Susceptibility to cartilage degeneration increases in an age-dependent manner and older cartilage exhibits increased catabolic factor expression leading to osteoarthritis (OA). While inhibition of cellular senescence can prevent age-related diseases, the understanding of the regulators governing cartilage senescence and the potential for senolytic intervention remains limited. Here, in vitro and in vivo results are reported, demonstrating for the first time that the transcriptional regulator, ZMIZ1, is upregulated in aged and OA cartilage, and that it acts through GATA4 to accelerate chondrocyte senescence and trigger cartilage deterioration. Furthermore, it is shown that K-7174 interferes with the ZMIZ1-GATA4 interaction and effectively hampers cartilage senescence and OA. It is proposed that inhibition of the ZMIZ1-GATA4 axis could be a valuable strategy for eliminating senescent chondrocytes and impeding OA development and that the relevant inhibitor, K-7174, could potentially be developed as a senolytic drug for managing cartilage senescence and age-related degeneration.

The specialized cell types of the mucociliary epithelium (MCE) lining the respiratory tract enable continuous airway clearing, with its defects leading to chronic respiratory diseases. The molecular mechanisms driving cell fate acquisition and temporal specialization during mucociliary epithelial development remain largely unknown. Here, we profile the developing <i>Xenopus</i> MCE from pluripotent to mature stages by single-cell transcriptomics, identifying multipotent early epithelial progenitors that execute multilineage cues before specializing into late-stage ionocytes and goblet and basal cells. Combining in silico lineage inference, in situ hybridization, and single-cell multiplexed RNA imaging, we capture the initial bifurcation into early epithelial and multiciliated progenitors and chart cell type emergence and fate progression into specialized cell types. Comparative analysis of nine airway atlases reveals an evolutionary conserved transcriptional module in ciliated cells, whereas secretory and basal types execute distinct function-specific programs across vertebrates. We uncover a continuous nonhierarchical model of MCE development alongside a data resource for understanding respiratory biology.

Chondrocytes secrete massive extracellular matrix (ECM) molecules that are produced, folded, and modified in the endoplasmic reticulum (ER). Thus, the ER-associated degradation (ERAD) complex-which removes misfolded and unfolded proteins to maintain proteostasis in the ER- plays an indispensable role in building and maintaining cartilage. Here, we examined the necessity of the ERAD complex in chondrocytes for cartilage formation and maintenance. We show that ERAD gene expression is exponentially increased during chondrogenesis, and disruption of ERAD function causes severe chondrodysplasia in developing embryos and loss of adult articular cartilage. ERAD complex malfunction also causes abnormal accumulation of cartilage ECM molecules and subsequent chondrodysplasia. ERAD gene expression is decreased in damaged cartilage from patients with osteoarthritis (OA), and disruption of ERAD function in articular cartilage leads to cartilage destruction in a mouse OA model.

The surface chemistry and physical characteristics of gold nanoparticles (AuNPs) influence their biological interactions and toxicological responses. However, the toxicological effects of surface charge on embryonic development remain poorly understood. In this study, we investigated the in vivo developmental toxicity and teratogenicity of differentially charged AuNPs during early embryogenesis of Xenopus laevis - a sensitive and ecologically relevant animal model for developmental toxicology. Our study indicated that cationic AuNPs induced significant embryotoxicity and teratogenicity including lethality, phenotypical abnormalities and disruption of gene expression associated with liver, digestive tract, neural, and eye development. In contrast, such effects, including lethality and malformations associated with changes in gene expression were not observed in embryos exposed to anionic AuNPs. In addition, cationic AuNPs affected ciliogenesis by reducing the number of multiciliated cells and disturbing cilia-driven fluid flow, a critical endpoint in nanoparticle-induced toxicity. Furthermore, gene expression profiles suggested that necroptosis might be the mechanism of cell death in embryos exposed to cationic AuNPs. Notably, the surface charge dependent AuNPs exposure leading to impaired ciliogenesis and activation of necroptosis during embryogenesis represents significant endpoints in nanotoxicology. Unlike previous studies focusing on zebrafish or rodents, this study provides the first systematic evaluation in X. laevis embryos with identical nanoparticle cores but distinct surface chemistries. Our study underscores the significance of nanoparticle surface functionalization in determining developmental toxicity and pinpoints the ecological risks imposed by cationic AuNPs during early embryonic development in aquatic systems.

TNF receptor-associated protein1 (TRAP1) is a mitochondrial molecular chaperon with high homology with a cytosolic chaperon HSP90. It has been shown that TRAP1 functions as an inhibitor for apoptosis by preventing cytochrome-c release from mitochondria. In addition, TRAP1 seems to play critical roles in metabolic processes for energy production, such as glycolysis and β-oxidation. It has also been reported that TRAP1 is a direct target of PTEN-induced kinase 1 (PINK1) and may be a cause of Parkinson's disease (PD) in humans. Although the biochemical functions of TRAP1 are under intense study for the physiology and treatment of various cancers, its roles in vertebrate development have not been reported. This study shows that <i>Xenopus</i> TRAP1 is strongly expressed in the developing muscle, kidney, and brain tissues. Perturbation of TRAP1 function by treating TRAP1 inhibiter GTPP or microinjection of antisense-morpholino oligo (MO) caused mild defects in striated muscle fiber formation. Furthermore, the looping patterns of developing kidney tubules were perturbed, indicating that TRAP1 function is necessary for proper kidney development.

The beating of cilia on multi-ciliated cells (MCCs) is essential for normal development and homeostasis in animals. But while the structure and function of basal bodies and axonemes have received significant attention recently, the distal tips of MCC cilia remain relatively poorly defined. Here, we characterize the molecular organization of the distal tip of vertebrate MCC cilia, characterizing two distinct domains occupied by distinct protein constituents. Using frog, mouse, and human MCCs, we find that two largely uncharacterized proteins, Ccdc78 and Ccdc33 occupy a previously undefined region at the extreme distal tip, and these are required for the normal organization of all other known tip proteins. Ccdc78 and Ccdc33 each display robust microtubule-bundling activity both <i>in vivo</i> and <i>in vitro</i>, yet each is independently required for normal length regulation of MCC cilia. Moreover, loss of each protein elicits a distinct pattern of defective cilia beating and resultant fluid flow. Thus, two previously undefined proteins form a key module essential for organizing and stabilizing the distal tip of motile cilia in vertebrate MCCs. We propose that these ill-defined proteins represent potential disease loci for motile ciliopathies.

The cilium is a microtubule-based organelle that plays a pivotal role in embryonic development and maintenance of physiological functions in the human body. In addition to their function as sensors that transduce diverse extracellular signals, including growth factors, fluid flow, and physical forces, cilia are intricately involved in cell cycle regulation and preservation of DNA integrity, as their formation and resorption dynamics are tightly linked to cell cycle progression. Recently, several studies have linked defects in specific ciliary proteins to the DNA damage response. However, it remains unclear whether and how primary cilia contribute to cancer development. Mebendazole (MBZ) is an anthelmintic drug with anticancer properties in some cancer cells. MBZ is continuously being tested for clinical studies, but the precise mechanism of its anticancer activities remains unknown. Here, using Xenopus laevis embryos as a model system, we discovered that MBZ significantly hinders cilia formation and induces DNA damage. Remarkably, primary cilium-bearing cancer cells exhibited heightened vulnerability to combined treatment with MBZ and conventional anticancer drugs. Our findings shed light on the specific influence of MBZ on cilia, rather than cytosolic microtubules, in triggering DNA damage, elucidating a previously unidentified mechanism underlying potential MBZ-mediated cancer therapy.

Abstract Enhancing the performance of thermoelectric materials remains critical for practical applications. Increasing the power factor and reducing the thermal conductivity are key strategies for improving the thermoelectric performance. Doping, incorporating secondary phases, and generating dislocations can be used to introduce defects and grain boundaries to improve the thermoelectric performance. The application of an ultrathin film as a coating on thermoelectric materials via atomic layer deposition (ALD) has recently attracted attention as a novel approach to enhance the performance. The excellent conformality of ALD enables the conformal deposition of ultrathin films on powder to enable the interfacial properties to be meticulously controlled even after sintering. Using ALD to deposit an ultrathin layer on the thermoelectric powder matrix induces various defects through the interactions of the coating material with the thermoelectric matrix, which provide exquisite control over the material properties. This review discusses the phenomena induced by applying ultrathin coatings to thermoelectric materials through ALD, elucidates the underlying mechanisms, and examines the effects on the thermoelectric performance. Based on these insights, innovative pathways for applying ALD to thermoelectric materials are proposed, and robust strategies for enhancing these properties through the precise modulation of diverse defects and interfaces are discussed.

Susceptibility to cartilage degeneration increases in an age-dependent manner and older cartilage exhibits increased catabolic factor expression leading to osteoarthritis (OA). While inhibition of cellular senescence can prevent age-related diseases, the understanding of the regulators governing cartilage senescence and the potential for senolytic intervention remains limited. Here, in vitro and in vivo results are reported, demonstrating for the first time that the transcriptional regulator, ZMIZ1, is upregulated in aged and OA cartilage, and that it acts through GATA4 to accelerate chondrocyte senescence and trigger cartilage deterioration. Furthermore, it is shown that K-7174 interferes with the ZMIZ1-GATA4 interaction and effectively hampers cartilage senescence and OA. It is proposed that inhibition of the ZMIZ1-GATA4 axis could be a valuable strategy for eliminating senescent chondrocytes and impeding OA development and that the relevant inhibitor, K-7174, could potentially be developed as a senolytic drug for managing cartilage senescence and age-related degeneration.

The specialized cell types of the mucociliary epithelium (MCE) lining the respiratory tract enable continuous airway clearing, with its defects leading to chronic respiratory diseases. The molecular mechanisms driving cell fate acquisition and temporal specialization during mucociliary epithelial development remain largely unknown. Here, we profile the developing <i>Xenopus</i> MCE from pluripotent to mature stages by single-cell transcriptomics, identifying multipotent early epithelial progenitors that execute multilineage cues before specializing into late-stage ionocytes and goblet and basal cells. Combining in silico lineage inference, in situ hybridization, and single-cell multiplexed RNA imaging, we capture the initial bifurcation into early epithelial and multiciliated progenitors and chart cell type emergence and fate progression into specialized cell types. Comparative analysis of nine airway atlases reveals an evolutionary conserved transcriptional module in ciliated cells, whereas secretory and basal types execute distinct function-specific programs across vertebrates. We uncover a continuous nonhierarchical model of MCE development alongside a data resource for understanding respiratory biology.