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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

Probiotic Pediococcus pentosaceus restored gossypol-induced intestinal barrier injury by increasing propionate content in Nile tilapia

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Journal of Animal Science and Biotechnology 2024年第4期15卷 1688-1703页

作者： Feifei Ding Nannan Zhou Yuan Luo Tong Wang Weijie Li Fang Qiao Zhenyu Du Meiling Zhang Laboratory of Aquaculture Nutrition and Environmental health(LANEH) School of Life SciencesEast China Normal UniversityShanghai 200241China

Background Intestinal barrier is a dynamic interface between the body and the ingested food components, however, dietary components or xenobiotics could compromise intestinal integrity, causing health risks to the host. Gossypol, a toxic component in cottonseed meal(CSM), caused intestinal injury in fish or other monogastric animals. It has been demonstrated that probiotics administration benefits the intestinal barrier integrity, but the efficacy of probiotics in maintaining intestinal health when the host is exposed to gossypol remains unclear. Here, a strain(YC) affiliated to Pediococcus pentosaceus was isolated from the gut of Nile tilapia(Oreochromis niloticus) and its potential to repair gossypol-induced intestinal damage was *** A total of 270 Nile tilapia(2.20 ± 0.02 g) were allotted in 3 groups with 3 tanks each and fed with 3 diets including CON(control diet), GOS(control diet containing 300 mg/kg gossypol) and GP(control diet containing 300 mg/kg gossypol and 10^(8) colony-forming unit(CFU)/g P. pentosaceus YC), respectively. After 10 weeks, addition of P. pentosaceus YC restored growth retardation and intestinal injury induced by gossypol in Nile tilapia. Transcriptome analysis and si RNA interference experiments demonstrated that NOD-like receptors(NLR) family caspase recruitment domain(CARD) domain containing 3(Nlrc3) inhibition might promote intestinal stem cell(ISC) proliferation, as well as maintaining gut barrier integrity. 16S r RNA sequencing and gas chromatography-mass spectrometry(GC-MS) revealed that addition of P. pentosaceus YC altered the composition of gut microbiota and increased the content of propionate in fish gut. In vitro studies on propionate's function demonstrated that it suppressed nlrc3 expression and promoted wound healing in Caco-2 cell *** The present study reveals that P. pentosaceus YC has the capacity to ameliorate intestinal barrier injury by modulating gut microbiota composition and elevating

关键词： Gut barrier injury Gossypol ISCs proliferation Nlrc3 Propionate

Physiological and pathological functions of circular RNAs in the nervous system

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Neural Regeneration Research 2024年第2期19卷 342-349页

作者： Min Zhou Shi Li Chuan Huang school of life sciences Chongqing UniversityChongqingChina

Circular RNAs(circRNAs)are a class of covalently closed single-stranded RNAs that are expressed during the development of specific cells and *** play crucial roles in physiological and pathological processes by sponging microRNAs,modulating gene transcription,controlling the activity of certain RNA-binding proteins,and producing functional peptides.A key focus of research at present is the functionality of circRNAs in the nervous system and several advances have emerged over the last 2 ***,the precise role of circRNAs in the nervous system has yet to be comprehensively *** this review,we first summarize the recently described roles of circRNAs in brain development,maturity,and ***,we focus on the involvement of circRNAs in various diseases of the central nervous system,such as brain cancer,chronic neurodegenerative diseases,acute injuries of the nervous system,and neuropathic pain.A better understanding of the functionality of circRNAs will help us to develop potential diagnostic,prognostic,and therapeutic strategies to treat diseases of the nervous system.

关键词： Alzheimer’s disease amyotrophic lateral sclerosis brain development circRNAs neuropathic pain Parkinson’s disease

Inonotus obliquus polysaccharides prevent UVB-induced skin photodamage by modulating Sirt3-activated Foxo3a/PINK1-Parkin pathway: an in vitro and in vivo study

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Food Science and Human Wellness 2024年

作者： Pei Lin Yin-ying Lu Hong-yu Shi Zhen-dong Chen Jun Lin school of life sciences and health Engineering Jiangnan University

Inonotus obliquus， an edible and medicinal fungus， has proven to be beneficial for relieving body aging. Previous research has shown that Inonotus obliquus polysaccharide (IOP) can effectively reduce oxidative stress and alleviate photoaging in UVB-treated HaCaT cells. However， the underlying mechanism is still unclear. This study aimed to investigate the mechanism through which IOP mitigates skin photodamage by modulating mitochondrial autophagy through both in vivo and in vitro experiments. The results indicated that IOP alleviated the thickening of the stratum corneum and inflammatory infiltration caused by UVB radiation. Moreover， IOP effectively inhibited the mRNA expression of MMP1 and MMP3 to prevent collagen breakdown and decreased the expression of aging-related proteins (P53 and P21) and inflammatory factors (TNF-α and IFN-γ) in UVB-induced mice. Both in vitro and in vivo studies demonstrated that IOP increased Sirt3 expression， activated the Foxo3a/PINK1-Parkin pathway and enhanced mitochondrial autophagy to reduce photodamage. Additionally， IOP could regulate the gut microbes in photodamaged mice and increase the relative abundance of Clostridium＿XlVa， Desulfovibrio， and Barnesiella， which are important for protecting the intestinal barrier and alleviating intestinal dysfunction. These results provide a theoretical foundation for the use of IOP as a natural component to reduce skin photodamage.

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HUNK inhibits cargo uptake and lysosomal traffic in the caveolar pathway via the AGAP3/ARF6

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Science Bulletin 2024年第2期69卷 173-178页

作者： Siyuan Jiang Xiaoqi Han Tihui Liu Ying He Zidong Zhao Tongfeng Liu Shuwen Cheng Jihang Zhang Liqiang Duan Yajuan Liu Tianyou Cheng Yong Liu Qinong Ye Shan Gao Zhongda Hospital Medical SchoolAdvanced Institute for Life and HealthSoutheast UniversityNanjing 20096China Medical school of Guizhou University Guiyang 550025China Shanxi Academy of Advanced Research and Innovation Taiyuan 030032China Zhongda Hospital School of Life Sciences and TechnologyAdvanced Institute for Life and HealthSoutheast UniversityNanjing 210096China Nanjing University Medical school Nanjing 210046China Hubei Key Laboratory of Cell Homeostasis College of Life SciencesTaiKang Center for Life and Medical SciencesWuhan UniversityWuhan 430072China Department of Medical Molecular Biology Beijing Institute of BiotechnologyCollaborative Innovation Center for Cancer MedicineBeijing 100850China

Endocytosis is a crucial cellular process that takes up cargos by enclosing them in membrane-bound vesicles,and transports cargos to different parts of the cell,such as the lysosomes[1].Endocytosis is classified into several mechanistically and morphologically pathways,including clathrin-mediated endocytosis(CME)and caveolae-mediated endocytosis(CavME)[1,2].

关键词： endocytosis cargo uptake

PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity

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Virologica Sinica 2024年第2期39卷 264-276页

作者： Ruiqi Sun Yanyu Guo Lilin Zhang Huixia Zhang Boxuan Yin Xiaoyang Li Changyan Li Liu Yang Lei Zhang Zexing Li Jinhai Huang school of life sciences Tianjin UniversityTianjin300072China

Porcine reproductive and respiratory syndrome virus(PRRSV)is a major economically devastating pathogen that has evolved various strategies to evade innate *** of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5(MDA5),a receptor that senses viral *** this study,the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed,and the detailed mechanisms were *** found that the interaction between P62 and MDA5 is enhanced due to two factors:the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2αand the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected *** a result of these modifications,the classic P62-mediated autophagy is ***,porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2(CCT2),which is enhanced by PRRSV *** interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of *** summary,enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways:the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2,leading to intense innate immune *** research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

关键词： Porcine reproductive and respiratory syndrome virus(PRRSV) nsp3 Autophagy MDA5

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease

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Neural Regeneration Research 2024年第5期19卷 1150-1155页

作者： Shuanglong Yi Linfang Wang Margaret S.Ho Shiping Zhang school of life Science and Technology ShanghaiTech UniversityShanghaiChina College of life sciences University of Chinese Academy of SciencesBeijingChina

Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy *** in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s ***,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the *** the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult *** from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in ***9 is persistently in contact with these *** glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate *** suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic ***,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial *** findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s *** results may provide new insights on the underlying mechanism of Parkinson’s disease.

关键词： Atg9 autophagy glia Parkinson’s disease

The IDD Transcription Factors:Their Functions in Plant Development and Environmental Response

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Phyton-International Journal of Experimental Botany 2024年第1期93卷 63-79页

作者： Jing Liu Defeng Shu Zilong Tan Mei Ma Huanhuan Yang Ning Guo Shipeng Li Dayong Cui school of life sciences Qilu Normal UniversityJinan250200China school of life sciences Shandong Normal UniversityJinan250014China

INDETERMINATE-DOMAIN proteins(IDDs)are a plant-specific transcription factor family characterized by a conserved ID domain with four zinc finger *** studies have demonstrated that IDDs coordinate a diversity of physiological processes and functions in plant growth and development,including floral transition,plant architecture,seed and root development,and hormone *** this review,we especially summarized the latest knowledge on the functions and working models of IDD members in Arabidopsis,rice,and maize,particularly focusing on their role in the regulatory network of biotic and abiotic environmental responses,such as gravity,temperature,water,and *** these mechanisms underlying the function of IDD proteins in these processes is important for improving crop yields by manipulating their ***,the review offers valuable insights into the functions and mechanisms of IDD proteins in plants,providing a foundation for further research and potential applications in agriculture.

关键词： INDETERMINATE DOMAIN flowering time root development shoot gravitropism plant immunity hormonal signaling environmental responses

SimHOEPI:A resampling simulator for generating single nucleotide polymorphism data with a high-order epistasis model

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Quantitative Biology 2024年第2期12卷 197-204页

作者： Yahan Li Xinrui Cai Junliang Shang Yuanyuan Zhang Jin-Xing Liu school of Computer Science Qufu Normal UniversityRizhaoChina school of Information and Control Engineering Qingdao University of TechnologyQingdaoChina school of health and life sciences University of Health and Rehabilitation SciencesQingdaoChina

Epistasis is a ubiquitous phenomenon in genetics,and is considered to be one of main factors in current efforts to unveil missing heritability of complex *** data is crucial for evaluating epistasis detection tools in genome-wide association studies(GWAS).Existing simulators normally suffer from two limitations:absence of support for high-order epistasis models containing multiple single nucleotide polymorphisms(SNPs),and inability to generate simulation SNP data *** this study,we proposed a simulator SimHOEPI,which is capable of calculating penetrance tables of high-order epistasis models depending on either prevalence or heritability,and uses a resampling strategy to generate simulation data *** of SimHOEPI are the preservation of realistic minor allele frequencies in sampling data,the accurate calculation and embedding of high-order epistasis models,and acceptable simulation time.A series of experiments were carried out to verify these properties from different *** results show that SimHOEPI can generate simulation SNP data independently with high-order epistasis models,implying that it might be an alternative simulator for GWAS.

关键词： high-order epistasis model penetrance table resampling strategy simulation single nucleotide polymorphisms