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Subtraction of liposome signals in cryo-EM structural determination of protein-liposome complexes

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Chinese Physics B 2024年第8期33卷 569-577页

作者：李首卿李明王玉梅李雪明 Institute of Physics Chinese Academy of SciencesBeijing 100190China University of Chinese Academy of sciences Beijing 100049China Key Laboratory for Protein sciences of Ministry of Education School of Life SciencesTsinghua UniversityBeijing 100084China State Key Laboratory of Membrane Biology School of Life SciencesTsinghua UniversityBeijing 100084China tsinghua–peking Joint center for life sciences Beijing 100084China Beijing Frontier Research center for Biological Structure Beijing 100084China School of life sciences Tsinghua UniversityBeijing 100084China Beijing Branch of Songshan Lake Materials Laboratory Beijing 100190China

Reconstituting membrane proteins in liposomes and determining their structure is a common method for determining membrane protein structures using single-particle cryo-electron microscopy(cryo-EM).However,the strong signal of liposomes under cryo-EM imaging conditions often interferes with the structural determination of the embedded membrane ***,we propose a liposome signal subtraction method based on single-particle two-dimensional(2D)classification average images,aimed at enhancing the reconstruction resolution of membrane *** analyzed the signal distribution characteristics of liposomes and proteins within the 2D classification average images of protein–liposome complexes in the frequency *** on this analysis,we designed a method to subtract the liposome signals from the original particle *** the subtraction,the accuracy of single-particle three-dimensional(3D)alignment was improved,enhancing the resolution of the final 3D *** demonstrated this method using a PIEZO1-proteoliposome dataset by improving the resolution of the PIEZO1 protein.

关键词： cryo-EM protein–liposome complexes liposome signal subtraction 2D classification averaging

A homing rescue gene drive with multiplexed gRNAs reaches high frequency in cage populations but generates functional resistance

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Journal of Genetics and Genomics 2024年第8期51卷 836-843页

作者： Shibo Hou Jingheng Chen Ruobing Feng Xuejiao Xu Nan Liang Jackson Champer center for Bioinformatics Center for Life SciencesSchool of Life SciencesPeking UniversityBeijing 100871China

CRISPR homing gene drives have considerable potential for managing populations of medically and agriculturally significant *** operate by Cas9 cleavage followed by homology-directed repair,copying the drive allele to the wild-type chromosome and thus increasing in frequency and spreading throughout a ***,resistance alleles formed by end-joining repair pose a significant *** address this,we create a homing drive targeting the essential hairy gene in Drosophila *** resistance alleles are recessive lethal,while drive carriers have a recoded“rescue”version of *** drive inheritance rate is moderate,and multigenerational cage studies show drive spread to 96%–97%of the ***,the drive does not reach 100%due to the formation of functional resistance alleles despite using four *** alleles have a large deletion but likely utilize an alternate start ***,revised designs targeting more essential regions of a gene may be necessary to avoid such functional *** of the rescue element’s native 3'UTR with a homolog from another species increases drive inheritance by 13%–24%.This was possibly because of reduced homology between the rescue element and surrounding genomic DNA,which could also be an important design consideration for rescue gene drives.

关键词： Genedrive Homing drive Rescueelement Population modification Multiplexed gRNAs Resistance alleles Cage study

An octopamine-specific GRAB sensor reveals a monoamine relay circuitry that boosts aversive learning

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National Science Review 2024年第5期11卷 186-201页

作者： Mingyue Lv Ruyi Cai Renzimo Zhang Xiju Xia Xuelin Li Yipan Wang Huan Wang Jianzhi Zeng Yifei Xue Lanqun Mao Yulong Li State Key Laboratory of Membrane Biology School of Life SciencesPeking University State Key Laboratory of Brain and Cognitive Science Institute of Biophysics Chinese Academy of Sciences PKU-IDG/Mc Govern Institute for Brain Research Yuanpei College Peking University peking-tsinghua center for life sciences Academy for Advanced Interdisciplinary Studies Peking University peking University–tsinghua University–National Institute of Biological sciences Joint Graduate Program Academy for Advanced Interdisciplinary Studies Peking University Institute of Molecular Physiology Shenzhen Bay Laboratory College of Chemistry Beijing Normal University Chinese Institute for Brain Research

Octopamine（OA）,analogous to norepinephrine in vertebrates,is an essential monoamine neurotransmitter in invertebrates that plays a significant role in various biological functions,including olfactory associative ***,the spatial and temporal dynamics of OA in vivo remain poorly understood due to limitations associated with the currently available methods used to detect *** overcome these limitations,we developed a genetically encoded GPCR activation-based（GRAB） OA sensor called *** sensor is highly selective for OA and exhibits a robust and rapid increase in fluorescence in response to extracellular *** GRABOA1.0,we monitored OA release in the Drosophila mushroom body（MB）,the fly's learning center,and found that OA is released in response to both odor and shock stimuli in an aversive learning *** OA release requires acetylcholine（ACh） released from Kenyon cells,signaling via nicotinic ACh ***,we discovered that OA amplifies aversive learning behavior by augmenting dopamine-mediated punishment signals via Octβ1R in dopaminergic neurons,leading to alterations in synaptic plasticity within the ***,our new GRABOA1.0sensor can be used to monitor OA release in real time under physiological conditions,providing valuable insights into the cellular and circuit mechanisms that underlie OA signaling.

关键词： octopamine dopamine GRAB sensor learning and memory

Activation of leukotriene B_(4)receptor 1 is a prerequisite for complement receptor 3-mediated antifungal responses of neutrophils

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Cellular & Molecular Immunology 2024年第3期21卷 245-259页

作者： Yan Xin Sihan Xiong Linghong Zhou Xin Lin Institute for Immunology and School of Medicine Tsinghua University100084BeijingChina tsinghua University-peking University center for life sciences 100084BeijingChina Department of Infectious Diseases Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency ResponseNational Medical Center for Infectious DiseasesHuashan HospitalFudan UniversityShanghai200040China

Invasive fungal infections are life-threatening,and neutrophils are vital cells of the innate immune system that defend against *** role of LTA4H-LTB_(4)-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly ***,we demonstrated that the LTA4H-LTB_(4)-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus,but not Cryptococcus neoformans infection,by regulating the antifungal activity of *** results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of ***,defective activation of the spleen tyrosine kinase(Syk)and extracellular signal-related kinase(ERK1/2)pathways in neutrophils accompanies this ***,BLT1 regulates CR3-mediated,β-1,3-glucan-induced neutrophil phagocytosis,while a physical interaction with CR3 with slight influence on its dynamics is *** findings thus demonstrate that the LTA4H-LTB_(4)-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.

关键词： LTA4H BLT1 Phagocytosis Complement receptor 3 Fungi

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

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Cellular & Molecular Immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong Lamao Meichao Gu Xuanxuan Jin Ying Liu Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao Thomas S.Fulford Adam P.Uldrich Catherine C.L Wong Wensheng Wei Biomedical Pioneering Innovation center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina center for Precision Medicine Multi-Omics Research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity The University of MelbourneParkvilleVIC3010Australia Cancer Immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key Laboratory for Complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate *** our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer *** found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T *** coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX ***,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer *** our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T ***,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell Cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite Immunotherapy

Streamlined process for effective and strand-selective mitochondrial base editing using mitoBEs

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Biophysics Reports 2024年第4期10卷 191-200页

作者： Xiaoxue Zhang Zongyi Yi Wei Tang Wensheng Wei Changping Laboratory Biomedical Pioneering Innovation center Peking-Tsinghua Center for Life Sciences Peking University Genome Editing Research Center State Key Laboratory of Protein and Plant Gene Research School of Life Sciences Peking University Academy for Advanced Interdisciplinary Studies Peking University

Mitochondrial base editing tools hold great promise for the investigation and treatment of mitochondrial diseases. Mitochondrial DNA base editors(mitoBEs) integrate a programmable transcriptionactivator-like effector(TALE) protein with single-stranded DNA deaminase(TadA8e-V106W,APOBEC1, etc.) and nickase(MutH, ***6I(C), etc.) to achieve heightened precision and efficiency in mitochondrial base editing. This innovative mitochondrial base editing tool exhibits a number of advantages, including strand-selectivity for editing, high efficiency, and the capacity to perform diverse types of base editing on the mitochondrial genome by employing various deaminases. In this context,we provide a detailed experimental protocol for mitoBEs to assist others in achieving proficient mitochondrial base editing.

关键词： Mitochondrial DNA base editors (mitoBEs) Transcription-activator-like effector (TALE) Deaminase Nickase

Meningeal lymphatic vasculature,a general target for glioblastoma therapy?

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Fundamental Research 2024年第2期4卷 267-269页

作者： Changping Zhou Han Xu Jincai Luo Laboratory of Vascular Biology Institute of Molecular MedicineCollege of Future TechnologyBeijing Key Laboratory of Cardiometabolic Molecular MedicinePeking UniversityBeijing 100871China

Glioblastoma(GBM)causes nearly universal mortality as a result of the failure of conventional therapies including surgical resection,targeted radiation therapy,and *** increasingly important treatment option is combining immunotherapy with other therapies in both preclinical and clinical *** central nervous system(CNS)has been historically considered an immune privileged area,but increasing evidence,including the recent rediscovery of meningeal lymphatic vessels(MLVs),has overturned this *** are populated by multiple immune cells and connect the CNS to the periphery by draining cerebrospinal fluid with soluble CNS antigens and immune cells into cervical lymph *** the past few years,more and more studies have indicated that MLVs are involved in the regulation of inflammation and the immune response in the pathogenesis of various CNS diseases including ***,we explore the critical interlinkages between MLVs and GBM therapies including chemotherapy,radiotherapy and immunotherapy,and propose the meningeal lymphatic vasculature as a general target for GBM therapy.

关键词： Meningeal lymphatic vessels Glioblastoma Immunity Vascular endothelial growth factor C Immune modulation

Arabidopsis AIP1-1 regulates the organization of apical actin filaments by promoting their turnover in pollen tubes

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Science China(life sciences) 2020年第2期63卷 239-250页

作者： Min Diao Xin Li Shanjin Huang Institute of Botany Chinese Academy of SciencesBeijing 100093China center for Plant Biology School of Life SciencesTsinghua UniversityBeijing 100084China University of Chinese Academy of sciences Beijing 100049China iHuman Institute Shanghai Tech UniversityShanghai 201210China

Apical actin filaments are highly dynamic structures that are crucial for rapid pollen tube growth, but the mechanisms regulating their dynamics and spatial organization remain incompletely understood. We here identify that AtAIP1-1 is important for regulating the turnover and organization of apical actin filaments in pollen tubes. AtAIP1-1 is distributed uniformly in the pollen tube and loss of function of AtAIP1-1 affects the organization of the actin cytoskeleton in the pollen tube. Specifically, actin filaments became disorganized within the apical region of aip1-1 pollen tubes. Consistent with the role of apical actin filaments in spatially restricting vesicles in pollen tubes, the apical region occupied by vesicles becomes enlarged in aip1-1 pollen tubes compared to WT. Using ADF1 as a representative actin-depolymerizing factor, we demonstrate that AtAIP1-1 enhances ADF1-mediated actin depolymerization and filament severing in vitro, although AtAIP1-1 alone does not have an obvious effect on actin assembly and disassembly. The dynamics of apical actin filaments are reduced in aip1-1 pollen tubes compared to WT. Our study suggests that AtAIP1-1 works together with ADF to act as a module in regulating the dynamics of apical actin filaments to facilitate the construction of the unique "apical actin structure" in the pollen tube.

关键词： pollen tube apical actin structure actin dynamics actin turnover ADF AIP1

Role of Notch signaling in regulating innate immunity and inflammation in health and disease

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Protein & Cell 2016年第3期7卷 159-174页

作者： Yingli Shang Sinead Smith Xiaoyu Hu School of Medicine and Institute for Immunology Tsinghua University Beijing 100084 China Department of Clinical Medicine Trinity College Dublin Dublin 2 Ireland

The Notch signaling pathway is conserved from Drosophila to mammals and is critically involved in developmental processes. In the immune system, it has been established that Notch signaling regulates multiple steps of T and B cell development in both central and peripheral lymphoid organs. Relative to the well documented role of Notch signaling in lymphocyte development, less is known about its role in regulating myeloid lineage development and function, especially in the context of acute and chronic inflammation. In this review article, we will describe the evidence accumulated during the recent years to support a key regulatory role of the Notch pathway in innate immune and inflammatory responses and discuss the potential implications of such regulation for pathogenesis and therapy of inflammatory disorders.

关键词： inflammation innate immunity macrophages Notch signaling RBP-J