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New transposon insertions are deleterious to genome stability. The RNA-directed DNA methylation (RdDM) pathway evolved to regulate transposon activity via DNA methylation. However, current studies have not yet clearly described the transposition regulation. ONSEN is a heat-activated retrotransposon that is activated at 37°C. The plant-specific SUPPRESSOR OF VARIEGATION 3–9 HOMOLOG (SUVH) family proteins function downstream of the RdDM pathway. The SUVH protein families are linked to TE silencing by two pathways, one through DNA methylation and the other through chromatin remodeling. In this study, we analyzed the regulation of ONSEN activity by SUVH2. We observed that ONSEN transcripts were increased; however, there was no transpositional activity in Arabidopsis suvh2 mutant. The suvh2 mutant produced siRNAs from the ONSEN locus under heat stress, suggesting that siRNAs are involved in suppressing transposition. These results provide new insights into the regulatory mechanisms of retrotransposons that involve siRNA in the RdDM pathway.

Cisplatin resistance continues to pose a significant challenge in the treatment of osteosarcoma, markedly impairing clinical outcomes. Accumulating evidence indicates that exosomal microRNAs (miRNAs) facilitate intercellular communication and play a critical role in drug resistance mechanisms. In this study, we conducted high-throughput sequencing of serum-derived exosomes and identified miR-20a-5p as significantly upregulated in cisplatin-resistant osteosarcoma patients. Functional analyses revealed that exosomes enriched with miR-20a-5p derived from cisplatin-resistant HOS cells (HOS-DDP) were internalized by sensitive HOS cells, thereby promoting cisplatin resistance through the inhibition of ferroptosis. Mechanistically, co-culture with miR-20a-5p - rich exosomes resulted in preserved mitochondrial morphology, reduced Fe 2+ and ROS accumulation, increased GSH levels, and suppressed T-SOD depletion under cisplatin-induced stress. Furthermore, exosomal miR-20a-5p was demonstrated to directly target and suppress the tumor suppressor RUNX3, a key regulator of ferroptotic pathways. Overexpression of RUNX3 restored ferroptosis and reversed the miR-20a-5p–mediated resistance phenotypes. Collectively, these findings elucidated that exosomal miR-20a-5p conferred cisplatin resistance in osteosarcoma by inhibiting ferroptosis via RUNX3 suppression, providing a promising therapeutic target for overcoming chemoresistance.

Two-dimensional (2D) COFs have been successfully applied for various applications, such as capillary electrochromatography (CEC). Compared with 2D COFs, three-dimensional (3D) COFs have higher surface area and lower density, which should have superior potential as the separation medium in CEC. However, the 3D COFs on the inner wall of capillary is hard to fabricate in situ. Up to date, the application of 3D COFs in open-tubular capillary electrochromatography (OT-CEC) is still considered a challenge. For the first time the COF-300-coated capillary was prepared by in situ growth (COF-300 was made from terephthalaldehyde and tetra-(4-anilyl)-methane) on OT-CEC. Benzene, methylbenzene, styrene, ethylbenzene, naphthalene, 1-methylnaphthalene, and propylbenzene were used to evaluate the performance of the COF-300-coated capillary by OT-CEC. For three consecutive runs, the intraday relative standard deviations (RSDs) of migration time and peak areas were 0.1–0.4% and 2.5–8.3%, respectively. The interday RSDs of migration time and peak areas were 0.2–0.5% and 1.0–10.8%, respectively. Five groups of aromatic co mpounds were used to further study the separation mechanism, which indicated that hydrophobic interaction and size selection interaction are the main factors. It should be noted that the COF-300-coated capillary can be used for more than 140 runs with no observable changes of the separation efficiency. Graphical abstract The 3D COF-300-coated capillary was prepared by in situ growth for OT-CEC. Six groups of aromatic compounds were separated by 3D COF-300-coated capillary. Size selection and hydrophobic interaction affect the migration time of analytes.

The RNA-directed DNA methylation (RdDM) pathway plays an essential role in the transposon silencing mechanism; the DDR complex, consisting of DRD1, DMS3, and RDM1, is an essential component of the RdDM pathway. ONSEN , identified in Arabidopsis , is a retrotransposon activated by heat stress at 37°C; however, studies on the regulation of ONSEN are limited. In this study, we analyzed the regulation of ONSEN activity by the DDR complex in Arabidopsis . We elucidated that loss of any component of the DDR complex increased ONSEN transcript levels. Transgenerational transposition of ONSEN was observed in the DDR-complex mutants treated with heat stress for 48 h. Furthermore, the DDR complex components DRD1, DMS3, and RDM1 played independent roles in suppressing ONSEN transcription and transposition. Moreover, we found that the duration of heat stress affects ONSEN activity. Therefore, the results of this study provide new insights into the retrotransposon regulatory mechanisms of the DDR complex in the RdDM pathway.

Background Osteosarcoma is one of the malignant tumors in children and adolescents patients. Uncontrolled and unlimited proliferation and metastasis lead to poor overall survival. CAFs play a pivotal role in the osteosarcoma tumor microenvironment, exerting significant influence on prognosis and treatment outcomes. However, there remains a need for further exploration into the intricate molecular mechanisms underlying CAFs. Methods Single-cell RNA sequencing was employed to characterize the microenvironment of osteosarcoma. Tissue exosomal miRNA sequencing was conducted on tumor tissues and adjacent normal tissues to screen for abnormal expression of exosomal miRNAs. WGCNA analysis was used to identify target exosomal miRNAs. The relative expression of miR-21-5p was analyzed using qRT-PCR. The proliferation rate and migration ability of tumor cells were assessed using the CCK8 and Transwell method, respectively. Exosomes derived from cells were extracted and characterized via transmission electron microscopy and NTA analysis. siRNA interference was utilized to disrupt the expression of miR-21-5p in CAFs. Experiments in vivo validated the role of exosomal miR-21-5p in promoting malignant characteristics in osteosarcoma. Results Single-cell RNA sequencing analysis of GSE162454 revealed the crucial role of CAFs in the pathogenesis of osteosarcoma. Tissue exosomal miRNA sequencing unveiled significant differential expression of miR-21-5p. Subsequently, aberrant upregulation of exosomal miR-21-5p exhibited a strong correlation with advanced clinical stage and poor prognosis in osteosarcoma. Further experiments in vitro indicated that elevated levels of miR-21-5p significantly enhanced proliferation and migration of osteosarcoma cells by suppressing ferroptosis. Moreover, experiments in vivo validated the capacity of CAFs-derived exosomal miR-21-5p to promote tumor growth and weight, thereby demonstrating their ability to deliver miR-21-5p to osteosarcoma cells and induce proliferation and migration through inhibition of ferroptosis. Conclusions Our findings indicate that exosomal miR-21-5p could potentially serve as a therapeutic target in osteosarcoma, providing initial evidence for further clinical investigation. Graphical Abstract

The Taklamakan Desert (TD) is a major source of mineral dust emissions into the atmosphere. These dust particles have the ability to darken the surface of snow on the surrounding high mountains after deposition, significantly impacting the regional radiation balance. However, previous field measurements have been unable to capture the effects of severe dust storms accurately, and their representation on regional scales has been inadequate. In this study, we propose a modified remote-sensing approach that combines data from the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite and simulations from the Snow, Ice, and Aerosol Radiative (SNICAR) model. This approach allows us to detect and analyze the substantial snow darkening resulting from dust storm deposition. We focus on three typical dust events originating from the Taklamakan Desert and observe significant snow darkening over an area of ∼ 2160, ∼ 610, and ∼ 640 km2 in the Tien Shan, Kunlun, and Qilian mountains, respectively. Our findings reveal that the impact of dust storms extends beyond the local high mountains, reaching mountains located approximately 1000 km away from the source. Furthermore, we observe that dust storms not only darken the snowpack during the spring but also in the summer and autumn seasons, leading to increased absorption of solar radiation. Specifically, the snow albedo reduction (radiative forcing) triggered by severe dust deposition is up to 0.028–0.079 (11–31.5 W m−2), 0.088–0.136 (31–49 W m−2), and 0.092–0.153 (22–38 W m−2) across the Tien Shan, Kunlun, and Qilian mountains, respectively. This further contributes to the aging of the snow, as evidenced by the growth of snow grain size. Comparatively, the impact of persistent but relatively slow dust deposition over several months during non-event periods is significantly lower than that of individual dust events. This highlights the necessity of giving more attention to the influence of extreme events on the regional radiation balance. This study provides a deeper understanding of how a single dust event can affect the extensive snowpack and demonstrates the potential of employing satellite remote sensing to monitor large-scale snow darkening.

Osteosarcoma is a primary malignant tumor, characterized by its high incidence and recurrence rate in children and adolescents. Ferroptosis, an iron-dependent form of regulated cell death, has recently been recognized as a potential therapeutic vulnerability in cancer treatment. However, its prognostic significance and underlying regulatory mechanisms in osteosarcoma remain largely unexplored. We constructed a prognostic model based on 12 ferroptosis-related genes using LASSO regression and validated across independent GEO cohorts (GSE21257 and GSE39055). We identified hub genes via machine learning algorithms (SVM, RF, XGBoost, BORUTA) and single-cell RNA sequencing. The exosomal transfer of COX4I2 protein from CAFs to 143B osteosarcoma cells was evaluated by Western blot, confocal microscopy, and transmission electron microscopy. Ferroptosis indicators, including Fe , MDA, ACSL4, and ROS levels, were assessed . We performed tumorigenicity assays in nude mice to validate biological function. The ferroptosis-based risk model exhibited robust prognostic performance. We identified COX4I2 as a stromal hub gene, highly enriched in cancer-associated fibroblasts (CAFs). Functional experiments demonstrated that exosome-mediated delivery of COX4I2 suppressed ferroptosis in osteosarcoma cells and enhancd cell proliferation and mitochondrial integrity. Studies further revealed that overexpression of exosomal COX4I2 markedly promoted tumor growth while inhibiting ferroptosis. These findings underscore the potential of exosomal COX4I2 as a biomarker and therapeutic target for ferroptosis-based interventions in osteosarcoma.

Therapeutic resistance is a formidable barrier in cancer treatment, necessitating innovative solutions to enhance drug efficacy. Exosomes, with their unparalleled biocompatibility, low immunogenicity, and robust cargo protection, have emerged as groundbreaking nanocarriers. This review unveils the transformative potential of exosomes in overcoming drug resistance - encompassing chemotherapy, targeted therapy, and immunotherapy - in a wide spectrum of tumors. Through advanced genetic and non-genetic modifications, exosomes can dramatically enhance drug targeting and cytotoxicity, offering unprecedented precision in treatment. We explore state-of-the-art exosome engineering techniques, their revolutionary applications in clinical trials, and their promise as the next Frontier in therapeutic innovation. This comprehensive review aims to capture the cutting-edge developments and future directions of exosome-based therapies, positioning them as a cornerstone of next-generation oncology.

MicroRNA (miRNA) is promising candidate for non-invasive diagnostic biomarker. Conventional CRISPR/Cas12a-based miRNA detection systems are constrained by reliance on reverse transcription, nucleic acid pre-amplification and costly fluorescently labeled reporters which introduce chemical modification complexity and background noise. To address these limitations, we herein developed a multifunctional switch that integrated target recognition, CRISPR/Cas12a system activation, intrinsic fluorescence signaling, and autonomous signal amplification within a single molecular architecture. As a proof of concept, this switch enabled a label-free CRISPR/Cas12a biosensing for miR-21 detection with a detection limit of 4.8 nM and robust performance in accuracy, precision, and selectivity. This proposed label-free CRISPR/Cas12a platform could be applied for real sample and is a promising candidate for point-of-care miRNA detection.

Transposable elements are present in a wide variety of organisms; however, our understanding of the diversity of mechanisms involved in their activation is incomplete. In this study, we analyzed the transcriptional activation of the ONSEN retrotransposon, which is activated by high-temperature stress in Arabidopsis thaliana . We found that its transcription is significantly higher in the Japanese ecotype Kyoto. Considering that transposons are epigenetically regulated, DNA methylation levels were analyzed, revealing that CHH methylation was reduced in Kyoto compared to the standard ecotype, Col-0. A mutation was also detected in the Kyoto CMT2 gene, encoding a CHH methyltransferase, suggesting that it may be responsible for increased expression of ONSEN . CHH methylation is controlled by histone modifications through a self-reinforcing loop between DNA methyltransferase and histone methyltransferase. Analysis of these modifications revealed that the level of H3K9me2, a repressive histone marker for gene expression, was lower in Kyoto than in Col-0. The level of another repressive histone marker, H3K27me1, was decreased in Kyoto; however, it was not impacted in a Col-0 cmt2 mutant. Therefore, in addition to the CMT2 mutation, other factors may reduce repressive histone modifications in Kyoto.