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Biallelic variants in RBM42 cause a multisystem disorder with neurological,facial,cardiac,and musculoskeletal involvement

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Protein & Cell 2024年第1期15卷 52-68页

作者： Yiyao Chen Bingxin Yang Xiaoyu Merlin Zhang Songchang Chen Minhui Wang Liya Hu Nina Pan Shuyuan Li Weihui Shi Zhenhua Yang Li Wang Yajing Tan Jian Wang Yanlin Wang Qinghe Xing Zhonghua Ma Jinsong Li He-Feng Huang Jinglan Zhang Chenming Xu institutes of Biomedical Sciences Fudan UniversityShanghai 200032China bstetrics and Gynecology Hospital Institute of Reproduction and DevelopmentFudan UniversityShanghai 200011China Intermational Peace Matermity and Child Health Hospital School of MedicineShanghai Jiao Tong UniversityShanghai 200030China Shanghai Key Laboratory of Embryo Original Diseases Shanghai 200030China State Key Laboratory of Cell Biology Shanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCAS Center for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China State Key Laboratory of Rice Biology the Key Laboratory of Molecular Biology of Crop Pathogens and InsectsInstitute of BiotechnologyZhejiang UniversityHangzhou 310058China Verna and Marrs McLean Department of Biochemistry and molecular Biology Baylor College of MedicineHoustonTX 77030USA Children's hospital of Fudan University Shanghai 201102China School of Life Science and Technology Shanghai Tech UniversityShanghai 201210China School of Life Science Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024ZhejiangChina Research Units of Embryo Original Diseases Chinese Academy of Medical Sciences(No.2019RU056)Shanghai 200011China

Here,we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 *** patient is a 2-year-old female with severe central nervous system(CNs)abnormalities,hypotonia,hearing loss,congenital heart defects,and dysmorphic facial *** whole-exome sequencing(WEs)reveals that the patient has two compound heterozygous variants,c.304C>T(p.R102*)and c.1312G>A(p.A438T),in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein *** p.A438T variant is in the RRM domain which impairs RBM42 pro-tein stability in ***,p.A438T disrupts the interaction of RBM42 with hnRNP K,which is the causa-tive gene for Au-Kline syndrome with overlapping disease characteristics seen in the index *** human R102*or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout△FgRbp1 in Fusarium while it was rescued by the wild-type(WT)human RBM42.A mouse model carying Rbm42 compound heterozygous variants,c.280C>T(p.Q94*)and c.1306_1308delinsACA(p.A436T),demonstrated gross fetal develop-mental defects and most of the double mutant animals died by ***-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing(As).Overall,we present clinical,genetic,and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.

关键词： RBM42 gene RNA-binding protein neurodevelopmental disorder Au-Kline syndrome alternative splicing

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Fasudil-modified macrophages reduce inflammation and regulate the immune response in experimental autoimmune encephalomyelitis

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Neural Regeneration Research 2024年第3期19卷 671-679页

作者： Chunyun Liu Shangde Guo Rong Liu Minfang Guo Qing Wang Zhi Chai Baoguo Xiao Cungen Ma Institute of Brain Science Shanxi Datong UniversityDatongShanxi ProvinceChina The Key Research Laboratory of Benefiting Qi for Acting Blood Cireulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese medicine/Research Center of Neurobiology Shanxi University of Chinese MedicineTaiyuanShanxi ProvinceChina Institute of Neurology Huashan HospitalInstitutes of Brain Science and State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina

Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous *** polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple *** study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune *** found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and ***,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified *** addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced *** findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for m

关键词： anti-inflammatory experimental autoimmune encephalomyelitis Fasudil macrophage multiple sclerosis pro-inflammatory Rho kinase

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A systematic review of salivary biomarkers in Parkinson's disease

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Neural Regeneration Research 2024年第12期19卷 2613-2625页

作者： Maria Ilenia De Bartolo Daniele Belvisi Romina Mancinelli Matteo Costanzo Claudia Caturano Giorgio Leodori Alfredo Berardelli Giovanni Fabbrini Giorgio Vivacqua IRCCS Neuromed PozzilliItaly Department of Human Neurosciences Sapienza University of RomeRomeItaly Department of Anatomical HistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly Department of experimental Morphology and Microscopy-Integrated Research Center(PRAAB)-Campus Biomedico University of Rome RomeItaly

The search fo r reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis,to detect neurodegeneration from the prodromal phase and to enforce disease-modifying *** the need for non-invasively accessible biomarke rs,the majo rity of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers,which require invasive collection *** represents an easily accessible biofluid and an incredibly wide source of molecular *** the present study,after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease,we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients.A comprehensive literature search on PubMed and SCOPUS led to the discovery of *** screening and exclusion,34 relevant articles were derived fo r systematic ***-synuclein,the histopathological hallmark of Parkinson's disease,has been the most investigated Parkinson's disease biomarker in saliva,with oligomeric alphasynuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls,while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein,and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's *** alpha-synuclein,other biomarkers to rgeting diffe rent molecular pathways have been explored in the saliva of Parkinson's disease patients:total tau,phosphorylated tau,amyloid-β1-42(pathological protein aggregation biomarkers);DJ-1,heme-oxygenase-l,metabolites(alte red energy homeostasis biomarkers);MAPLC-3beta(aberrant proteostasis biomarker);cortisol,tumor necrosis factor-alpha(inflammation biomarkers);DNA methylation,miRNA(DNA/RNA defects biomarkers);acetylcholinesterase activity(synaptic and neuronal network

关键词： alpha-synuclein amyloid-beta autophagy DJ-1 neurodegeneration neuroinflammation Parkinson's disease salivary biomarkers tau

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Harnessing innate immune pathways for therapeutic advancement in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1506-1564页

作者： Ankang Hu Li Sun Hao Lin Yuheng Liao Hui Yang Ying Mao Department of Neurosurgery Huashan HospitalFudan UniversityShanghaiP.R.China Institute for Translational Brain Research Shanghai Medical CollegeFudan University ShanghaiPR.China National Center for Neurological Disorders Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration Shanghai Clinical Medical Center of NeurosurgeryNeurosurgical Institute of Fudan UniversityHuashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science Institutes of Brain ScienceShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)and Key Laboratory of Metabolism and Molecular Medicine(Ministry of Education)and Molecular and Cell Biology LabInstitutes of Biomedical SciencesShanghai Medical College of Fudan UniversityShanghaiP.R.China

The innate immune pathway is receiving increasing attention in cancer *** pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal *** targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical ***,to date,the clinical success of drugs targeting the innate immune pathway remains ***,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor *** uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate *** this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell *** propose that within the TME,the innate immune pathway exhibits multidimensional *** diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling *** pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative *** our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.

关键词： drugs therapeutic innate

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Genomic Mosaicism of the Brain:Origin,Impact,and Utility

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Neuroscience Bulletin 2024年第6期40卷 759-776页

作者： Jared H.Graham Johannes C.M.Schlachetzki Xiaoxu Yang Martin W.Breuss Department of Pediatrics Section of Clinical Genetics and MetabolismUniversity of Colorado School of MedicineAurora80045-2581COUSA Department of Cellular and molecular medicine University of California San DiegoLa Jolla92093-0021San DiegoCAUSA Department of Neurosciences University of California San DiegoLa Jolla92093-0021San DiegoCAUSA Rady Children’s Institute for Genomic medicine San Diego92123CAUSA

Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic ***,research focused on the impact of genomic mosaicism on clinical phenotype—motivated by its involvement in cancers and overgrowth *** recently,we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental ***,we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and *** the field of genomic mosaicism has a rich history,technological advances in the last decade have changed our approaches and greatly improved our *** will provide current definitions and an overview of contemporary detection approaches for genomic ***,we will discuss the impact and utility of genomic mosaicism.

关键词： Genomics Brain development Brain homeostasis Genomic mosaicism

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Single-neuron neurodegeneration as a degenerative model for Parkinson’s disease

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Neural Regeneration Research 2024年第3期19卷 529-535页

作者： Sandro Huenchuguala Juan Segura-Aguilar Escuela de Tecnología Médica Facultad de SaludUniversidad Santo TomásLos CarrerasOsornoChile molecular&Clinical Pharmacology Instituto de Ciencias Biomedicas(ICBM)Faculty of medicineUniversity of ChileIndependenciaSantiagoChile

The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal *** preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical ***,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic *** lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big *** our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic *** exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic *** endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in t

关键词： 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 6-hydroxydopamine aminochrome dopaminergic neurons DT-diaphorase exogenous neurotoxins glutathione transferase M2-2

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Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

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Zoological Research 2024年第2期45卷 253-262页

作者： Yang Han Jiale Zhou Renquan Zhang Yuru Liang Liangxue Lai Zhanjun Li Key Laboratory of Zoonosis Research Ministry of EducationCollege of Animal ScienceJilin UniversityChangchunJilin 130062China CAS Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative MedicineSouth China Institute for Stem Cell Biology and Regenerative MedicineGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouGuangdong 510530China Guangzhou Regenerative medicine and Health Guang Dong Laboratory(GRMH-GDL) GuangzhouGuangdong 510005China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene *** field of genome modification in rabbits has progressed ***,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic *** models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to *** review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

关键词： Genome editing Animal model Rabbit CRISPR/Cas9 Genetic diseases

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Generation of brain vascular heterogeneity:recent advances from the perspective of angiogenesis

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Neural Regeneration Research 2025年第7期20卷 2013-2014页

作者： Nathanael J.Lee Ryota L.Matsuoka Department of Neurosciences Lerner Research InstituteCleveland ClinicClevelandOHUSA Department of molecular medicine Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandOHUSA

Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose and oxygen through its vascular *** vasculature consists of highly divergent blood vessel branches,giving rise to a dense network of capillaries that supply blood to all cells across the *** elaborated vascular network is thought to develop via angiogenesis,a process in which new blood vessels grow from pre-existing *** capillaries exhibit organotypic features distinct from other tissues and are formed primarily by two major endothelial cell(EC)types:those that form the semi-permeable blood-brain barrier(BBB)and those that develop highly permeable pores known as fenestrae(Matsuoka et al.,2022).The structural and functional differences between BBB and fenestrated vascular ECs represent a fundamental feature of brain vasculature and form the foundation for both brain function and homeostasis.

关键词： angiogenesis homeostasis network

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PICOTEES:a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants from Chinese children cohorts

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Journal of Genetics and Genomics 2024年第2期51卷 243-251页

作者： Xinran Dong Yulan Lu Lanting Guo Chuan Li Qi Ni Bingbing Wu Huijun Wang Lin Yang Songyang Wu Qi Sun Hao Zheng Wenhao Zhou Shuang Wang Center for molecular medicine Children's Hospital of Fudan UniversityShanghai 201102China Key Laboratory of Birth Defects Children's Hospital of Fudan UniversityShanghai 201102China Department of Bioinformatics Hangzhou Nuowei Information Technology Co.LtdHangzhouZhejiang 310000China The Third Research Institute of the Ministry of Public Security Shanghai 200031China Xiamen Campus of Children's Hospital of Fudan University XiamenFujian 361006China institutes for Systems Genetics West China HospitalChengduSichuan 610041China Shanghai Putuo People's Hospital Tongji UniversityShanghai 200060China

The growth in biomedical data resources has raised potential privacy concerns and risks of genetic information leakage. For instance, exome sequencing aids clinical decisions by comparing data through web services, but it requires significant trust between users and providers. To alleviate privacy concerns, the most commonly used strategy is to anonymize sensitive data. Unfortunately, studies have shown that anonymization is insufficient to protect against reidentification attacks. Recently, privacy-preserving technologies have been applied to preserve application utility while protecting the privacy of biomedical data. We present the PICOTEES framework, a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants (https://***:3000/). PICOTEES enables privacy-preserving queries of the phenotype spectrum for a single variant by utilizing trusted execution environment technology, which can protect the privacy of the user's query information, backend models, and data, as well as the final results. We demonstrate the utility and performance of PICOTEES by exploring a bioinformatics dataset. The dataset is from a cohort containing 20,909 genetic testing patients with 3,152,508 variants from the Children's Hospital of Fudan University in China, dominated by the Chinese Han population (>99.9%). Our query results yield a large number of unreported diagnostic variants and previously reported pathogenicity.

关键词： Privacy protecti on Rare diseases in children Genetic testing Web system Trusted executi on envir onment

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Identifying the stability of housekeeping genes to be used for the quantitative real-time PCR normalization in retinal tissue of streptozotocin-induced diabetic rats

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International Journal of Ophthalmology(English edition) 2024年第5期17卷 794-805页

作者： Muhammad Zulfiqah Sadikan Nurul Alimah Abdul Nasir Mohammad Johari Ibahim Igor Iezhitsa Renu Agarwal Department of Pharmacology Faculty of MedicineManipal University College Malaysia(MUCM)Bukit BaruMelaka 75150Malaysia Centre for Neuroscience Research(NeuRon) Faculty of MedicineUniversiti Teknologi MARASungai Buloh CampusSungai BulohSelangor 47000Malaysia Department of Medical Education Faculty of MedicineUniversiti Teknologi MARASungai Buloh CampusSungai BulohSelangor 47000Malaysia Department of Biochemistry and molecular medicine Faculty of MedicineUniversiti Teknologi MARASungai Buloh CampusSungai BulohSelangor 47000Malaysia School of medicine International Medical UniversityBukit JalilKuala Lumpur 57000Malaysia Department of Pharmacology and Bioinformatics Volgograd State Medical UniversityVolgograd 400131Russia

AIM:To investigate the stability of the seven housekeeping genes:beta-actin(ActB),glyceraldehyde-3-phosphate dehydrogenase(GAPDH),18s ribosomal unit 5(18s),cyclophilin A(CycA),hypoxanthine-guanine phosphoribosyl transferase(HPRT),ribosomal protein large P0(36B4)and terminal uridylyl transferase 1(U6)in the diabetic retinal tissue of rat ***:The expression of these seven genes in rat retinal tissues was determined using real-time quantitative reverse transcription polymerase chain reaction(RT-qPCR)in two groups;normal control rats and streptozotocininduced diabetic *** stability analysis of gene expression was investigated using geNorm,NormFinder,BestKeeper,and comparative delta-Ct(ΔCt)***:The 36B4 gene was stably expressed in the retinal tissues of normal control animals;however,it was less stable in diabetic *** 18s gene was expressed consistently in both normal control and diabetic rats’retinal *** this gene was the best reference for data normalisation in RT-qPCR studies that used the retinal tissue of streptozotocin-induced diabetic ***,there was no ideal gene stably expressed for use in all experimental ***:Identifying relevant genes is a need for achieving RT-qPCR validity and reliability and must be appropriately achieved based on a specific experimental setting.

关键词： housekeeping genes stability real-time reverse transcription polymerase chain reaction retinal tissue streptozotocin-induced diabetic rats

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