Renal toxicity of Aconitum plants? A study based on a new mass spectrometry scanning strategy and computer virtual screening.

BACKGROUND: Radix Aconiti Lateralis (Fuzi), a mono-herbal preparation of Aconitum herbs in the genus Aconitum, is commonly used in traditional Chinese medicine (TCM) to treat critical illnesses. The curative effect of Fuzi is remarkable. However, the toxic effects of Fuzi are still a key clinical focus, and the substances inducing nephrotoxicity are still unclear. Therefore, this study proposes a research model combining "in vitro and in vivo component mining-virtual multi-target screening-active component prediction-literature verification" to screen potential nephrotoxic substances rapidly. METHOD: The UHPLC-Q-Exactive-Orbitrap MS analysis method was used for the correlation analysis of Fuzi's in vitro-in vivo chemical substance groups. On this basis, the key targets of nephrotoxicity were screened by combining online disease databases and a protein-protein interaction (PPI) network. The computer screening technique was used to verify the binding mode and affinity of Fuzi's components with nephrotoxic targets. Finally, the potential material basis of Fuzi-induced nephrotoxicity was screened. RESULTS: Eighty-one Fuzi components were identified. Among them, 35 components were absorbed into the blood. Based on the network biology method, 21 important chemical components and three potential key targets were screened. Computer virtual screening revealed that mesaconine, benzoylaconine, aconitine, deoxyaconitine, hypaconitine, benzoylhypaconine, benzoylmesaconine, and hypaconitine may be potential nephrotoxic substances of Fuzi. CONCLUSIONS: Fuzi may interact with multiple components and targets in the process of inducing nephrotoxicity. In the future, experiments can be designed to explore further. This study provides a reference for screening Fuzi nephrotoxic components and has certain significance for the safe use of Fuzi.

CoCo-ST: Comparing and Contrasting Spatial Transcriptomics data sets using graph contrastive learning.

Traditional feature dimension reduction methods have been widely used to uncover biological patterns or structures within individual spatial transcriptomics data. However, these methods are designed to yield feature representations that emphasize patterns or structures with dominant high variance, such as the normal tissue spatial pattern in a precancer setting. Consequently, they may inadvertently overlook patterns of interest that are potentially masked by these high-variance structures. Herein we present our graph contrastive feature representation method called CoCo-ST (Comparing and Contrasting Spatial Transcriptomics) to overcome this limitation. By incorporating a background data set representing normal tissue, this approach enhances the identification of interesting patterns in a target data set representing precancerous tissue. Simultaneously, it mitigates the influence of dominant common patterns shared by the background and target data sets. This enables discerning biologically relevant features crucial for capturing tissue-specific patterns, a capability we showcased through the analysis of serial mouse precancerous lung tissue samples.

The evolution of lung adenocarcinoma precursors is associated with chromosomal instability and transition from innate to adaptive immune response/evasion.

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8+ and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms.

Joint multi-omics discriminant analysis with consistent representation learning using PANDA.

Integrative multi-omics analysis provides deeper insight and enables better and more realistic modeling of the underlying biology and causes of diseases than does single omics analysis. Although several integrative multi-omics analysis methods have been proposed and demonstrated promising results in integrating distinct omics datasets, inconsistent distribution of the different omics data, which is caused by technology variations, poses a challenge for paired integrative multi-omics methods. In addition, the existing discriminant analysis-based integrative methods do not effectively exploit correlation and consistent discriminant structures, necessitating a compromise between correlation and discrimination in using these methods. Herein we present PAN-omics Discriminant Analysis (PANDA), a joint discriminant analysis method that seeks omics-specific discriminant common spaces by jointly learning consistent discriminant latent representations for each omics. PANDA jointly maximizes between-class and minimizes within-class omics variations in a common space and simultaneously models the relationships among omics at the consistency representation and cross-omics correlation levels, overcoming the need for compromise between discrimination and correlation as with the existing integrative multi-omics methods. Because of the consistency representation learning incorporated into the objective function of PANDA, this method seeks a common discriminant space to minimize the differences in distributions among omics, can lead to a more robust latent representations than other methods, and is against the inconsistency of the different omics. We compared PANDA to 10 other state-of-the-art multi-omics data integration methods using both simulated and real-world multi-omics datasets and found that PANDA consistently outperformed them while providing meaningful discriminant latent representations. PANDA is implemented using both R and MATLAB, with codes available at https://github.com/WuLabMDA/PANDA.

Tenofovir Alafenamide versus Tenofovir Disoproxil Fumarate for Preventing Vertical Transmission in Chronic Hepatitis B Mothers: A Systematic Review and Meta-Analysis.

OBJECTIVE: International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent HBV mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the two regimens are lacking. DESIGN: In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to March 31, 2024, and extracted data from cohort studies and RCTs in highly viremic mothers. The outcomes of interest were the reduction of MTCT and safety in the TDF-treated, TAF-treated, and control groups. RESULTS: We included 31 studies with 2,588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1,600 receiving no treatment. Compared to the control, TDF therapy reduced the MTCT rate in infants aged 6-12 months (risk ratio: 0.10, 95% confidence interval 0.07-0.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.16-7.61). Network meta-analysis showed the equal efficacy of the two regimens in reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.15-7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking: 0.77 vs. 0.72), while receiving a placebo during pregnancy had the lowest efficacy (probability ranking 0.01). There were no safety concerns for mothers and infants in all regimens. CONCLUSION: Compared to placebo or no treatment, maternal TDF and TAF prophylaxis are equally effective and without safety concerns in reducing MTCT in highly viremic mothers.

Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production.

Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells (DCs) and T cells, ultimately leading to increased production of cytokines such as interleukin (IL)-23 and IL-17A. It is established that the cGAS-STING pathway is essential for psoriatic inflammation, however, the specific role of cGAS-STING signaling in DCs within this context remains unclear. In this study, we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod (IMQ)-treated mice. Using a conditional Sting-knockout transgenic mouse model, we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17- and IFN-γ-producing T cells in psoriatic inflammation. Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells, and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model. Furthermore, we explored the therapeutic potential of the STING inhibitor C-176, which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response. Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.

Rosmarinic acid mitigates intestinal inflammation and oxidative stress in bullfrogs (Lithobates catesbeiana) fed high soybean meal diets.

High proportions of soybean meal in aquafeed have been confirmed to induce various intestinal pathologies. This study aims to investigate the regulatory effects of rosmarinic acid (RA), an antioxidant with anti-inflammatory and antimicrobial properties, when added to high soybean meal feeds in different doses, (0, 0.5, 1, and 4 g/kg). During the 56-day feeding trial, results indicated that, compared to the control group without RA (0 g/kg), the 1 g/kg and 4 g/kg RA groups increased bullfrog survival rates and total weight gain while reducing feed coefficient. Additionally, these doses markedly suppressed the expression of key intestinal inflammatory markers (tlr5, myd88, tnfα, il1ß, cxcl8, cxcl12) and the activity and content of intestinal antioxidants (CAT, MDA, GSH, GPX). Concurrently, RA significantly downregulated the transcription levels of antioxidant-related genes (cat, gpx5, cyba, cybb, mgst, gclc, gsta, gstp), suggesting RA's potential to alleviate intestinal inflammation and oxidative stress induced by high soybean meal and to help downregulate and restore normal expression of antioxidant enzyme genes. However, the 0.5 g/kg RA group did not show a significant improvement in survival rates; instead, it upregulated the transcription of some antioxidant genes (cat, gpx5, cyba, cybb), revealing the complexity and dose-dependency of RA's antioxidant action. Furthermore, RA supplementation significantly reshaped the intestinal microbial community structure and relative abundance in bullfrogs, particularly affecting the genera Hafnia, Phascolarctobacterium, and Lactococcus. Notably, high doses of RA (1 g/kg, 4 g/kg) were able to downregulate pathways associated with the enrichment of gut microbiota in diseases such as Parkinson's, Staphylococcus aureus infection, and Systemic lupus erythematosus, suggesting its potential in anti-inflammatory action and health maintenance to prevent potential diseases.

Cancer literacy differences of basic knowledge, prevention, early detection, treatment and recovery: a cross-sectional study of urban and rural residents in Northeast China.

Background: Cancer literacy as a potential health intervention tool directly impacted the success of cancer prevention and treatment initiatives. This study aimed to evaluate the cancer literacy in Northeast China, and explore the factors contributing to urban-rural disparities. Methods: A cross-sectional survey was conducted in 14 cities across Liaoning Province, China, from August to October 2021, using the multistage probability proportional to size sampling (PPS) method. The survey comprised 4,325 participants aged 15-69 and encompassed 37 core knowledge-based questions spanning five dimensions. Associations between sociodemographic factors and the cancer literacy rate were evaluated using chi-square tests and multivariate logistic regression model. Results: The overall cancer literacy rate was 66.9% (95% CI: 65.6-68.2%). In the primary indicators, cancer literacy were highest in treatment (75.8, 95% CI: 74.2-77.4%) and early detection (68.2, 95% CI: 66.8-69.6%), followed by basic knowledge (67.2, 95% CI: 65.8-68.6%), recovery (62.6, 95% CI: 60.7-64.5%) and prevention (59.7, 95% CI: 58.2-61.3%). Regarding secondary indicators, the awareness rates regarding cancer-related risk factors (54.7, 95% CI: 52.8-56.5%) and early diagnosis of cancer (54.6, 95% CI: 52.7-56.6%) were notably inadequate. Rural participates exhibited lower cancer literacy across all dimensions compared to urban. Multi-factor analysis showed that factors such as advanced age, limited education or low household income were barriers to health literacy in rural areas. Conclusion: Strengthening awareness concerning prevention and early detection, particularly among key populations, and bridging the urban-rural cancer literacy gap are imperative steps toward achieving the Healthy China 2030 target.

NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice.

BACKGROUND: Cancer is the leading cause of death among older adults. Although the integration of immunotherapy has revolutionized the therapeutic landscape of cancer, the complex interactions between age and immunotherapy efficacy remain incompletely defined. Here, we aimed to elucidate the relationship between aging and immunotherapy resistance. METHODS: Flow cytometry was performed to evaluate the infiltration of immune cells in the tumor microenvironment (TME). In vivo T cell proliferation, cytotoxicity and migration assays were performed to evaluate the antitumor capacity of tumor antigen-specific CD8+ T cells in mice. Real-time quantitative PCR (qPCR) was used to investigate the expression of IFN-γ-associated gene and natural killer (NK)-associated chemokine. Adoptive NK cell transfer was adopted to evaluate the effects of NK cells from young mice in overcoming the immunotherapy resistance of aged mice. RESULTS: We found that elderly patients with advanced non-small cell lung cancer (aNSCLC) aged ≥ 75 years exhibited poorer progression-free survival (PFS), overall survival (OS) and a lower clinical response rate after immunotherapy. Mechanistically, we showed that the infiltration of NK cells was significantly reduced in aged mice compared to younger mice. Furthermore, the aged NK cells could also suppress the activation of tumor antigen-specific CD8+ T cells by inhibiting the recruitment and activation of CD103+ dendritic cells (DCs). Adoptive transfer of NK cells from young mice to aged mice promoted TME remodeling, and reversed immunotherapy resistance. CONCLUSION: Our findings revealed the decreased sensitivity of elderly patients to immunotherapy, as well as in aged mice. This may be attributed to the reduction of NK cells in aged mice, which inhibits CD103+ DCs recruitment and its CD86 expression and ultimately leads to immunotherapy resistance.

Proto-oncogene c-Myb potentiates cisplatin resistance of ovarian cancer cells by downregulating lncRNA NKILA and modulating cancer stemness and LIN28A-let7 axis.

Ovarian cancer is a major gynecological cancer that has poor prognosis associated mainly to its late diagnosis. Cisplatin is an FDA approved ovarian cancer therapy and even though the therapy is initially promising, the patients mostly progress to resistance against cisplatin. The underlying mechanisms are complex and not very clearly understood. Using two different paired cell lines representing cisplatin-sensitive and the cisplatin-resistant ovarian cancer cells, the ES2 and the A2780 parental and cisplatin-resistant cells, we show an elevated proto-oncogene c-Myb in resistant cells. We further show down-regulated lncRNA NKILA in resistant cells with its de-repression in resistant cells when c-Myb is silenced. NKILA negatively correlates with cancer cell and invasion but has no effect on cellular proliferation or cell cycle. C-Myb activates NF-κB signaling which is inhibited by NKILA. The cisplatin resistant cells are also marked by upregulated stem cell markers, particularly LIN28A and OCT4, and downregulated LIN28A-targeted let-7 family miRNAs. Whereas LIN28A and downregulated let-7s individually de-repress c-Myb-mediated cisplatin resistance, the ectopic expression of let-7s attenuates LIN28A effects, thus underlying a c-Myb-NKILA-LIN28A-let-7 axis in cisplatin resistance of ovarian cancer cells that needs to be further explored for therapeutic intervention.

IFN-α/ß/IFN-γ/IL-15 pathways identify GBP1-expressing tumors with an immune-responsive phenotype.

Immunotherapy is widely used in cancer treatment; however, only a subset of patients responds well to it. Significant efforts have been made to identify patients who will benefit from immunotherapy. Successful anti-tumor immunity depends on an intact cancer-immunity cycle, especially long-lasting CD8+ T-cell responses. Interferon (IFN)-α/ß/IFN-γ/interleukin (IL)-15 pathways have been reported to be involved in the development of CD8+ T cells. And these pathways may predict responses to immunotherapy. Herein, we aimed to analyze multiple public databases to investigate whether IFN-α/ß/IFN-γ/IL-15 pathways could be used to predict the response to immunotherapy. Results showed that IFN-α/ß/IFN-γ/IL-15 pathways could efficiently predict immunotherapy response, and guanylate-binding protein 1 (GBP1) could represent the IFN-α/ß/IFN-γ/IL-15 pathways. In public and private cohorts, we further demonstrated that GBP1 could efficiently predict the response to immunotherapy. Functionally, GBP1 was mainly expressed in macrophages and strongly correlated with chemokines involved in T-cell migration. Therefore, our study comprehensively investigated the potential role of GBP1 in immunotherapy, which could serve as a novel biomarker for immunotherapy and a target for drug development.

Pediatric anesthesia in China.

In China, healthcare has lagged relative to its economic boom during the past 40 years. While the top tier hospitals offer pediatric perioperative care like high-income countries, lower-tier hospitals deliver lesser services of variable quality and safety related to equipment, supplies, clinician education, and availability. The national residency training program and the pediatric anesthesia fellowship program was established in 2013 and 2018 respectively. Increasing clinician workload from patient demand and a lack of consistency in quality and capability between rural and urban areas remain challenging.

Enhancing antitumor efficacy of oncolytic virus M1 via albendazole-sustained CD8+ T cell activation.

The immune response plays a crucial role in the functionality of oncolytic viruses. In this study, Albendazole, an antihelminthic drug known to modulate the immune checkpoint PD-L1, was combined with the oncolytic virus M1 (OVM1) to treat mice with either prostate cancer (RM-1) or glioma (GL261) tumors. This combination therapy enhanced anti-tumor effects in immunocompetent mice, but not in immunodeficient ones, without increasing OVM1 replication. Instead, it led to an increase in the number of CD8+ T cells within the tumor, downregulated the expression of PD1 on CD8+ T cells, and upregulated activation markers such as Ki67, CD44, and CD69 and the secretion of cytotoxic factors including interferon (IFN)-γ, granzyme B, and tumor necrosis factor (TNF)-α. Consistently, it enhanced the in vitro tumor-killing activity of lymphocytes from tumor-draining lymph nodes or spleens. The synergistic effect of Albendazole on OVM1 was abolished by depleting CD8+ T cells, suggesting a CD8+ T cell-dependent mechanism. In addition, Albendazole and OVM1 therapy increased CTLA4 expression in the spleen, and the addition of CTLA4 antibodies further enhanced the anti-tumor efficacy in vivo. In summary, Albendazole can act synergistically with oncolytic viruses via CD8+ T cell activation, and the Albendazole/OVM1 combination can overcome resistance to CTLA4-based immune checkpoint blockade therapy.

Targeting LRP6: A new strategy for cancer therapy.

Targeting specific molecular drivers of tumor growth is a key approach in cancer therapy. Among these targets, the low-density lipoprotein receptor-related protein 6 (LRP6), a vital component of the Wnt signaling pathway, has emerged as an intriguing candidate. As a cell-surface receptor and vital co-receptor, LRP6 is frequently overexpressed in various cancer types, implicating its pivotal role in driving tumor progression. The pursuit of LRP6 as a target for cancer treatment has gained substantial traction, offering a promising avenue for therapeutic intervention. Here, this comprehensive review explores recent breakthroughs in our understanding of LRP6's functions and underlying molecular mechanisms, providing a profound discussion of its involvement in cancer pathogenesis and drug resistance. Importantly, we go beyond discussing LRP6's role in cancer by discussing diverse potential therapeutic approaches targeting this enigmatic protein. These approaches encompass a wide spectrum, including pharmacological agents, natural compounds, non-coding RNAs, epigenetic factors, proteins, and peptides that modulate LRP6 expression or disrupt its interactions. In addition, also discussed the challenges associated with developing LRP6 inhibitors and their advantages over Wnt inhibitors, as well as the drugs that have entered phase II clinical trials. By shedding light on these innovative strategies, we aim to underscore LRP6's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.

Erratum: CircNT5E promotes the proliferation and migration of bladder cancer via sponging miR-502-5p: Erratum.

[This corrects the article DOI: 10.7150/jca.53385.].

A Moving Least-Squares/Level-Set Particle Method for Bubble and Foam Simulation.

We present a novel particle-grid scheme for simulating bubble and foam flow. At the core of our approach lies a particle representation that combines the computational nature of moving least-squares particles and particle level-set methods. Specifically, we assign a dedicated particle system to each individual bubble, enabling accurate tracking of its interface evolution and topological changes in a foaming fluid system. The particles within each bubble's particle system serve dual purposes. Firstly, they function as a surface discretization, allowing for the solution of surfactant flow physics on the bubble's membrane. Additionally, these particles act as interface trackers, facilitating the evolution of the bubble's shape and topology within the multiphase fluid domain. The combination of particle systems from all bubbles contributes to the generation of an unsigned level-set field, further enhancing the simulation of coupled multiphase flow dynamics. By seamlessly integrating our particle representation into a multiphase, volumetric flow solver, our method enables the simulation of a broad range of intricate bubble and foam phenomena. These phenomena exhibit highly dynamic and complex structural evolution, as well as interfacial flow details.

Corrigendum: Targeting JUN, CEBPB and HDAC3: a novel strategy to overcome drug resistance in hypoxic glioblastoma.

[This corrects the article DOI: 10.3389/fonc.2019.00033.].

Roles of endophytic fungi in medicinal plant abiotic stress response and TCM quality development.

Medicinal plants, as medicinal materials and important drug components, have been used in traditional and folk medicine for ages. However, being sessile organisms, they are seriously affected by extreme environmental conditions and abiotic stresses such as salt, heavy metal, temperature, and water stresses. Medicinal plants usually produce specific secondary metabolites to survive such stresses, and these metabolites can often be used for treating human diseases. Recently, medicinal plants have been found to partner with endophytic fungi to form a long-term, stable, and win-win symbiotic relationship. Endophytic fungi can promote secondary metabolite accumulation in medicinal plants. The close relationship can improve host plant resistance to the abiotic stresses of soil salinity, drought, and extreme temperatures. Their symbiosis also sheds light on plant growth and active compound production. Here, we show that endophytic fungi can improve the host medicinal plant resistance to abiotic stress by regulating active compounds, reducing oxidative stress, and regulating the cell ion balance. We also identify the deficiencies and burning issues of available studies and present promising research topics for the future. This review provides guidance for endophytic fungi research to improve the ability of medicinal plants to resist abiotic stress. It also suggests ideas and methods for active compound accumulation in medicinal plants and medicinal material development during the response to abiotic stress.

Uncertainty Estimation and Out-of-Distribution Detection for Deep Learning-Based Image Reconstruction using the Local Lipschitz.

Accurate image reconstruction is at the heart of diagnostics in medical imaging. Supervised deep learning-based approaches have been investigated for solving inverse problems including image reconstruction. However, these trained models encounter unseen data distributions that are widely shifted from training data during deployment. Therefore, it is essential to assess whether a given input falls within the training data distribution. Current uncertainty estimation approaches focus on providing an uncertainty map to radiologists, rather than assessing the training distribution fit. In this work, we propose a method based on the local Lipschitz metric to distinguish out-of-distribution images from in-distribution with an area under the curve of 99.94% for True Positive Rate versus False Positive Rate. We demonstrate a very strong relationship between the local Lipschitz value and mean absolute error (MAE), supported by a Spearman's rank correlation coefficient of 0.8475, to determine an uncertainty estimation threshold for optimal performance. Through the identification of false positives, we demonstrate the local Lipschitz and MAE relationship can guide data augmentation and reduce uncertainty. Our study was validated using the AUTOMAP architecture for sensor-to-image Magnetic Resonance Imaging (MRI) reconstruction. We demonstrate our approach outperforms baseline techniques of Monte-Carlo dropout and deep ensembles as well as the state-of-the-art Mean Variance Estimation (MVE) network approach. We expand our application scope to MRI denoising and Computed Tomography (CT) sparse-to-full view reconstructions using UNET architectures. We show our approach is applicable to various architectures and applications, especially in medical imaging, where preserving diagnostic accuracy of reconstructed images remains paramount.

DNA methylation remodeling and the functional implication during male gametogenesis in rice.

BACKGROUND: Epigenetic marks are reprogrammed during sexual reproduction. In flowering plants, DNA methylation is only partially remodeled in the gametes and the zygote. However, the timing and functional significance of the remodeling during plant gametogenesis remain obscure. RESULTS: Here we show that DNA methylation remodeling starts after male meiosis in rice, with non-CG methylation, particularly at CHG sites, being first enhanced in the microspore and subsequently decreased in sperm. Functional analysis of rice CHG methyltransferase genes CMT3a and CMT3b indicates that CMT3a functions as the major CHG methyltransferase in rice meiocyte, while CMT3b is responsible for the increase of CHG methylation in microspore. The function of the two histone demethylases JMJ706 and JMJ707 that remove H3K9me2 may contribute to the decreased CHG methylation in sperm. During male gametogenesis CMT3a mainly silences TE and TE-related genes while CMT3b is required for repression of genes encoding factors involved in transcriptional and translational activities. In addition, CMT3b functions to repress zygotic gene expression in egg and participates in establishing the zygotic epigenome upon fertilization. CONCLUSION: Collectively, the results indicate that DNA methylation is dynamically remodeled during male gametogenesis, distinguish the function of CMT3a and CMT3b in sex cells, and underpin the functional significance of DNA methylation remodeling during rice reproduction.