Advanced Science最新文献

Vascular calcification is a highly regulated process in cardiovascular disease (CVD) and is strongly correlated with morbidity and mortality, especially in the adverse stage of vascular remodeling after coronary artery bypass graft surgery (CABG). However, the pathogenesis of vascular graft calcification, particularly the role of endothelial-smooth muscle cell interaction, is still unclear. To test how ECs interact with SMCs in artery grafts, single-cell analysis of wild-type mice is first performed using an arterial isograft mouse model and found robust cytokine-mediated signaling pathway activation and SMC proliferation, together with upregulated endothelial tripartite motif 35 (TRIM35) expression. Unexpectedly, severe SMC calcification in artery grafts is found in TRIM35 conditional endothelial knockout (cKO) mice. Calcified medium (comprising calcium chloride and beta-glycerophosphate)-induced calcium deposition in vitro is also found in SMCs cocultured with TRIM35 knockout endothelium. This extraordinary phenomenon is further confirmed to be induced by increased MMP10 secretion. Mechanistically, endothelial TRIM35 inhibits MMP10 expression and secretion by promoting K63-linked ubiquitination of RelB and maintaining its nuclear localization, consequently inhibiting nuclear transcription of MMP10 through the noncanonical NF-κB signaling pathway. Targeting MMP10 in situ in arterial isografts can effectively alleviate vascular calcification caused by conditional endothelial TRIM35 knockout. These findings demonstrated that TRIM35 inhibited vascular calcification during arterial isograft remodeling, a process that is driven by the aberrant secretion of endothelial MMP10. Targeting MMP10 pathway may be a potential therapeutic strategy for vascular calcification in vessel grafts.

Corneal substitutes with structural and compositional characteristics resembling those of natural corneas have attracted considerable attention. However, biomimicking the complex hierarchical organization of corneal stroma is challenging. In this study, humanized corneal stroma-like adhesive patches (HCSPs) are prepared through a multi-step process. First, polyethylene glycol diacrylate is cast and cured within decellularized porcine cornea (DPC) templates. The DPCs are then enzymatically digested to obtain hydrogel skeletons, which are finally integrated with human corneal extracellular matrix and methacrylate gelatin. HCSPs replicate the ultrastructure, protein components, and optical properties of human corneas and exhibit improved anti-swelling and anti-degradation capabilities compared with conventional DPCs and recombinant human collagen patches. HCSPs can deliver methacrylate gelatin at the ocular surface temperature (37 °C) and achieve stable adhesion to the corneal stroma upon 405 nm light irradiation. Furthermore, HCSPs promote the survival and migration of corneal epithelial and stromal cells while preserving their phenotypes. In rabbit models of lamellar keratoplasty and microperforation repair, HCSPs accelerate epithelial healing, minimize suture-associated complications, and maintain structural stability. These findings suggest that HCSPs are promising donor corneal substitutes for clinical applications.

Phonon modal nonequilibrium is believed to widely exist around nanoscale hotspots, which can significantly affect the performance of nano-electronic and optoelectronic devices. However, such a phenomenon has not been explicitly observed in 3D device semiconductors at the nanoscale. Here, by employing a tip-enhanced Raman thermal measurement approach, substantial phonon nonequilibrium in gallium nitride near sub-10 nm laser-excited hotspots is directly revealed for the first time. As further evidence, quantitative agreements between measurements and accurate first-principles-based phonon Boltzmann transport equation calculations are obtained. The large nonequilibrium is attributed to the strong Fröhlich coupling of electrons with longitudinal optical phonons and the large acoustic-optical phonon frequency gap in gallium nitride, which is further demonstrated in other common III-V semiconductors. This work establishes a viable approach for understanding nanoscale nonequilibrium phonon transport and can potentially benefit the future modulation of hot carrier dynamics.

Gram-positive bacteria pose significant threats to human health, necessitating the development of targeted bacterial detection and eradication strategies. Nevertheless, current approaches often suffer from poor targeting specificity. Herein, the study utilizes purple rice lixivium to synthesize biomass carbon dots (termed BCDs) with wheat germ agglutinin-like residues for precisely targeting Gram-positive bacteria. Subsequently, fluorescein isothiocyanate (FITC) molecules are grafted onto BCDs to yield FITC-labeled BCDs (termed CDFs), which can selectively and rapidly (≤5 min) stain bacterial cell wall and particularly target the peptidoglycan component. Strikingly, CDFs achieve superselective visualization of Gram-positive bacteria even in the presence of mammalian cells and Gram-negative bacteria. Furthermore, protoporphyrin (PpIX) molecules are conjugated onto BCDs to yield PpIX-modified BCDs (termed CDPs), which can induce bacterial aggregation and in situ generate singlet oxygen for realizing enhanced antibacterial photodynamic therapy (PDT). At the minimum bactericidal concentration of CDPs (PpIX: 5 µg mL^-1), CDP-mediated PDT disrupts bacterial structure and metabolism pathways, thereby affecting bacterial interactions to eradicate biofilms. Importantly, CDP-mediated PDT efficiently modulates antiinflammatory responses to promote wound healing in the bacteria-infected mice. This study underscores the significance of harnessing renewable and cost-effective biomass resources for preparing Gram-positive bacteria-targeting theranostic agents, which may find potential clinical applications in the future.

Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether hyperlactatemia exacerbates hepatic ischemia-reperfusion injury (IRI) after donor liver implantation remains unclear. Here, the role of hyperlactatemia in hepatic IRI is explored. In this work, hyperlactatemia is found to exacerbate ferroptosis during hepatic IRI. Lactate-primed lysine acetyltransferase 8 (KAT8) is determined to directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene-edited mice, evidence indicating that PCK2 exacerbates hepatic ferroptosis during IRI is generated. Mechanistically, PCK2 lactylate at Lys100 acts as a critical inducer of ferroptosis during IRI by competitively inhibiting the Parkin-mediated polyubiquitination of 3-oxoacyl-ACP synthase (OXSM), thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis (mtFAS) and the potentiation of oxidative phosphorylation and the tricarboxylic acid cycle. More importantly, targeting PCK2 is demonstrated to markedly ameliorate hyperlactatemia-mediated ferroptosis during hepatic IRI. Collectively, the findings support the use of therapeutics targeting PCK2 to suppress hepatic ferroptosis and IRI in patients with hyperlactatemia during LT.

Flexible memristors are promising candidates for multifunctional neuromorphic computing applications, overcoming the limitations of conventional computing devices. However, unpredictable switching behavior and poor mechanical stability in conventional memristors present significant challenges to achieving device reliability. Here, a reliable and flexible memristor using zirconium-oxo cluster (Zr₆O₄OH₄(OMc)₁₂) as the resistive switching layer is demonstrated. The optimization of the structural rigidity of the hybrid oxo-cluster network by thermal polymerization allows the precise formation of dispersed conductive cluster networks, enhancing the repeatability of the resistive switching with mechanical flexibility. The optimized memristor exhibits endurance of ∼10⁴ cycles and stable memory retention performance up to 10⁴ s, maintaining a high I_ON/I_OFF ratio of 10⁴ under a bending radius of 2.5 mm. Moreover, the device achieves a pattern recognition accuracy of 97.44%, enabled by highly symmetric analog switching with multilevel conductance states. These results highlight that hybrid metal-oxo clusters can provide novel material design principles for flexible and reliable neuromorphic applications, contributing to the development of artificial neural networks.

Angiostrongylus cantonensis (AC) is the leading cause of eosinophilic meningoencephalitis worldwide. The neuroimmune interactions between peripheral and central immune systems in angiostrongyliasis remain unclear. In this study, significant infiltration of eosinophils, myeloid cells, macrophages, neutrophils, and Ly6C monocytes is observed in the brains of AC-infected mice, with macrophages being the most abundant. RNA-seq and SMART-seq analysis of pattern recognition receptor (PRR) and DNA sensor gene sets revealed a marked increase in Z-DNA binding protein 1 (Zbp1) expression in infected mice. Confocal microscopy, RT-qPCR, western blotting, and immunohistochemistry further confirmed that Zbp1 is specifically upregulated in macrophages and microglia. Using Zbp1-knockout mice and flow cytometry, it is found that knockout of Zbp1 enhanced lymphocyte infiltration and natural killer cell cytotoxicity, modulating the immune microenvironment in the central nervous system (CNS) during AC infection. Mechanistically, it is revealed that in macrophage Zbp1 directly binds to receptor-interacting protein 3 (RIP3) to promote its phosphorylation, subsequently facilitating the phosphorylation of mixed lineage kinase domain-like protein (Mlkl). The activated Zbp1-pRIP3-pMlkl axis leads to necroptosis and upregulates pro-inflammatory cytokines including TNF-α, IL-1α, CXCL9, CXCL10 in macrophages, which recruits and activates immune cells. These findings offer new insights into the pathogenic mechanisms of angiostrongyliasis and suggest potential therapeutic strategies.

Ischemic stroke is the most common cerebrovascular disease and the leading cause of permanent disability worldwide. Recent studies have shown that stroke development and prognosis are closely related to abnormal tryptophan metabolism. Here, significant downregulation of 3-hydroxy-kynurenamine (3-HKA) in stroke patients and animal models is identified. Supplementation with 3-HKA improved long-term neurological recovery, reduced infarct volume, and increased ipsilateral cerebral blood flow after distal middle cerebral artery occlusion (MCAO). 3-HKA promoted angiogenesis, functional blood vessel formation, and blood-brain barrier (BBB) repair. Moreover, 3-HKA inhibited A1-like (neurotoxic) astrocyte activation but promoted A2-like (neuroprotective) astrocyte polarization. Proteomic analysis revealed that 3-HKA inhibited AIM2 inflammasome activation after stroke, and co-labeling studies indicated that AIM2 expression typically increased in astrocytes at 7 and 14 days after stroke. Consistently, in co-cultures of primary mouse brain microvascular endothelial cells and astrocytes, 3-HKA promoted angiogenesis after oxygen-glucose deprivation (OGD). AIM2 overexpression in astrocytes abrogated 3-HKA-driven vascular remodeling in vitro and in vivo, suggesting that 3-HKA may regulate astrocyte-mediated vascular remodeling by impeding AIM2 inflammasome activation. In conclusion, 3-HKA may promote post-stroke vascular remodeling by regulating A1/A2 astrocyte activation, thereby improving long-term neurological recovery, suggesting that supplementation with 3-HKA may be an efficient therapy for stroke.

Oxygen usually exists in the form of diatomic molecules at ambient conditions. At high pressure, it undergoes a series of phase transitions from diatomic O₂ to O₈ cluster and ultimately dissociates into a polymeric O₄ spiral chain structure. Intriguingly, the commonly found cyclic hexameric molecules in other group VIA elements (e.g., S₆ and Se₆) are never reported in the bulk oxygen. Through extensive computational crystal structure search, herein it is reported that such hexameric O₆ molecules can exist in a stable compound HeO₃ above 1.9 TPa. The first-principles calculations reveal that, during the reaction by mixing oxygen with helium, the insertion of helium does not only expand the lattice volume, but also relieves the electron lone pair repulsion among diatomic O₂, and thus significantly promoting the formation of cyclic O₆ molecules. Furthermore, the transition pathway calculations demonstrate that molecular O₂ is dissociated first, and then six oxygen atoms form a polymeric digital 2-shaped intermediate O₆. Subsequently, each unstable intermediate O₆ decomposes into two intermedia O₃ trimers. Finally, O₃ trimers transform into cyclic O₆ molecules at high pressure. This study expands the known molecular forms of oxygen and suggests a route to the synthesis of intriguing cyclic O₆ molecules.