmission of undoped silicon for 1064-nm continuous wave,uniformly distributed carriers across the entire thickness of the absorber are excited,and efficient free carrier absorption of the terahertz wave is obtained.We use only a 500-μm thick absorber and achieve absorption greater than 90%in the range of 0.58 to 1.92 THz,with a peak value of 99%.More important,the absorber can be switched between two working states of nonabsorption and high-efficiency absorption by changing the pump power,which means the modulation depth reaches 100%.This simple and high-performance implementation scheme provides a new idea for the design of terahertz tunable absorbers.

Cerebral Dopamine Neurotrophic Factor:A Potential Therapeutic Agent for Parkinson's Disease

The application of neurotrophic factors （NTFs） is a promising therapeutic strategy for neurodegenerative disorders such as Parkinson＇s disease （PD）. Many NTFs have been reported to enhance the survival, regeneration, and differentiation of neurons and to induce synaptic plasticity. However, because of their potential side-effects and low efficacy after clinical administration, more potent treatments for neurodegenerative disorders are being sought. Cerebral dopamine neurotrophic factor （CDNF）, a newly-identified NTF homologous to mesencephalic astrocyte-derived NTF, is structurally and functionally different from other NTFs, providing new hope especially for PD patients. In various animal models of PD, CDNF is efficient in protecting and repairing dopaminergic neurons, and it inhibits endoplasmic reticulum stress, neuroinflam- mation, and apoptosis. Recent progress in all facets of CDNF research has enabled researchers to better under- stand its beneficial effects in the treatment of PD.

Postoperative infection caused by Acinetobacter baumannii misdiagnosed as a free-living amoeba species in a humeral head hemiarthroplasty patient:a case report

Background:Acinetobacter baumannii is ubiquitous,facultative intracellular,and opportunistic bacterial pathogen.Its unique abilities allow it to survive in a diverse range of environments,including health care settings,leading to nosocomial infections.And its exceptional ability to develop resistance to multiple antibiotics leaves few drug options for treatment.It has been recognized as a leading cause of nosocomial pneumonia and bacteremia over the world.Case presentation:In this case,a 73-year-old woman presented with a Neer Group VI proximal humeral fracture.Six hours after a successfully performed hemiarthroplasty,she developed continuous fever.Clinical examination revealed that the vitals were regular.Laboratory and radiographic examinations revealed only elevated procalcitonin levels.Blood culture revealed no bacterial or fungal growth.Cooling treatment and empirical broad-spectrum antibiotic therapy showed no apparent effect.Conclusions:We report a postoperative infection caused by Acinetobacter baumannii.The infectious pathogen was identified via molecular DNA sequencing and was initially misidentified as a free-living amoeba species upon microscopic examinations.The patient was mistreated with antiamebic combination therapy.Her symptoms persisted for over 4 months and were eventually followed by her death.

Mid-infrared active metasurface based on Si/VO_(2) hybrid meta-atoms

Active metasurfaces whose optical properties can be tuned by an external stimulus have attracted great research interest recently. Introduction of VO_(2)phase change material in all-dielectric metasurfaces has been demonstrated to modulate the resonance wavelength and amplitude in the visible to near-infrared wavelength range. In this study, we report a mid-infrared active metasurface based on Si∕VO_(2)hybrid meta-atoms. By incorporating VO_(2)thin films in different locations of Si∕VO_(2)all-dielectric nanodisks, we demonstrate different modulation amplitude of the electric or magnetic resonance scattering cross sections, leading to drastically different transmission spectrum upon VO_(2)insulator to metal phase transition. The physical mechanism is originated from the field profiles of the resonance modes, which interact with VO_(2)differently depending on its locations. Based on this mechanism, we experimentally demonstrated a large modulation of the transmittance from 82% to 28% at the 4.6 μm wavelength. Our work demonstrates a promising potential of VO_(2)-based active all-dielectric metasurface for mid-infrared photonic applications such as infrared camouflage, chemical/biomedical sensing, optical neuromorphic computing, and multispectral imaging.

Multi-omics analysis based on 3D-bioprinted models innovates therapeutic target discovery of osteosarcoma

Current in vitro models for osteosarcoma investigation and drug screening,including two-dimensional(2D)cell culture and tumour spheroids(i.e.cancer stem-like cells),lack extracellular matrix(ECM).Therefore,results from traditional models may not reflect real pathological processes in genuine osteosarcoma histological structures.Here,we report a three-dimensional(3D)bioprinted osteosarcoma model(3DBPO)that contains osteosarcoma cells and shrouding ECM analogue in a 3D frame.Photo-crosslinkable bioinks composed of gelatine methacrylamide and hyaluronic acid methacrylate mimicked tumour ECM.We performed multi-omics analysis,including transcriptomics and DNA methylomics,to determine differences between the 3DBPO model and traditional models.Compared with 2D models and tumour spheroids,our 3DBPO model showed significant changes in cell cycle,metabolism,adherens junctions,and other pathways associated with epigenetic regulation.The 3DBPO model was more sensitive to therapies targeted to the autophagy pathway.We showed that simulating ECM yielded different osteosarcoma cell metabolic characteristics and drug sensitivity in the 3DBPO model compared with classical models.We suggest 3D printed osteosarcoma models can be used in osteosarcoma fundamental and translational research,which may contribute to novel therapeutic strategy discovery.