Research最新文献_第7页

Youthful Brain-Derived Extracellular Vesicle-Loaded GelMA Hydrogel Promotes Scarless Wound Healing in Aged Skin by Modulating Senescence and Mitochondrial Function. 年轻的脑源性细胞外囊泡装载GelMA水凝胶通过调节衰老和线粒体功能促进衰老皮肤无疤痕伤口愈合。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-28 eCollection Date: 2025-01-01 DOI: 10.34133/research.0644

Yuzhu Wu, Jiajie Mao, Yanyan Zhou, Gaoying Hong, Haiyan Wu, Zihe Hu, Xiaoyuan Huang, Jue Shi, Zhijian Xie, Yanhua Lan

{"title":"Youthful Brain-Derived Extracellular Vesicle-Loaded GelMA Hydrogel Promotes Scarless Wound Healing in Aged Skin by Modulating Senescence and Mitochondrial Function.","authors":"Yuzhu Wu, Jiajie Mao, Yanyan Zhou, Gaoying Hong, Haiyan Wu, Zihe Hu, Xiaoyuan Huang, Jue Shi, Zhijian Xie, Yanhua Lan","doi":"10.34133/research.0644","DOIUrl":"10.34133/research.0644","url":null,"abstract":"Slow wound healing in the elderly has attracted much attention recently due to the associated infection risks and decreased longevity. The \"brain-skin axis\" theory suggests that abnormalities in the brain and nervous system can lead to skin degeneration because abnormal mental states, like chronic stress, can have negative physiological and functional effects on the skin through a variety of processes, resulting in delayed wound healing and accelerated skin aging. However, it remains unclear whether maintaining a youthful brain has beneficial effects on aged skin healing. In light of this, we identified youthful brain-derived extracellular vesicles (YBEVs) and created a composite GelMA hydrogel material that encourages scarless wound healing in aged skin. We found that YBEVs reduce the expression of senescence, senescence-associated secretory phenotypes, and inflammation-associated proteins, and even restore dysfunction in senescent cells. Furthermore, by encouraging collagen deposition, angiogenesis, epidermal and dermal regeneration, and folliculogenesis, we demonstrated that YBEV-containing composite hydrogels accelerated scarless wound healing in skin wounds of aged rats. The pro-repairing speed and effect of this composite hydrogel even matched that of young rats. Subsequent proteomic analysis revealed the presence of numerous proteins within YBEVs, some of which may play a role in the regulation of skin energy intake, particularly through oxidative phosphorylation and mitochondrial function. In conclusion, the findings suggest that maintaining a youthful brain could potentially alleviate skin aging, and the proposed YBEVs-GelMA hydrogel emerges as a promising strategy for addressing age-related impairments in skin healing.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0644"},"PeriodicalIF":11.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754422","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}

引用次数: 0

Transport of Volatiles in Agglutinates from Lunar Regolith of Chang'e-5 Mission. 嫦娥五号月球风化层中凝集物挥发物的输运。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-27 eCollection Date: 2025-01-01 DOI: 10.34133/research.0638

Long Li, Guang Zhang, Hui Zhang, Yuan Xiao, Shaofan Zhao, Jian Song, Wei Yao, Weihua Wang, Zhigang Zou, Mengfei Yang

{"title":"Transport of Volatiles in Agglutinates from Lunar Regolith of Chang'e-5 Mission.","authors":"Long Li, Guang Zhang, Hui Zhang, Yuan Xiao, Shaofan Zhao, Jian Song, Wei Yao, Weihua Wang, Zhigang Zou, Mengfei Yang","doi":"10.34133/research.0638","DOIUrl":"10.34133/research.0638","url":null,"abstract":"Agglutinate particles, an important component resulting from micrometeoroids impacts, account for about 13.4% to 84.7% of the volume of lunar regolith depending on its maturity. They are crucial in the soil's evolution and the migration of volatile substances. Here, we examined a representative agglutinate particle from Chang'e-5 samples and modeled how volatiles move through its porous framework. Our analysis revealed that the agglutinate's surface features a patchy distribution of smooth, open pores, as shown by both surface and 3-dimensional structural assessments. By integrating elemental distribution data, we propose that the formation of these smooth, open pores is primarily due to the flow of gaseous volatiles, byproducts of intricate physiochemical reactions occurring in the lunar surface layer during impacts by micrometeoroids. Numerical models of volatile transport in the porous agglutinate have been developed for different flow regimes. These models demonstrate that under the intense conditions of impacts, the transport of volatiles occurs at a remarkably high velocity. Consequently, it is improbable that water would accumulate within the porous structure of lunar soil agglutinates. Nevertheless, understanding this process is valuable for gaining a deeper understanding of the lunar regolith's development and for potential future endeavors in extracting water from the lunar surface.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0638"},"PeriodicalIF":11.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731153","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}

引用次数: 0

When Large Language Models Meet Evolutionary Algorithms: Potential Enhancements and Challenges. 当大型语言模型遇到进化算法：潜在的增强和挑战。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-27 eCollection Date: 2025-01-01 DOI: 10.34133/research.0646

Chao Wang, Jiaxuan Zhao, Licheng Jiao, Lingling Li, Fang Liu, Shuyuan Yang

{"title":"When Large Language Models Meet Evolutionary Algorithms: Potential Enhancements and Challenges.","authors":"Chao Wang, Jiaxuan Zhao, Licheng Jiao, Lingling Li, Fang Liu, Shuyuan Yang","doi":"10.34133/research.0646","DOIUrl":"10.34133/research.0646","url":null,"abstract":"Pre-trained large language models (LLMs) exhibit powerful capabilities for generating natural text. Evolutionary algorithms (EAs) can discover diverse solutions to complex real-world problems. Motivated by the common collective and directionality of text generation and evolution, this paper first illustrates the conceptual parallels between LLMs and EAs at a micro level, which includes multiple one-to-one key characteristics: token representation and individual representation, position encoding and fitness shaping, position embedding and selection, Transformers block and reproduction, and model training and parameter adaptation. These parallels highlight potential opportunities for technical advancements in both LLMs and EAs. Subsequently, we analyze existing interdisciplinary research from a macro perspective to uncover critical challenges, with a particular focus on evolutionary fine-tuning and LLM-enhanced EAs. These analyses not only provide insights into the evolutionary mechanisms behind LLMs but also offer potential directions for enhancing the capabilities of artificial agents.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0646"},"PeriodicalIF":11.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731265","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}

引用次数: 0

Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice. 人类和小鼠中APBB1通过与KAT5和GDF15的相互作用对精原干细胞命运决定和男性生育能力的基本调控

IF 11 1区综合性期刊

Research Pub Date : 2025-03-27 eCollection Date: 2025-01-01 DOI: 10.34133/research.0647

Dai Zhou, Bang Liu, Lvjun Liu, Guangmin Liu, Fang Zhu, Zenghui Huang, Shusheng Zhang, Zuping He, Liqing Fan

{"title":"Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice.","authors":"Dai Zhou, Bang Liu, Lvjun Liu, Guangmin Liu, Fang Zhu, Zenghui Huang, Shusheng Zhang, Zuping He, Liqing Fan","doi":"10.34133/research.0647","DOIUrl":"10.34133/research.0647","url":null,"abstract":"Spermatogonial stem cells (SSCs) are essential for initiating and maintaining normal spermatogenesis, and notably, they have important applications in both reproduction and regenerative medicine. Nevertheless, the molecular mechanisms controlling the fate determinations of human SSCs remain elusive. In this study, we identified a selective expression of APBB1 in dormant human SSCs. We demonstrated for the first time that APBB1 interacted with KAT5, which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation. Intriguingly, Apbb1-/- mice assumed the disrupted spermatogenesis and markedly reduced fertility. SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation, which resulted in the impaired spermatogenesis. Notably, 4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia (NOA), and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1-/- mice. Additionally, we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis. Collectively, our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0647"},"PeriodicalIF":11.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731151","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}

引用次数: 0

High-Performance Room-Temperature Terahertz Photodetection Using 2-Dimensional Electron Gas Channel Transport. 利用二维电子气通道输运的高性能室温太赫兹光探测。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-26 eCollection Date: 2025-01-01 DOI: 10.34133/research.0656

Mengjuan Liu, Yongzhen Li, Ziyang Ren, Yao Wang, Haiming Zhu, Qinxi Qiu, Nasir Ali, He Zhu, Jiaqi Zhu, Weien Lai, Zhiming Huang, Huizhen Wu

{"title":"High-Performance Room-Temperature Terahertz Photodetection Using 2-Dimensional Electron Gas Channel Transport.","authors":"Mengjuan Liu, Yongzhen Li, Ziyang Ren, Yao Wang, Haiming Zhu, Qinxi Qiu, Nasir Ali, He Zhu, Jiaqi Zhu, Weien Lai, Zhiming Huang, Huizhen Wu","doi":"10.34133/research.0656","DOIUrl":"10.34133/research.0656","url":null,"abstract":"Room-temperature (RT) terahertz (THz) detection finds widespread applications in security inspection, communication, biomedical imaging, and scientific research. However, the state-of-the-art detection strategies are still limited by issues such as low sensitivity, narrow response range, slow response speed, complex fabrication techniques, and difficulties in scaling up to large arrays. Here, we present a high-sensitivity, broadband-response, and high-speed RT THz detection strategy by utilizing a deep subwavelength metal-semiconductor-metal (MSM) structure. The spontaneously formed 2-dimensional electron gas (2DEG) at the CdTe/PbTe interface provides a superior transport channel characterized by high carrier concentration, low scattering, and high mobility. The synergy of the electromagnetic induced well effect formed in the MSM structure, and the efficient and rapid transport capabilities of the 2DEG channel give rise to an impressive performance improvement. The proposed 2DEG photodetector exhibits a broad frequency range from 22 to 519 GHz, an ultralow noise equivalent power of 3.0 × 10-14 W Hz-1/2 at 166 GHz, and a short response time of 6.7 μs. This work provides an effective route for the development of high-performance RT THz detection strategies, paving the way for enhanced THz technology applications.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0656"},"PeriodicalIF":11.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721185","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}

引用次数: 0

Precision Microbiome: A New Era of Targeted Therapy with Core Probiotics. 精密微生物组：核心益生菌靶向治疗的新时代。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-26 eCollection Date: 2025-01-01 DOI: 10.34133/research.0658

Xiuyu Fang, Yuhao Wang, Hong Wei, Yuan Huang

引用次数: 0

Dynamic Tumor Immunology-on-a-Chip for Peripheral Blood-Derived Tumor-Reactive T Cell Expansion. 动态肿瘤免疫芯片用于外周血源性肿瘤反应性T细胞扩增。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-21 eCollection Date: 2025-01-01 DOI: 10.34133/research.0639

Xin Shou, Yunru Yu, Dan Wu, Peihua Lu, Miaoqing Zhao, Yuanjin Zhao

{"title":"Dynamic Tumor Immunology-on-a-Chip for Peripheral Blood-Derived Tumor-Reactive T Cell Expansion.","authors":"Xin Shou, Yunru Yu, Dan Wu, Peihua Lu, Miaoqing Zhao, Yuanjin Zhao","doi":"10.34133/research.0639","DOIUrl":"10.34133/research.0639","url":null,"abstract":"Adoptive T cell therapy has shown great promise in the treatment of solid tumors, which, however, poses a great challenge to obtain autologous tumor-reactive T cells in a cost-effective manner. Here, we present a dynamic tumor immunology-on-a-chip, mimicking immune responses, for achieving the enrichment and expansion of tumor-reactive T cells. Tumor spheroids with uniform size can be generated by seeding tumor cells in hydrogel-embedded micropillar arrays, and could be trapped upon removal of hydrogel. Then, T cells were infused and fully contacted with these tumor spheroids under biomimetic flow conditions provided by herringbone-patterned microgrooves arrays. We found that the tamed tumor-reactive T cells could be fully activated and a rapid clonal proliferation was realized during the cultivation. In addition, these tumor-reactive T cells exhibited a specific and powerful tumor-killing capability in vitro. Thus, the suggested dynamic microfluidic chips with staged structure-transformable properties realize both the producible formation of tumor spheroids and the recapitulation of tumor-immune crosstalk to expand tumor-reactive T cells. These features indicate that the dynamic and reproducible tumor immunology-on-a-chip has potential in the preparation of therapeutic T cell products for clinical cancer immunotherapy.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0639"},"PeriodicalIF":11.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693130","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}

引用次数: 0

Upcycling of Degraded Prussian Blue into Layered Materials for Sodium-Ion Battery. 降解普鲁士蓝升级回收制备钠离子电池层状材料。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-21 eCollection Date: 2025-01-01 DOI: 10.34133/research.0643

Weng-Lam Wong, Jiahui Xu, Yun Zhao, Yadong Wang, Hao Du, Junhao Zhang, Yuqiong Kang, Yuqing Chen, Feiyu Kang, Baohua Li

{"title":"Upcycling of Degraded Prussian Blue into Layered Materials for Sodium-Ion Battery.","authors":"Weng-Lam Wong, Jiahui Xu, Yun Zhao, Yadong Wang, Hao Du, Junhao Zhang, Yuqiong Kang, Yuqing Chen, Feiyu Kang, Baohua Li","doi":"10.34133/research.0643","DOIUrl":"10.34133/research.0643","url":null,"abstract":"Prussian blue and Prussian blue analogs are widely used in sodium-ion batteries (SIBs). In this study, we upcycle the degraded Prussian blue directly into layered materials for SIBs through thermal treatment. Prussian blue thermally decomposes to form metal oxides, which then recrystallize into layered metal oxides with metal-nitrogen bond on their surface under suitable temperature conditions. This transformation method is similar to solid-state synthesis, allowing for the pre-addition of necessary components before material conversion to optimize the composition and integrity of the target materials. Based on in situ x-ray diffraction observations of the crystal structure changes of Prussian blue at different temperatures, we demonstrate 1,000 °C as the optimal temperature for converting to layered materials. These materials exhibit an initial discharge capacity of 122.3 mAh g-1 and good rate and cycling stability. We hope that this research will promote the sustainable development of the SIB industry.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0643"},"PeriodicalIF":11.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693131","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}

引用次数: 0

Altered Gut Microbiota Contributes to Acute-Respiratory-Distress-Syndrome-Related Depression through Microglial Neuroinflammation. 肠道菌群改变通过小胶质神经炎症导致急性呼吸窘迫综合征相关抑郁

IF 11 1区综合性期刊

Research Pub Date : 2025-03-19 eCollection Date: 2025-01-01 DOI: 10.34133/research.0636

Bowen Zhu, Zheng Gu, Hongbin Hu, Jie Huang, Zhenhua Zeng, Haoxuan Liang, Ziyi Yuan, Shiwei Huang, Yuetan Qiu, Xiang-Dong Sun, Youtan Liu

{"title":"Altered Gut Microbiota Contributes to Acute-Respiratory-Distress-Syndrome-Related Depression through Microglial Neuroinflammation.","authors":"Bowen Zhu, Zheng Gu, Hongbin Hu, Jie Huang, Zhenhua Zeng, Haoxuan Liang, Ziyi Yuan, Shiwei Huang, Yuetan Qiu, Xiang-Dong Sun, Youtan Liu","doi":"10.34133/research.0636","DOIUrl":"10.34133/research.0636","url":null,"abstract":"Acute respiratory distress syndrome (ARDS) survivors often suffer from long-term psychiatric disorders such as depression, but the underlying mechanisms remain unclear. Here, we found marked alterations in the composition of gut microbiota in both ARDS patients and mouse models. We investigated the role of one of the dramatically changed bacteria-Akkermansia muciniphila (AKK), whose abundance was negatively correlated with depression phenotypes in both ARDS patients and ARDS mouse models. Specifically, while fecal transplantation from ARDS patients into naive mice led to depressive-like behaviors, microglial activation, and intestinal barrier destruction, colonization of AKK or oral administration of its metabolite-propionic acid-alleviated these deficits in ARDS mice. Mechanistically, AKK and propionic acid decreased microglial activation and neuronal inflammation through inhibiting the Toll-like receptor 4/nuclear factor κB signaling pathway. Together, these results reveal a microbiota-dependent mechanism for ARDS-related depression and provide insight for developing a novel preventative strategy for ARDS-related psychiatric symptoms.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0636"},"PeriodicalIF":11.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664394","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}

引用次数: 0

Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism. Notch2信号通过抑制嘌呤核苷酸代谢驱动心肌肥厚。

IF 11 1区综合性期刊

Research Pub Date : 2025-03-18 eCollection Date: 2025-01-01 DOI: 10.34133/research.0635

Yuhong Wang, Yizhe Li, Shihong Chen, Tingting Yu, Weiyan Sun, Jiao Liu, Huiwen Ren, Yao Zhou, Lu Wang, Xixi Tao, Ronglu Du, Wenlong Shang, Yinxiu Li, Danyang Tian, Bei Wang, Yujun Shen, Qian Liu, Ying Yu

{"title":"Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide Metabolism.","authors":"Yuhong Wang, Yizhe Li, Shihong Chen, Tingting Yu, Weiyan Sun, Jiao Liu, Huiwen Ren, Yao Zhou, Lu Wang, Xixi Tao, Ronglu Du, Wenlong Shang, Yinxiu Li, Danyang Tian, Bei Wang, Yujun Shen, Qian Liu, Ying Yu","doi":"10.34133/research.0635","DOIUrl":"10.34133/research.0635","url":null,"abstract":"Gain-of-function mutations of Notch2 cause the rare autosomal dominant disorder known as Hajdu-Cheney syndrome (HCS). Most patients with HCS develop congenital heart disease; however, the precise mechanisms remain elusive. Here, a murine model expressing the human Notch2 intracellular domain (hN2ICD) in cardiomyocytes (hN2ICD-TgCM) was generated and the mice spontaneously developed ventricular diastolic dysfunction with preserved ejection fraction and cardiac hypertrophy. Ectopic hN2ICD expression promoted cardiomyocyte hypertrophy by suppressing adenylosuccinate lyase (ADSL)-mediated adenosine 5'-monophosphate (AMP) generation, which further enhanced the activation of the mammalian target of rapamycin complex 1 pathway by reducing AMP-activated kinase activity. Hairy and enhancer of split 1 silencing abrogated hN2ICD-induced cardiomyocyte hypertrophy by increasing Adsl transcription. Importantly, pharmacological activation of AMP-activated kinase ameliorated cardiac hypertrophy and dysfunction in hN2ICD-TgCM mice. The frameshift mutation in Notch2 exon 34 (c.6426dupT), which causes early-onset HCS, induces AC16 human cardiomyocyte hypertrophy through suppressing ADSL-mediated AMP generation. Thus, targeting Notch2-mediated purine nucleotide metabolism may be an attractive therapeutic approach to heart failure treatment.","PeriodicalId":21120,"journal":{"name":"Research","volume":"8 ","pages":"0635"},"PeriodicalIF":11.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658479","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}

引用次数: 0