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MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB

SIGNAL TRANSDUCTION AND TARGETED THERAPY 2024年第1期9卷 1-19页

作者： Wang, Xiujian Tao, Xiao Chen, Pengjie Jiang, Penglei Li, Wenxiao chang, hefeng Wei, Cong Lai, Xinyi Zhang, Hao Pan, Yihan Ding, Lijuan Liang, Zuyu Cui, Jiazhen Shao, Mi Teng, Xinyi Gu, Tianning Wei, Jieping Kong, Delin Si, Xiaohui Han, Yingli Fu, Huarui Lin, Yu Yu, Jian Li, Xia Wang, Dongrui Hu, Yongxian Qian, Pengxu Huang, He Zhejiang Univ Affiliated Hosp 1 Bone Marrow Transplantat Ctr Sch Med Hangzhou 310003 Peoples R China Zhejiang Univ Med Ctr Liangzhu Lab Liangzhu Lab 1369 West Wenyi Rd Hangzhou 311121 Peoples R China Zhejiang Univ Inst Hematol Hangzhou 310003 Peoples R China Zhejiang Prov Engn Lab Stem Cell & Immun Therapy Hangzhou 310003 Peoples R China Zhejiang Univ Ctr Stem Cell & Regenerat Med Sch Med Hangzhou 310058 Peoples R China Wenzhou Med Univ Affiliated Hosp 3 Dept Hematol Wenzhou 325200 Peoples R China

Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.

关键词： JunB metabolism stimulation

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Interconnections between diabetic corneal neuropathy and diabetic retinopathy:diagnostic and therapeutic implications

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Neural Regeneration Research 2025年第8期20卷 2169-2180页

作者： Mingyi Yu Faith Teo En Ning chang Liu Yu-Chi Liu Tissue Engineering and Stem Cell Group Singapore Eye Research InstituteSingapore Yong Loo Lin School of Medicine National University of SingaporeSingapore Department of Cornea and External Eye Disease Singapore National Eye CenterSingapore Ophthalmology and Visual Sciences Academic Clinical Program Duke-NUS Medical SchoolSingapore

Diabetic corneal neuropathy and diabetic retinopathy are ocular complications occurring in the context of diabetes *** corneal neuropathy refers to the progressive damage of corneal *** retinopathy has traditionally been considered as damage to the retinal ***,growing evidence suggests that diabetic retinopathy is a complex neurovascular disorder resulting from dysfunction of the neurovascular unit,which includes both the retinal vascular structures and neural *** retinopathy is one of the leading causes of blindness and is frequently screened for as part of diabetic ocular ***,diabetic corneal neuropathy is commonly overlooked and underdiagnosed,leading to severe ocular surface *** studies have found that these two conditions tend to occur together,and they share similarities in their pathogenesis pathways,being triggered by a status of chronic *** review aims to discuss the interconnection between diabetic corneal neuropathy and diabetic retinopathy,whether diabetic corneal neuropathy precedes diabetic retinopathy,as well as the relation between the stage of diabetic retinopathy and the severity of corneal *** also endeavor to explore the relevance of a corneal screening in diabetic eyes and the possibility of using corneal nerve measurements to monitor the progression of diabetic retinopathy.

关键词： cornea corneal nerves diabetes diabetic corneal neuropathy diabetic retinopathy retina

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Aligned Ion Conduction Pathway of Polyrotaxane‑Based Electrolyte with Dispersed Hydrophobic Chains for Solid‑State Lithium–Oxygen Batteries

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Nano-Micro Letters 2025年第2期17卷 169-186页

作者： Bitgaram Kim Myeong‑chang Sung Gwang‑Hee Lee Byoungjoon Hwang Sojung Seo Ji‑Hun Seo Dong‑Wan Kim Department of Materials Science and Engineering Korea University145 Anam‑RoSeongbuk‑GuSeoul 02841Republic of Korea School of Civil Environmental and Architectural EngineeringKorea University145 Anam‑RoSeongbuk‑GuSeoul 02841Republic of Korea Materials Science and Chemical Engineering Center Institute for Advanced Engineering(IAE)Yongin 17180Republic of Korea

A critical challenge hindering the practical application of lithium–oxygen batteries(LOBs)is the inevitable problems associated with liquid electrolytes,such as evaporation and safety *** study addresses these problems by proposing a modified polyrotaxane(mPR)-based solid polymer electrolyte(SPE)design that simultaneously mitigates solvent-related problems and improves ***-SPE exhibits high ion conductivity(2.8×10^(−3)S cm^(−1)at 25℃)through aligned ion conduction pathways and provides electrode protection ability through hydrophobic chain *** this mPR-SPE into solid-state LOBs resulted in stable potentials over 300 *** situ Raman spectroscopy reveals the presence of an LiO_(2)intermediate alongside Li_(2)O_(2)during oxygen *** situ X-ray diffraction confirm the ability of the SPE to hinder the permeation of oxygen and moisture,as demonstrated by the air permeability *** present study suggests that maintaining a low residual solvent while achieving high ionic conductivity is crucial for restricting the sub-reactions of solid-state LOBs.

关键词： Solid polymer electrolyte Lithium-oxygen batteries Polyrotaxane ion conductivity Hydrophobic chain

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MXene Hybridized Polymer with Enhanced Electromagnetic Energy Harvest for Sensitized Microwave Actuation and Self‑Powered Motion Sensing

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Nano-Micro Letters 2025年第3期17卷 265-279页

作者： Yu‑Ze Wang Yu‑chang Wang Ting‑Ting Liu Quan‑Liang Zhao Chen‑Sha Li Mao‑Sheng Cao School of Materials Science and Engineering Beijing Institute of TechnologyBeijing 100081People’s Republic of China School of Materials Science and Engineering Peking UniversityBeijing 100871People’s Republic of China School of Mechanical and Material Engineering North China University of TechnologyBeijing 100144People’s Republic of China Key Laboratory of Functional Inorganic Material Chemistry Ministry of Education of the People’s Republic of ChinaHeilongjiang UniversityHarbin 150080People’s Republic of China

Polymeric microwave actuators combining tissue-like softness with programmablemicrowave-responsive deformation hold great promise for mobile intelligentdevices and bionic soft robots. However, their application is challenged by restricted electromagneticsensitivity and intricate sensing coupling. In this study, a sensitized polymericmicrowave actuator is fabricated by hybridizing a liquid crystal polymer with Ti3C2Tx(MXene). Compared to the initial counterpart, the hybrid polymer exhibits unique spacechargepolarization and interfacial polarization, resulting in significant improvements of230% in the dielectric loss factor and 830% in the apparent efficiency of electromagneticenergy harvest. The sensitized microwave actuation demonstrates as the shortenedresponse time of nearly 10 s, which is merely 13% of that for the initial shape memory polymer. Moreover, the ultra-low content of MXene (upto 0.15 wt%) benefits for maintaining the actuation potential of the hybrid polymer. An innovative self-powered sensing prototype that combinesdriving and piezoelectric polymers is developed, which generates real-time electric potential feedback (open-circuit potential of ~ 3 mV) duringactuation. The polarization-dominant energy conversion mechanism observed in the MXene-polymer hybrid structure furnishes a new approachfor developing efficient electromagnetic dissipative structures and shows potential for advancing polymeric electromagnetic intelligent devices.

关键词： Microwave absorption Electromagnetic response Energy harvest Self-sensing Soft actuator

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High‑Entropy Electrode Materials:Synthesis,Properties and Outlook

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Nano-Micro Letters 2025年第1期17卷 472-506页

作者： Dongxiao Li chang Liu Shusheng Tao Jieming Cai Biao Zhong Jie Li Wentao Deng Hongshuai Hou Guoqiang Zou Xiaobo Ji College of Chemistry and Chemical Engineering Central South UniversityChangsha 410083People’s Republic of China School of Chemistry and Chemical Engineering Hunan Institute of EngineeringXiangtan 411104People’s Republic of China

High-entropy materials represent a new category of high-performance materials,first proposed in 2004 and extensively investigated by researchers over the past two *** definition of high-entropy materials has continuously *** the last ten years,the discovery of an increasing number of high-entropy materials has led to significant advancements in their utilization in energy storage,electrocatalysis,and related domains,accompanied by a rise in techniques for fabricating high-entropy electrode ***,the research emphasis has shifted from solely improving the performance of high-entropy materials toward exploring their reaction mechanisms and adopting cleaner preparation ***,the current definition of high-entropy materials remains relatively vague,and the preparation method of high-entropy materials is based on the preparation method of single metal/low-or medium-entropy *** should be noted that not all methods applicable to single metal/low-or medium-entropy materials can be directly applied to high-entropy *** this review,the definition and development of high-entropy materials are briefly ***,the classification of high-entropy electrode materials is presented,followed by a discussion of their applications in energy storage and catalysis from the perspective of synthesis ***,an evaluation of the advantages and disadvantages of various synthesis methods in the production process of different high-entropy materials is provided,along with a proposal for potential future development directions for high-entropy materials.

关键词： High-entropy Energy storage Electrode materials

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Comparative proteomic analysis of plasma exosomes reveals the functional contribution of N-acetyl-alpha-glucosaminidase to Parkinson’s disease

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Neural Regeneration Research 2025年第10期20卷 2998-3012页

作者： Yuan Zhao Yidan Zhang Xin Liu Jian Zhang Ya Gao Shuyue Li Cui chang Xiang Liu Guofeng Yang Department of Geriatrics Second Hospital of Hebei Medical UniversityShijiazhuangHebei ProvinceChina Department of Neurosurgery The Second Hospital of Hebei Medical UniversityShijiazhuangHebei ProvinceChina

Parkinson’s disease is the second most common progressive neurodegenerative disorder,and few reliable biomarkers are available to track disease *** proteins,DNA,mRNA,and lipids carried by exosomes reflect intracellular changes,and thus can serve as biomarkers for a variety of *** this study,we investigated alterations in the protein content of plasma exosomes derived from patients with Parkinson’s disease and the potential therapeutic roles of these proteins in Parkinson’s *** a tandem mass tag-based quantitative proteomics approach,we characterized the proteomes of plasma exosomes derived from individual patients,identified exosomal protein signatures specific to patients with Parkinson’s disease,and identified N-acetyl-alpha-glucosaminidase as a differentially expressed protein.N-acetyl-alpha-glucosaminidase expression levels in exosomes from the plasma of patients and healthy controls were validated by enzyme-linked immunosorbent assay and western *** results demonstrated that the exosomal N-acetyl-alpha-glucosaminidase concentration was not only lower in Parkinson’s disease,but also decreased with increasing Hoehn-Yahr stage,suggesting that N-acetyl-alpha-glucosaminidase could be used to rapidly evaluate Parkinson’s disease ***,western blot and immunohistochemistry analysis showed that N-acetyl-alpha-glucosaminidase levels were markedly reduced both in cells treated with 1-methyl-4-phenylpyridinium and cells overexpressingα-synuclein compared with control ***,N-acetyl-alpha-glucosaminidase overexpression significantly increased cell viability and inhibitedα-synuclein expression in 1-methyl-4-phenylpyridinium-treated *** together,our findings demonstrate for the first time that exosomal N-acetyl-alpha-glucosaminidase may serve as a biomarker for Parkinson’s disease diagnosis,and that N-acetyl-alpha-glucosaminidase may reduceα-synuclein expression and 1-methyl-4-phenylpyridinium-induced n

关键词： biomarker diagnosis exosomes N-acetyl-alpha-glucosaminidase Parkinson’s disease proteomic α-synuclein

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Direct Photolithography of WO_(x)Nanoparticles for High‑Resolution Non‑Emissive Displays

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Nano-Micro Letters 2025年第3期17卷 297-309页

作者： chang Gu Guojian Yang Wenxuan Wang Aiyan Shi Wenjuan Fang Lei Qian Xiaofei Hu Ting Zhang Chaoyu Xiang Yu‑Mo Zhang Laboratory of Optoelectronic Information Technology and Devices Ningbo Institute of Materials Technology and EngineeringChinese Academy of SciencesNingbo 315201People’s Republic of China Hangzhou Bay Laboratory of Advanced Nano‑Optoelectronic Materials and Devices Qianwan Institute of CNITECHNingbo 315336People’s Republic of China Smart Materials for Architecture Research Lab Innovation Center of Yangtze River DeltaZhejiang UniversityJiaxing 314100People’s Republic of China University of Science and Technology of China Hefei 230026People’s Republic of China State Key Lab of Supramolecular Structure and Materials College of ChemistryJilin UniversityChangchun 130012People’s Republic of China

High-resolution non-emissive displays based on electrochromic tungsten oxides(WOx)are crucial for future near-eye virtual/augmented reality interactions,given their impressive attributes such as high environmental stability,ideal outdoor readability,and low energy ***,the limited intrinsic structure of inorganic materials has presented a significant challenge in achieving precise patterning/pixelation at the micron ***,we successfully developed the direct photolithography for WOx nanoparticles based on in situ photo-induced ligand *** strategy enabled us to achieve ultra-high resolution efficiently(line width3600 cycles),as well as promising applications in electronic logos,pixelated displays,flexible electronics,*** success and advancements presented here are expected to inspire and accelerate research and development(R&D)in high-resolution non-emissive displays and other ultra-fine micro-electronics.

关键词： Electrochromic Direct photolithography WOx nanoparticles In situ photo-induced ligand exchange High-resolution displays

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MET receptor tyrosine kinase promotes the generation of functional synapses in adult cortical circuits

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Neural Regeneration Research 2025年第5期20卷 1431-1444页

作者： Yuehua Cui Xiaokuang Ma Jing Wei chang Chen Neha Shakir Hitesch Guirram Zhiyu Dai Trent Anderson Deveroux Ferguson Shenfeng Qiu Basic Medical Sciences University of Arizona College of Medicine-PhoenixPhoenixAZUSA Department of Medicine University of Arizona College of Medicine-PhoenixPhoenixAZUSA

Loss of synapse and functional connectivity in brain circuits is associated with aging and neurodegeneration,however,few molecular mechanisms are known to intrinsically promote synaptogenesis or enhance synapse *** have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine *** investigate whether enhancing MET in adult cortex has synapse regenerating potential,we created a knockin mouse line,in which the human MET gene expression and signaling can be turned on in adult(10–12 months)cortical neurons through doxycycline-containing *** found that similar to the developing brain,turning on MET signaling in the adult cortex activates small GTPases and increases spine density in prefrontal projection *** findings are further corroborated by increased synaptic activity and transient generation of immature silent *** MET signaling resulted in an increasedα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-Daspartate(AMPA/NMDA)receptor current ratio,indicative of enhanced synaptic function and *** data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult *** findings may have implications for regenerative therapy in aging and neurodegeneration conditions.

关键词： aging circuit connectivity cortical circuits molecular mechanisms neural regeneration neurodegeneration synapses

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Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

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Neural Regeneration Research 2025年第5期20卷 1483-1494页

作者： Xihang Chen Zhifeng Chen Menghua Li Weiwei Guo Shuolong Yuan Liangwei Xu chang Lin Xi Shi Wei Chen Shiming Yang Senior Department of Otolaryngology Head and Neck Surgery Chinese PLA General HospitalChinese PLA Medical SchoolBeijingChina State Key Laboratory of Hearing and Balance Science BeijingChina National Clinical Research Center for Otolaryngologic Diseases BeijingChina Key Laboratory of Hearing Science Ministry of EducationBeijingChina Beijing Key Laboratory of Hearing Impairment Prevention and Treatment BeijingChina Department of Otorhinolaryngology Head and Neck Surgery The First Affiliated Hospital of Fujian Medical UniversityFuzhouFujian ProvinceChina Department of Otolaryngology Head and Neck Surgery The 940th Hospital of Joint Logistics Support Force of Chinese PLALanzhouGansu ProvinceChina Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikouHainan ProvinceChina Academician Workstation of Hainan University School of Pharmaceutical SciencesYazhou BaySanyaHainan ProvinceChina

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory ***,there are currently no effective pharmacological interventions for patients with noise-induced hearing ***,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory *** established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 *** found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with *** noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with *** findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell ***,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy *** treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)*** conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing *** findings suggest that inhibiting lysine-specific demethylase 1 is a

关键词： 4-hydroxynonenal apoptosis autophagy cleaved caspase-3 inflammation NOD-like receptor family pyrin domain-containing 3(NLRP3) noise-induced hearing loss oxidative stress Sestrin2 tranylcypromine

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循环加载与卸围压组合扰动下红砂岩损伤破裂与渗透特性

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岩土工程学报 2025年第1期47卷 48-56页

作者：姚玮俞缙周先齐常方强常旭厦门理工学院土木工程与建筑学院福建厦门361024 华侨大学福建省隧道与城市地下空间工程技术研究中心福建厦门361021

为探究深地工程开挖诱导岩体损伤破裂及渗透性演化规律,开展了同步测定波速与渗透率的循环加载与卸围压组合扰动三轴试验,研究了不同条件下红砂岩的损伤与渗透性演化规律。结果表明:①岩石在不同组合扰动阶段具有不同的应力应变曲线形态... 详细信息

为探究深地工程开挖诱导岩体损伤破裂及渗透性演化规律,开展了同步测定波速与渗透率的循环加载与卸围压组合扰动三轴试验,研究了不同条件下红砂岩的损伤与渗透性演化规律。结果表明:①岩石在不同组合扰动阶段具有不同的应力应变曲线形态,其末端形态取决于在何种扰动阶段破坏,初始应力比为决定组合扰动诱发岩石破坏难易的主要因素;②总峰值轴向应变随初始应力比增大而增大,其中组合扰动轴向应变占比始终较低,总峰值体积应变绝对值随初始应力比增大而先增大后减小,其中组合扰动体积应变占比较高;③在初始加载阶段,波速增大,渗透率降低,在组合扰动阶段,波速下降,渗透率增加,且损伤与体积应变近似呈线性关系,损伤与渗透率随扰动次数增加均呈先慢后快的增长趋势,且拐点分别近似在一条直线上;④岩石在组合扰动卸围压阶段破坏为单剪切破坏模式,在组合扰动循环加载阶段破坏为共轭剪切破坏模式;⑤双高(高初始应力比与高初始围压)条件将显著加剧岩体开挖失稳破坏风险。

关键词：深地工程组合扰动力学特性损伤渗透性

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