Research最新文献

Human bone marrow stem cells (hBMSCs) play an important role during the fracture healing phase. Previous clinical studies by our research group found that fracture healing time was obviously delayed in patients who underwent splenectomy, for combined traumatic fractures and splenic rupture, which is most likely related to the dysregulation of immune inflammatory function of the body after splenectomy. A large number of studies have reported that the inflammatory factor interleukin-1β plays an important role in the multi-directional differentiation ability and immune regulation of BMSC, but its specific regulatory mechanism needs to be further studied. Recently, long noncoding RNAs (lncRNAs) have attracted remarkable attention owing to their close relationship with stem cell osteogenesis and potential role in various bone diseases. In this study, we explored the molecular mechanism of a novel lncRNA, LncMSTRG.11341.25 (LncMSTRG25), in terms of its effects on osteogenic differentiation of hBMSCs. Our results reveal significant up-regulation of LncMSTRG25, osteogenic differentiation markers during the osteogenic differentiation of hBMSCs, and decreased expression of miR-939-5p with an increase in differentiation time. LncMSTRG25 knockdown significantly inhibited the osteogenic ability of hBMSCs. When we knocked down PAX8 alone, we found that the osteogenic ability of hBMSCs was also significantly reduced. The interaction between LncMSTRG25 and PAX8 was verified using the RNA immunoprecipitation assay, RNA pull-down assays, silver staining, and the dual-luciferase reporter. The results show that LncMSTRG25 can function as a sponge to adsorb miR-939-5p, inducing the osteogenic differentiation of hBMSCs by activating PAX8. These findings deepen our understanding of the regulatory role of lncRNA-miRNA-mRNA networks in the immune microenvironment of bone marrow, and highlight the important role played by the spleen as an immune organ in fracture healing.

We apply the recently developed concept of the nucleon energy-energy correlator (NEEC) for the gluon sector to investigate the long-range azimuthal angular correlations in proton-proton collisions at the Large Hadron Collider. The spinning gluon in these collisions will introduce substantial nonzero $\text{cos}\left(2\varphi \right)$ asymmetries in both Higgs boson and top quark pair productions, where $\varphi$ is the azimuthal angle between the forward and backward energy correlators in the NEEC observables. The genesis of the $\text{cos}\left(2\varphi \right)$ correlation lies in the intricate quantum entanglement. Owing to the substantial $\text{cos}\left(2\varphi \right)$ effect, the NEEC observable in Higgs boson and $t\overline{t}$ production emerges as a pivotal avenue for delving into quantum entanglement and scrutinizing the Bell inequality at high-energy colliders.

Developing advanced tissue-engineered membranes with biocompatibility, suitable mechanical qualities, and anti-fibrotic and anti-inflammatory actions is important for tympanic membrane (TM) repair. Here, we present a novel acoustically transmitted decellularized fish swim bladder (DFB) loaded with mesenchymal stem cells (DFB@MSCs) for TM perforation (TMP) repair. The DFB scaffolds are obtained by removing the cellular components from the original FB, which retains the collagen composition that favors cell proliferation. Benefitting from their spatially porous structures and excellent mechanical properties, the DFB scaffolds can provide a suitable microenvironment and mechanical support for cell growth and tissue regeneration. In addition, by loading mesenchymal stem cells on the DFB scaffolds, the resultant DFB@MSCs system exhibits remarkable anti-fibrotic and anti-inflammatory effects, together with the ability to promote cell migration and angiogenesis. In vivo experiments confirm that the prepared DFB@MSCs scaffolds can not only alleviate inflammatory response caused by TMP but also promote new vessel formation, TM repair, and hearing improvement. These features indicate that our proposed DFB@MSCs stent is a prospective tool for the clinical repair of TM.

Simulated microgravity (SMG) poses substantial challenges to astronaut health, particularly impacting osteoblast function and leading to disuse osteoporosis. This study investigates the adverse effects of SMG on osteoblasts, focusing on changes in mitochondrial dynamics and their consequent effects on cellular energy metabolism and mechanotransduction pathways. We discovered that SMG markedly reduced the expression of osteoblast differentiation markers and promoted mitochondrial fission, as indicated by an increase in punctate mitochondria, a decrease in mitochondrial length, and a reduction in cristae density. These mitochondrial alterations are linked to elevated reactive oxygen species levels, a decrease in ΔΨm, and a metabolic shift from oxidative phosphorylation to glycolysis, resulting in decreased adenosine triphosphate production, which are all indicative of mitochondrial dysfunction. Our results showed that treatment with mitochondrial division inhibitor-1 (mdivi-1), a mitochondrial fission inhibitor, effectively inhibited these SMG-induced effects, thereby maintaining mitochondrial structure and function and promoting osteoblast differentiation. Furthermore, SMG disrupted critical mechanotransduction processes, by affecting paxillin expression, the RhoA-ROCK-Myosin II pathway, and actin dynamics, which subsequently altered nuclear morphology and disrupted Yes-associated protein signaling. Notably, treatment with mdivi-1 prevented these disruptions in mechanotransduction pathways. Moreover, our study showed that SMG-induced chromatin remodeling and histone methylation, which are epigenetic barriers to osteogenic differentiation, can be reversed by targeting mitochondrial fission, further highlighting the significance of mitochondrial dynamics in osteoblast function in an SMG environment. Therefore, targeting mitochondrial fission emerges as a promising therapeutic strategy to alleviate osteoblast dysfunction under SMG conditions, providing novel approaches to maintain bone health during prolonged space missions and safeguard the astronaut well-being.

Osteoarthritis (OA) is the most prevalent joint disease, yet effective disease-modifying OA drugs (DMOADs) remain elusive. Targeting macrophage polarization has emerged as a promising avenue for OA treatment. This study identified skatole through high-throughput screening as an efficient modulator of macrophage polarization. In vivo experiments demonstrated that skatole administration markedly reduced synovitis and cartilage damage in both destabilization of medial meniscus (DMM)-induced OA mice and monosodium iodoacetate (MIA)-induced OA rats. Mechanistically, skatole activated signal transducer and activator of transcription 6 (Stat6) signaling, promoting M2 macrophage polarization, while inhibiting nuclear factor-κB (NFκB) and mitogen-activated protein kinase (MAPK) signaling pathways to suppress M1 polarization. RNA-sequencing analysis, targeted metabolomics, and mitochondrial stress tests further revealed that skatole treatment shifted macrophages toward oxidative phosphorylation for energy production. Additionally, it up-regulated genes associated with glutathione metabolism and reactive oxygen species (ROS) pathways, reducing intracellular ROS production. The CUT&Tag assay results indicated that the downstream transcription factor p65 of NFκB can directly bind to gene loci related to inflammation, oxidative phosphorylation, and glutathione metabolism, thereby modulating gene expression. This regulatory process is inhibited by skatole. At the chondrocyte level, conditional medium from skatole-treated M1 macrophages balanced anabolism and catabolism in mouse chondrocytes and inhibited apoptosis. In IL1β-treated chondrocytes, skatole suppressed inflammation and catabolism without affecting apoptosis or anabolism. Overall, skatole maintains immune microenvironment homeostasis by modulating macrophage polarization in joints and preserves cartilage function by balancing chondrocyte anabolism and catabolism, effectively alleviating OA. These findings suggest skatole's potential as a DMOAD.

The study of many phenomena in the terahertz (THz) frequency spectral range has emerged as a promising playground in modern science and technology, with extensive applications in high-speed communication, imaging, sensing, and biosensing. Many THz metamaterial designs explore quantum physics phenomena embedded into a classical framework and exhibiting various unexpected behaviors. For spatial THz waves, the effects inspired by quantum phenomena include electromagnetically induced transparency (EIT), Fano resonance, bound states in the continuum (BICs), and exceptional points (EPs) in non-Hermitian systems. They facilitate the realization of extensive functional metadevices and applications. For on-chip THz waves, quantum physics-inspired topological metamaterials, as photonic analogs of topological insulators, can ensure robust, low-loss propagation with suppressed backscattering. These trends open new pathways for high-speed on-chip data transmission and THz photonic integrated circuits, being crucial for the upcoming 6G and 7G wireless communication technologies. Here, we summarize the underlying principles of quantum physics-inspired metamaterials and highlight the latest advances in their application in the THz frequency band, encompassing both spatial and on-chip metadevice realizations.

Metals have traditionally served as the primary functional phase in the development of metamaterials exhibiting epsilon-near-zero (ENZ) and epsilon-negative (EN) responses, albeit with persisting ambiguities regarding their response mechanisms. This paper presents the tunable ENZ (ε' ~ 0) and EN (ε' < 0) parameters at the 20-MHz to 1-GHz region based on Cu/CaCu₃Ti₄O₁₂ (Cu/CCTO) metacomposites. By means of first-principles calculations and multi-physics simulations, the underlying mechanisms governing ENZ and EN responses are unveiled. The intricate pathways through which metacomposites achieve 2 dielectric response mechanisms are delineated: At low Cu content, a weak EN response (|ε'| < 200) was excited by electric dipole resonance, accompanied by ENZ effect; conversely, at high Cu content, due to the increase in effective electron concentration, plasmonic oscillation behavior occurs in the constructed 3-dimensional Cu network, resulting in strong EN response (|ε'| ~ 1,000) in the radio frequency band. These phenomena are explicated through 2 distinct Cu/CCTO models: Cu in an isolated state and a connected network state. This study not only comprehensively elucidates the 2 EN response mechanisms achieved by typical metacomposites with metals as functional phases but also delves into their associated electromagnetic shielding and thermal properties, providing a theoretical basis for their practical applications.

Sepsis-associated encephalopathy (SAE) is a severe and frequent septic complication, characterized by neuronal damage as key pathological features. The astrocyte-microglia crosstalk in the central nervous system (CNS) plays important roles in various neurological diseases. However, how astrocytes interact with microglia to regulate neuronal injury in SAE is poorly defined. In this study, we aim to investigate the molecular basis of the astrocyte-microglia crosstalk underlying SAE pathogenesis and also to explore the new therapeutic strategies targeting this crosstalk in this devastating disease. We established a human astrocyte/microglia coculture system on a microfluidic device, which allows real-time and high-resolution recording of glial responses to inflammatory stimuli. Based on this microfluidic system, we can test the responses of astrocytes and microglia to lipopolysaccharide (LPS) treatment, and identify the molecular cues that mediate the astrocyte-microglia crosstalk underlying the pathological condition. In addition, the SAE mouse model was utilized to determine the state of glial cells and evaluate the therapeutic effect of drugs targeting the astrocyte-microglia crosstalk in vivo. Here, we found that activated astrocytes and microglia exhibited close spatial interaction in the SAE mouse model. Upon LPS exposure for astrocytes, we detected that more microglia migrated to the central astrocyte culture compartment on the microfluidic device, accompanied by M1 polarization and increased cell motility in microglia. Cytokine array analysis revealed that less interleukin 11 (IL11) was secreted by astrocytes following LPS treatment, which further promoted reprogramming of microglia to pro-inflammatory M1 phenotype via the nuclear factor-κB (NF-κB) signaling pathway. Intriguingly, we found that IL11 addition markedly rescued LPS-induced neuronal injuries on the microfluidic system and brain injury in the SAE mouse model. This study defines an unknown crosstalk of astrocyte-microglia mediated by IL11, which contributed to the neuropathogenesis of SAE, and suggested a potential therapeutic value of IL11 in the devastating disease.

Na_v1.7 is considered a promising target for developing next-generation analgesic drugs, given its critical role in human pain pathologies. Although most reported inhibitors with strong in vitro activity and high selectivity share the aryl sulfonamide scaffold, they failed to demonstrate marked clinical efficacy. Therefore, exploring new Na_v1.7-selective antagonists is quite urgent to the development of next-generation analgesic drugs. Here, we report a highly effective 1H-indole-3-propionamide inhibitor, WN2, identified through an integrated drug discovery strategy. Notably, the structure of WN2 is quite different from previously reported aryl sulfonamide inhibitors. Molecular dynamics simulations and experimental findings reveal that the R configuration of WN2 (WN2-R) is the preferred form (IC₅₀ = 24.7 ± 9.4 nM) within the VSDIV pocket of Na_v1.7. WN2-R exhibits impressive analgesic effects in acute and chronic inflammatory pain, as well as neuropathic pain models in mice. Additionally, it displays favorable subtype selectivity and positive drug safety in acute toxicity studies. Pharmacokinetic studies indicate that WN2-R has high bioavailability (F = 20.29%), highlighting its considerable potential for drug development. Our study establishes WN2-R as a novel Na_v1.7-selective inhibitor with a unique structural scaffold, offering a promising candidate for the next generation of analgesic drugs.

Soft electronics, known for their bendable, stretchable, and flexible properties, are revolutionizing fields such as biomedical sensing, consumer electronics, and robotics. A primary challenge in this domain is achieving low power consumption, often hampered by the limitations of the conventional von Neumann architecture. In response, the development of soft artificial synapses (SASs) has gained substantial attention. These synapses seek to replicate the signal transmission properties of biological synapses, offering an innovative solution to this challenge. This review explores the materials and device architectures integral to SAS fabrication, emphasizing flexibility and stability under mechanical deformation. Various architectures, including floating-gate dielectric, ferroelectric-gate dielectric, and electrolyte-gate dielectric, are analyzed for effective weight control in SASs. The utilization of organic and low-dimensional materials is highlighted, showcasing their plasticity and energy-efficient operation. Furthermore, the paper investigates the integration of functionality into SASs, particularly focusing on devices that autonomously sense external stimuli. Functionalized SASs, capable of recognizing optical, mechanical, chemical, olfactory, and auditory cues, demonstrate promising applications in computing and sensing. A detailed examination of photo-functionalized, tactile-functionalized, and chemoreception-functionalized SASs reveals their potential in image recognition, tactile sensing, and chemosensory applications, respectively. This study highlights that SASs and functionalized SAS devices hold transformative potential for bioelectronics and sensing for soft-robotics applications; however, further research is necessary to address scalability, long-time stability, and utilizing functionalized SASs for prosthetics and in vivo applications through clinical adoption. By providing a comprehensive overview, this paper contributes to the understanding of SASs, bridging research gaps and paving the way toward transformative developments in soft electronics, biomimicking and biointegrated synapse devices, and integrated systems.