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Abstract In nature, coenzyme-independent oxidases have evolved in selective catalysis using isolated substrate-binding pockets. Single-atom nanozymes (SAzymes), an emerging type of non-protein artificial enzymes, are promising to simulate enzyme active centers, but owing to the lack of recognition sites, realizing substrate specificity is a formidable task. Here we report a metal-ligand dual-site SAzyme (Ni-DAB) that exhibited selectivity in uric acid (UA) oxidation. Ni-DAB mimics the dual-site catalytic mechanism of urate oxidase, in which the Ni metal center and the C atom in the ligand serve as the specific UA and O2 binding sites, respectively, characterized by synchrotron soft X-ray absorption spectroscopy, in situ near ambient pressure X-ray photoelectron spectroscopy, and isotope labeling. The theoretical calculations reveal the high catalytic specificity is derived from not only the delicate interaction between UA and the Ni center but also the complementary oxygen reduction at the beta C site in the ligand. As a potential application, a Ni-DAB-based biofuel cell using human urine is constructed. This work unlocks an approach of enzyme-like isolated dual sites in boosting the selectivity of non-protein artificial enzymes.

Abstract Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) belongs to a family of metalloreductases, which indirectly aid in uptake of iron and copper ions. Its role in hepatocellular carcinoma (HCC) remains to be characterized. Here, we report that STEAP2 expression was upregulated in HCC tumors compared with paired adjacent non-tumor tissues by RNA sequencing, RT-qPCR, Western blotting, and immunostaining. Public HCC datasets demonstrated upregulated STEAP2 expression in HCC and positive association with tumor grade. Transient and stable knockdown (KD) of STEAP2 in HCC cell lines abrogated their malignant phenotypes in vitro and in vivo, while STEAP2 overexpression showed opposite effects. STEAP2 KD in HCC cells led to significant alteration of genes associated with extracellular matrix organization, cell adhesion/chemotaxis, negative enrichment of an invasiveness signature gene set, and inhibition of cell migration/invasion. STEAP2 KD reduced intracellular copper levels and activation of stress-activated MAP kinases including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEAP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited copper-mediated cell migration. Thus, STEAP2 plays a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.

The global challenges of biodiversity loss and climate change necessitate the implementation of integrated conservation strategies. A forward-looking framework is necessary to reconcile climate change adaptation and mitigation efforts with biodiversity goals, supporting effective long-term planning and management of protected areas (PAs) network. This study develops a comprehensive approach to identify priority areas for biodiversity conservation until 2050, integrating assessments of species distributions, climate change exposure and carbon storage under distinct shared socioeconomic pathways. The Middle and Lower Yangtze River Basin (MLYRB) in China serves as a case study. Using an ensemble species distribution modeling (ESDM) method, we predicted the distributions of 435 threatened terrestrial vertebrate species and plants. We then mapped their richness in the MLYRB. Distance-based climate velocity analysis was performed to identify climate change coldspots and hotspots. The patch-generating land use simulation (PLUS) model and InVEST model were coupled to simulate carbon storage changes. Systematic conservation planning tool, Zonation, was used to prioritize species conservation hotspots. By examining the co-occurrence of these hotspots with climate change coldspots/hotspots and areas of high carbon storage, conservation priorities for the MLYRB were revealed. Our findings indicate that 18.27–24.94 % of the MLYRB risks over 20 % species richness declines by 2050 under various scenarios, while increases over 10 % are projected for only 0.81–1.75 % of the area. Co-occurrence analysis highlights significant associations, such as a 32.26 % overlap between species conservation hotspots and climate change hotspots in SSP1–2.6. Particularly noteworthy is the substantial co-occurrence (57.93–59.50 % across scenarios) between areas maximizing species conservation and carbon storage. The identified conservation priority areas, covering 41.95 % of the MLYRB (441554 km2), hold potential for long-term species conservation, climate resilience, and nature-based climate solutions by 2050. However, only 6.08 % of these priorities currently benefit from protection. These results offer valuable guidance for region-specific landscape management and conservation policy aligned with international goals. The presented methodology provides a broader application, serving as a valuable resource for prioritizing conservation efforts in other regions integrating biodiversity, climate change adaptation, and mitigation goals.

Abstract Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.

Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer.

IntroductionConstructing an accurate and comprehensive knowledge graph of specific diseases is critical for practical clinical disease diagnosis and treatment, reasoning and decision support, rehabilitation, and health management. For knowledge graph construction tasks (such as named entity recognition, relation extraction), classical BERT-based methods require a large amount of training data to ensure model performance. However, real-world medical annotation data, especially disease-specific annotation samples, are very limited. In addition, existing models do not perform well in recognizing out-of-distribution entities and relations that are not seen in the training phase.MethodIn this study, we present a novel and practical pipeline for constructing a heart failure knowledge graph using large language models and medical expert refinement. We apply prompt engineering to the three phases of schema design: schema design, information extraction, and knowledge completion. The best performance is achieved by designing task-specific prompt templates combined with the TwoStepChat approach.ResultsExperiments on two datasets show that the TwoStepChat method outperforms the Vanillia prompt and outperforms the fine-tuned BERT-based baselines. Moreover, our method saves 65% of the time compared to manual annotation and is better suited to extract the out-of-distribution information in the real world.

Abstract Background MicroRNA (miRNA)-based therapies have shown great potential in myocardial repair following myocardial infarction (MI). MicroRNA-302 (miR302) has been reported to exert a protective effect on MI. However, miRNAs are easily degraded and ineffective in penetrating cells, which limit their clinical applications. Exosomes, which are small bioactive molecules, have been considered as an ideal vehicle for miRNAs delivery due to their cell penetration, low immunogenicity and excellent stability potential. Herein, we explored cardiomyocyte-targeting exosomes as vehicles for delivery of miR302 into cardiomyocyte to potentially treat MI. Methods To generate an efficient exosomal delivery system that can target cardiomyocytes, we engineered exosomes with cardiomyocyte specific peptide (CMP, WLSEAGPVVTVRALRGTGSW). Afterwards, the engineered exosomes were characterized and identified using transmission electron microscope (TEM) and Nanoparticle Tracking Analysis (NTA). Later on, the miR302 mimics were loaded into the engineered exosomes via electroporation technique. Subsequently, the effect of the engineered exosomes on myocardial ischemia and reperfusion (I/R) injury was evaluated in vitro and in vivo, including MTT, ELISA, real-time quantitative polymerase chain reaction (PCR), western blot, TUNNEL staining, echocardiogram and hematoxylin and eosin (HE) staining. Results Results of in vitro experimentation showed that DSPE-PEG-CMP-EXO could be more efficiently internalized by H9C2 cells than unmodified exosomes (blank‐exosomes). Importantly, compared with the DSPE-PEG-CMP-EXO group, DSPE-PEG-CMP-miR302-EXO significantly upregulated the expression of miR302, while exosomes loaded with miR302 could enhance proliferation of H9C2 cells. Western blot results showed that the DSPE-PEG-CMP-miR302-EXO significantly increased the protein level of Ki67 and Yap, which suggests that DSPE-PEG-CMP-miR302-EXO enhanced the activity of Yap, the principal downstream effector of Hippo pathway. In vivo, DSPE-PEG-CMP-miR302-EXO improved cardiac function, attenuated myocardial apoptosis and inflammatory response, as well as reduced infarct size significantly. Conclusion In conclusion, our findings suggest that CMP-engineered exosomes loaded with miR302 was internalized by H9C2 cells, an in vitro model for cardiomyocytes coupled with potential enhancement of the therapeutic effects on myocardial I/R injury.

Automatic driving technology has high accuracy and real-time requirements for pedestrian identification and localization. Pedestrian detection is a basic and necessary function in vision-based pedestrian detection systems and collision warning, which can effectively avoid traffic accidents and improve road driving safety to a certain extent. In this paper, a lightweight solution based on the FCOS-DEFPN model is proposed for real-time pedestrian detection. Based on the FCOS model, this paper proposes the FCOS-DEFPN model, which achieves the lightweight of the network by replacing the ResNet50 backbone network with the MobilenetV3 network and using the depth separable convolution instead of the ordinary convolution for parameter compression. While maintaining the detection accuracy, this paper introduces data enhancement methods such as Random Erasing and Morsia to simulate pedestrian occlusion and small target scenarios to improve the robustness of the model. For the pedestrian occlusion scenario, this paper introduces a lightweight attention network ECA, which helps to extract pedestrian features better. For small-target multi-scale pedestrians, the DEFPN feature pyramid network is proposed, which acquires feature information at multiple scales by attentional fusion of feature layers at different scales from top-down, bottom-up, and front-back. The experimental results show that the proposed model is enhanced in terms of detection accuracy for occluded and small-target pedestrians, and satisfies real-time pedestrian detection under the premise of robustness in complex scenes.

Pedestrian trajectory prediction is a key technology in surveillance systems and autonomous driving. However, due to the high uncertainty and dynamic spatial-temporal dependence of pedestrian movement, timely and accurate pedestrian trajectory prediction, especially long-term prediction, is still an open challenge. However, the existing models lack an effective modeling method for temporal dependence and spatial interaction modeling. To solve these problems, in this paper, we propose a novel paradigm of Sparse Transformer Networks with Spatial-Temporal Graph (STGSTN), which captures complex spatial-temporal interactions by stacking spatial-temporal Transformer blocks and improves the accuracy of pedestrian trajectory prediction by combining dynamic spatial dependence and long-range temporal dependence. We propose a new variant of sparse spatial transformer combined with graph neural networks, which uses the self-attention mechanism to dynamically model spatial dependencies to capture the state of pedestrian movement. The multi-head attention mechanism is also used to jointly model various patterns of spatial dependence. In addition, the sparse temporal transformer is used to learn the sparse attention map for time modeling, and then the long-range temporal dependence between pedestrians is modeled. Compared with the existing work, STGSTN can effectively and efficiently train long-range spatial-temporal dependencies. Experimental results show that STGSTN is competitive with state-of-the-art techniques on the ETH-UCY dataset, especially for long-term prediction. The performance of STGSTN may be limited by the quality of the training data, and its generalization to highly dynamic or crowded environments remains a challenge. Future work will focus on addressing these limitations and exploring additional contextual information to further enhance prediction accuracy.

Brain-computer interface (BCI) based motor imagery (MI) can assist stroke patients in upper limb rehabilitation and help restore motor function to a certain extent. However, the classical MI paradigm distinguishes different limbs and cannot effectively meet the needs of upper limb rehabilitation training for patients. Therefore, this paper designed a new paradigm for three motor imagery actions targeting different joints of the unilateral upper limb, and electroencephalogram (EEG) data from 20 healthy participants were collected for research analysis. A deep neural network model combining an attention mechanism for multiple frequency bands and a deep convolutional network were proposed to adaptively assign weight to the EEG data in different frequency bands. Then feature extraction was performed for each frequency band to learn further and to classify features. This model can obtain an average accuracy of 69.2% for the subject-independent case with the triple classification in the designed fine motor imagery (FMI) dataset, which is better than other controlled methods. Furthermore, ablation experiments were conducted for each module, demonstrating the effectiveness of each module. These results manifest the feasibility of our proposed method and the potential of FMI paradigm for BCI, providing a new training tool for upper limb rehabilitation after stroke.

Background: and purpose: Radiotherapy (RT) is an effective treatment for most malignant chest tumors. However, radiation-induced myocardial fibrosis (RIMF) is a serious side effect of RT. Currently, due to the mechanism of RIMF has not been fully elucidated, there is a lack of effective therapeutic approach. In this study, we aimed to investigate the role and possible mechanisms of bone marrow mesenchymal stem cells (BMSCs) in the therapy of RIMF. Materials and methods: Twenty-four New Zealand white rabbits were allotted into four groups (n = 6). Rabbits in the Control group received neither irradiation nor treatment. A single dose of 20 Gy heart X-irradiation was applied to the RT group, RT + PBS group and RT + BMSCs group. Rabbits in the RT + PBS group and RT + BMSCs group were injected with 200 μL PBS or 2 × 106 cells via pericardium puncture 24 h following irradiation, respectively. Echocardiography was used to test the cardiac function; Then the heart samples were collected, and processed for histopathological, Western blot and immunohistochemistry investigations. Results: It was observed that BMSCs have therapeutic effect on RIMF. Compared with the Control group, inflammatory mediators, oxidative stress and apoptosis were significantly increased, meanwhile, cardiac function was remarkably decreased in the RT group and RT + PBS group. However, in the BMSCs group, BMSCs significantly improved cardiac function, decreased inflammatory mediators, oxidative stress and apoptosis. Furthermore, BMSCs remarkably reduced the expression level of TGF-β1 and the phosphorylated-Smad2/3. Conclusions: In conclusion, our research indicates BMSCs have the potential to alleviate RIMF through TGF-β1/Smad2/3 and would be a new therapeutic approach for patients with myocardial fibrosis.

Snow detection is imperative in remote sensing for various applications, including climate change monitoring, water resources management, and disaster warning. Recognizing the limitations of current deep learning algorithms in cloud and snow boundary segmentation, as well as issues like detail snow information loss and mountainous snow omission, this paper presents a novel snow detection network based on Swin-Transformer and U-shaped dual-branch encoder structure with geographic information (SD-GeoSTUNet), aiming to address the above issues. Initially, the SD-GeoSTUNet incorporates the CNN branch and Swin-Transformer branch to extract features in parallel and the Feature Aggregation Module (FAM) is designed to facilitate the detail feature aggregation via two branches. Simultaneously, an Edge-enhanced Convolution (EeConv) is introduced to promote snow boundary contour extraction in the CNN branch. In particular, auxiliary geographic information, including altitude, longitude, latitude, slope, and aspect, is encoded in the Swin-Transformer branch to enhance snow detection in mountainous regions. Experiments conducted on Levir_CS, a large-scale cloud and snow dataset originating from Gaofen-1, demonstrate that SD-GeoSTUNet achieves optimal performance with the values of 78.08%, 85.07%, and 92.89% for IoU_s, F1_s, and MPA, respectively, leading to superior cloud and snow boundary segmentation and thin cloud and snow detection. Further, ablation experiments reveal that integrating slope and aspect information effectively alleviates the omission of snow detection in mountainous areas and significantly exhibits the best vision under complex terrain. The proposed model can be used for remote sensing data with geographic information to achieve more accurate snow extraction, which is conducive to promoting the research of hydrology and agriculture with different geospatial characteristics.

Although the fundamental processes and chemical changes in metabolic programs have been elucidated in many cancers, the expression patterns of metabolism-related genes in head and neck squamous cell carcinoma (HNSCC) remain unclear. The mRNA expression profiles from the Cancer Genome Atlas included 502 tumour and 44 normal samples were extracted. We explored the biological functions and prognosis roles of metabolism-associated genes in patients with HNSCC. The results indicated that patients with HNSCC could be divided into three molecular subtypes (C1, C2 and C3) based on 249 metabolism-related genes. There were markedly different clinical characteristics, prognosis outcomes, and biological functions among the three subtypes. Different molecular subtypes also have different tumour microenvironments and immune infiltration levels. The established prognosis model with 17 signature genes could predict the prognosis of patients with HNSCC and was validated using an independent cohort dataset. An individual risk scoring tool was developed using the risk score and clinical parameters; the risk score was an independent prognostic factor for patients with HNSCC. Different risk stratifications have different clinical characteristics, biological features, tumour microenvironments and immune infiltration levels. Our study could be used for clinical risk management and to help conduct precision medicine for patients with HNSCC.

This comprehensive review delves into the complex interplay between mitochondrial gene defects and pancreatic cancer pathogenesis through a multiomics approach. By amalgamating data from genomic, transcriptomic, proteomic, and metabolomic studies, we dissected the mechanisms by which mitochondrial genetic variations dictate cancer progression. Emphasis has been placed on the roles of these genes in altering cellular metabolic processes, signal transduction pathways, and immune system interactions. We further explored how these findings could refine therapeutic interventions, with a particular focus on precision medicine applications. This analysis not only fills pivotal knowledge gaps about mitochondrial anomalies in pancreatic cancer but also paves the way for future investigations into personalized therapy options. This finding underscores the crucial nexus between mitochondrial genetics and oncological immunology, opening new avenues for targeted cancer treatment strategies.

Abstract Background Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m6A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in‐depth understanding of the crosstalk between histone acetylation and m6A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6A modifications in the regulation of tumorigenesis of ocular melanoma. Methods Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m6A RNA modification level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets and tagmentation, single‐cell sequencing, methylated RNA immunoprecipitation‐sequencing (meRIP‐seq), and m6A individual nucleotide resolution cross‐linking and immunoprecipitation‐sequencing (miCLIP‐seq), were performed to reveal the mechanisms of HDACis on methyltransferase‐like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real‐time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA‐binding protein immunoprecipitation‐qPCR, meRIP‐seq, miCLIP‐seq, and RNA stability assay were adopted to investigate the mechanism by which m6A levels of FAT4 were affected. Results First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo‐histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m6A‐YTH N6‐methyladenosine RNA‐binding protein 1‐dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14‐mediated m6A modification in tumorigenesis. Conclusions These results demonstrate that HDACis exert anti‐cancer effects by orchestrating m6A modification, which unveiling a “histone‐RNA crosstalk” of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.

Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Despite significant advances in current drug therapies, issues such as poor drug targeting and severe side effects persist. In recent years, nanomedicine has been extensively applied in the research and treatment of CVDs. Among these, biomembrane-modified biomimetic nanodrug delivery systems (BNDSs) have emerged as a research focus due to their unique biocompatibility and efficient drug delivery capabilities. By modifying with biological membranes, BNDSs can effectively reduce recognition and clearance by the immune system, enhance biocompatibility and circulation time in vivo, and improve drug targeting. This review first provides an overview of the classification and pathological mechanisms of CVDs, then systematically summarizes the research progress of BNDSs in the treatment of CVDs, discussing their design principles, functional characteristics, and clinical application potential. Finally, it highlights the issues and challenges faced in the clinical translation of BNDSs.

Abstract Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer1,2. PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation3–5. Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 (EGR1), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.

Before 2008, China lacked high-coverage regional surface observation data, making it difficult for the China Meteorological Administration Land Data Assimilation System (CLDAS) to directly backtrack high-resolution, high-quality land assimilation products. To address this issue, this paper proposes a deep learning model named UNET_DCA, based on the UNET architecture, which incorporates a Dual Cross-Attention module (DCA) for multiscale feature fusion by introducing Channel Cross-Attention (CCA) and Spatial Cross-Attention (SCA) mechanisms. This model focuses on the near-surface 10-m wind field and achieves spatial downscaling from 6.25 km to 1 km. We conducted training and validation using data from 2020–2021, tested with data from 2019, and performed ablation experiments to validate the effectiveness of each module. We compared the results with traditional bilinear interpolation methods and the SNCA-CLDASSD model. The experimental results show that the UNET-based model outperforms SNCA-CLDASSD, indicating that the UNET-based model captures richer information in wind field downscaling compared to SNCA-CLDASSD, which relies on sequentially stacked CNN convolution modules. UNET_CCA and UNET_SCA, incorporating cross-attention mechanisms, outperform UNET without attention mechanisms. Furthermore, UNET_DCA, incorporating both Channel Cross-Attention and Spatial Cross-Attention mechanisms, outperforms UNET_CCA and UNET_SCA, which only incorporate one attention mechanism. UNET_DCA performs best on the RMSE, MAE, and COR metrics (0.40 m/s, 0.28 m/s, 0.93), while UNET_DCA_ars, incorporating more auxiliary information, performs best on the PSNR and SSIM metrics (29.006, 0.880). Evaluation across different methods indicates that the optimal model performs best in valleys, followed by mountains, and worst in plains; it performs worse during the day and better at night; and as wind speed levels increase, accuracy decreases. Overall, among various downscaling methods, UNET_DCA and UNET_DCA_ars effectively reconstruct the spatial details of wind fields, providing a deeper exploration for the inversion of high-resolution historical meteorological grid data.

Urban rivers are vital for urbanization and regional economic development, which can provide water for living, industrial and agricultural needs of urban residents, and regulate the hydrological environment in the urban. The exploration of urban rivers health based on resilience theory can provide important reference for urban rivers restoration and resilience urban construction. To this purpose, this study explores the health status of Jialu River during 2011–2020 from the perspective of resilience. First, a comprehensive indicator system based on the resilience theory was established for the health analysis of urban rivers. Second, an urban rivers resilience index (URRI) was developed utilizing the improved FCM-EWM-MABAC method to accurately illuminate the health states of urban rivers. Final, the health state of Jialu River from 2011 to 2022 was diagnosed using the comprehensive indicator system and URRI. Our results suggested that the Jialu River’s health state showed a rapid improvement trend from ordinary state in 2011 to good state in 2020. The health status of resistance, recovery and adaptability subsystems displayed different degrees of improvement during the study period, and the growth trend of adaptability subsystem was the most obvious. Over the past decade, the resilience state of Jialu River had improved by implementing a series of governance measures, but there is still room for improvement. This study can provide significant references for future work on the water resource conservation and sustainable development in rapidly economic developing regions.

Objective: To investigate the frailty, as estimated by accumulated health deficits, in association with the symptomatic carotid atherosclerosis and in relation to five-year cardiovascular (CVD) outcomes. Methods: This is a five-year prospective cohort study. Secondary analysis of data from the Beijing Longitudinal Study on Aging. Community-dwelling people aged 55+ years (n = 1257) have been followed between 2009 and 2014, and having carotid ultrasonography examinations with no CVD events at baseline. Frailty was quantified using the deficit accumulation-based frailty index (FI), constructed from 37 health deficits assessed at baseline. The association between the degree of frailty and carotid atherosclerosis was examined using odds ratios (OR) with multivariate logistic regression analyses. Effects of frailty on the probability of five-year cardiovascular events and mortality were evaluated using Cox proportional hazard ratios (HR). The analyses were adjusted for demographics, baseline carotid atherosclerosis status, and CVD risk factors. Results: The FI showed characteristic properties and was independently associated with the major carotid atherosclerosis symptoms, including carotid artery intima-media thickening (the most frail vs. the least frail: OR = 4.39: 1.98–7.82), carotid plaque (OR = 3.41: 1.28–6.54), and carotid plaque stability (OR = 1.19, 95 % CI: 1.01–3.59). Compared with the least frail, the most frail individuals were more likely to develop a cardiovascular event in five years, including myocardial infarction (HR = 3.38, 95 % CI = 1.84–6.19), stroke (HR = 1.26, 95 % CI = 1.00–5.87), CVD death (HR = 6.33, 95 % CI = 1.69–11.02), and all-cause death (HR = 5.95, 95 % CI = 2.74–8.95). Conclusion: Deficit accumulation was closely associated with carotid atherosclerosis risks and strongly predicted five-year CVD events. The frailty index can be used to help identify older adults at high risks of CVD for improved preventive healthcare.

Vehicle trajectory prediction is a key technology in autonomous driving, one of the aims of which is to ensure the safety of vehicle travelling and lane changing. Especially in complex traffic scenarios, it is critical to accurately predict the vehicle trajectory so that the automated driving system can make appropriate response actions to help the vehicle driver avoid accidents to the greatest extent possible. Some studies on vehicle trajectory prediction have used recurrent networks (LSTMs) to extract temporal correlations and additional convolutional neural networks (CNNs) to capture spatial correlations. This hybrid model can be added more operations, so we propose a new CNN-LSTM hybrid model containing multi-module, interaction regions and spatial-temporal attention mechanisms (IA-CSTM). In this paper, the traffic scene is divided into multiple interaction regions, and vehicles in different regions have different impacts on the predicted vehicles. The model has multiple modules that deal with vehicle information in different interaction regions. The model will cross-fuse vehicle information in important interaction regions to enhance the model’s perception of vehicle information. Multiple modules are linked through a spatial-temporal attention mechanism and capture the relevance of the vehicle in the interaction region to predicted vehicle.

Uveal melanoma (UM) is the most frequent and life-threatening ocular malignancy in adults. Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis. However, a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic. Herein, using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers, we observed that disruptor of telomeric silencing-1-like (DOT1L), a methyltransferase of histone H3 lysine 79 (H3K79), was activated in UM, especially in the high-risk group. Concordantly, a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells, both in vitro and in vivo. Combining Cleavage Under Targets and Tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and bioinformatics analysis, we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase (NAPRT) and epigenetically activated its expression. Importantly, NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide (NAD+) synthesis. Therapeutically, DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79 (H3K79me2) in the NAPRT promoter, thereby inhibiting the malignant behaviors of UM. Conclusively, our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.

Abstract Background The intensive interplay between aberrant epigenetic events and metabolic remodeling represents one of the hallmarks of tumors, including colon cancer. The functions of Bromodomain Containing Protein BRD‐9 in colon cancer remains indefinite. We aimed to identify the biological roles and clinical significance of BRD9 in colon cancer. Methods The univariate‐ and multi‐variate Cox regression models were used to screen risk epigenetic regulators. Kaplan–Meier analysis and Pearson correlation analysis were used to assess clinical significance of BRD9. CCK‐8 assays, colony formation assay, Transwell, and soft‐agar assay were performed to determine the in vitro roles of BRD9. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of colon cancer cells were evaluated by a Seahorse XF Extracellular Flux Analyzer. In vivo models and RT‐qPCR, western blotting, and Chromatin Immunoprecipitation (ChIP) assay were conducted to explore the functional roles of BRD9 in COAD. Results In the study, we detected the expressions of 662 epigenetic regulators in COAD and identified a series of 42 hazard epigenetic factors with p

Abstract Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post‐transcriptional levels. Epigenetic modifiers, chromatin remodelers and non‐coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic‐metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

Abstract Magnetic tunnel junction (MTJ) with magnesium oxide (MgO) tunnel barrier is the core element of spin transfer torque-based magnetic random access memory. For the application in the space environment, the total ionizing dose radiation effects on MTJs need to be evaluated. In this work, the MTJs were exposed to X-ray radiation with different doses of up to 10 Mrad(Si). Measurements of current induced magnetization switching (CIMS) behavior of these MTJs were performed before and after radiation. The results show negligible changes in the tunneling magnetoresistance and current switching properties after 8 Mrad(Si) X-ray radiation. However, with a total dose of 9 Mrad(Si), a significant reduction in junction resistance of a fairly large number of MTJs was observed, which showed characteristics of MTJ breakdown. Moreover, in this study, all experimental MTJs became functionally disabled due to MgO breakdown under 10 Mrad(Si) X-ray radiation. The CoFeB/MgO/CoFeB interface microstructure was observed using X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy (HRTEM). Interfacial structural results indicate that the MgO degradation and breakdown behavior caused by X-ray ionizing radiation can give rise to radiation-induced oxygen vacancies across the tunnel barrier oxide layer.

Abstract Cholesterol metabolism is highly correlated with risks of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the underlying mechanisms of activation of cholesterol biogenesis remain inconclusive. KIF11 is a key component of the bipolar spindle and expresses highly in various malignancies. However, its functional role in PDAC tumorigenesis is still unclear. This study aims to elucidate the oncogenic functions of KIF11 in stimulating cholesterol metabolism, thereby driving PDAC progression. We utilized bioinformatics analysis to identify that KIF11 expressed highly in tumor samples versus paired normal tissues and high KIF11 correlated with high clinical stages of patients. Patients with high KIF11 had worse survival outcomes relative to those with low KIF11. Gene set enrichment analysis (GSEA) revealed that KIF11 correlated intensively with the mevalonate (MVA) metabolic pathway. Positive associations were observed between KIF11 and MVA‐signature (HMGCR, FDFT1, SQLE, and MSMO1). KIF11 could elevate the free cholesterol content of PDAC cells and targeting MVA inhibited the in vitro growth of KIF11‐overexpressing cells. Mechanistically, we found KIF11 could interact with SREBP2, the master regulator of MVA. High KIF11 could increase SREBP2 proteins, but not alter their mRNA levels. KIF11 could attenuate the ubiquitination‐mediated degradation of SREBP2, thereby enhancing its stability and accumulation. Accordingly, KIF11 stimulated the expressions of MVA‐signature and free cholesterol contents depending on SREBP2. In addition, KIF11 depended on SREBP2 to promote cell growth, migration, stemness, and colony formation abilities. The subcutaneous xenograft models indicated that targeting MVA biogenesis (atorvastatin) is effective to restrict the in vivo growth of KIF11high PDAC. Taken together, our study identified that KIF11 could activate the MVA cross talk to drive PDAC progression and inhibiting the KIF11/MVA axis provided a therapeutic vulnerability in the treatment of PDAC.

Both oxidative stress and the immune response are associated with heart failure (HF). In this study, our aim was to identify the hub genes associated with oxidative stress andimmune infiltration of HF by bioinformatics analysis and experimental verification. The expression profile of GSE36074 was obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were screened by GEO2R. The genes related to oxidative stress were extracted from GeneCards websites. Then, the functional enrichment analysis of oxidative stress-related DEGs (OSRDEGs) was performed using DAVID. In addition, we constructed a protein-protein interaction (PPI) network using the STRING database and screened for hub genes with Cytoscape software. We also used CIBERSORTx to analyze immune infiltration in mice heart tissues between the TAC and Sham groups and explored the correlation between immune cells and hub genes. Finally, the hub genes were carried out using reverse transcription quantitative PCR (RT-qPCR), immunohistochemistry (IHC) and western blot. A total of 136 OSRDEGs were found in GSE36074. Enrichment analysis revealed that these OSRDEGs were enriched in the mitochondrion, HIF-1, FoxO, MAPK and TNF signaling pathway. The five hub genes (Mapk14, Hif1a, Myc, Hsp90ab1, and Hsp90aa1) were screened by the cytoHubba plugin. The correlation analysis between immune cells and hub genes showed that Mapk14 was positively correlated with Th2 Cells, while Hif1a and Hsp90ab1exhibited a negative correlation with Th2 Cells; Myc exhibited a negative correlation with Monocytes; whereas, Hsp90aa1 was negatively correlated with NK Resting. Finally, five hub genes were validated by RT-qPCR, IHC and western blot. Mapk14, Hif1a, Myc, Hsp90ab1, and Hsp90aa1 are hub genes of HF and may play a critical role in the oxidative stress of HF. This study may provide new targets for the treatment of HF, and the potential immunotherapies are worthy of further study.

ObjectiveSingle-pill amlodipine besylate (AML) plus losartan (LOS) has been used to treat inadequately controlled hypertension after antihypertensive monotherapy; however, relevant data in China are limited. This study aimed to compare the efficacy and safety of single-pill AML/LOS and LOS alone in Chinese patients with inadequately controlled hypertension after LOS treatment.MethodsIn this multicenter, double-blind, randomized, controlled phase III clinical trial, patients with inadequately controlled hypertension after 4 weeks of LOS treatment were randomized to receive daily single-pill AML/LOS (5/100 mg, AML/LOS group, N = 154) or LOS (100 mg, LOS group, N = 153) tablets for 8 weeks. At weeks 4 and 8 of treatment, sitting diastolic and systolic blood pressure (sitDBP and sitSBP, respectively) and the BP target achievement rate were assessed.ResultsAt week 8, the sitDBP change from baseline was greater in the AML/LOS group than in the LOS group (−8.84 ± 6.86 vs. −2.65 ± 7.62 mmHg, P

Hearing loss is the most common congenital sensory impairment. Mutations or deficiencies of the GJB2 gene are the most common genetic cause of congenital non-syndromic deafness. Pathological changes such as decreased potential in the cochlea, active cochlear amplification disorders, cochlear developmental disorders and macrophage activation have been observed in various GJB2 transgenic mouse models. In the past, researchers generally believed that the pathological mechanisms underlying GJB2-related hearing loss comprised a K+ circulation defect and abnormal ATP-Ca2+ signals. However, recent studies have shown that K+ circulation is rarely associated with the pathological process of GJB2-related hearing loss, while cochlear developmental disorders and oxidative stress play an important, even critical, role in the occurrence of GJB2-related hearing loss. Nevertheless, these research has not been systematically summarized. In this review, we summarize the pathological mechanisms of GJB2-related hearing loss, including aspects of K+ circulation, developmental disorders of the organ of Corti, nutrition delivery, oxidative stress and ATP-Ca2+ signals. Clarifying the pathological mechanism of GJB2-related hearing loss can help develop new prevention and treatment strategies.

Abstract The inaccuracy of power sharing is a classic problem of droop control when an islanded AC microgrid suffers from high loads and line impedance differences. It degrades system performance and even destroys system stability. This paper originally presents a multi‐objective optimisation droop control method to solve such a problem. And three objective functions are presented according to the characteristics of microgrids. First, a complete small‐signal model of a microgrid in autonomous operation mode is established. Next, this paper derives constraint conditions for the stable microgrid. Then, this paper originally designs three objective functions for constructing a multi‐objective optimisation (MOO) problem to improve control performance. The multiobjective evolutionary algorithm based on decomposition (MOEA/D) is used to obtain the Pareto optimal frontier of the MOO problem. The fuzzy affiliation function method is used to choose the best solution from the generated Pareto optimal frontier. Finally, simulations verified the validity and superiority of the presented method.

Abstract Background Frailty can be operationalized based on the accumulation of deficits using a frailty index (FI) and is associated with an increased risk of adverse health outcomes. Here, we aim to compare validity of a FI from laboratory data with that of the common clinical FI for prediction of mortality in adults aged 55 + years, also examine whether combined FI could improve identification of adults aged 55 + years at increased risk of death. Methods Data for this analysis were obtained from the Beijing Longitudinal Study of Aging that involved 1,257 community-dwelling Chinese people, aged 55 + years at baseline. The main outcome measure was 5-year mortality. An FI-self-report based on 30 self-reported health-related data was constructed. An FI-lab was developed using laboratory data, in addition to pulse, systolic and diastolic blood pressure, pulse pressure, body mass index (BMI) and waist. A combined FI comprised all items from each FI. Kaplan–Meier survival curve and Cox proportional hazards models were performed to evaluate the risk of each FI on death. The area under receiver operating characteristic(ROC) curves were used to compare the discriminative performance of each FI. Results Of 1257 participants, 155 died and 156 lost at the end of the 5-year follow-up. The mean FI-self-report score was 0.11 ± 0.10, the FI-lab score was 0.33 ± 0.14 and FI-combined score was 0.19 ± 0.09. Higher frailty level defined by each FI was associated with higher risk of death. After adjustment for age and sex, Cox proportional hazards models showed that the higher scores of frailty were associated with a higher risk of mortality for each FI, the hazard ratios for the FI-self-report and FI-lab and FI-combined were 1.04 (1.03 to 1.05) and 1.02 (1.01 to 1.03) and 1.05 (1.04 to 1.07), respectively. The areas under the ROC curve were 0.79 (0.77–0.82) for the FI-self-report, 0.77(0.75–0.80) for the FI-lab and 0.81(0.78–0.82) for FI-combined. Conclusions A FI from laboratory data can stratify older adults at increased risk of death alone and in combination with FI based on self-report data. Assessment in clinical settings of creating an FI using routine collected laboratory data needs to be further developed.

Abstract The associations of blood pressure components with cardiovascular risks and death remain unclear, and the definition of wide pulse pressure (PP) is still controversial. Using data from 1257 participants without a history of cardiovascular disease, who were followed for 4.84 years, we performed multivariable Cox regression analyses to assess how systolic blood pressure (SBP), diastolic blood pressure (DBP), and PP contribute to risks of cardiovascular events and all‐cause death. Among all participants, SBP and PP were significantly associated with the risks of cardiovascular events and all‐cause death (all p < .05). DBP was not significantly associated with the risk of all‐cause death; rather, it was only associated with a marginally significant 1% increased risk for cardiovascular events (p = 0.051). In participants aged

Abstract Background The precise temporal and spatial regulation of N5‐methylcytosine (m5C) RNA modification plays essential roles in RNA metabolism, and is necessary for the maintenance of epigenome homeostasis. Howbeit, the mechanism underlying the m5C modification in carcinogenesis remains to be fully addressed. Methods Global and mRNA m5C levels were determined by mRNA isolation and anti‐m5C dot blot in both retinoblastoma (RB) cells and clinical samples. Orthotopic intraocular xenografts were established to examine the oncogenic behaviours of RB. Genome‐wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5C‐methylated RNA immunoprecipitation sequencing (m5C‐meRIP‐seq). Organoid‐based single‐cell analysis and gene‐correlation analysis were performed to verify the NSUN2/ALYREF/m5C‐PFAS oncogenic cascade. Results Herein, we report that NSUN2‐mediated m5C RNA methylation fuels purine biosynthesis during the oncogenic progression of RB. First, we discovered that global and mRNA m5C levels were significantly enriched in RBs compared to normal retinas. In addition, tumour‐specific NSUN2 expression was noted in RB samples and cell lines. Therapeutically, targeted correction of NSUN2 exhibited efficient therapeutic efficacy in RB both in vitro and in vivo. Through multiomics analyses, we subsequently identified phosphoribosylformylglycinamidine synthase (PFAS), a vital enzyme in purine biosynthesis, as a downstream candidate target of NSUN2. The reintroduction of PFAS largely reversed the inhibitory phenotypes in NSUN2‐deficient RB cells, indicating that PFAS was a functional downstream target of NSUN2. Mechanistically, we found that the m5C reader protein ALYREF was responsible for the recognition of the m5C modification of PFAS, increasing its expression by enhancing its RNA stability. Conclusions Conclusively, we initially demonstrated that NSUN2 is necessary for oncogenic gene activation in RB, expanding the current understanding of dynamic m5C function during tumour progression. As the NSUN2/ALYREF/m5C‐PFAS oncogenic cascade is an important RB trigger, our study suggests that a targeted m5C reprogramming therapeutic strategy may be a novel and efficient anti‐tumour therapy approach.

Background: The impacts of rapid urbanization and industrialization often cause toxic metal contamination in agricultural soils, which has been a global environmental issue. Methods: Agricultural soil samples were obtained from Lanzhou city, a typical industrial city in northwestern China. The levels of six toxic metals (i.e., Cd, Cr, Cu, Pb, Sb, and Zn) were determined in soil samples using Inductively Coupled Plasma Optical Emission Spectrometer. Afterwards, enrichment, contamination, ecological and health risks of them were comprehensively evaluated. Results: The average concentrations of toxic metals were 0.30, 79.7, 21.6, 26.7, 0.97, and 69.0 mg kg−1 for Cd, Cr, Cu, Pb, Sb, and Zn, respectively in soils. Cd was moderately enrichment while other metals were minimally enriched in soils of Lanzhou. The agricultural soils were characterized by moderate to considerable contamination of Cd and low contamination of other metals. Moreover, Cd might cause noticeable ecological risks at most sites. In addition, the average target hazard quotient (THQ) for children was 0.727, almost ten times higher than that for adults. Cr, Pb, and Sb were the most sensitive factors affecting the health risk assessment and contributed over 99% to the THQ. Conclusion: Lithogenic source, industrial and mining activities, and phosphorus fertilizer usage were the three main factors affecting the concentrations of Cd, Cr, Cu, Pb, Sb, and Zn in agricultural soils of Lanzhou, which should be taken into consideration in future supervision and management. Health risks of these metals, especially Cd, Cr, and Sb, for children should receive considerable attention due to their health hazard.

Abstract Background ApoE gene polymorphism and serum total homocysteine (tHcy) has been reportedly associated with cognition. In this study, we assessed the association of combined ApoE gene polymorphism and tHcy with cognition in Chinese elder adults. Methods A cross- sectional study was carried out by recruiting 1458 community-dwelling people aged 55+ and above in Beijing in 2009. All participants were interviewed using a standard questionnaire and underwent a physical examination. The mini-mental scale examination (MMSE) score was used in assessing cognitive function. Fasting venous blood samples were taken for ApoE rs429358, rs7412 genotyping, tHcy and other serum lipid measurements. Results Participants with high serum tHcy level showed a relatively lower orientation, attention abilities as well as the total MMSE score than the group with normal tHcy after adjusting confounding factors. ApoE rs429358 and rs7412 variants were observed to have the highest serum TC and TG level in the subjects with high serum tHcy level (p

Immersive virtual technology has been widely used to modulate sociocognitive processes, such as changing individuals’ implicit attitudes towards specific groups. As to measure the effect, the implicit association test (IAT) is the most used one. However, IAT itself is controversial for its construct validity and commonly requires participants to quit virtual environments (VEs) to complete. Here, we propose an alternative paradigm, the “interpersonal distance paradigm”, which measures attitudes using interpersonal distance and can be conducted in VEs. We conducted a user study measuring weight stigma to compare the effectiveness of the interpersonal distance paradigm with two classical paradigms: the questionnaire and IAT. Results revealed a floor effect in the questionnaire method and no significant correlation between the two classic paradigms. The measurement of interpersonal distance showed a weak positive correlation with the questionnaire score, but not with IAT score. In future research, the results of more measurement methods should be combined to obtain more accurate results to better evaluate this new paradigm’s validity. The accurate results can help quantify the effects of the programs aiming at reducing weight stigma.

IntroductionInflammatory bowel diseases (IBDs) are associated with both immune abnormalities and dysbiosis, characterized by a loss of Faecalibacterium prausnitzii (F. prausnitzii). However, the reason for F. prausnitzii deficiency remains unclear.Methods16S rDNA seque­ncing and IgA enzyme-linked immunosorbent assay (ELISA) were applied to identify bacterial community and IgA changes in ulcerative colitis (UC) patients. Forced immunization with F. prausnitzii in rabbits was conducted. To screen for potential IgA-reactive proteins in F. prausnitzii lysates, we performed western blotting and mass spectrometry analyses. Pyruvate: ferredoxin oxidoreductase (PFOR) was cloned and purified, then the immunoreactivity of PFOR was verified in peripheral blood mononuclear cells (PBMCs) through PCR, ELISpot assay and single-cell sequencing (scRNA-seq). Finally, the UC fecal dysbiosis was re-analyzed in the context of the phylogenetic tree of PFOR.ResultsF. prausnitzii was underrepresented in UC patients with elevated F. prausnitzii-reactive IgA in the fecal supernatant. Forced immunization with F. prausnitzii in rabbits led to high interferon-γ (IFN-γ) transcription in the colon, along with beta diversity disturbance and intestinal inflammation. PFOR was identified as an IgA-binding antigen of F. prausnitzii and the immunoreactivity was validated in PBMCs, which showed elevated expression of inflammatory cytokines. The scRNA-seq revealed enhanced signals in both T regulatory cells (Tregs) and monocytes after PFOR incubation. Furthermore, phylogenetic analysis revealed that PFOR was a common but conserved protein among the gut bacteria.DiscussionOur results collectively suggest that PFOR is a bioactive protein in the immune system and may contribute to host-microbial crosstalk. Conserved but bioactive microbial proteins, such as PFOR, warrant more attention in future host-microbial interaction studies.

Epithelial malignant transformation and tumorous development were believed to be closely associated with the loss of its microenvironment integrity and homeostasis. The tumor-suppressive molecules Maspin and p53 were demonstrated to play a crucial role in body epithelial and immune homeostasis. Downregulation of Maspin and mutation of p53 were frequently associated with malignant transformation and poor prognosis in various human cancers. In this review, we focused on summarizing the progress of the molecular network of Maspin in studying epithelial tumorous development and its response to clinic treatment and try to clarify the underlying antitumor mechanism. Notably, Maspin expression was reported to be transcriptionally activated by p53, and the transcriptional activity of p53 was demonstrated to be enhanced by its acetylation through inhibition of HDAC1. As an endogenous inhibitor of HDAC1, Maspin possibly potentiates the transcriptional activity of p53 by acetylating the p53 protein. Hereby, it could form a “self-propelling” antitumor mechanism. Thus, we summarized that, upon stimulation of cellular stress and by integrating with p53, the aroused Maspin played the epigenetic surveillant role to prevent the epithelial digressional process and retune the epithelial homeostasis, which is involved in activating host immune surveillance, regulating the inflammatory factors, and fine-tuning its associated cell signaling pathways. Consequentially, in a normal physiological condition, activation of the above “self-propelling” antitumor mechanism of Maspin and p53 could reduce cellular stress (e.g., chronic infection/inflammation, oxidative stress, transformation) effectively and achieve cancer prevention. Meanwhile, designing a strategy of mimicking Maspin’s epigenetic regulation activity with integrating p53 tumor-suppressive activity could enhance the chemotherapy efficacy theoretically in a pathological condition of cancer.

Background: Tumor-associated macrophages (TAMs) are one of the most abundant immune cells in the pancreatic cancer stroma and are related to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. Therefore, targeting tumor-associated macrophages is a possible strategy for the treatment of pancreatic cancer.Purpose: We would like to investigate the role of sphingomyelin synthase 2 (SMS2) and the effect of the synthase 2 selective inhibitor YE2 in TAMs and the pancreatic tumor microenvironment. In addition, we also would like to investigate the mechanism by which YE2 attenuates macrophage M2 polarization.Methods: YE2 was utilized to treat macrophages (in vitro) and mice (in vivo). Western blotting and real-time PCR were used to detect the protein levels and mRNA levels of macrophage M2 polarization markers and their downstream signaling pathways. Sphingomyelin synthase 2 gene knockout (KO) mice and their controls were used to establish a PANC-02 orthotopic pancreatic cancer model, and immune cell infiltration in the tumor tissue was analyzed by immunohistochemistry (IHC).Results: We found that sphingomyelin synthase 2 mRNA expression is positively correlated with tumor-associated macrophages, the immunosuppressive microenvironment, and poor prognosis in pancreatic ductal adenocarcinoma patients. Sphingomyelin synthase 2 deficiency was confirmed to have an inhibitory effect on the growth of orthotopic PANC-02 tumors in vivo. The deficiency not only reduced the infiltration of tumor-associated macrophages but also regulated other immune components in the tumor microenvironment. In tissue culture, YE2 inhibited M2 polarization in both bone marrow-derived macrophages (BMDMs) and THP-1 macrophages and eliminated the protumor effect of M2 macrophages. In the mouse model, YE2 treatment reduced the infiltration of TAMs and regulated other immune components in the tumor microenvironment, slowing the progression of PANC-02 tumors. In terms of mechanism, we found that the inhibition of sphingomyelin synthase 2 could downregulate the expression of IL4Rα and CSF1R, thereby attenuating M2 polarization.Conclusion: The sphingomyelin synthase 2 inhibitor YE2 or sphingomyelin synthase 2 deficiency can prevent macrophage M2 polarization in pancreatic cancer, and sphingomyelin synthase 2 could be a new potential target for the treatment of pancreatic cancer.

Abstract Long non-coding RNA (lncRNA) is receiving increasing attention in embryonic stem cells (ESCs) research. However, the roles of lncRNA in the differentiation of ESCs into pacemaker-like cells are still unclear. Therefore, the present study aims to explore the roles and mechanisms of lncRNA in the differentiation of ESCs into pacemaker-like cells. ESCs were cultured and induced differentiation to pacemaker-like cells. RNA sequencing was used to identify the differential expression lncRNAs during the differentiation of ESCs into pacemaker-like cells. Cell morphology observation, flow cytometry, quantitative real-time polymerase chain reaction, western blot, and immunofluorescence were used to detect the differentiation of ESCs into pacemaker-like cells. LncRNA and genes overexpression or knockdown through transfected adenovirus in the differentiation process. The fluorescence in situ hybridization (FISH) detected the lncRNA location in the differentiated ESCs. Luciferase reporter gene assay, methylation-specific PCR, chromatin immunoprecipitation assay, and RNA immunoprecipitation assay were performed to reveal the mechanism of lncRNA-regulating HCN4 expression. Rescue experiments were used to confirm that lncRNA regulates the differentiation of ESCs into pacemaker-like cells through HCN4. We cultured the ESCs and induced the differentiation of ESCs into pacemaker-like cells successfully. The expression of lncRNA RCPCD was significantly decreased in the differentiation of ESCs into pacemaker-like cells. Overexpression of RCPCD inhibited the differentiation of ESCs into pacemaker-like cells. RCPCD inhibited the expression of HCN4 by increasing HCN4 methylation at the promoter region through DNMT1, DNMT2, and DNMT3. RCPCD inhibited the differentiation of ESCs into pacemaker-like cells by inhibiting the expression of HCN4. Our results confirm the roles and mechanism of lncRNA RCPCD in the differentiation of ESCs into pacemaker-like cells, which could pave the path for the development of a cell-based biological pacemaker.

BackgroundTo evaluate the safety and efficacy of hybutimibe plus atorvastatin for lipid control in hypercholesterolemia patients with atherosclerotic cardiovascular disease risk equivalent.MethodsIn this double-blind phase III study, we 1:1 randomly assigned 255 hypercholesterolemia patients with atherosclerotic cardiovascular disease to receive hybutimibe plus atorvastatin or placebo plus atorvastatin. The primary endpoint was the rate of change of plasma low-density lipoprotein-cholesterol (LDL-C) level at 12 weeks from baseline. The secondary endpoints were plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), non-HDL-C, apoprotein (Apo) B, and 2-, 4-, 8-, and 12-week Apo A1 levels change rate and rates of change of plasma LDL-C levels at 2, 4, and 8 weeks from baseline.ResultsFrom April 2016 to January 2018, 128 in the hybutimibe plus atorvastatin group and 125 in the atorvastatin group were included in modified intention-to-treat (mITT) analysis. After 12 weeks of treatment, LDL-C level changed from 2.61 mmol/L (±0.30) at baseline to 2.18 mmol/L (±0.45) in the hybutimibe plus atorvastatin group and from 2.58 (±0.31) mmol/L to 2.40 (± 0.46) mmol/L in the atorvastatin group (P < 0.0001), in mITT. The change rate in the hybutimibe plus atorvastatin group was significantly higher than that in the atorvastatin group (P < 0.0001); the estimated mean rates of change were −16.39 (95% confidence interval: −19.04, −13.74) and −6.75 (−9.48, −4.02), respectively. Consistently, in per-protocol set (PPS) analysis, the rate of change of LDL-C in the hybutimibe plus atorvastatin group was significantly higher than that in atorvastatin group. Significant decreases in the change rates of non-HDL-C, TC, and Apo B at 2, 4, 8, and 12 weeks (all P < 0.05) were observed for hybutimibe plus atorvastatin, while the differences were not significant for HDL-C, TG, and Apo-A1 (all P > 0.05). During the study period, no additional side effects were reported.ConclusionsHybutimibe combined with atorvastatin resulted in significant improvements in LDL-C, non-HDL-C, TC, and Apo B compared with atorvastatin alone. The safety and tolerability were also acceptable, although additional benefits of hybutimibe plus atorvastatin were not observed compared with atorvastatin alone in HDL-C, TG, and Apo-A1.

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Abstract Background The genus Lactobacillus is an important component of the gastrointestinal tract of human and animals and commonly considered as probiotic. L. taiwanensis has long been proposed to be a probiotic whereas understanding on this species is still in its infancy. Genomic information of L. taiwanensis is fairly limited. Extensive characterization of its beneficial traits is needed. Results A new strain CLG01 of L. taiwanensis was isolated from mouse Peyer’s patches. We established its probiotic profile through in vitro experiments. Complete genome of this strain was also sequenced and analyzed. L. taiwanensis CLG01 showed robust tolerance to acid and a degree of tolerance to bile salt with a promising antibacterial activity against a broad spectrum of pathogenic bacteria. In vitro treatment of mouse RAW 264.7 macrophage cells with heat-killed bacteria and bacterial supernatant of L. taiwanensis CLG01 resulted in enhancement of immune responses and upregulated expression of TNF-α and IL-6. The strain CLG01 also increased the IL-10 production of macrophages when co-treated with lipopolysaccharide (LPS). Complete genome of L. taiwanensis CLG01 contained a 1.89 Mb chromosome and two plasmids. Further genomic analysis revealed the presence of genes related to its resistance to different stresses and the beneficial effects mentioned above. Moreover, biosynthetic gene clusters (BGCs) encoding antimicrobial peptides, like bacteriocin, linear azol(in)e-containing peptide (LAP) and lanthipeptide, were also identified in the genome of L. taiwanensis CLG01. Conclusions L. taiwanensis CLG01, isolated from mouse Peyer’s patches, is the first L. taiwanensis strain with both phenotypes and genotypes systematically studied. These preliminary data confirmed the role of L. taiwanensis CLG01 as a potential probiotic candidate with antibacterial and immunomodulatory activity, which provide insight for further investigation to this species.

Objective To explore the association of depression, as well as untreated hypertension or diabetes with all-cause death in community-based postmenopausal women in Beijing. Methods A cohort of 863 community-based postmenopausal women with no history of cardiovascular heart disease (CHD), stroke, cancer, or dementia was investigated on 20 July–28 September 2009 at baseline. Depression was diagnosed using the 30-item Center for Epidemiologic Studies Depression (CES-D) scale with CES-D ≥ 11. Meanwhile, data on health behavior, physical comorbidity, and social support at baseline were collected. These individuals were followed up from 20 July to 30 August 2014. All-cause mortality and cause of death were surveyed. Results After a median follow-up of 4.97 years, 120 subjects died of all-cause. Twenty-four died of stroke, 19 died of myocardial infarction, 21 died of cancer. The others died of aging, infection, and accident. Depression and untreated HP were significantly associated with all-cause mortality in Cox models after full adjustment for all of the potential confounders (Depression HR: 2.16, 95%CI: 1.35–3.46; Untreated hypertension HR: 1.84, 95%CI: 1.12–3.02). However, negative correlation of untreated diabetes on all-cause mortality was observed in this population (HR: 1.36, 95%CI: 0.75–2.49). When depression was co-existing with hypertension/diabetes, the HR for mortality elevated significantly (Depression co-existing with hypertension HR = 3.87, 95% CI: 2.07–7.23; Depression co-existing with diabetes HR = 5.02, 95% CI: 1.5–16.79). Conclusions It is suggested we should take sufficient care of postmenopausal females with depression and control blood pressure and glucose more effectively. Abbreviations: HP: Hypertension; DM: Diabetes; TC: Cholesterol; TG: Triglyceride; BMI: Body-Mass Index; CES-D: Center for Epidemiologic Studies Depression; CDC: Centers for Disease Control and Prevention; HR: Hazard Ratio; CI: Confidence Interval; ADL: Activities of daily living scale

Visible infrared person re-identification (VI-ReID) is an extremely challenging task. VI-ReID suffers from two challenges. One is the cross-modality discrepancy due to different camera spectrums, the other is the intra-modality variation caused by the noise of background clutter or occlusion. We propose a global-level and local-level constraints network (GLoC-Net) to learn discriminative feature representations. It mainly contains two aspects. 1) We employ a non-local attention mechanism for extracting shared features to mitigate the cross-modality discrepancy, and present the division operation of local features to alleviate the problem that the non-local attention mechanism is less robust to noise. 2) We propose joint constraints of global-level and local-level to alleviate the intra-modality variation, which makes the algorithm more robust to noise. Experiments demonstrate that the superior performance of proposed method compared with the state-of-the-arts.

Under the framework of event triggering, this paper discusses a novel integral sliding mode (ISM) anti-disturbance algorithm for a class of nonlinear systems with mismatched disturbances. For the sake of describing more irregular disturbances, T-S fuzzy disturbance models are imported by choosing different basis functions and the corresponding disturbance observer (DO) is then put forward to realize the estimation of unknown disturbances. By utilizing the trigger threshold condition with the estimation information, both the integral sliding surface (ISS) and the event-triggered ISM controller are designed for compensating mismatched disturbances. It is guaranteed that the state trajectories can reach the ISS within a pre-designed finite time. Moreover, not only the system stability, but also the favorable tracking performance and the boundedness of the minimum trigger interval are simultaneously be achieved. Finally, the simulation results of an A4D aircraft model further embody the effective of designed control algorithm.

MicroRNAs (miRNAs) delivered by gastric cancer (GC)-secreted extracellular vesicles (GC-EVs) are associated with the immune escape in GC. Microarray analysis based on the GEO: GSE112369 dataset identified the presence of poorly expressed CXXC finger protein 4 (CXXC4) in GC, which was validated in clinical samples of GC patients. Moreover, prediction based on TargetScan analysis demonstrated the putative miR-675-3p binding site in the 3′ UTR region of CXXC4. Thereby, our study aims to determine the role of GC-EV-encapsulated miR-675-3p in GC. First, CXXC4 was found to be negatively correlated with programmed cell death 1 ligand 1 (PD-L1). The effects of mitogen-activated protein kinase (MAPK) signaling on GC were evaluated using activator of the MAPK pathway. The overexpression of CXXC4 led to a downregulated MAPK signaling pathway, thus decreasing PD-L1 expression to augment the proliferation and activation of T cells co-cultured with GC HGC-27 cells. GC-EV-encapsulated miR-675-3p negatively regulated the expression of its target gene CXXC4. GC-EV-encapsulated miR-675-3p increased PD-L1 expression to stimulate the immune escape in vitro and EV-encapsulated miR-675-3p accelerated cisplatin resistance in vivo. Collectively, the aforementioned findings present a mechanism in which EV-mediated miR-675-3p upregulates PD-L1 expression, promoting immune escape in GC.

Urban river sediments usually serve as a sink for potentially toxic elements (PTEs) during the process of urbanization. A systematic evaluation of human influence, contamination, and risk assessment of PTEs in urban river sediments is essential for sustaining river health. In this study, 24 sediment samples were collected from 5 rivers in Qingdao, a coastal urbanized city in East China. Zinc had the highest concentration (141 ± 134 mg/kg), followed by Cr, Cu, Pb, Ni, Co, As, and Cd. Generally, the PTE concentrations were higher in eastern rivers than those in western rivers affected by intensive industrialization and urbanization. The principal component analysis identified three principal components: natural origins (As, Co, Cr, and Ni), urban activities (Cd, Cu, Pb, and Zn), and atmospheric deposition (Pb), respectively. The excessive concentrations of Cd and Pb were frequently appeared in the sampling sites, with the anthropogenic contribution rates of 8.4%–77% and 6.6%–87%, respectively. Additionally, the river sediments experienced moderate contamination of As, Cd, Cu, Pb, and Zn. Among the PTEs, Cd had moderate ecological risk and others had low risk. The results of Monte Carlo simulation were generally in accordance with the detected contamination and risk levels, except for several elements (Cu and Zn) with huge spatial heterogeneity. According to the Monte Carlo simulation, the river sediments could undergo extremely high contamination and high ecological risk of the PTEs in the worst situation. Thus, it becomes essential that PTEs in the urban rivers should not be overlooked before their discharge into the sea.

Abstract Extrachromosomal DNA (ecDNA), gene-encoding extrachromosomal particles of DNA, is often present in tumor cells. Recent studies have revealed that oncogene amplification via ecDNA is widespread across a diverse range of cancers. ecDNA is involved in increasing tumor heterogeneity, reverting tumor phenotypes, and enhancing gene expression and tumor resistance to chemotherapy, indicating that it plays a significant role in tumorigenesis. In this review, we summarize the characteristics and genesis of ecDNA, connect these characteristics with their concomitant influences on tumorigenesis, enumerate the oncogenes encoded by ecDNA in multiple cancers, elaborate the roles of ecDNA in tumor pathogenesis and progression, and propose the considerable research and therapeutic prospects of ecDNA in cancer.

Abstract Background The monocyte/high-density lipoprotein ratio (MHR) has emerged as a promising alternative biomarker in the fields of cardiovascular disease and atrial fibrillation (AF). This retrospective study was aimed to explore the predictive value of the MHR for the late recurrence of AF after radiofrequency ablation. Methods From April 2015 to October 2018, patients with paroxysmal AF who had undergone radiofrequency catheter ablation at Subei People’s Hospital of Jiangsu Province were enrolled in our study. All the participants were observed until November 2019 after the procedure. During the postoperative follow up, the patients were categorized into the recurrence group and maintenance of sinus rhythm group based on who had experienced AF recurrence. Results One hundred twenty-five patients were diagnosed with paroxysmal AF, with an average age of 61.2 ± 9.3 years. Forty-seven patients had developed late recurrence during a mean follow up of 25.1 ± 12.0 months. The AF recurrence event rates were significantly increased in the highest MHR tertile compared with those in the lowest MHR tertile (22.0% vs. 57.1%; P