N6-methyladenosine (m6A) RNA modification in fibrosis and collagen-related diseases.

Fibrosis is an abnormal tissue healing process characterized by the excessive accumulation of ECM components, such as COL I and COL III, in response to tissue injury or chronic inflammation. Recent advances in epitranscriptomics have underscored the importance of m6A modification in fibrosis. m6A, the most prevalent modification in eukaryotic RNA, is catalyzed by methyltransferases (e.g., METTL3), removed by demethylases (e.g., FTO), and recognized by reader proteins (e.g., YTHDF1/2). These modifications are crucial in regulating collagen metabolism and associated diseases. Understanding the role of m6A modification in fibrosis and other collagen-related conditions holds promise for developing targeted therapies. This review highlights the latest progress in this area.

Poison Turned Panacea: Arsenic Trioxide Loaded Hydrogel for Inhibiting Scar Formation in Wound Healing.

Without intervention, the natural wound healing process can often result in scarring, which can have detrimental effects on both the physical and mental well-being of patients. Therefore, it is crucial to develop biomaterials that can promote healing without scarring. Regulating the Yes-associated protein-1/PDZ-binding motif (YAP/TAZ) signaling pathway is possible to reduce excessive fibrosis of fibroblasts and proliferation of vascular endothelial cells, ultimately impacting scar formation. Arsenic trioxide (ATO), an ancient drug with medicinal and toxic properties, has shown promise in regulating this pathway. An ATO-loaded hydrogel dressing (ATO@CS/SA) was created to facilitate scarless wound healing, utilizing chitosan (CS) and sodium alginate (SA) to prevent direct contact of ATO with the wound tissue and minimize potential side effects. In vitro studies demonstrated that low concentrations of ATO did not impact cell viability and even promoted proliferation and migration. Co-culturing the hydrogel with fibroblasts and vascular endothelial cells led to decreased expression levels of YAP and TAZ. Animal studies over a 90-day period revealed significant inhibition of scar formation with this system. Histological experiments further confirmed that the decreased expression of YAP and TAZ was responsible for this outcome. In conclusion, when administered at the appropriate dose, ATO can be repurposed from a traditional poison to a therapeutic agent, effectively suppressing excessive cell fibrosis and blood vessel proliferation and offering a novel approach to scar-free treatment.

Intelligent response micelles with high andrographolide loading for the effective treatment of atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease which associated with a maladaptive immune response driven by macrophages. In the development of AS, macrophages have gradually become new therapeutic targets due to their involvement in numerous inflammatory-related pathological processes in AS. However, despite significant breakthroughs in the development of macrophages targeting nanocarriers, unsatisfactory drug loading, and inexact drug release limited the development of nano-therapy. Therefore, developing a high drug-loading nanocarrier that can accurately release drugs at AS lesions is quite essential. Herein, we optimized double moieties coupled mPEG-PLA copolymer micelles via phenylboronic acid (PBA)-terminated on the hydrophobic chain and cRGD coupled in hydrophilic chain to enhance AS therapy. The micelles loaded with andrographolide (AND) exhibited advanced drug loading capacity, as PBA could form a reversible boronic ester with AND at physiological pH. The cRGD-modified AND-loaded micelles (RPPPA) could be efficaciously internalized by macrophages and efficiently prevent macrophages from differentiating to foam cells. After intravenous administration, RPPPA could accumulate in plaques and exert therapeutic effects. The optimistic therapeutic results of atherosclerosis were shown in RPPPA, included the fewer plaques, a smaller necrotic core, a more stabilized fibrous cap, and lower macrophages and MMP-9, compared with the control group. To sum up, the proposed encouraging therapy can contribute to high drug loading, exact target, and precise drug release as well as reduce inflammation for AS treatment.

Diversity of soybean rhizobia in Northeast China and their application.

Biological nitrogen fixation is the main source of nitrogen in ecosystems. The diversity of soil rhizobia and their effects on soybeans need further research. In this study, we collected soybean rhizosphere samples from eight sites in the black soil soybean planting area in Northeast China. A total of 94 strains of bacteria were isolated and identified using the 16S rRNA and symbiotic genes (nodC, nifH) analysis, of which 70 strains were identified as rhizobia belonging to the genus Bradyrhizobium. To further validate the application effects of rhizobia, we selec-ted seven representative indigenous rhizobia based on the results of phylogenetic analysis, and conducted laboratory experiments to determine their nodulation and the impacts on soybeans. The results showed that, compared to the control without rhizobial inoculation, all the seven indigenous rhizobia exhibited good promoting and nodulation abilities. Among them, strains H7-L22 and H34-L6 performed the best, with the former significantly increasing plant height by 25.7% and the latter increasing root nodule dry weight by 20.9% to 67.1% compared to other indi-genous rhizobia treatments. We tested these two efficient rhizobia strains as soybean rhizobial inoculants in field experiments. The promoting effect of mixed rhizobial inoculants was significantly better than single ones. Compared to the control without inoculation, soybean yield increased by 8.4% with the strain H7-L22 treatment and by 17.9% with the mixed inoculant treatment. Additionally, there was a significant increase in the number of four-seed pods in soybeans. In conclusion, the application of rhizobial inoculants can significantly increase soybean yield, thereby reducing dependence on nitrogen fertilizer during soybean production, improving soil health, and promoting green development in agriculture in the black soil region of Northeast China.

Enhanced interleukin-16-CD4 signaling in CD3 T cell mediates neuropathic pain via activating astrocytes in female mice.

Immune cells and interleukins play a crucial role in female-specific pain signaling. Interleukin 16 (IL-16) is a cytokine primarily associated with CD4+ T cell function. While previous studies have demonstrated the important role of spinal CD4+ T cells in neuropathic pain, the specific contribution of IL-16 to neuropathic pain remains unclear. In this study, by using a spinal nerve ligation (SNL)-induced neuropathic pain mice model, we found that SNL induced an increase in IL-16 mRNA levels, which persisted for a longer duration in female mice compared to male mice. Immunofluorescence analysis further confirmed enhanced IL-16- and CD4-positive signals in the spinal dorsal horn following SNL surgery in female mice. Knockdown of spinal IL-16 by siRNA or inhibition of CD4 by FGF22-IN-1, a CD4 inhibitor, attenuated established mechanical and thermal pain hypersensitivity induced by SNL. Furthermore, female mice injected with IL-16 intrathecally exhibited significant spontaneous pain, mechanical and thermal hyperalgesia, all of which could be alleviated by FGF22-IN-1 or a CD3 antibody. Additionally, IL-16 induced astrocyte activation but not microglial activation in the spinal dorsal horn of female mice. Meanwhile, astrocyte activation could be suppressed by the CD3 antibody. These results provide compelling evidence that IL-16 promotes astrocyte activation via CD4 on CD3+ T cells, which is critical for maintaining neuropathic pain in female mice.

An explainable predictive model of direct pulp capping in carious mature permanent teeth.

OBJECTIVE: To introduce a novel approach for predicting the personalized probability of success of DPC treatment in carious mature permanent teeth using explainable machine learning (ML) models. METHODS: Clinical data were obtained from our previous single-center retrospective study, comprising 393 carious mature permanent teeth from 372 patients who underwent DPC and attended 1-year follow-up between January 2015 and February 2021. Six ML models were derived based on 80 % cases of the cohort, with the remaining 20 % cases used for validation. Shapley additive explanation (SHAP) values were utilized to assess feature importance and the clinical relevance of prediction models. RESULTS: Within the cohort, 9.67 % (38 out of 393) of teeth experienced failure at the 1-year follow-up after DPC treatment. Among the six evaluated ML models, the XGBoost model exhibited the highest discriminative ability. By prioritizing features based on their importance, streamlined and interpretable XGBoost model with 11 features were developed for 1-year prognostication post-DPC. The model demonstrated predictive accuracy with area under the curve (AUC) scores of 0.86 for the 1-year prediction. The final model has been translated into a web application to facilitate clinical decision-making. CONCLUSION: By incorporating demographic and clinical examination data, the XGBoost model offered a user-friendly tool for dentists to predict personalized probability of success, thereby improving personalized dental care and patient counseling. The utilization of SHAP for model interpretation provided transparent insights into the decision-making process.

Employee perceived overqualification and innovation performance: the roles of self-oriented perfectionism and job crafting.

Leveraging the trait activation theory, the study constructs a model featuring moderated chain mediation to explore how perceived overqualification influences employee innovation performance. After conducting two surveys with Chinese employees, this study collects 363 valid questionnaires. The findings reveal that perceived overqualification is positively related to employee innovation performance. Both self-oriented perfectionism and job crafting are partial mediators between perceived overqualification and innovation performance, and they collectively play a chain mediating role. Furthermore, independent self-construction positively moderates the link between perceived overqualification and self-oriented perfectionism, and informal status positively moderates the relationship between job crafting and employee innovation performance. Additionally, the indirect influence of perceived overqualification on employee innovation performance is moderated by independent self-construction and informal status. This study adds to the current body of literature on perceived overqualification and offers practical implications for organizations aiming to enhance innovation performance.

A Novel Role for the Longevity-Associated Protein SLC39A11 as a Manganese Transporter.

The identification of aging- and longevity-associated genes is important for promoting healthy aging. By analyzing a large cohort of Chinese centenarians, we previously found that single-nucleotide polymorphisms (SNPs) in the SLC39A11 gene (also known as ZIP11) are associated with longevity in males. However, the function of the SLC39A11 protein remains unclear. Here, we found that SLC39A11 expression is significantly reduced in patients with Hutchinson-Gilford progeria syndrome (HGPS). In addition, we found that zebrafish with a mutation in slc39a11 that significantly reduces its expression have an accelerated aging phenotype, including a shortened average lifespan, muscle atrophy and reduced swimming, impaired muscle regeneration, gut damage, and abnormal morphology in the reproductive system. Interestingly, these signs of premature aging were more pronounced in male zebrafish than in females. RNA-sequencing analysis revealed that cellular senescence may serve as a potential mechanism for driving this slc39a11 deficiency-induced phenotype in mutant zebrafish. Moreover, immunofluorescence showed significantly increased DNA damage and reactive oxygen species signaling in slc39a11 mutant zebrafish. Using inductively coupled plasma mass spectrometry (ICP-MS), we found that manganese significantly accumulates in slc39a11 mutant zebrafish, as well as in the serum of both global Slc39a11 knockout and hepatocyte-specific Slc39a11 knockout mice, suggesting that this metal transporter regulates systemic manganese levels. Finally, using cultured human fibroblasts, we found that both knocking down SLC39A11 and exposure to high extracellular manganese increased cellular senescence. These findings provide compelling evidence that SLC39A11 serves to protect against the aging process, at least in part by regulating cellular manganese homeostasis.

Global changes of miRNA expression indicates an increased reprogramming efficiency of induced mammary epithelial cells by repression of miR-222-3p in fibroblasts.

Background: Our previous studies have successfully reported the reprogramming of fibroblasts into induced mammary epithelial cells (iMECs). However, the regulatory relationships and functional roles of MicroRNAs (miRNAs) in the progression of fibroblasts achieving the cell fate of iMECs are insufficiently understood. Methods: First, we performed pre-and post-induction miRNAs sequencing analysis by using high-throughput sequencing. Following that, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment studies were used to determine the primary roles of the significantly distinct miRNAs and targeted genes. Finally, the effect of miR-222-3p on iMECs fate reprogramming in vitro by transfecting. Results: As a result goat ear fibroblasts (GEFs) reprogramming into iMECs activates a regulatory program, involving 79 differentially expressed miRNAs. Besides, the programming process involved changes in multiple signaling pathways such as adherens junction, TGF-ß signaling pathway, GnRH secretion and the prolactin signaling pathway, etc. Furthermore, it was discovered that the expression of miR-222-3p downregulation by miR-222-3p inhibitor significantly increase the reprogramming efficiency and promoted lipid accumulation of iMECs.

Regulatory roles of RNA methylation in vascular lesions in ocular and cardiopulmonary diseases.

RNA methylation is a widespread regulatory mechanism that controls gene expression in physiological processes. In recent years, the mechanisms and functions of RNA methylation under diseased conditions have been increasingly unveiled by RNA sequencing technologies with large scale and high resolution. In this review, the fundamental concept of RNA methylation is introduced, and the common types of transcript methylation and their machineries are described. Then, the regulatory roles of RNA methylation, particularly N6-methyladenosine and 5-methylcytosine, in the vascular lesions of ocular and cardiopulmonary diseases are discussed and compared. The ocular diseases include corneal neovascularization, retinopathy of prematurity, diabetic retinopathy, and pathologic myopia; whereas the cardiopulmonary ailments involve atherosclerosis and pulmonary hypertension. This review hopes to shed light on the common regulatory mechanisms underlying the vascular lesions in these ocular and cardiopulmonary diseases, which may be conducive to developing therapeutic strategies in clinical practice.

In vitro evaluation of the impact of a bioceramic root canal sealer on the mechanical properties of tooth roots.

Bacground/purpose: Endodontically treated teeth are more prone to vertical root fracture with the mechanical property changes to some extent during root canal treatment. This study aimed to investigate the effects of a bioceramic sealer on the mechanical properties of tooth roots. Materials and methods: Dentin discs were dried by two different methods (ethanol drying and paper points drying) and then filled with a BC sealer named iRoot SP. SEM and EDS were used to analyze the newly formed minerals in dentin tubules. Elastic modulus and hardness of the secondary dentin in areas proximal to the primary dentin (PD-SD) and areas proximal to canal or iRoot SP (SD-C/SD-iRoot SP) were measured using nanoindentation technique. The compressive strength of roots filled with iRoot SP were tested by compressive loading test. Results: (1) Penetration and mineralization: Paper points drying was more conducive to iRoot SP adhesion, spreading and penetration into the dentin tubules than 95% ethanol drying. (2) Micromechanical properties: After filling root canal with iRoot SP, the elastic modulus and hardness of SD-iRoot SP were higher than those of PD-SD (P = 0.001 and P = 0.000). (3) Fracture resistance: The compressive strength of the roots filled with iRoot SP was not significantly different from that of the roots unprepared and unfilled (P = 0.957), but was higher than that of the roots prepared and unfilled (P = 0.009). Conclusion: Excessive drying (95% ethanol drying method) is not conducive to the penetration and mineralization of the BC sealer iRoot SP into dentin tubules. The good bioactivity of iRoot SP was responsible for increasing the elastic modulus and hardness of dentin, which strengthened the prepared roots.

[Non-targeted renal metabolomics reveals multi-target effects of Dahuang Zhechong Pills on renal aging in rats].

This study aims to observe the effects of the traditional Chinese medicine prescription Dahuang Zhechong Pills(DHZCP on renal aging and explore its potential multi-target effects. Rats were assigned into the normal, model, DHZCP, and vitamin E(VE)groups. Firstly, the rat model of D-galactose(D-gal)-induced renal aging was established. During the modeling period, the rats in the 4 groups were administrated with double distilled water, double distilled water, DHZCP suspension, and VE suspension, respectively,by gavage every day. On day 60 of intervention, the indicators of renal aging and injury in rats were measured, including the function,histopathological characteristics, senescence-associated ß-galactosidase( SA-ß-gal) staining, and expression levels of Klotho and proteins associated with cell cycle arrest and senescence-associated secretory phenotype(SASP) in the renal tissue. Moreover, nontargeted metabolomic analysis of the renal tissue was performed for the 4 groups of rats to screen out the potential biomarkers and metabolic pathways. Finally, the signaling pathways of key targets were preliminarily validated. The results showed that DHZCP and VE significantly improved the renal function, histopathological features of renal tubular/interstitial tissue, and degree of SA-ß-gal staining, up-regulated the expression level of Klotho, and down-regulated the expression levels of proteins associated with cell cycle arrest and SASP in the renal tissue of the aging rats. In addition, DHZCP and VE regulated the metabolites in the renal tissue of the aging rats. There were 21 common differential metabolites. Among them, 5 differential metabolites were significantly increased in the aging rats and recovered after DHZCP or VE treatment, and they were involved in the lipid metabolism and energy metabolism pathways. The areas under the curves of the groups in comparison varied within the range of 0. 88-1. DHZCP regulated multiple signaling pathways, such as the adenosine monophosphate-activated protein kinase(AMPK), cyclic guanosine monophosphate-protein kinase G( c GMP-PKG), cyclic adenylic acid( c AMP), phosphatidylinositol-3-kinase-protein kinase B( PI3K-Akt), mammalian target of rapamycin(mTOR), and autophagy signaling pathways. In addition, it affected the multiple metabolic pathways, such as renin secretion, longevity regulation pathway, diabetic cardiomyopathy, and niacin and nicotinamide metabolism. DHZCP and VE significantly up-regulated the expression level of the key proteins in the AMPK signaling pathway in the renal tissue of the aging rats. In all, DHZCP and VE could mitigate renal aging and injury. DHZCP exerted multi-target effects via multiple signaling pathways and metabolic pathways in the kidney, in which the AMPK signaling pathway may be one of the key targets for action.

Gelatin-nanocellulose stabilized emulsion-filled hydrogel beads loaded with curcumin: Preparation, encapsulation and release behavior.

In this study, the curcumin was firstly encapsulated in gelatin (GLT) and/or cellulose nanocrystals (CNC) stabilized emulsions, then further mixed with sodium alginate (SA) to form emulsion-filled hydrogel beads loaded with curcumin (Cur). The Cur-loaded emulsions showed a droplet size of 20.3-24.4 µm with a uniform distribution. Introducing CNC and/or SA increased the viscosity of emulsions accompanied by viscoelastic transition, while the modulus was reduced due to destruction of GLT gel. Cur was doubly immobilized in the hydrogel beads with >90 % of encapsulation efficiency. The results of simulated gastrointestinal tract experiments revealed that the beads possessed a good pH sensitivity and controlled release behavior to prolong the retention of Cur in the gastrointestinal tract. After 6 h of UV irradiation, the Cur-loaded emulsion-filled hydrogel beads showed a higher antioxidant activity than that of pure Cur, effectively delaying the photodegradation of Cur. In addition, the beads had better stability in aqueous and acidic environments, which was favorable for prolonging the release of Cur. These results suggest that the emulsion-filled hydrogel beads have great potential for the delivery of lipophilic bioactive molecules.

Current trends and advances in antiviral therapy for chronic hepatitis B.

ABSTRACT: Chronic hepatitis B virus (HBV) infection is a global public health concern. Existing antiviral drugs, including nucleos(t)ide analogs and interferon-α, can suppress HBV replication and improve the prognosis. However, the persistence of covalently closed circular DNA (cccDNA), the integration of HBV-DNA into the host genome, and compromised immune responses impede the successful treatment of hepatitis B. While achieving a functional cure of HBV remains elusive with the current treatment methods, this is the goal of new therapeutic approaches. Therefore, developing novel antiviral drugs is necessary for achieving a functional or complete cure for chronic hepatitis B. In recent years, substantial progress has been made in drug discovery and development for HBV infection. Direct-acting antiviral agents such as entry inhibitors, capsid assembly modulators, subviral particle release inhibitors, cccDNA silencers, and RNA interference molecules have entered clinical trials. In addition, several immunomodulatory agents, including toll-like receptor agonists, therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also making their way toward clinical use. In this review, we summarize the recent progress and limitations of chronic hepatitis B treatment and discuss perspectives on approaches to achieving functional cure. Although it will take some time for these new antiviral drugs to be widely used in clinical practice, combination therapy may become a preferable treatment option in the future.

Diaporchalasin A, a new PDE4 inhibitory cytochalasin from Conus marmoreus-derived fungus Diaporthe sp. XMA007.

A novel cytochalasin named diaporchalasin A (1) bearing a cinnamenyl and an epoxy-macrocycloketone, and a new benzenepropionic acid derivative (2), and two known compounds (3 and 4) were isolated from Conus marmoreus-derived fungus Diaporthe sp. XMA007. Their structures were elucidated through detailed spectroscopic analysis, and the absolute configuration of 1 was determined by conformational analysis and TDDFT-ECD calculation. Their activity evaluation on PDE4 inhibition and breast cancer cell cytotoxicity were conducted, and compound 1 showed moderate inhibition on PDE4.

Brain implantation of tissue-level-soft bioelectronics via embryonic development.

The design of bioelectronics capable of stably tracking brain-wide, single-cell, and millisecond-resolved neural activities in the developing brain is critical to the study of neuroscience and neurodevelopmental disorders. During development, the three-dimensional (3D) structure of the vertebrate brain arises from a 2D neural plate 1,2 . These large morphological changes previously posed a challenge for implantable bioelectronics to track neural activity throughout brain development 3-9 . Here, we present a tissue-level-soft, sub-micrometer-thick, stretchable mesh microelectrode array capable of integrating into the embryonic neural plate of vertebrates by leveraging the 2D-to-3D reconfiguration process of the tissue itself. Driven by the expansion and folding processes of organogenesis, the stretchable mesh electrode array deforms, stretches, and distributes throughout the entire brain, fully integrating into the 3D tissue structure. Immunostaining, gene expression analysis, and behavioral testing show no discernible impact on brain development or function. The embedded electrode array enables long-term, stable, brain-wide, single-unit-single-spike-resolved electrical mapping throughout brain development, illustrating how neural electrical activities and population dynamics emerge and evolve during brain development.

Predictive nomogram of high-risk patients with active tuberculosis in latent tuberculosis infection.

INTRODUCTION: The absence of predictive models for early latent tuberculosis infection (LTBI) progression persists. This study aimed to create a screening model to identify high-risk LTBI patients prome to active tuberculosis (ATB) reactivation. METHODOLOGY: Patients with confirmed ATB were enrolled alongside LTBI individuals as a reference, with relevant clinical data gathered. LASSO regression cross-validation reduced data dimensionality. A nomogram was developed using multiple logistic regression, internally validated with Bootstrap resampling. Evaluation included C-index, receiver operating characteristic (ROC) curve, and calibration curves, with clinical utility assessed through decision curve analysis. RESULTS: The final nomogram incorporated serum albumin (OR = 1.337, p = 0.046), CD4+ (OR = 1.010, p = 0.004), and CD64 index (OR = 0.009, p = 0.020). The model achieved a C-index of 0.964, an area under the ROC curve of 0.962 (95% CI: 0.926-0.997), sensitivity of 0.971, and specificity of 0.910. Internal validation showed a mean absolute error of 0.013 and 86.4% identification accuracy. The decision curve indicated substantial net benefit at a risk threshold exceeding 10% (1: 9). CONCLUSIONS: This study established a biologically-rooted nomogram for high-risk LTBI patients prone to ATB reactivation, offering strong predictability, concordance, and clinical value. It serves as a personalized risk assessment tool, accurately identifying patients necessitating priority prophylactic treatment, complementing existing host risk factors effectively.

Passive green space exposure leading to lower aggression: The mediating role of sense of control.

Green spaces, integral to natural environments, have been extensively studied for their positive impact on mental health, yet their influence on social behavior, particularly aggression, is less explored. While prior research has predominantly emphasized the effects of actively engaging with nature, the significant role of passive nature exposure-a more common daily occurrence-has often been overlooked. We conducted two studies to explore the influence of passive green space exposure on aggression and the mediating effect of the sense of control. Study 1 (N = 240) utilized a cross-sectional survey to assess the relationship between passive green space exposure, sense of control, and aggression. Study 2 (N = 260) employed a single-factor between-subjects experimental design to further explore these relationships in a controlled environment. The results from both studies indicated that passive green space exposure is negatively related to aggression, and that this relationship is partially mediated by an increased sense of control. Specifically, passive green space exposure was found to negatively predict aggression by bolstering individuals' sense of control. These findings underscore the potential of enhancing the sense of control through environmental factors like green spaces as an effective strategy to reduce aggression. This study enriches our understanding of the broader impacts of green spaces, extending beyond mental health to include social behaviors. We discussed both the theoretical and practical implications of our findings, highlighting how urban planning and environmental design can incorporate green spaces to foster community well-being and mitigate aggressive behaviors.

Robust analyzes for longitudinal clinical trials with missing and non-normal continuous outcomes.

Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group. We develop a robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions. Under the proposed framework, sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in the covariates and the response variables. Accompanied by the subsequent mean imputation and robust model analysis, the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality. Moreover, our proposed method guarantees the analysis model robust-ness of the ATE estimation in the sense that its asymptotic results remain intact even when the analysis model is misspecified. The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.