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Large-Scale CRISPR Screen of LDLR Pathogenic Variants

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research 2024年第2期2023卷 213-225页

作者： Mengjing Li Lerong Ma Yiwu Chen Jianing Li Yanbing Wang Wenni You Hongming Yuan Xiaochun Tang Hongsheng Ouyang Daxin Pang Key Lab for Zoonoses research Ministry of EducationAnimal Genome Editing Technology Innovation CenterCollege of Animal SciencesJilin UniversityChangchunJilin Province 130062China The Institute of Translational Medicine Tianjin Union Medical Center of Nankai UniversityTianjin 300071China Chongqing researchInstitute Jilin UniversityChongqing 401123China Chongqing Jitang Biotechnology research Institute Co.Ltd. ChongqingChina

Familial hypercholesterolemia(FH)is a frequently occurring genetic disorder that is linked to early-onset cardiovascular *** left untreated,patients with this condition can develop severe cardiovascular ***,many patients remain undiagnosed,and even when diagnosed,the treatment is often not *** mutations in the LDLR gene are the primary cause of FH,predicting whether novel variants are pathogenic is not a straightforward *** the functionality of LDLR variants is crucial in uncovering the genetic basis of *** study utilized CRISPR/Cas9 cytosine base editors in pooled screens to establish a novel approach for functionally assessing tens of thousands of LDLR variants on a large scale.A total of more than 100 single guide RNAs(sgRNAs)targeting LDLR pathogenic mutations were successfully screened with relatively high *** of these,5 sgRNAs were further subjected to functional verification studies,including 1 in the promoter,1 in the antisense RNA,1 in the exon,and 2 in the *** for the variant caused by the sgRNA located at intron 16,the functionalities of the other LDLR variants were all *** high similarity of LDLR intron sequences may lead to some false ***,these results confirm the reliability of the large-scale screening strategy for functional analysis of LDLR variants,and the screened candidate pathogenic mutations could be used as an auxiliary means of clinical gene detection to prevent FH-induced heart disease.

关键词： LDLR Screen straight

MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment

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Bone research 2024年第1期12卷 153-164页

作者： Jiakang Yang Jing Shuai Lixuen Siow Jingyi Lu Miao Sun Wenyue An Mengfei Yu Baixiang Wang Qianming Chen Stomatology Hospital School of StomatologyZhejiang University School of MedicineZhejiang Provincial Clinical Research Center for Oral DiseasesKey Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhou 310000China

Reconstruction of irregular oral-maxillofacial bone defects with an inflammatory microenvironment remains a challenge,as chronic local inflammation can largely impair bone ***,we used magnesium silicate nanospheres(MSNs)to load microRNA-146a-5p(miR-146a)to fabricate a nanobiomaterial,MSN+miR-146a,which showed synergistic promoting effects on the osteogenic differentiation of human dental pulp stem cells(hDPSCs).In addition,miR-146a exhibited an anti-inflammatory effect on mouse bone marrow-derived macrophages(BMMs)under lipopolysaccharide(LPS)stimulation by inhibiting the NF-κB pathway via targeting tumor necrosis factor receptor-associated factor 6(TRAF6),and MSNs could simultaneously promote M2 polarization of ***-146a was also found to inhibit osteoclast ***,the dual osteogenic-promoting and immunoregulatory effects of MSN+miR-146a were further validated in a stimulated infected mouse mandibular bone defect model via delivery by a photocuring ***,the MSN+miR-146a complex revealed good potential in treating inflammatory irregular oralmaxillofacial bone defects.

关键词： inflammatory healing stimulation

Comprehensive transcriptional atlas of human adenomyosis deciphered by the integration of single-cell RNA-sequencing and spatial transcriptomics

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Protein & Cell 2024年第7期15卷 530-546页

作者： Tao Chen Yiliang Xu Xiaocui Xu Jianzhang Wang Zhiruo Qiu Yayuan Yu Xiaohong Jiang Wanqi Shao Dandan Bai Mingzhu Wang Shuyan Mei Tao Cheng Li Wu Shaorong Gao Xuan Che Department of Obstetrics and Gynecology Affiliated Women and Children Hospital of Jiaxing UniversityJiaxing 314000China Shanghai Key Laboratory of Maternal Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Key Laboratory of animal Bioengineering and Disease Prevention of Shandong Province College of Animal Science and TechnologyShandong Agricultural UniversityTaian 271018China Women’s Hospital School of MedicineZhejiang UniversityHangzhou 310013China Postgraduate training base Alliance of Wenzhou Medical University Wenzhou Medical UniversityWenzhou 325035China Jiaxing University Master Degree Cultivation Base Zhejiang Chinese Medical UniversityHangzhou 310053China Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic OncologyClinical and Translational Research CenterShanghai First Maternity and Infant HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

Adenomyosis is a poorly understood gynecological disorder lacking effective *** persists regarding“invagination”and“metaplasia”*** endometrial-myometrial junction(EMJ)connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis,but its in-depth study is just *** single-cell RNA sequencing and spatial profiling,we mapped transcriptional alterations across eutopic endometrium,lesions,and *** lesions,we identified unique epithelial(LGR5+)and invasive stromal(PKIB+)subpopulations,along with WFDC1+progenitor cells,supporting a complex interplay between“invagination”and“metaplasia”theories of ***,we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin ***-cell communication differed markedly between ectopic and eutopic endometrium,with aberrant signaling in lesions involving pleiotrophin,TWEAK,and WNT *** study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified,dysfunctional signaling,and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.

关键词： adenomyosis single-cell RNA sequencing spatial transcriptomics endometrial-myometrial junction progenitor cells

Long non-coding RNAs with essential roles in neurodegenerative disorders

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Neural Regeneration research 2024年第6期19卷 1212-1220页

作者： Wandi Xiong Lin Lu Jiali Li Key Laboratory of animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province Kunming Institute of Zoology the Chinese Academy of Sciences Tsinghua-Peking center for Life Sciences National Institute on Drug Dependence Peking University PKU/McGovern Institute for Brain research Peking University Institute of Mental Health National Clinical Research Center for Mental Disorders Key Laboratory of Mental Health and Peking University Sixth Hospital Peking University

Recently, with the advent of high-resolution and high-throughput sequencing technologies, an increasing number of long non-coding RNAs(lncRNAs) have been found to be involved in the regulation of neuronal function in the central nervous system with specific spatiotemporal patterns, across different neurodegenerative diseases. However, the underlying mechanisms of lncRNAs during neurodegeneration remain poorly understood. This review provides an overview of the current knowledge of the biology of lncRNAs and focuses on introducing the latest identified roles, regulatory mechanisms, and research status of lncRNAs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Finally, this review discusses the potential values of lncRNAs as diagnostic biomarkers and therapeutic targets for neurodegenerative diseases, hoping to provide broader implications for developing effective treatments.

关键词： Alzheimer's disease amyotrophic lateral sclerosis biomarker Huntington's disease long non-coding RNAs neurodegenerative diseases Parkinson's disease therapy transcriptional regulation translational regulation

Identification of novel genes associated with atherosclerosis in Bama miniature pig

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animal Models and Experimental Medicine 2024年第3期7卷 377-387页

作者： Dengfeng Ding Yuqiong Zhao Yunxiao Jia Miaomiao Niu Xuezhuang Li Xinou Zheng Hua Chen Laboratory animal center Chinese PLA General HospitalBeijingChina

Background:Atherosclerosis is a chronic cardiovascular disease of great ***,it is difficult to establish a direct connection between conventional small animal models and clinical *** pig's genome,physiology,and anatomy reflect human biology better than other laboratory animals,which is crucial for studying the pathogenesis of ***:We used whole-genome sequencing data from nine Bama minipigs to perform a genome-wide linkage analysis,and further used bioinformatic tools to filter and identify underlying candidate *** gene function prediction was performed using the online prediction tool STRING *** and immunofluorescence were used to detect the expression of proteins encoded by candidate ***:We mapped differential single nucleotide polymorphisms(SNPs)to genes and obtained a total of 102 differential genes,then we used GO and KEGG pathway enrichment analysis to identify four candidate genes,including SLA-1,SLA-2,SLA-3,and *** cause changes in the primary and tertiary structures of SLA-I and TAP2 proteins,the primary structures of these two proteins have undergone amino acid changes,and the tertiary structures also show slight *** addition,immunohistochemistry and immunofluorescence results showed that the expression changes of TAP2 protein in coronary arteries showed a trend of increasing from the middle layer to the inner ***:We have identified SLA-I and TAP2 as potential susceptibility genes of atherosclerosis,highlighting the importance of antigen processing and immune response in atherogenesis.

关键词： atherosclerosis candidate genes genome-wide linkage analysis major histocompatibility complex whole genome sequencing

A novel live attenuated vaccine candidate protects chickens against subtype B avian metapneumovirus

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Journal of Integrative Agriculture 2024年第5期23卷 1658-1670页

作者： Lingzhai Meng Mengmeng Yu Suyan Wang Yuntong Chen Yuanling Bao Peng Liu Xiaoyan Feng Tana He Ru Guo Tao Zhang Mingxue Hu Changjun Liu Xiaole Qi Kai Li Li Gao Yanping Zhang Hongyu Cui Yulong Gao Avian Immunosuppressive Diseases Division State Key Laboratory for Animal Disease Control and PreventionHarbin Veterinary Research InstituteChineseAcademy of Agricultural SciencesHarbin150069China Avian ImmunosuppressiveDiseases DivisionStateKey LaboratoryforAnimal Disease Cont National Poultry Laboratory animal Resource center Harbin 150069China

Avian metapneumovirus(aMPV) is a highly contagious pathogen that causes acute upper respiratory tract diseases in chickens and turkeys, resulting in serious economic losses. Subtype B aMPV has recently become the dominant epidemic strain in China. We developed an attenuated aMPV subtype B strain by serial passaging in Vero cells and evaluated its safety and efficacy as a vaccine candidate. The safety test showed that after the 30th passage, the LN16-A strain was fully attenuated, as clinical signs of infection and histological lesions were absent after *** LN16-A strain did not revert to a virulent strain after five serial passages in chickens. The genomic sequence of LN16-A differed from that of the parent wild-type LN16(wtLN16) strain and had nine amino acid mutations. In chickens, a single immunization with LN16-A induced robust humoral and cellular immune responses, including the abundant production of neutralizing antibodies, CD4^(+) T lymphocytes, and the Th1(IFN-γ) and Th2(IL-4 and IL-6)cytokines. We also confirmed that LN16-A provided 100% protection against subtype B aMPV and significantly reduced viral shedding and turbinate inflammation. Our findings suggest that the LN16-A strain is a promising live attenuated vaccine candidate that can prevent infection with subtype B aMPV.

关键词： avian metapneumovirus attenuated protection vaccine candidate chickens

Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

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Oncology research 2024年第2期32卷 325-337页

作者： JIE ZHAO XUANTAO YANG HAIXI ZHANG XUEZHONG GU Department of Hematology The First People’s Hospital of Yunnan ProvinceYunnan Province Clinical Research Center for Hematologic DiseaseYunnan Province Clinical Center for Hematologic DiseaseKunming650032China Department of Pathology The First People’s Hospital of Yunnan ProvinceKunming650032China

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence *** is a new-generation proteasome inhibitor that is used as the first-line therapy for ***,the development of drug resistance is a pervasive obstacle to treating ***,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic *** elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM *** gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion *** upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion ***,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion ***,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor ***,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion *** suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor *** studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

关键词： Multiple myeloma Carfilzomib Drug resistance Major histocompatibility complex TNFRSF1A

Establishment of acquired tracheoesophageal fistula using a modified magnetic compression technique in rabbits and its postmodeling evaluation

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World Journal of Gastrointestinal Surgery 2024年第5期16卷 1385-1394页

作者： Han Meng Fu-Yao Nan Na Kou Qin-Yan Hong Ming-Sheng Lv Ju-Bo Li Bao-Jie Zhang Hang Zou Lei Li Hong-Wu Wang Respiratory Disease center Dongzhimen HospitalBeijing University of Chinese MedicineBeijing 100029China The First clinical Medical College Beijing University of Chinese MedicineBeijing 100700China Department of animal Experimental center National Center for CardiovascularFuwai HospitalBeijing 100037China

BACKGROUND Previous studies have validated the efficacy of both magnetic compression and surgical techniques in creating rabbit tracheoesophageal fistula(TEF)*** compression achieves a 100%success rate but requires more time,while surgery,though less frequently successful,offers rapid model establishment and technical maturity in larger animal *** To determine the optimal approach for rabbit disease modeling and refine the *** TEF models were created in 12 rabbits using both the modified magnetic compression technique and *** of the time to model establishment,success rate,food and water intake,weight changes,activity levels,bronchoscopy findings,white blood cell counts,and biopsies were *** response to the failures encountered during modified magnetic compression modeling,we increased the sample size to 15 rabbit models and assessed the repeatability and stability of the models,comparing them with the original magnetic compression *** The modified magnetic compression technique achieved a 66.7%success rate,whereas the success rate of the surgery technique was 33.3%.Surviving surgical rabbits might not meet subsequent experimental requirements due to TEF-related *** the modified magnetic compression group,one rabbit died,possibly due to magnet corrosion,and another died from tracheal magnet *** events occurred during the second round of modified magnetic compression modeling,with one rabbit possibly succumbing to aggravated lung *** operation time of the first round of modified magnetic compression was 3.2±0.6 min,which was significantly reduced to 2.1±0.4 min in the second round,compared to both the first round and that of the original *** The modified magnetic compression technique exhibits lower stress responses,a simple procedure,a high success rate,and lower modeling costs,making it a more appropriate choice for constructing TEF models in

关键词： Tracheoesophageal fistula Modified magnetic compression technique Post-modeling evaluation Pneumonia Malnutrition

Optogenetics in oral and craniofacial research

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第8期25卷 656-671页

作者： Qinmeng ZHANG Luyao SONG Mengdie FU Jin HE Guoli YANG Zhiwei JIANG Stomatology Hospital School of StomatologyZhejiang University School of MedicineZhejiang Provincial Clinical Research Center for Oral DiseasesKey Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhou 310000China Zhejiang University School of Medicine Hangzhou 310058China

Optogenetics combines optics and genetic engineering to control specific gene expression and biological functions and has the advantages of precise spatiotemporal control,noninvasiveness,and high *** modified photosensory sensors are engineered into proteins to modulate conformational changes with light ***,optogenetic techniques can provide new insights into oral biological processes at different levels,ranging from the subcellular and cellular levels to neural circuits and behavioral ***,we introduce the origins of optogenetics and highlight the recent progress of optogenetic approaches in oral and craniofacial research,focusing on the ability to apply optogenetics to the study of basic scientific neural mechanisms and to establish different oral behavioral test models in vivo(orofacial movement,licking,eating,and drinking),such as channelrhodopsin(ChR),archaerhodopsin(Arch),and halorhodopsin from Natronomonas pharaonis(NpHR).We also review the synergic and antagonistic effects of optogenetics in preclinical studies of trigeminal neuralgia and maxillofacial *** addition,optogenetic tools have been used to control the neurogenic differentiation of dental pulp stem cells in translational *** the scope of optogenetic tools is increasing,there are limited large animal experiments and clinical studies in dental *** future directions include exploring therapeutic strategies for addressing loss of taste in patients with coronavirus disease 2019(COVID-19),studying oral bacterial biofilms,enhancing craniomaxillofacial and periodontal tissue regeneration,and elucidating the possible pathogenesis of dry sockets,xerostomia,and burning mouth syndrome.

关键词： Lasers Cell differentiation Bacterial virulence Nervous system Neurophysiology Behavioral science