Research最新文献

{"title":"New Insights into Monocyte-Derived Macrophages in Glioblastoma.","authors":"Xuetong Li, Wei Gao, Xinmiao Long, Minghua Wu","doi":"10.34133/research.0836","DOIUrl":"10.34133/research.0836","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly aggressive brain tumor characterized by an immunosuppressive microenvironment that importantly contributes to treatment resistance. Monocyte-derived macrophages (MDMs), which comprise approximately 50% of the cellular population within the GBM microenvironment, represent a major subset of tumor-associated macrophages. These cells drive tumor progression by promoting angiogenesis, immune evasion, and the phenotypic transformation of tumor cells. MDM infiltration is mediated by specific signaling pathways and regulated by the disruption of the blood-brain barrier and tumor-associated hypoxia. Recent technological advances have uncovered substantial heterogeneity among macrophages, including hypoxia-induced, lipid-metabolizing, phagocytic, and interferon-activated subtypes. This functional diversity is shaped by tumor-specific genetic alterations and metabolic reprogramming. Therapeutic approaches focusing on MDMs include inhibiting their recruitment, enhancing phagocytic activity, employing genetically engineered macrophage, and modulating metabolic pathways. While preclinical studies suggest that these approaches may improve efficacy when combined with immune checkpoint inhibitors, the dynamic spatiotemporal heterogeneity and adaptability of macrophages within the tumor microenvironment remain substantial therapeutic challenges. Future development in combination therapies, integrating single-cell multi-omics, spatial metabolic profiling, and targeted interventions, will be critical to precisely modulate MDMs, overcome immune tolerance, and improve patient outcomes.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0836"},"PeriodicalIF":10.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In Situ</i>: Microbial Aerodynamic Microneedles for Targeted Drug Delivery Systems.","authors":"Chenyu Zong, Fei Wang, Wenguo Cui","doi":"10.34133/research.0775","DOIUrl":"10.34133/research.0775","url":null,"abstract":"<p><p><i>In situ</i> microbial aerodynamic microneedles (MM-MNs) represent an autonomous transdermal drug delivery platform that utilizes the gas generated by microbial metabolism (e.g., H₂, NO, and H₂S) to propel drugs into deep tissues, surpassing the penetration limits of traditional microneedles reliant on external stimuli (heat/light/mechanical force). By leveraging controlled microbial metabolism, MM-MNs enable energy-independent, spatiotemporally precise delivery with enhanced targeting and bioavailability. Gas-driven propulsion combines with bioactive gas functions (e.g., NO-induced vasodilation and H₂S-mediated anti-inflammation) to modulate disease microenvironments. The system's biocompatibility (probiotic strains and <i>Lactobacillus</i>) and scalability (cost-effective patch design) further support its potential for localized therapies (skin diseases and tumors) with minimized systemic exposure. This innovation bridges microbial biotechnology and precision medicine, offering a paradigm shift in transdermal delivery.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0775"},"PeriodicalIF":10.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection.","authors":"Tao Yu, Xiaolu Li, Chao Wang, Yanyan Yang, Xiuxiu Fu, Tianxiang Li, Wentao Wang, Xiangyu Liu, Xiaoxin Jiang, Ding Wei, Jian-Xun Wang","doi":"10.34133/research.0799","DOIUrl":"10.34133/research.0799","url":null,"abstract":"<p><p>Aortic dissection (AD) is a cardiovascular disorder with a high mortality rate. Lysine Lactylation (Kla), a novel posttranslational modification, critically regulates inflammation, tumors, and cardiovascular diseases. However, its specific role in AD pathogenesis remains unexplored. Using modification omics, we conducted a macroscopic analysis of the occurrence of extensive lactylation modification in aortic dissection and identified extensive lactylation, particularly in the adenosine triphosphatase activity pathway. Among these proteins, adenosine triphosphate (ATP) synthase F1 subunit α (ATP5F1A), a subunit in the ATP synthase complex, exhibited pronounced lactylation at the K531, catalyzed by sirtuin 3 (Sirt3). Through site-directed mutagenesis (K531R/K531E), we validated the key mechanism of lactylation activation at the K531 site of ATP5F1A and the regulatory enzymes. Functionally, K531 lactylation impairs ATP synthase activity, elevates reactive oxygen species generation, reduces ATP generation, and induces mitochondrial structural abnormalities. These effects ultimately contribute to the phenotypic transformation of human aortic vascular smooth muscle cells and enhanced synthesis and secretion of matrix metalloproteinases. In addition, we assessed the potential therapeutic effect of lactylation inhibition in aortic dissection using a mouse model and a drug based in vivo lactate alteration strategy. In conclusion, targeting the lactate-Sirt3-ATP5F1A axis represents a promising therapeutic strategy for blocking the progression of aortic dissection.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0799"},"PeriodicalIF":10.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significant but Overlooked: Atmospheric HONO Formation from Surface Ammonium Oxidation with Superoxide Radicals.","authors":"Hong Wang, Zehui Hu, Shujun Liu, Xin Zhang, Meijia Jiang, Yanjuan Sun, Fan Dong","doi":"10.34133/research.0819","DOIUrl":"10.34133/research.0819","url":null,"abstract":"<p><p>Resolving the sources of HONO formation is an indispensable aspect in understanding the enhancement of atmospheric oxidation. However, the contributing sources of high HONO formation rate remain unclear during humid haze episodes. The photochemical conversion of surface nitrate (NO₃ ^-), considered as the dominant contributor to the daytime HONO generation, exhibits severe constraint under high relative humidity (RH) conditions. Unexpectedly, ammonium (NH₄ ⁺) on the surface of photoactive mineral dust shows a gradual acceleration of HONO generation with increasing RH under simulated solar irradiation, especially at high RH. This reversed observation stems from a change in the photochemical pathway for the HONO formation from NO₃ ^- and NH₄ ⁺. The photochemical conversion of surface NO₃ ^- is determined by photogenerated electrons (NO₃ ^-→NO₂→NO₂ ^-→HONO), while the superoxide radical (∙O₂ ^-) generated during photochemical reaction drives the surface NH₄ ⁺ to directly form HONO with the pathway (NH₄ ⁺∙+∙O₂ ^-→NO₂ ^- + H₂O→HONO). Under high RH conditions, oxygen molecules (O₂) have greatly better access to photogenerated electrons than NO₂, resulting in an interruption of the procedure from NO₂ to NO₂ ^- during NO₃ ^- conversion. Therefore, the favorably generated ∙O₂ ^- fuels the photochemical conversion of surface NH₄ ⁺ while inhibiting the conversion of NO₃ ^- to diurnal HONO formation. This work highlights the overlooked contribution of HONO formation from NH₄ ⁺, especially under high RH conditions, and advances the understanding of a renewed role for O₂ in atmospheric chemical processes.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0819"},"PeriodicalIF":10.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Speech-Controlled Reconfigurable Intelligent Metasurface for Real-Time Wireless Power Transfer and Communication.","authors":"Lin Dong, Liming Si, Yueze Liu, Qitao Shen, Pengcheng Tang, Genhao Wu, Rong Niu, Qingqing Wu, Weiren Zhu","doi":"10.34133/research.0831","DOIUrl":"10.34133/research.0831","url":null,"abstract":"<p><p>As the Internet of Things (IoT) continues to evolve, a growing number of wireless sensors have been integrated into daily life, posing new challenges to energy supply and communication. Point-to-point dynamic wireless power transfer and communication, enabled by user-based positioning and tracking services, hold great potential in the IoT. Here, we propose a speech-controlled reconfigurable intelligent metasurface (RIS) that translates natural-language commands into dynamically shaped electromagnetic beams by combining speech interaction, low-power RIS control, and a template matching algorithm, supporting real-time data communication and wireless power transfer for both static and moving targets. Unlike conventional RISs that rely on pre-defined control and external processing units, our approach provides the metasurface with visual and linguistic perception capabilities, enabling a paradigm shift from passive reconfiguration to active multimodal intelligence. The experimental results confirm the effectiveness of the speech-controlled RIS, while the measured results demonstrate that the RIS can provide a stable dc output that exceeds 4.61 V on dynamic targets. By enabling intuitive human-device interaction and effectively meeting the power supply requirements of small sensors, the proposed concept demonstrates strong application potential in IoT scenarios.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0831"},"PeriodicalIF":10.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcranial High-Frequency Terahertz Stimulation Alleviates Anxiety-like Behavior in Mice via a Noninvasive Approach.","authors":"Pan Wang, Chaoyang Tan, Wenyu Peng, Zekun Yan, Wenrui Jiang, Han Zhao, Huaxing Si, Jingchen Jia, Chunkui Zhang, Jian Wang, Yuchen Tian, Kun Chen, Yuefan Yang, Zhenyu Wu, Kangning Xie, Yuanming Wu, Mingming Zhang, Tao Chen","doi":"10.34133/research.0766","DOIUrl":"10.34133/research.0766","url":null,"abstract":"<p><p>Terahertz waves, positioned between infrared and microwave frequencies, have important potential in various fields, but their potential for in vivo biomedical applications has mostly remained untapped. In the present study, we focused on testing the potential of noninvasive high-frequency terahertz stimulation (HFTS) as a treatment for anxiety in mice. Mice were subjected to acute restraint stress to induce anxiety and then clustered into anxiety-susceptible and anxiety-resilient groups using the <i>K</i>-means algorithm. We developed an anxiety phenotype prediction classifier utilizing the naïve Bayes algorithm to accurately categorize mice. Noninvasive HFTS was targeted at the anterior cingulate cortex across the skulls of anxiety-susceptible mice, resulting in a marked anxiolytic effect. The underlying mechanism of HFTS's anxiolytic effect was subsequently elucidated through in vivo and in vitro electrophysiological and morphological methods, revealing that HFTS decreases the excitability of pyramidal neurons in the anterior cingulate cortex by enhancing voltage-gated K⁺ channel and leak K⁺ channel conductance. The study not only expands the potential applications of HFTS, particularly its noninvasive use, in the regulation of anxiety-like disorders but also introduces innovative methodologies and insights that have the potential to lay the groundwork for future research in the field of physical biomedicine.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0766"},"PeriodicalIF":10.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Amniotic Epithelial Stem Cell Exosomes Regulate Chondrocyte Ferroptosis through ACTA2-AS1-Targeted Binding to ACSL4 for Osteoarthritis Intervention.","authors":"Xiaofei Wang, Zhimin Wu, Lei Xu, Linbing Lou, Yuxia Yang, Jian Zhang, Haixiang Miao, Cunyi Xia, Zhiwei Peng, Dongsheng Yang, Zhiwen Tao, Xiangji Meng, Wenkang Liu, Meijuan Yuan, Jingcheng Wang, Wenyong Fei, Jihang Dai","doi":"10.34133/research.0814","DOIUrl":"10.34133/research.0814","url":null,"abstract":"<p><p>The inhibition of ferroptosis, a widespread form of nonapoptotic cell death, is considered a promising therapeutic approach for osteoarthritis (OA). Human amniotic epithelial stem cells (hAESCs) maintain multipotent differentiation potential, no tumorigenicity, low immunogenicity, and anti-inflammatory properties, rendering them highly biocompatible stem cells. Exosomes (Exo) are vesicular carriers for intercellular communication that participate importantly in regulating disease progression through paracrine signaling. In our study, under inflammatory stress conditions, actin alpha 2, smooth muscle antisense RNA1 (ACTA2-AS1) transcription was up-regulated in hAESCs, further delivered to chondrocytes via hAESC-derived Exo. Subsequently, ACTA2-AS1 could suppress ferroptosis in chondrocytes by facilitating the degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), a key regulator of ferroptosis, thereby modulating the progression of OA. In conclusion, for the first time, this study demonstrates the modulatory role of hAESC ACSL4 expression by releasing ACTA2-AS1-enriched Exo, leading to inhibited ferroptosis in chondrocytes and ultimately ameliorating OA progression. Thus, targeting Exo-mediated communication may offer novel therapeutic approaches for addressing OA linked to iron metabolism irregularities.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0814"},"PeriodicalIF":10.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering Mitochondria: Unveiling Their Roles in Mechanosensing and Mechanotransduction.","authors":"Jiaxuan Yu, Ye Huang, Yujie Qin, Jingfei Zhu, Tian Zhao, Hao Wu, Xi Ye, Xiang Qin, Shun Li, Yungchang Chen, Yiyao Liu, Tingting Li","doi":"10.34133/research.0816","DOIUrl":"10.34133/research.0816","url":null,"abstract":"<p><p>Mitochondria are highly dynamic organelles that are responsible for essential cellular functions such as calcium regulation, reactive oxygen species (ROS) production, metabolism, and apoptosis initiation. Mitochondrial dysfunctions are associated with a variety of pathologies, and the onset and progression of disease are accompanied by alterations in extracellular biochemical and mechanical signals. Recent studies have demonstrated that physicochemical cues, especially mechanical cues, exert pivotal roles in the organization of mitochondrial network and their metabolic functions. Therefore, understanding the mechanisms that orchestrate mitochondrial morphology and function is essential for elucidating their role in both health and disease. This review discusses novel insights into the recent advances regarding mitochondrial dysfunction across a spectrum of diseases and describes the effect of various factors. It then highlights the recently discovered mechanisms, particularly those involving matrix mechanical cues and cellular mechanical cues, summarizing the multiple pathways of mechanotransduction, such as integrin, Piezo1/TRPV4, and YAP/TAZ signaling pathways. Last, the review explores the potential future directions, stressing that understanding mitochondrial dysfunction is crucial for developing effective therapies to improve mitochondrial function and address related diseases.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0816"},"PeriodicalIF":10.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extrachromosomal Circular DNA MIRECD Enhances Necroptosis and Predicts Prognosis of Myocardial Infarction.","authors":"Yiheng Zhao, Yujia Zhou, Shuchen Zhang, Boyang Xiang, Xiang Zhou","doi":"10.34133/research.0803","DOIUrl":"10.34133/research.0803","url":null,"abstract":"<p><p>Recent researches have revealed the potential utility of extrachromosomal circular DNAs (eccDNAs) as biomarkers in various diseases. However, the association between plasma eccDNAs and myocardial infarction (MI) remains unclear. In this study, we extracted plasma eccDNA from blood samples of individuals with acute MI and conducted Circle-Seq. We identified an MI-related eccDNA (MIRECD) with high expression levels in the plasma of patients with MI. Sanger sequencing validated its loop construction and sequence. Mechanistically, MIRECD could aggravate necroptosis via regulating the expression of mixed-lineage-kinase-domain-like pseudokinase (MLKL). Kaplan-Meier analysis demonstrated that the incidences of major adverse cardiac events (MACEs) and cardiovascular mortality were higher in individuals with elevated MIRECD levels. Univariate and multivariate Cox regression analyses indicated that MIRECD independently predicted the occurrence of MACEs in patients with MI. The addition of MIRECD enhanced the discrimination and reclassification ability compared with conventional risk factors. In conclusion, our study identified a novel eccDNA, MIRECD, which might regulate myocardial necroptosis through MLKL. MIRECD has the potential to serve as a reliable indicator for predicting the prognosis and stratifying the risk of MI.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0803"},"PeriodicalIF":10.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Inspired Lineage-Specific Matrix for Endogenous Neurogenesis in Spinal Cord Injury.","authors":"Bo Wu, Xuejiao Lei, Xufang Ru, Jiangling Zhou, Hao Liu, Yibo Gan, Yan Wang, Wenyan Li","doi":"10.34133/research.0821","DOIUrl":"10.34133/research.0821","url":null,"abstract":"<p><p>Spinal cord injury (SCI) poses substantial challenges, often leading to permanent disability and requiring adequate neuronal regeneration for functional repair. Decellularized spinal cord (DSC) matrices hold promise due to their native 3-dimensional (3D) structure and extracellular matrix (ECM)-derived biochemical components. However, their limited mechanical properties and insufficient availability of growth factors hinder their effectiveness. To address these limitations, this study introduces a core-shell design that reinforces DSC with a hydrogel-based matrix capable of delivering essential growth factors while preserving its natural structure. By leveraging 3D printing and electrostatic adsorption, the engineered matrix retains the topological features of DSC while introducing new topographical and neurogenic cues. These instructive cues facilitated an 11-fold increase in the number of newly generated neuronal cells, demonstrating lineage-specific neuronal regeneration in vivo. Mechanistically, the synergistic effects of ECM-inspired structure and biochemical cues activated the ITGA2/ITGA11-ERK/AKT signaling axis and promoted M2 macrophage/microglia polarization, thereby reducing cavity and scar formation. This optimized microenvironment enhanced endogenous neurogenesis and supported functional recovery after SCI. Overall, this study developed a structure-inspired lineage-specific matrix that effectively stimulates endogenous neuronal regeneration, highlighting its potential for advancing spinal cord repair strategies.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0821"},"PeriodicalIF":10.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}