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Diagnostic and Therapeutic Micrornas in Primary Myelofibrosis

Proceedings of the Singapore National Academy of Science 2020年第2期14卷 91-109页

作者： Roxana Manaila Vlad Moisoiu Erik Knutsen Mihnea P. Dragomir George A. Calin Clinical Institute of Urology and Renal Transplantation Cluj-Napoca Romania Contributed equally to this manuscript. Faculty of Physics Babeş-Bolyai University Cluj-Napoca Romania Department of Medical Biology Faculty of Health Sciences UiT — The Arctic University of Norway Tromsø Norway Department of Surgery Fundeni Clinical Hospital Carol Davila University of Medicine and Pharmacy Bucharest Romania Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston TX USA The Center for RNA Interference and Non-Coding RNAs The University of Texas MD Anderson Cancer Center Houston TX USA

Primary myelofibrosis (PMF) is a pluripotent hematopoietic stem cell-derived malignancy, included in the heterogeneous group of myeloproliferative neoplasms (MPNs). PMF diagnosis is based on a composite assessment of clinical and laboratory data. The three major diagnostic criteria are: screening for driver mutations, exclusion of other conditions that can cause myelofibrosis, and bone marrow biopsy displaying megakaryocyte changes and fibrosis. PMF treatment options are only partially disease-modifying and consist mainly of symptom control. Recently, a new targeted therapy was introduced for PMF patients, JAK-STAT inhibitors (i.e. ruxolitinib). However, specific subgroups of patients do not benefit from the JAK-STAT inhibitors: (1) those who are carrying JAK2 mutations, but ruxolitinib does not reduce the spleen size; (2) triple negative patients (no JAK2 , CALR , or MPL mutations); and (3) those who discontinue JAK-STAT therapy because of side effects. These subgroups are in need of new therapeutic approaches. Mature micrornas (mirnas) range from 16 to 28 nucleotides (nt) in length and regulate specific messenger rnas at the post-transcriptional level. Numerous in vitro and in vivo studies have reported specific mirnas, as well as complex mirna networks, to be dysregulated in PMF. Several of these mirnas were shown to be implicated in essential events of PMF pathophysiology: increase of bone marrow fibrosis, progression to acute myeloid leukemia, resistance to JAK-STAT inhibitors, and activation of differentiation of hematopoietic stem/progenitor cells into megakaryocytes. Hence, we propose mirnas as a potential minimally invasive diagnostic tool for PMF and as therapeutic targets that could address the unmet medical needs of these patients.

关键词： Primary myelofibrosis myeloproliferative neoplasms microrna network theory JAK-STAT inhibitors ruxolitinib miR-379/656 cluster microrna therapy

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Association between nonalcoholic Fatty Liver Disease and Carotid Artery Disease in a Community-Based Chinese Population： A Cross-Sectional Study

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Chinese Medical Journal 2018年第19期131卷 2269-2276页

作者： Yu-Chen Guo Yong Zhou Xing Gao Yan Yao Bin Geng Qing-Hua Cui Ji-Chun Yang Hong-Pu Hu Department of Health Information Management Institute of Medical Information Peking Union Medical College & Chinese Academy of Medical Sciences Beijing 100020 China Beijing Institute of Heart Lung and Blood Vessel Diseases Beijing Anzhen Hospital Capital Medical University Beijing 100029 China Department of Cardiology Beijing Anzhen Hospital Capital Medical University Beijing 100029 China Hypertension Center Fuwai Hospital Chinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Cardiovascular Disease Beijing 100037 China Department of Biomedical Informatics School of Basic Medical Sciences Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education Center for Non-coding RNA Medicine Peking University Health Science Center Beijing 100191 China Department of Physiology and Pathophysiology School of Basic Medical Sciences Peking University Health Science Center Beijing 100191 China

Background： nonalcoholic fatty liver disease （NAFLD） is one of the most common chronic liver diseases with a high prevalence in the general population. The association between NAFLD and cardiovascular disease has been well addressed in previous studies. However, whether NAFLD is associated with carotid artery disease in a community-based Chinese population remained unclear. The aim of this study was to investigate the association between NAFLD and carotid artery disease. Methods： A total of 2612 participants （1091 men and 1521 women） aged 40 years and older from Jidong of Tangshan city （China） were selected for this study. NAFLD was diagnosed by abdominal ultrasonography. The presence of carotid stenosis or plaque was evaluated by carotid artery ultrasonography. Logistic regression was used to analyze the association between NAFLD and carotid artery disease. Results： Participants with NAFLD have a higher prevalence of carotid stenosis （12.9% vs. 4.6%） and carotid plaque （21.9% vs. 15.0%） than those without NAFLD. After adjusting for age, gender, smoking status, income, physical activity, diabetes, hypertension, triglyceride, waist-hip ratio, and high-density lipoprotein, NAFLD is significantly associated with carotid stenosis （odds ratio [OR]： 2.06, 95% confidence interval [CI]： 1.45-2.91）, but the association between NAFLD and carotid plaque is not statistically significant （OR： 1. 10, 95% CI： 0.86-1.40）. Conclusion： A significant association between NAFLD and carotid stenosis is found in a Chinese population.

关键词： Association Carotid Artery Disease Carotid Stenosis nonalcoholic Fatty Liver Disease

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Lncrnas-directed PTEN enzymatic switch governs epithelial-mesenchymal transition

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细胞研究（英文版） 2019年第4期29卷 286-304页

作者： Qingsong Hu Chunlai Li Shouyu Wang Yajuan Li Bo Wen Yanyan Zhang Ke Liang Jun Yao Youqiong Ye Heidi Hsiao Tina K.Nguyen Peter K.Park Sergey D.Egranov David H.Hawke Jeffrey R.Marks Leng Han Mien-Chie Hung Bing Zhang Chunru Lin Liuqing Yang Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing Jiangsu Province China Department of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 USA Lester and Sue Smith Breast Center Baylor College of Medicine Houston TX 77030 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Institute of Immunology Third Military Medical University 400038 Chongqing China Department of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston McGroven Medical School Houston TX 77030 USA Department of Systems Biology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Surgery Duke University School of Medicine Durham NC 27710 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA program in Cancer Biology Graduate School of Biomedical Sciences The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA program in Cancer Biology Graduate School of Biomedical Sciences The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Center for RNA Interference and Non-Coding RNAs The University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Despite the structural consenvation of PTEN with dual-specificity phosphatases,there have been no reports regarding the regulatory mechanisms that underlie this potential dual-phosphatase ***,we report that K27-linked polyubiquitination of PTEN at lysines 66 and 80 switches its phosphoinositide/protein tyrosine phosphatase activity to protein serine/threonine phosphatase ***,high glucose,TGF-β,CTGF,SHH,and IL-6 induce the expression of a long non-coding rna,GAEA (Glucose Aroused for EMT Activation),which associates with an rna-binding E3 ligase,MEX3C,and enhances its enzymatic activity,leading to the K27-linked polyubiquitination of *** MEX3C-catalyzed PTENK27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase *** this altered enzymatic activity,PTENK27-polyub dephosphorylates the phosphoserine/threonine residues of TWlST1,SNAI1,and YAP1,leading to accumulation of these master regulators of *** with genetic inhibition of PTENK27polyUb,by a single nucieotide mutation generated using CRISPR/Cas9 (PtenK80R/K80R),exhibit inhibition of EMT markers during mammary gland morphogenesis in pregnancy/lactation and during cutaneous wound healing *** findings illustrate an unexpected paradigm in which the Incrna-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development.

关键词： Epithelial-mesenchymal transition Long non-coding rnas Ubiquitylation

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The Sierra Platinum Service for generating peak-calls for replicated ChIP-seq experiments

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BMC Research Notes 2018年第1期11卷 1-5页

作者： Wiegreffe, Daniel Müller, Lydia Steuck, Jens Zeckzer, Dirk Stadler, Peter F. Image and Signal Processing Group Department of Computer Science University of Leipzig Augustusplatz 10 Leipzig 04109 Germany Natural Language Processing Department Department of Computer Science University of Leipzig Augustusplatz 10 Leipzig 04109 Germany Bioinformatics Group Department of Computer Science University of Leipzig Härtelstraße 16-18 Leipzig 04107 Germany Interdisciplinary Center for Bioinformatics University of Leipzig Härtelstraße 16-18 Leipzig 04107 Germany Max Planck Institute MIS Inselstraße 22 Leipzig 04103 Germany Fraunhofer Institute for Cell Therapy and Immunology IZI Perlickstraße 1 Leipzig 04103 Germany Institute for Theoretical Chemistry University of Vienna Währinger Straße 17 Vienna 1090 Austria Center for Non-coding RNA in Technology and Health University of Copenhagen Grønnegårdsvej 3 Copenhagen 1870 Denmark Santa Fe Institute 1399 Hyde Park Road Santa Fe 87501 NM United States

Objective: Sierra Platinum is a fast and robust peak-caller for replicated ChIP-seq experiments with visual quality-control and -steering. The required computing resources are optimized but still may exceed the resources available to researchers at biological research institutes. Results: Sierra Platinum Service provides the full functionality of Sierra Platinum: using a web interface, a new instance of the service can be generated. Then experimental data is uploaded and the computation of the peaks is started. Upon completion, the results can be inspected interactively and then downloaded for further analysis, at which point the service terminates. © 2018 The Author(s).

关键词： ChIP-seq Histone modifications Peak-caller Replicate analysis

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Erratum to: Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer

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Breast Cancer Research 2012年第6期14卷 1-2页

作者： Valerie Cortez Monica Mann Seshidhar Tekmal Ratna K Vadlamudi Takayoshi Suzuki Naoki Miyata Cristian Rodriguez-Aguayo Gabriel Lopez-Berestein Anil K Sood Department of Obstetrics and Gynecology University of Texas Health Science Center San Antonio TX 78229 USA Department of Cell and Structural Biology University of Texas Health Science Center San Antonio TX 78229 USA Cancer Therapy and Research Center University of Texas Health Science Center San Antonio TX 78229 USA Graduate School of Medical Science Kyoto Prefectural University of Medicine 13 Taishogun Nishitakatsukasa-Cho Kita-ku Kyoto 403-8334 Japan PRESTO Japan Science and Technology Agency 4-1-8 Honcho Kawaguchi Saitama 332-0012 Japan Graduate School of Pharmaceutical Sciences Nagoya City University 3-1 Tanabe-dori Mizuho-ku Nagoya Aichi 467-8673 Japan Department of Gynecologic Oncology University of Texas MD Anderson Cancer Center Houston TX 78030 USA Center for RNA Interference and Non-coding RNA University of Texas MD Anderson Cancer Center Houston TX 78030 USA Department of Cancer Biology University of Texas MD Anderson Cancer Center Houston TX 78030 USA

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A novel tissue engineered nerve graft constructed with autologous vein and nerve microtissue repairs a longsegment sciatic nerve defect

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Neural Regeneration Research 2021年第1期16卷 143-149页

作者： Jing Wang Ya-Qiong Zhu Yu Wang Hong-Guang Xu Wen-Jing Xu Yue-Xiang Wang Xiao-Qing Cheng Qi Quan Yong-Qiang Hu Chang-Feng Lu Yan-Xu Zhao Wen Jiang Chen Liu Liang Xiao Wei Lu Chen Zhu Ai-Yuan Wang Spine Research Center of Wannan Medical College Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution(Wannan Medical College)Department of Spine SurgeryYijishan HospitalThe First Affiliated Hospital of Wannan Medical CollegeWuhuAnhui ProvinceChina Department of Ultrasound Chinese PLA General HospitalBeijingChina Department of Orthopedic Surgery Key Laboratory of Musculoskeletal Trauma&War Injuries PLABeijing Key Lab of Regenerative Medicine in OrthopedicsChinese PLA General HospitalBeijingChina Medical College of Nankai University TianjinChina The Neural Regeneration Co-Innovation Center of Jiangsu Province NantongJiangsu ProvinceChina Department of Anesthesiology the Second Affiliated Hospital of Inner Mongolia Medical UniversityHuhhotInner Mongolia Autonomous RegionChina Department of Orthopedic Surgery Yan’an University Affiliated HospitalYan’anShaanxi ProvinceChina Department of Orthopedic Surgery the First Affiliated Hospital of Medical CollegeShihezi UniversityShiheziXinjiang Uygur Autonomous RegionChina Department of Orthopedic Surgery The First Peoples’Hospital of Yunnan ProvinceKunmingYunnan ProvinceChina Department of Orthopedic Surgery Anhui Provincial HospitalThe First Affiliated Hospital of University of Science and Technology of ChinaHeifeiAnhui ProvinceChina

Veins are easy to obtain,have low immunogenicity,and induce a relatively weak inflammatory ***,veins have the potential to be used as conduits for nerve ***,because of the presence of venous valves and the great elasticity of the venous wall,the vein is not conducive to nerve *** this study,a novel tissue engineered nerve graft was constructed by combining normal dissected nerve microtissue with an autologous vein graft for repairing 10-mm peripheral nerve defects in *** with rats given the vein graft alone,rats given the tissue engineered nerve graft had an improved sciatic static index,and a higher amplitude and shorter latency of compound muscle action ***,rats implanted with the microtissue graft had a higher density and thickness of myelinated nerve fibers and reduced gastrocnemius muscle atrophy compared with rats implanted with the vein ***,the tissue engineered nerve graft had a lower ability to repair the defect than autogenous nerve *** summary,although the tissue engineered nerve graft constructed with autologous vein and nerve microtissue is not as effective as autologous nerve transplantation for repairing long-segment sciatic nerve defects,it may nonetheless have therapeutic potential for the clinical repair of long sciatic nerve *** study was approved by the Experimental Animal Ethics Committee of Chinese PLA General Hospital(approval No.2016-x9-07)on September 7,2016.

关键词： in vivo injury motor neurological function peripheral nerve injury rat recovery regeneration repair

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An intermediate level of abstraction for computational systems chemistry

arXiv

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arXiv 2017年

作者： Andersen, Jakob L. Flamm, Christoph Merkle, Daniel Stadler, Peter F. Earth-Life Science Institute Tokyo Institute of Technology Tokyo152-8550 Japan Department of Mathematics and Computer Science University of Southern Denmark Denmark Research Network Chemistry Meets Microbiology University of Vienna WienA-1090 Austria Institute for Theoretical Chemistry University of Vienna Austria Department of Computer Science University of Leipzig Germany Max Planck Institute for Mathematics in the Sciences Leipzig Germany Fraunhofer Institute for Cell Therapy and Immunology Leipzig Germany Center for non-coding RNA in Technology Health University of Copenhagen Denmark Santa Fe Institute Santa Fe United States

Computational techniques are required for narrowing down the vast space of possibilities to plausible prebiotic scenarios, since precise information on the molecular composition, the dominant reaction chemistry, and the conditions for that era are scarce. The exploration of large chemical reaction networks is a central aspect in this endeavour. While quantum chemical methods can accurately predict the structures and reactivities of small molecules, they are not efficient enough to cope with large-scale reaction systems. The formalization of chemical reactions as graph grammars provides a generative system, well grounded in category theory, at the right level of abstraction for the analysis of large and complex reaction networks. An extension of the basic formalism into the realm of integer hyperflows allows for the identification of complex reaction patterns, such as auto-catalysis, in large reaction networks using optimization techniques. Copyright © 2017, The Authors. All rights reserved.

关键词： Formal languages

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Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells

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Experimental and Clinical Endocrinology & Diabetes 2021年第8期130卷 498-508页

作者： Han Yan Zhenzhen Chen Haizeng Zhang Weili Yang Xiangyang Liu Yuhong Meng Rui Xiang Zhe Wu Jingjing Ye Yujing Chi Jichun Yang Department of Physiology and Pathophysiology School of Basic Medical Sciences Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education Center for Non-coding RNA Medicine Peking University Health Science Center Beijing 100191 China Hypertension Center Fuwai Hospital Chinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Cardiovascular Disease National Center for Cardiovascular Diseases Beijing 100037 China Beijing Key Laboratory of diabetes Research and Care Beijing Tongren Hospital Capital Medical University Beijing 100730 China Department of Gastroenterology Peking University People’s Hospital Beijing 100044 China Department of Central Laboratory & Institute of Clinical Molecular Biology Peking University People’s Hospital Beijing 100044 China

FAM3A is a recently identified mitochondrial protein that stimulates pancreatic-duodenal homeobox 1 (PDX1) and insulin expressions by promoting ATP release in islet β cells. In this study, the role of intracellular ATP in FAM3A-induced PDX1 expression in pancreatic β cells was further examined. Acute FAM3A inhibition using sirna transfection in mouse pancreatic islets significantly reduced PDX1 expression, impaired insulin secretion, and caused glucose intolerance in normal mice.

关键词： FAM3A pancreatic β cells intracellular ATP PDX1 insulin secretion

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Double-network hydrogel enhanced by SS31-loaded mesoporous polydopamine nanoparticles:Symphonic collaboration of near-infrared photothermal antibacterial effect and mitochondrial maintenance for full-thickness wound healing in diabetes mellitus

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Bioactive Materials 2023年第9期27卷 409-428页

作者： Qing-Song Deng Yuan Gao Bi-Yu Rui Xu-Ran Li Po-Lin Liu Zi-Yin Han Zhan-Ying Wei Chang-Ru Zhang Fei Wang Helen Dawes Tong-He Zhu Shi-Cong Tao Shang-Chun Guo Department of Orthopedic Surgery Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RoadShanghai200233China School of Medicine Shanghai Jiao Tong University227 South Chongqing RoadShanghai200025China Institute of Microsurgery on Extremities Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RoadShanghai200233China Department of Rheumatology The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical UniversityNo.29XinglongxiangTianning DistrictChangzhou213000China Shanghai Clinical Research Centre of Bone Diseases Department of Osteoporosis and Bone DiseasesShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200233China Shanghai Key Laboratory of Orthopedic Implants Department of Orthopedic SurgeryShanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineNo.639 Zhizaoju RoadShanghai200011China Clinical and Translational Research Center for 3D Printing Technology Medical 3D Printing Innovation Research CenterShanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai200125China Department of Orthopedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopedicsRuijin HospitalShanghai Jiao Tong University School of Medicine197 Ruijin Second RoadShanghai200025China Faculty of Health and Life Science Oxford Brookes UniversityHeadington RoadOxfordOX30BPUK NIHR Oxford Health Biomedical Research Centre OxfordOX37JXUK College of Medicine and Health St Lukes CampusUniversity of ExeterHeavitree RoadExeterEX12LUUK School of Chemistry and Chemical Engineering Shanghai Engineering Research Center of Pharmaceutical Intelligent EquipmentShanghai Frontiers Science Research Center for Druggability of Cardiovascular Non-Coding RNAInstitute for Frontier Medical TechnologyShanghai University of

Diabetic wound healing has become a serious healthcare *** high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction,resulting in chronic inflammation,abnormal vascular function,and tissue *** solve these issues,we developed a double-network hydrogel,constructed with pluronic F127 diacrylate(F127DA)and hyaluronic acid methacrylate(HAMA),and enhanced by SS31-loaded mesoporous polydopamine nanoparticles(MPDA NPs).As components,SS31,a mitochondria-targeted peptide,maintains mitochondrial function,reduces mitochondrial reactive oxygen species(ROS)and thus regulates macrophage polarization,as well as promoting cell proliferation and migration,while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation,but also control release of SS31 in response to *** F127DA/HAMA-MPDA@SS31(FH-M@S)hydrogel has characteristics of adhesion,superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31(M@S)*** addition,in a diabetic rat full thickness skin defect model,the FH-M@S hydrogel promoted macrophage M2 polarization,collagen deposition,neovascularization and wound ***,the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration.

关键词： Mesoporous polydopamine nanoparticles(MPDA NPs) SS31 Photothermal antibacterial Mitochondrial function maintenance Diabetic wound healing

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Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

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Genetics in Medicine 2025年第4期27卷 101251页

作者： Cali, Elisa Quirin, Tania Rocca, Clarissa Efthymiou, Stephanie Riva, Antonella Marafi, Dana Zaki, Maha S. Suri, Mohnish Dominguez, Roberto Elbendary, Hasnaa M. Alavi, Shahryar Abdel-Hamid, Mohamed S. Morsy, Heba Mau-Them, Frederic Tran Nizon, Mathilde Tesner, Pavel Ryba, Lukáš Zafar, Faisal Rana, Nuzhat Saadi, Nebal W. Firoozfar, Zahra Gencpinar, Pinar Unay, Bulent Ustun, Canan Bruel, Ange-Line Coubes, Christine Stefanich, Jennifer Sezer, Ozlem Agolini, Emanuele Novelli, Antonio Vasco, Gessica Lettori, Donatella Milh, Mathieu Villard, Laurent Zeidler, Shimriet Opperman, Henry Strehlow, Vincent Issa, Mahmoud Y. El Khassab, Hebatallah Chand, Prem Ibrahim, Shahnaz Rashidi-Nezhad, Ali Miryounesi, Mohammad Larki, Pegah Morrison, Jennifer Cristian, Ingrid Thiffault, Isabelle Bertsch, Nicole L. Noh, Grace J. Pappas, John Moran, Ellen Marinakis, Nikolaos M. Traeger-Synodinos, Joanne Hosseini, Susan Abbaszadegan, Mohammad Reza Caumes, Roseline Vissers, Lisenka E.L.M. Neshatdoust, Maedeh Montazer Zohour, Mostafa El Fahime, Elmostafa Canavati, Christina Kamal, Lara Kanaan, Moien Askander, Omar Voinova, Victoria Levchenko, Olga Haider, Shahzhad Halbach, Sara S. Elias Maia, Rayana Mansoor, Salehi Jain, Vivek Tawde, Sanjukta Challa, Viveka Santhosh R. Gowda, Vykuntaraju K. Srinivasan, Varunvenkat M. Victor, Lucas Alves Pinero-Banos, Benito Hague, Jennifer ElAwady, Heba Ahmed Maria de Miranda Henriques-Souza, Adelia Cheema, Huma Arshad Anjum, Muhammad Nadeem Idkaidak, Sara Alqarajeh, Firas Atawneh, Osama Mor-Shaked, Hagar Harel, Tamar Zifarelli, Giovanni Bauer, Peter Kok, Fernando Kitajima, Joao Paulo Monteiro, Fabiola Josahkian, Juliana Lesca, Gaetan Chatron, Nicolas Ville, Dorothe Murphy, David Neul, Jeffrey L. Mullegama, Sureni V. Begtrup, Amber Herman, Isabella Mitani, Tadahiro Posey, Jennifer E. Tay, Chee Geap Javed, Iram Carr, Lucinda Kanani, Farah Beecroft, Fiona Hane, Lee Abdelkreem, Elsayed Macek, Milan Bispo, Luciana Elmaksoud, Marwa Abd Hashemi-Gorji, Farzad Pehlivan, Davut Amor, David J. Jamra, Rami Abou Chung, Wend Department of Neuromuscular Diseases University College London Queen Square Institute of Neurology London United Kingdom RNA Molecular Biology Fonds de la Recherche Scientifique (F.R.S./FNRS) Université libre de Bruxelles (ULB) Biopark campus Gosselies Belgium Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa Genoa Italy Department of Molecular and Human Genetics Baylor College of Medicine Houston TX United States Department of Pediatrics Faculty of Medicine Kuwait University Safat Kuwait Clinical Genetics Department Human Genetics and Genome Research Institute National Research Centre Cairo Egypt UK National Paediatric Ataxia Telangiectasia Clinic Nottingham University Hospitals NHS Trust Nottingham United Kingdom Nottingham Clinical Genetics Service Nottingham University Hospitals NHS Trust Nottingham United Kingdom Department of Physiology Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Palindrome Isfahan Iran Medical Molecular Genetics Department Human Genetics and Genome Research Institute National Research Centre Cairo Egypt Human Genetics Department Medical Research Institute Alexandria University Egypt Unité Fonctionnelle 6254 d'Innovation en Diagnostique Génomique des Maladies Rares Pôle de Biologie CHU Dijon Bourgogne Dijon France INSERM UMR1231 GAD Dijon France Service de génétique médicale CHU de Nantes Nantes France Institut du thorax INSERM CNRS UNIV Nantes Nantes France Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic Department of Paediatric Neurology Children's Hospital and Institute of Child Health Multan Pakistan College of Medicine/University of Baghdad Unit of Pediatric Neurology Children Welfare Teaching Hospital Baghdad Iraq İzmir Katip Çelebi University Tepecik Training and Research Department of Pediatric Neurology Izmir Türkiye U

Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rrna processing. Conclusion: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of “ribosomopathies.” © 2024 The Authors

关键词： ACTL6B Autism BAFopathies Epileptic-dyskinetic encephalopathy Ribosomopathies

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