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Inhibition mechanisms of CRISPR-Cas9 by Acr ⅡA25.1 and AcrⅡA32

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Science China life Sciences 2024年第9期67卷 1781-1791页

作者： Jianlin Zheng Yuwei Zhu Tengjin Huang Wenbo Gao Jiale He Zhiwei Huang HIT center for life Sciences School of Life Science and Technology Harbin Institute of Technology Westlake center for Genome Editing Westlake Laboratory of Life Sciences and Biomedicine School of Life Sciences Westlake University

In the ongoing arms race between bacteria and bacteriophages, bacteriophages have evolved anti-CRISPR proteins to counteract bacterial CRISPR-Cas systems. Recently, Acr ⅡA25.1 and Acr ⅡA32 have been found to effectively inhibit the activity of Spy Cas9 both in bacterial and human cells. However, their molecular mechanisms remain elusive. Here, we report the cryo-electron microscopy structures of ternary complexes formed by Acr ⅡA25.1 and Acr ⅡA32 bound to Spy Cas9-sg RNA. Using structural analysis and biochemical experiments, we revealed that Acr ⅡA25.1 and Acr ⅡA32 recognize a novel, previously-unidentified anti-CRISPR binding site on Spy Cas9. We found that both Acr ⅡA25.1 and Acr ⅡA32 directly interact with the WED domain, where they spatially obstruct conformational changes of the WED and PI domains, thereby inhibiting Spy Cas9 from recognizing protospacer adjacent motif(PAM) and unwinding double-stranded DNA. In addition,they may inhibit nuclease activity by blocking the dynamic conformational changes of the Spy Cas9 surveillance complex. In summary, our data elucidate the inhibition mechanisms of two new anti-CRISPR proteins, provide new strategies for the modulation of Spy Cas9 activity,and expand our understanding of the diversity of anti-CRISPR protein inhibition mechanisms.

关键词： anti-CRISPR cryo-EM SpyCas9 AcrIIA25.1 AcrIIA32 inhibiton

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

Di-and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair

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Science China(life Sciences) 2024年第6期67卷 1089-1105页

作者： Runfa Chen Meng-Jie Zhao Yu-Min Li Ao-Hui Liu Ru-Xin Wang Yu-Chao Mei Xuefeng Chen Hai-Ning Du Hubei Key Laboratory of Cell Homeostasis College of Life SciencesTaiKang Center for Life and Medical SciencesFrontier Science Center for Immunology and MetabolismHubei Clinical Research Center of Emergency and ResuscitationEmergency Center of Zhongnan HospitalWuhan UniversityWuhan 430072China Hubei Key Laboratory of Cell Homeostasis College of Life SciencesTaiKang Center for Life and Medical SciencesFrontier Science Center for Immunology and MetabolismWuhan UniversityWuhan 430072China

Histone H3 Lys36(H3K36)methylation and its associated modifiers are crucial for DNA double-strand break(DSB)repair,but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is ***,we unveil the distinct roles of H3K36 dimethylation(H3K36me2)and H3K36 trimethylation(H3K36me3)in DSB repair via non-homologous end joining(NHEJ)or homologous recombination(HR).Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency.y Ku70 and Rfa1 bind H3K36me2-or H3K36me3-modified peptides and chromatin,*** these interactions impairs y Ku70 and Rfa1 recruitment to damaged H3K36me2-or H3K36me3-rich loci,increasing DNA damage sensitivity and decreasing repair ***,H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit y Ku70 or Rfa1 under DSB ***,human KU70 and RPA1,the homologs of y Ku70 and Rfa1,exclusively associate with H3K36me2 and H3K36me3 in a conserved *** findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways,highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.

关键词： histone H3K36 methylation Ku70 RPA non-homologous end joining homologous recombination

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Interplant communication:an emerging battlefield in plant-aphid-virus interactions

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Science China(life Sciences) 2024年第5期67卷 1069-1071页

作者： Yunjing Wang Qian Gong Yule Liu MOE Key Laboratory of Bioinformatics and center for Plant Biology School of Life SciencesTsinghua UniversityBeijing 100084China Tsinghua-Peking center for life Sciences Beijing 100084China

Plants constantly face threats from various organisms,including pathogens and *** the pathogens,plant viruses are obligate intracellular parasites that infect plants and cause serious crop yield losses.

关键词： plant Plants communication

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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

Transcriptional regulation in the development and dysfunction of neocortical projection neurons

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Neural Regeneration Research 2024年第2期19卷 246-254页

作者： Ningxin Wang Rong Wan Ke Tang Precise Genome Engineering center School of Life SciencesGuangzhou UniversityGuangzhouGuangdong ProvinceChina

Glutamatergic projection neurons generate sophisticated excitatory circuits to integrate and transmit information among different cortical areas,and between the neocortex and other regions of the brain and spinal *** development of cortical projection neurons is regulated by certain essential events such as neural fate determination,proliferation,specification,differentiation,migration,survival,axonogenesis,and *** processes are precisely regulated in a tempo-spatial manner by intrinsic factors,extrinsic signals,and neural *** generation of correct subtypes and precise connections of projection neurons is imperative not only to support the basic cortical functions(such as sensory information integration,motor coordination,and cognition)but also to prevent the onset and progression of neurodevelopmental disorders(such as intellectual disability,autism spectrum disorders,anxiety,and depression).This review mainly focuses on the recent progress of transcriptional regulations on the development and diversity of neocortical projection neurons and the clinical relevance of the failure of transcriptional modulations.

关键词： autism spectrum disorders cognition differentiation excitatory circuits intellectual disability neocortex neurodevelopmental disorders projection neuron specification transcriptional regulation

Shallow sub-lakes are essential for sustaining the successful wintering of waterbirds in Poyang Lake,China

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Avian Research 2024年第2期15卷 219-228页

作者： Mengjie Lu Zhen Zhang Peng Chen Changxin Xu Bin Gao Luzhang Ruan School of life Sciences Nanchang UniversityNanchang330031China Jiangxi Province Key Laboratory of Watershed Ecosystem Change and Biodiversity Center for Watershed EcologyInstitute of Life Science and School of Life SciencesNanchang UniversityNanchang330031China

For migratory waterbirds,the quality of wintering habitat is related to spring migration and successful breeding in the next *** availability of food resources in the habitat is critical and varies within water *** the water-level fluctuations in Poyang Lake have been extremely variable interannually in recent years,the wintering waterbird populations have remained relatively ***,the mechanism of maintaining the stability is worth *** study aimed to compare the distribution of vegetation and herbivorous wa-terbirds in 2015-2016 and 2016-2017,focusing on three shallow sub-lakes and one main lake *** results showed that the emergence of tubers and the growth of Carex *** a continuous food supply and habitat for wintering waterbirds with a gradual decline in the water *** sub-lakes supported almost all of the tuber-eating waterbirds(1.42-1.62×10^(5))and most geese(1.34-1.53×10^(6)).However,the main lake area,covered with Persicaria hydropiper,did not provide adequate and accessible *** resulted in almost no distribution of tuber-eating waterbirds,with only a few geese congregating in early *** results demonstrated that the shallow sub-lakes under human control provided a different environment from the main lake and are key to sustaining the successful wintering of hundreds of thousands of migratory waterbirds in Poyang ***,we recommend refining the anthropogenic management of the shallow sub-lakes to regulate the water level to ensure the carrying capacity of Poyang Lake.

关键词： Anthropogenic management Carrying capacity Seasonal lake Water level Wintering habitat

Mechanism of action of cordycepin in the treatment of hepatocellular carcinoma via regulation of the Hippo signaling pathway

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Food Science and Human Wellness 2024年第2期13卷 1040-1054页

作者： Xiaomin Li Qing Liu Songyu Xie Xiaoping Wu Junsheng Fu College of life Sciences Mycological Research CenterFujian Agriculture and Forestry UniversityFuzhou 350002China

Hepatocellular carcinoma(HCC)is one of the common most malignant *** study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of *** results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing *** sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling *** regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 *** results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling *** in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and ***,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 *** summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.

关键词： Cordycepin Hepatocellular carcinoma Hippo signaling pathway GBP3 ETV5

Invasive weed disrupts facilitation of nutrient uptake in grass-clover assemblage

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Soil Ecology Letters 2024年第1期6卷 89-96页

作者： Wei Zhang Rick Muir Nicholas Dickinson Faculty of Agriculture and life Sciences Lincoln UniversityLincoln 7647New Zealand

Nutrient constraints in low-fertility soil were modified by different species ***-clover assemblages benefited both species in terms of nutrient *** of competition and facilitation is *** invasive weed removed essential nutrients from the grazing *** investigate the interplay of competition and facilitation between plants in low-fertility pasture grasslands of new Zealand,we compared nutrient uptake and acquisition of key nutrients of three species from different func-tional *** of Pilosella officinarum(mouse-eared hawk-weed,an invasive weed),Trifolium repens(white clover,a nitrogen fixer)and Dactylis glomerata(cocksfoot,a pasture grass)were planted into a soil with low-to-deficient concentrations of key *** yields were achieved by the grass growing alone but,when the clover and grass had grown together,there were complementary benefits in terms of procurement of a wide range of nutrients from soil despite lower root *** inva-sive weed negated these benefits,and soil nutrients were exploited less efficiently when Pilosella had grown alone or in a mixture with the other *** from the weed removed the benefits of grass-legume *** findings are interpreted to suggest that requirements for legumes to be the main source of nitrogen in pasture grasslands may be compromised unless competitive weeds are controlled to avoid disrupted procurement of key *** is likely these constraints to nutrient procurement would similarly impact conservation grasslands.

关键词： soil ferility facilitation species coexistence weed invasion legumes