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    In Situ Sustained Macrophage-Targeted Nanomicelle-Hydrogel Microspheres for Inhibiting Osteoarthritis

    XiaoXiao LiXingchen LiJielai YangYawei Du...
    1-16页
    查看更多>>摘要：There are still challenges in applying drug nanocarriers for in situ sustained macrophage targeting and regulation,due to the rapid clearance of nanocarriers and burst drug release invivo.Herein,a nanomicelle-hydrogel microsphere,characterized by its macrophage-targeted nanosized secondary structure that allows it to accurately bind to M1 macrophages through active endocytosis,is employed for in situ sustained macrophage targeting and regulation,and addresses the insufficient osteoarthritis therapeutic efficacy caused by rapid clearance of drug nanocarriers.The 3-dimensional structure of a microsphere can prevent the rapid escape and clearance of a nanomicelle,thus keeping it in joints,while the ligand-guided secondary structure can carry drugs to accurately target and enter M1 macrophages,and release drugs via the transition from hydrophobicity to hydrophilicity of nanomicelles under inflammatory stimulation inside the macrophages.The experiments show that the nanomicelle-hydrogel microsphere can in situ sustainably target and regulate M1 macrophages for more than 14 days in joints,and attenuate local"cytokine storm"by continuous M1 macrophage apoptosis promotion and polarization inhibition.This micro/nano-hydrogel system shows excellent ability to sustainably target and regulate macrophage,realizes the improvement of drug utilization and efficacy inside the macrophage,and thereby can be a potential platform for treating macrophage-related diseases.
      原文链接:
    • NETL
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    Unresolved Excess Accumulation of Myelin-Derived Cholesterol Contributes to Scar Formation after Spinal Cord Injury

    Bolin ZhengYijing HeShuai YinXu Zhu...
    17-32页
    查看更多>>摘要：Spinal cord injury triggers complex pathological cascades,resulting in destructive tissue damage and incomplete tissue repair.Scar formation is generally considered a barrier for regeneration in the central nervous system.However,the intrinsic mechanism of scar formation after spinal cord injury has not been fully elucidated.Here,we report that excess cholesterol accumulates in phagocytes and is inefficiently removed from spinal cord lesions in young adult mice.Interestingly,we observed that excessive cholesterol also accumulates in injured peripheral nerves but is subsequently removed by reverse cholesterol transport.Meanwhile,preventing reverse cholesterol transport leads to macrophage accumulation and fibrosis in injured peripheral nerves.Furthermore,the neonatal mouse spinal cord lesions are devoid of myelin-derived lipids and can heal without excess cholesterol accumulation.We found that transplantation of myelin into neonatal lesions disrupts healing with excessive cholesterol accumulation,persistent macrophage activation,and fibrosis.Myelin internalization suppresses macrophage apoptosis mediated by CD5L expression,indicating that myelin-derived cholesterol plays a critical role in impaired wound healing.Taken together,our data suggest that the central nervous system lacks an efficient approach for cholesterol clearance,resulting in excessive accumulation of myelin-derived cholesterol,thereby inducing scar formation after injury.
      原文链接:
    • NETL
    • NSTL
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    PDGFR in PDGF-BB/PDGFR Signaling Pathway Does Orchestrates Osteogenesis in a Temporal Manner

    Fangqian WangYuxiao YeZengjie ZhangWangsiyuan Teng...
    33-48页
    查看更多>>摘要：Platelet-derived growth factor-BB(PDGF-BB)/platelet-derived growth factor receptor-β(PDGFR-β)pathway is conventionally considered as an important pathway to promote osteogenesis;however,recent study suggested its role during osteogenesis to be controversial.Regarding the differential functions of this pathway during 3 stages of bone healing,we hypothesized that temporal inhibition of PDGF-BB/PDGFR-β pathway could shift the proliferation/differentiation balance of skeletal stem and progenitor cells,toward osteogenic lineage,which leads to improved bone regeneration.We first validated that inhibition of PDGFR-β at late stage of osteogenic induction effectively enhanced differentiation toward osteoblasts.This effect was also replicated in vivo by showing accelerated bone formation when block PDGFR-β pathway at late stage of critical bone defect healing mediated using biomaterials.Further,we found that such PDGFR-β inhibitor-initiated bone healing was also effective in the absence of scaffold implantation when administrated intraperitoneally.Mechanistically,timely inhibition of PDGFR-β blocked extracellular regulated protein kinase 1/2 pathway,which shift proliferation/differentiation balance of skeletal stem and progenitor cell to osteogenic lineage by upregulating osteogenesis-related products of Smad to induce osteogenesis.This study offered updated understanding of the use of PDGFR-β pathway and provides new insight routes of action and novel therapeutic methods in the field of bone repair.
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    Solution-Processed Hybrid Europium(Ⅱ)Iodide Scintillator for Sensitive X-Ray Detection

    Xue ZhaoPengfei FuPan LiHainan Du...
    49-57页
    查看更多>>摘要：Lead halide perovskite nanocrystals have recently demonstrated great potential as x-ray scintillators,yet they still suffer toxicity issues,inferior light yield(LY)caused by severe self-absorption.Nontoxic bivalent europium ions(Eu2+)with intrinsically efficient and self-absorption-free d-f transition are a prospective replacement for the toxic Pb2+.Here,we demonstrated solution-processed organic-inorganic hybrid halide BA10Eul12(BA denotes C4H9NH4+)single crystals for the first time.BA10Eul12 was crystallized in a monoclinic space group of P21/c,with photoactive sites of[Eul6]4-octahedra isolated by BA+cations,which exhibited high photoluminescence quantum yield of 72.5％and large Stokes shift of 97 nm.These properties enable an appreciable LY value of 79.6％of LYSO(equivalent to～27,000 photons per MeV)for BA10Eul12.Moreover,BA10Eul12 shows a short excited-state lifetime(151 ns)due to the parity-allowed d-f transition,which boosts the potential of BA10Eul12 for use in real-time dynamic imaging and computer tomography applications.In addition,BA10Eul12 demonstrates a decent linear scintillation response ranging from 9.21 μGyair s-1 to 145 μGyair s-1 and a detection limit as low as 5.83 nGyair s-1.The x-ray imaging measurement was performed using BA10Eul12 polystyrene(PS)composite film as a scintillation screen,which exhibited clear images of objects under x-ray irradiation.The spatial resolution was determined to be 8.95 Ip mm-1 at modulation transfer function=0.2 for BA10Eul12/PS composite scintillation screen.We anticipate that this work will stimulate the exploration of d-f transition lanthanide metal halides for sensitive x-ray scintillators.
      原文链接:
    • NETL
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    Phosphorylation Promotes the Accumulation of PERIOD Protein Foci

    Mengna LiShujing LiLuoying Zhang
    59-69页
    查看更多>>摘要：Circadian clock drives the 24-h rhythm in our behavior and physiology.The molecular clock consists of a series of transcriptional/translational feedback loops operated by a number of clock genes.A very recent study reported that the clock protein PERIOD(PER)is organized into discrete foci at the nuclear envelope in fly circadian neurons,which is believed to be important for controlling the subcellular localization of clock genes.Loss of inner nuclear membrane protein lamin B receptor(LBR)leads to disruption of these foci,but how they are regulated is yet unknown.Here,we found that PER foci are likely phase-separated condensates,the formation of which is mediated by intrinsically disordered region in PER.Phosphorylation promotes the accumulation of these foci.Protein phosphatase 2A,which is known to dephosphorylate PER,hampers the accumulation of the foci.On the other hand,the circadian kinase DOUBLETIME(DBT)which phosphorylates PER enhances the accumulation of the foci.LBR likely facilitates PER foci accumulation by destabilizing the catalytic subunit of protein phosphatase 2A,MICROTUBULE STAR(MTS).In conclusion,here,we demonstrate a key role for phosphorylation in promoting the accumulation of PER foci,while LBR modulates this process by impinging on the circadian phosphatase MTS.
      原文链接:
    • NETL
    • NSTL
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    Quantum Neural Network for Quantum Neural Computing

    Min-Gang ZhouZhi-Ping LiuHua-Lei YinChen-Long Li...
    71-80页
    查看更多>>摘要：Neural networks have achieved impressive breakthroughs in both industry and academia.How to effectively develop neural networks on quantum computing devices is a challenging open problem.Here,we propose a new quantum neural network model for quantum neural computing using(classically controlled)single-qubit operations and measurements on real-world quantum systems with naturally occurring environment-induced decoherence,which greatly reduces the difficulties of physical implementations.Our model circumvents the problem that the state-space size grows exponentially with the number of neurons,thereby greatly reducing memory requirements and allowing for fast optimization with traditional optimization algorithms.We benchmark our model for handwritten digit recognition and other nonlinear classification tasks.The results show that our model has an amazing nonlinear classification ability and robustness to noise.Furthermore,our model allows quantum computing to be applied in a wider context and inspires the earlier development of a quantum neural computer than standard quantum computers.
      原文链接:
    • NETL
    • NSTL
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    Transcranial Magneto-Acoustic Stimulation Attenuates Synaptic Plasticity Impairment through the Activation of Piezo1 in Alzheimer's Disease Mouse Model

    Fangxuan ChuRuxin TanXin WangXiaoqing Zhou...
    81-95页
    查看更多>>摘要：The neuropathological features of Alzheimer's disease include amyloid plaques.Rapidly emerging evidence suggests that Piezo1,a mechanosensitive cation channel,plays a critical role in transforming ultrasound-related mechanical stimuli through its trimeric propeller-like structure,but the importance of Piezo1-mediated mechanotransduction in brain functions is less appreciated.However,apart from mechanical stimulation,Piezo1 channels are strongly modulated by voltage.We assume that Piezo1 may play a role in converting mechanical and electrical signals,which could induce the phagocytosis and degradation of Aβ,and the combined effect of mechanical and electrical stimulation is superior to single mechanical stimulation.Hence,we design a transcranial magneto-acoustic stimulation(TMAS)system,based on transcranial ultrasound stimulation(TUS)within a magnetic field that combines a magneto-acoustic coupling effect electric field and the mechanical force of ultrasound,and applied it to test the above hypothesis in 5xFAD mice.Behavioral tests,in vivo electrophysiological recordings,Golgi-Cox staining,enzyme-linked immunosorbent assay,immunofluorescence,immunohistochemistry,real-time quantitative PCR,Western blotting,RNA sequencing,and cerebral blood flow monitoring were used to assess whether TMAS can alleviate the symptoms of AD mouse model by activating Piezo1.TMAS treatment enhanced autophagy to promote the phagocytosis and degradation of β-amyloid through the activation of microglial Piezo1 and alleviated neuroinflammation,synaptic plasticity impairment,and neural oscillation abnormalities in 5xFAD mice,showing a stronger effect than ultrasound.However,inhibition of Piezo1 with an antagonist,GsMTx-4,prevented these beneficial effects of TMAS.This research indicates that Piezo1 can transform TMAS-related mechanical and electrical stimuli into biochemical signals and identifies that the favorable effects of TMAS on synaptic plasticity in 5xFAD mice are mediated by Piezo1.
      原文链接:
    • NETL
    • NSTL
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    Hierarchical Spinning of Janus Textiles with Anisotropic Wettability for Wound Healing

    Han ZhangLingyu SunJiahui GuoYuanjin Zhao...
    97-105页
    查看更多>>摘要：Wound healing and tissue repair are recognized as basic human health problems worldwide.Attempts to accelerate the reparative process are focused on developing functional wound dressings.Herein,we present novel Janus textiles with anisotropic wettability from hierarchical microfluidic spinning for wound healing.The hydrophilic hydrogel microfibers from microfluidics are woven into textiles for freeze-drying treatment,followed by the deposition of electrostatic spinning nanofibers composed of hydrophobic polylactic acid(PLA)and silver nanoparticles.The electrospun nanofiber layer can be well coupled with the hydrogel microfiber layer to generate Janus textiles with anisotropic wettability due to the roughness of the hydrogel textile surface and the incomplete evaporation of PLA solution when reaching the surface.For wound treatment with the hydrophobic PLA side contacting the wound surface,the wound exudate can be pumped from the hydrophobic to the hydrophilic side based on the wettability differential derived drainage force.During this process,the hydrophobic side of the Janus textile can prevent excess fluid from infiltrating the wound again,preventing excessive moisture and preserving the breathability of the wound.In addition,the silver nanoparticles contained in the hydrophobic nanofibers could impart the textiles with good antibacterial effect,which further promote the wound healing efficiency.These features indicate that the described Janus fiber textile has great application potential in the field of wound treatment.
      原文链接:
    • NETL
    • NSTL
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    Living Chinese Herbal Scaffolds from Microfluidic Bioprinting for Wound Healing

    Xiaocheng WangJinxuan JiaMengying NiuWenzhao Li...
    107-118页
    查看更多>>摘要：Biological scaffolds have been widely employed in wound healing applications,while their practical efficiency is compromised by insufficient oxygen delivery to the 3-dimensional constructs and inadequate nutrient supply for the long-term healing process.Here,we present an innovative living Chinese herbal scaffold to provide a sustainable oxygen and nutrient supply for promoting wound healing.Through a facile microfluidic bioprinting strategy,a traditional Chinese herbal medicine(Panax notoginseng saponins[PNS])and a living autotrophic microorganism(microalgae Chlorella pyrenoidosa[MA])were successfully encapsulated into the scaffolds.The encapsulated PNS could be gradually released from the scaffolds,which promoted cell adhesion,proliferation,migration,and tube formation in vitro.In addition,benefiting from the photosynthetic oxygenation of the alive MA,the obtained scaffolds would produce sustainable oxygen under light illumination,exerting a protective effect against hypoxia-induced cell death.Based on these features,we have demonstrated through in vivo experiments that these living Chinese herbal scaffolds could efficiently alleviate local hypoxia,enhance angiogenesis,and thereby accelerate wound closure in diabetic mice,indicating their great potential in wound healing and other tissue repair applications.
      原文链接:
    • NETL
    • NSTL
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    The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer

    Ding DingHaitao ZhaoDali WeiQinglai Yang...
    119-130页
    查看更多>>摘要：Serving as targeting ligands,aptamers have shown promise in precision medicine.However,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers'clinical translation.To bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(68Ga)radiolabeled aptamers.The specificity and binding affinity of a radiolabeled aptamer,named 68Ga[Ga]-NOTA-SGC8,were maintained as proven in vitro.Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human body.Taking advantage of the cutting-edge total-body PET,the aptamers,distribution pattern in the human body was acquired in a dynamic fashion.This study revealed that radiolabeled aptamers are harmless to normal organs and most of them are accumulated in the kidney and cleared from the bladder via urine,which agrees with preclinical studies.Meanwhile,a physiologically based pharmacokinetic model of aptamer was developed,which could potentially predict therapeutic responses and plan personalized treatment strategies.This research studied the biosafety and dynamic pharmacokinetics of aptamers in the human body for the first time,as well as demonstrated the capability of novel molecular imaging fashion in drug development.
      原文链接:
    • NETL
    • NSTL
    • 万方数据