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phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1204-1221页

作者： Xiaohui Chen Meichun Gao Yongzhen Xia Xin Wang Jingbo Qin Hongying He Weirong Liu Xiaowei Zhang Shuangzhou Peng Zhiping Zeng Ying Su Xiaokun Zhang School of Pharmaceutical Science Fujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamen 361002China NucMito Pharmaceuticals Co. Ltd.Xiamen 361000China Department of Clinical Laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor *** pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to *** Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer ***,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 *** vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent *** studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related ***,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 ***,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

关键词： XS561 Nur77 Bcl-2 Apoptosis Mitochondria phase separation TNBC TAMR

phase separation of GRP7 facilitated by FERONIAmediated phosphorylation inhibits mRNA translation to modulate plant temperature resilience

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Molecular Plant 2024年第3期17卷 460-477页

作者： Fan Xu Long Wang Yingbin Li Junfeng Shi Dorothee Staiger Feng Yu state Key Laboratory of Chemo/Biosensing and Chemometrics College of Biologyand Hunan Key Laboratory of Plant Functional Genomics and Developmental RegulationHunanUniversityChangsha 410082P.R.China State Key Laboratory of Hybrid Rice Hunan Agricultural Biotechnology Research InstituteHunan Academy of Agricultural SciencesChangsha 410125P.R.China RNA Biology and Molecular Physiology Faculty of BiologyBielefeld University33615 BielefeldGermany

Changes in ambient temperature profoundly affect plant growth and ***,the molecu-larbasis of plant acclimation to temperature fluctuation is of great *** this study,we discovered that GLYCINE-RICH RNA-BINDING PROTEIN 7(GRP7)contributes to cold and heat tolerance in Arabidopsis *** found that exposure to a warm temperature rapidly induces GRP7 condensates in planta,which can be reversed by transfer to a lower *** biology and biochemical assays revealed that GRP7 undergoes liquid-liquid phase separation(LLPS)in vivo and in *** of GRP7 in the cyto-plasm contributes to the formation of stress granules that recruit RNA,along with the translation machinery component eukaryotic initiation factor 4E1(elF4E1)and the mRNA chaperones COLD SHOCK PROTEIN 1(CSP1)and CSP3,to inhibit ***,natural variations in GRP7 affecting the residue phos-phorylated by the receptorkinase FERONIA alter its capacity to undergo LLPS and correlate with the adap-tation of some Arabidopsis accessions to a widertemperature *** together,ourfindings illustrate the role of translational control mediated by GRP7 LLPS to confer plants with temperature resilience.

关键词： fluctuating temperature glycine-rich RNA-binding protein phase separation cold shock proteins translation

Physical information-enhanced graph neural network for predicting phase separation

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Chinese Physics B 2024年第7期33卷 278-283页

作者：张亚强王煦文王雅楠郑文 Institute of Public-Safety and Big Data College of Computer Science and Technology(College of Data Science)Taiyuan University of TechnologyJinzhong 030600China Shanxi Engineering Research Centre for Intelligent Data Assisted Treatment Changzhi Medical CollegeChangzhi 046000China Innovation Academy for Microsatellites of Chinese Academy of Sciences Shanghai 200050China

Although phase separation is a ubiquitous phenomenon, the interactions between multiple components make it difficult to accurately model and predict. In recent years, machine learning has been widely used in physics simulations. Here,we present a physical information-enhanced graph neural network(PIENet) to simulate and predict the evolution of phase separation. The accuracy of our model in predicting particle positions is improved by 40.3% and 51.77% compared with CNN and SVM respectively. Moreover, we design an order parameter based on local density to measure the evolution of phase separation and analyze the systematic changes with different repulsion coefficients and different Schmidt *** results demonstrate that our model can achieve long-term accurate predictions of order parameters without requiring complex handcrafted features. These results prove that graph neural networks can become new tools and methods for predicting the structure and properties of complex physical systems.

关键词： graph neural network phase separation machine learning dissipative particle dynamics

Long-term functional maintenance of primary hepatocytes in vitro using macroporous hydrogels engineered through liquid-liquid phase separation

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Nano Research 2024年第3期17卷 1725-1736页

作者： Yang Sun Sheng Yin Jian Cui Zhongxia Wang Yueying Han Ding Ma Shuo Wang Junhua Wu Yi Cao Chunping Jiang Xiaosong Gu Jinan Microecological Biomedicine Shandong Laboratory Jinan 250021China Collaborative Innovation Center of Advanced Microstructures National Laboratory of Solid State MicrostructureKey Laboratory of Intelligent Optical Sensing and ManipulationMinistry of EducationDepartment of PhysicsNanjing UniversityNanjing 210093China Department of Hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210093China National Institute of Healthcare Data Science at Nanjing University Nanjing UniversityNanjing 210093China

Preserving the functionality of hepatocytes in vitro poses a significant challenge in liver tissue engineering and bioartificial liver,as these cells rapidly lose their metabolic and functional characteristics after *** by the macroporous structures found in native liver tissues,here we develop synthetic hydrogel scaffolds that closely mimic the liver’s structural organization through the phase separation between polyethylene glycol(PEG)and *** hydrogels exhibit interconnected macroporous structures and appropriate mechanical properties,providing an optimal microenvironment conducive to hepatocyte adhesion and the formation of sizable *** to two-dimensional hepatocyte cultures,enhanced functionalities of hepatocytes cultured in our macroporous hydrogels were observed for 14 days,as evidenced by quantitative reverse-transcription–polymerase chain reactions(qRT-PCR),immunofluorescence,and enzyme linked immunosorbent assay(ELISA)*** sequencing data further confirmed the establishment of cell–cell interactions among hepatocytes when cultured in our ***,these hepatocytes maintained a protein expression lineage that closely resembled freshly isolated hepatocytes,particularly in the Notch and tumor necrosis factor(TNF)signaling *** results suggest that the macroporous hydrogels are attractive scaffolds for liver tissue engineering.

关键词： liver tissue engineering phase separation hepatocytes macroporous hydrogel

Hydrogel bioadhesives harnessing nanoscale phase separation for Achilles tendon repairing

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Nano Research 2024年第2期17卷 778-787页

作者： Jun Zhang Xingmei Chen Jingseng Lin Pei Zhang Iek Man Lei Yue Tao Jiajun Zhang Tian Luo Ji Liu Department of Mechanical and Energy Engineering Southern University of Science and TechnologyShenzhen 518055China Research and Innovation Center SKG Health TechnologyShenzhen 518000China SAFE(Shenzhen)Medical Technology Company Limited Shenzhen 518000China Shenzhen Key Laboratory of Biomimetic Robotics and Intelligent Systems Department of Mechanical and Energy EngineeringSouthern University of Science and TechnologyShenzhen 518055China Guangdong Provincial Key Laboratory of Human-Augmentation and Rehabilitation Robotics in Universities Southern University of Science and TechnologyShenzhen 518055China

Repairing Achilles tendon has emerged as a long-standing challenge in the orthopaedic *** suture is the gold standard for re-attaching and repairing the fractured Achilles tendons in clinical surgeries,it is still subjected to numerous adverse side-effects,including chronic inflammatory,tendon tissue re-rupture,scar formation,and post-surgical peritendinous *** this work,we develop a class of hydrogel bioadhesives with tailored nanoscale phase separation for Achilles tendon *** address the existing limitations of sutures,our hydrogel bioadhesives encompass three core functionalities:(i)instant and tough adhesion to Achilles tendon tissues,(ii)extraordinary long-term adhesion robustness under wet and dynamic in vivo conditions,and(iii)anti-postsurgical peritendinous *** our hydrogel bioadhesives with sutures,such kind of integrated approach enables a conformable yet robust biointerface with the tendon tissues,and prevents the fibroblast migration and formation of connective tissues,thus facilitating the tendon *** hydrogel bioadhesives reported here open up new opportunities for the repairing of fractured Achilles tendons in diverse and complicated clinical scenarios.

关键词： hydrogels phase separation bioadhesion robustness tendon repairing

Tough Semi-interpenetrating Polyvinylpyrrolidone/Polyacrylamide Hydrogels Enabled by Bioinspired Hydrogen-bonding Induced phase separation

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Chinese Journal of Polymer Science 2024年第5期42卷 591-603,I0006页

作者： Qiong-Jun Xu Zhao-Yang Yuan Chang-Cheng Wang Hao Liang Yu Shi Hai-Tao Wu Hu Xu Jing Zheng Jin-Rong Wu State Key Laboratory of Polymer Materials Engineering College of Polymer Science and EngineeringSichuan UniversityChengdu610065China

Semi-interpenetrating(semi-IPN)hydrogels formed by the continuous interpenetration of cross-linked polymer network and linear non-crosslinked polymer with multifunctionality are widely used in biomedical and other ***,the negative impact of linear polymer on the homogeneity of the cross-linked network often leads to a decrease in the mechanical properties of semi-IPN hydrogels and severely limits their ***,a bioinspired hydrogen-bonding induced phase separation strategy is presented to construct the tough semi-IPN polyvinylpyrrolidone/polyacrylamide hydrogels(named PVP/PAM hydrogels),including the linear polymer polyvinylpyrrolidone(PVP)and cross-linked polyacrylamide(PAM)*** resultant PVPx/PAM hydrogels exhibit unique phase separation induced by the hydrogen bonding between PVP and PAM and affected by the amount of substance of ***,the phase separation of PVPx/PAM hydrogels results in excellent mechanical properties with a strain of 2590%,tensile strength of 0.28 MPa and toughness of 2.17 MJ/m^(3).More importantly,the hydrogen bonding between PVP and PAM firstly disrupts to dissipate energy under external forces,so the PVPx/PAM hydrogels exhibit good self-recovery properties and outperform chemically cross-linked PAM hydrogels in impact resistance and damping *** is believed that the PVPx/PAM hydrogels with hydrogen-bonding induced phase separation possess more potential application prospects.

关键词： Tough Semi-interpenetrating networks Polyvinylpyrrolidone/polyacrylamide Hydrogels phase separation

A phase separation-fortified bi-specific adaptor for conditional tumor killing

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Science China(Life Sciences) 2024年第7期67卷 1385-1397页

作者： Yuyan Liu Yuting Zhu Weifan Xu Pilong Li State Key Laboratory of Membrane Biology Frontier Research Center for Biological StructureTsinghua University-Peking University Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

A common approach in therapeutic protein development involves employing synthetic ligands with multivalency,enabling sophisticated control of signal *** the emerging concept of liquid-liquid phase separation(LLPS)and its ability to organize cell surface receptors into functional compartments,we herein have designed modular ligands with phase-separation modalities to engineer programmable interreceptor communications and precise control of signal pathways,thus inducing the rapid,potent,and specific apoptosis of tumor *** their simplicity,these“triggers”,named phase-separated Tumor Killers(hereafter referred to as psTK),are sufficient to yield interreceptor clustering of death receptors(represented by DR5)and tumor-associated receptors,with notable features:LLPSmediated robust high-order organization,well-choreographed conditional activation,and broad-spectrum capacity to potently induce apoptosis in tumor *** development of novel therapeutic proteins with phase-separation modalities showcases the power of spatially reorganizing signal *** approach facilitates the diversification of cell fate and holds promising potential for targeted therapies against challenging tumors.

关键词： phase separation therapeutic proteins receptor-ligand interactions DR5 tumor apoptosis

Effect of phase separation Size on the Properties of Self-healing Elastomer

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Chinese Journal of Polymer Science 2024年第6期42卷 798-804页

作者： Jun Xu Lei Zhu Xian-Qi Feng Cong Sui Wen-Peng Zhao Shou-Ke Yan School of Chemical Engineering Qingdao University of Science&TechnologyQingdao266042China College of Engineering Yanching institute of TechnologyLangfang065210China Key Laboratory of Rubber-plastics Qingdao University of Science&TechnologyQingdao266042China State Key Laboratory of Chemical Resource Engineering Beijing University of Chemical TechnologyBeijing100029China

Regulation of phase structure has been recognized as one of the most effective ways to fabricate self-healing polymers with high mechanical *** mechanical properties of the resultant polymers are certainly affected by the size of separated phase ***,the study on this aspect is absence,because it can hardly exclude the influence of variation in monomer proportion required for tuning the separated phase ***,we report the first study on tuning the phase size through reversible addition-fragmentation chain transfer(RAFT)polymerization without changing the proportion of *** expected,the size of separated phase has been successfully mediated from 15 nm to 9 nm by tuning the molecular weight of the chain transfer *** is found that the mechanical strength and the self-healing efficiency of the resultant polymers increase simultaneously with the decrease of phase *** study on the formation kinetics of hydrogen bonds reveals that the decrease of phase size can facilitate the re-bonding rate of hydrogen bonds,even if the migration of polymer chains is restricted.

关键词： Self-healing polymers phase separation Reversible addition-fragmentation chain transfer

Plant RNA-binding proteins:phase separation dynamics and functional mechanisms underlying plant development and stress responses

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Molecular Plant 2024年第4期17卷 531-551页

作者： Sheng Fan Yu Zhang Shaobo Zhu Lisha Shen Temasek Life Sciences Laboratory 1 Research LinkNational University of Singapore1 Research LinkSingapore 117604Singapore Department of Biological Sciences National University of Singapore14 Science Drive 4Singapore 117543Singapore

RNA-binding proteins(RBPs)accompany RNA from synthesis to decay,mediating every aspect of RNA metabolism and impacting diverse cellular and developmental processes in *** RBPs undergo phase separation along with their bound RNA to form and function in dynamic membraneless biomolecular condensates for spatiotemporal coordination or regulation of RNA *** evidence suggests that phase-separating RBPs with RNA-binding domains and intrinsically disordered regions play important roles in plant development and stress ***,we summarize the current knowledge about how dynamic partitioning of RBPs into condensates controls plant development and enables sensing of experimental changes to confer growth plasticity under stress conditions,with a focus on the dynamics and functional mechanisms of RBP-rich nuclear condensates and cytoplasmic granules in mediating RNA *** also discuss roles of multiple factors,such as environmental signals,protein modifications,and N6-methyladenosine RNA methylation,in modulating the phase separation behaviors of RBPs,and highlight the prospects and challenges for future research on phase-separating RBPs in crops.

关键词： RNA-binding proteins phase separation biomolecular condensates RNA metabolism development stress resilience