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Neurodegenerative diseases:a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration 2021年第2期10卷 195-212页

作者： Dunhui Li Craig Stewart McIntosh Frank Louis Mastaglia Steve Donald Wilton May Thandar Aung-Htut Centre for Molecular Medicine and Innovative Therapeutics Health Futures InstituteMurdoch UniversityPerthWestern AustraliaAustralia Perron Institute for Neurological and Translational Science Centre for Neuromuscular and Neurological DisordersThe University of Western AustraliaPerthWestern AustraliaAustralia

Precursor messenger RNA(pre-mRNA)splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions(introns)and ligates coding regions(exons)into a continuous message(mature mRNA).This process is highly regulated and can be highly flexible through a process known as alternative splicing,which allows for several transcripts to arise from a single gene,thereby greatly increasing genetic plasticity and the diversity of proteome.Alternative splicing is particularly prevalent in neuronal cells,where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis,migration and synaptic function.The continuous changes in splicing patterns and a high demand on many cis-and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects.The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function.Several of the most common neurodegenerative diseases involve some form of splicing defect(s),such as Alzheimer’s disease,Parkinson’s disease and spinal muscular atrophy.Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics.Here we review our current understanding of the effects alternative splicing has on neuronal differentiation,neuronal migration,synaptic maturation and regulation,as well as the impact on neurodegenerative diseases.We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

关键词： Neurodegenerative diseases Parkinson’s disease Alzheimer’s disease Alternative splicing Splicing defects Antisense oligonucleotides Splice-switching Disease-modifying treatment

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Anti-inflammatory and analgesic activities of Melanthera scandens

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Asian Pacific Journal of Tropical Biomedicine 2012年第2期2卷 144-148页

作者： Jude E Okokon Anwanga E Udoh Samuel G frank louis U Amazu Department of Pharmacology and Toxicology Faculty of PharmacyUniversity of Uyo Department of Science Technology Akwa Ibom State PolytechnicIkot Osurua Department of Pharmacology and Therapeutice.College of Medicine Evans Enwerem University

Objective:To evaluate the anti-inflammatory and analgesic activities of leaf extract of Melanthera scandens(M.scandens).Methods:The crude leaf extract(39-111 mg/kg)of M.scandens was investigated for anti-inflammatory and analgesic activities using various experimental models.The anti-inflammatory activity was investigated using carragenin,egg-albumin induced oedema models,while acetic acid,formalin-induced paw licking and thermal-induced pain models were used to evaluate the antinociceptive property.Results:The extract caused a significant(P<0.05-0.001)dose-dependent reduction of inflammation and pains induced by different agents used.Conclusions:The leaf extract possesses anti-inflammatory and analgesic effects which may be mediated through the phytochemical constituents of the plant.

关键词： Melanthera scandens Anti-inflammatory Analgesic

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Lack of Evidence for Decreased Protein Stability in the 2397 (Met) Haplotype of the Leucine Rich Repeat Kinase 2 Protein Implicated in Parkinson’s Disease

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Advances in Parkinson's Disease 2017年第4期6卷 113-123页

作者： Ryan S. Anderton Lauren Hill Rhiannon Morris frank L. mastaglia Wayne Greene Sherif Boulos School of Health Sciences and Institute for Health Research University of Notre Dame Australia Fremantle WA USA Perron Institute for Neurological and Translational Sciences Nedlands WA USA Centre for Neuromuscular and Neurological Disorders University of Western Australia Nedlands WA USA Institute for Immunology and Infectious Diseases Murdoch University Perth WA USA School of Veterinary and Life Sciences Murdoch University Perth WA USA

Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the leading genetic cause of autosomal dominant familial Parkinson’s disease. We previously reported that two mutations within the ROC domain, namely R1441C and A1442P, exhibit increased protein degradation leading to lowered steady state LRRK2 protein levels in HEK293 cells. More recently, the common WD40 domain LRRK2 haplotype, Met2397, which is a risk factor for Crohn’s disease, has been shown to lower steady state protein levels in HEK293 cells. In view of recent evidence implicating LRRK2 and inflamemation in PD, we investigated the effects of Met2397 on LRRK2 expression, and compared them to the Thr2397 variant and other LRRK2 mutants. In this study, we transfected HEK293 cells with plasmid constructs encoding the different LRRK2 variants, and analyzed the resulting protein levels by Western blot and flow cytometry. Here we found that both the Met2397 and Thr2397 haplotypes yield similar levels of LRRK2 protein expression and do not appear to impact cell viability in HEK293 cells, compared to other LRRK mutants. Thus, we have concluded that the Met2397 haplotype is unlikely to play a role in LRRK2 mediated or idiopathic PD.

关键词： Parkinson’s Disease LRRK2 Met2397 Thr2397 A1442P R1441C

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The effects of a supervised Pilates training program on balance in Parkinson’s disease

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Advances in Parkinson's Disease 2013年第2期2卷 58-61页

作者： Liam Johnson David Putrino Ian James Julian Rodrigues Rick Stell Gary Thickbroom frank L. mastaglia Australian Neuro-Muscular Research Institute Movement Disorders Clinic Queen Elizabeth II Medical Centre Centre for Neuro- muscular & Neurological Disorders University of Western Australia Crawley Australia Australian NeuroMuscular Research Institute Movement Disorders Clinic Queen Elizabeth II Medical Centre Centre for Neuromuscular & Neurological Disorders University of Western Australia Crawley Australia Australian Neuro-Muscular Research Institute Movement Disorders Clinic Queen Elizabeth II Medical Centre Centre for Neuromuscular & Neurological Disorders University of Western Australia Crawley Australia Australian NeuroMuscular Research Institute Movement Disorders Clinic Queen Elizabeth II Medical Centre Centre for Neuromuscular & Neurological Disorders University of Western Australia Crawley Australia School of Psychological and Clinical Sciences Charles Darwin University Darwin Australia Department of Mathematics and Statistics Murdoch University Murdoch Australia

Pilates therapy improves core muscle function and axial stability but its effects on balance in idiopathic Parkinson’s disease (IPD) have not been evaluated. The objective of this study was to evaluate the effects of a Pilates exercise program on postural stability and balance confidence in people with IPD. Ten IPD patients (Hoehn & Yahr Stage 1-3) with a history of falls or nearfalls had the following assessments before and after completion of a 6-week supervised Pilates exercise program: Activities-Specific Balance Confidence Scale (ABC);Berg Balance Scale (BBS);Schwab and England Scale (SES);Unified Parkinson’s Disease Rating Scale (UPDRS);pull-test;timed-up-and-go (TUG);5-metre walk;static and dynamic posturography. There were significant improvements in BBS score, 5-metre walk time and TUG after the training program, as well as improvement trends in some posturographic measures. Participants also reported improved balance confidence with Activities of Daily Living (ADLs). Our findings suggest that Pilates therapy can be beneficial in IPD and warrants further evaluation in a larger study.

关键词： Parkinson’s Disease Pilates Postural Instability Static Dynamic Posturography

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鹤舞飞扬首尔路易威登之家与路易威登首尔Espace文化艺术空间

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室内设计与装修 2020年第2期 70-73页

作者： frank Gehry Peter Marino

首尔路易威登之家坐落于江南区狎鸥亭洞,由建筑师弗兰克·盖里(frank Gehry)和彼得·马里诺(Peter Marino)携手完成,用设计向韩国传统及文化表达了敬意。蜿蜒起伏的玻璃建筑与巴黎路易威登基金会大楼遥相呼应,这也是弗兰克·盖里在韩国... 详细信息

首尔路易威登之家坐落于江南区狎鸥亭洞,由建筑师弗兰克·盖里(frank Gehry)和彼得·马里诺(Peter Marino)携手完成,用设计向韩国传统及文化表达了敬意。蜿蜒起伏的玻璃建筑与巴黎路易威登基金会大楼遥相呼应,这也是弗兰克·盖里在韩国的首个作品。除了由彼得·马里诺设计的形态各异的零售空间外,该建筑还将在整个玻璃顶层设置路易威登首尔Espace文化艺术空间,近距离展示瑞士雕塑家贾科梅蒂的作品,为此次路易威登之家的盛大开幕造势。

关键词：弗兰克·盖里马里诺玻璃建筑贾科梅蒂江南区彼得路易威登蜿蜒起伏

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Effects of Adrenalectomy and Corticosterone on Hippocampal Lesions Induced by Trimethyltin

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Biomedical and Environmental Sciences 1989年第1期2卷 54-64页

作者： louis W.CHANG AUBREY J. HOUGH frank G. BIVINS DAVID COCKERILL Department of Pathology University of Arkansas for Medical Sciences 4301 West Markham Little Rock Arkansas 72205

The effects of adrenalectomy and corticosterone supplementation on the neurotoxicity of trimethyltin (TMT) were tested. CD-1 mice with or without adrenalectomy were injected with TMT at a dose of 3.0mg/kg body wt. At 48h post-TMT administration, the animals were killed for pathological examination. It was found that the adrenalectomized animals developed even more severe lesions in the hippocampal formation (fascia dentata granule cells) than the intact animals. When animals were given a supplement of corticosterone pellets at doses of 0.15, 1.5, and 7.5mg, there was a reduction of lesion development. Total alleviation of pathology was seen at the two higher doses of supplementation. Our present investigation strongly indicates that there may be a close and important interrelationship between TMT-induced neurotoxicity and adrenal function. 1989 Academic Press, Inc.

关键词： dentata administration granule intact hippocampal fascia killed adrenal doses injected

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ISOTOPIC ANALYSIS OF SUPERNOVA SiC AND Si3N4 GRAINS FROM THE QINGZHEN(EH3) CHONDRITE

ISOTOPIC ANALYSIS OF SUPERNOVA SiC AND Si3N4 GRAINS FROM THE...

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中国科学院地质与地球物理研究所第十届(2010年度)学...

作者： frank GYNGARD ERNST ZINNER Laboratory for Space Sciences and the Physics Department Washington UniversitySt.LouisMO 63130USA

We report Al-Mg,Ca,and Ti isotopic data in 16 silicon carbide grains and four silicon nitride grains from the Qingzhen enstatite chondrite.Previous C,N,and Si isotopic measurements had identified these grains as type X grains,believed to have an origin in TypeⅡsupernovae(SNe).The grains analyzed include both subtypes X1 and X2.Twelve SiC and three SiN grains show evidence for initial A1,and eight SiC grains evidence for Ti;11 SiC grains have Ti excesses,possibly indicating the initial presence of V.A correlation with subtype is shown for Ti:X2 grains that have the highest inferred Ti/Ti ratios.A weaker correlation exists for N ratios:X2 grains with C/C>300 have higher N/N ratios than X1 grains.We compare our data and data from previous reports with the SN models by Rauscher et al.The SN models can explain the C and N isotopic ratios fairly well if material from the N-rich spike in the He/N zone of the 25 MSN model is used.They also can explain the Ti/Ti ratios of the X1 and X2 grains.For the latter,substantial contributions from the inner Ni core are required. They indicate that not for all grains the Ti excesses can be attributed to decay of V and material from the He/C zone,where Ti is produced by neutron capture,is needed.The SN models,however,fail in explaining the Si isotopic ratios of most of the grains in a satisfactory fashion and the distinction between X1 and X2 grains.They also fail in explaining the observed correlation between the A1/Al ratios and C/C(and N/N)ratios.

关键词： dust extinction-nuclear reactions nucleosynthesis abundances-supernovae general

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小剂量质子束治疗局限性脉络膜血管瘤

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美国医学会眼科杂志（中文版） 2005年第3期17卷 184-184页

作者： Eric Frau frank Rumen George Noel Sabine Delacroix Jean-louis Habrand Hervé Offret 李扬（译）

目的：评价质子束治疗并发性局限性脉络膜血管瘤的有效性及其安全性。方法：这是一项回顾性非随机研究。对象为法国Villejuif Gustave—Roussy研究所的连续17例患者，患有局限性脉络膜血管瘤合并浆液性视网膜脱离。每只患眼接受总计20... 详细信息

目的：评价质子束治疗并发性局限性脉络膜血管瘤的有效性及其安全性。方法：这是一项回顾性非随机研究。对象为法国Villejuif Gustave—Roussy研究所的连续17例患者，患有局限性脉络膜血管瘤合并浆液性视网膜脱离。每只患眼接受总计20钴当量（CGEs），每天15s5CGEs，共4天。有效检查包括初始和最终最佳矫正视力，裂隙灯检查，眼压，眼底检查，荧光造影以及吲哚青绿血管造影。肿瘤的厚度通过B超测量。

关键词：局限性脉络膜血管瘤质子束治疗小剂量浆液性视网膜脱离吲哚青绿血管造影裂隙灯检查非随机研究其安全性矫正视力

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路易威登入驻巴黎大皇宫,呈现品牌时光之旅

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艺术界 2016年第1期 77-77页

作者：赵玉 frank Qian

＂飞行、航行、旅行＂可谓是2015年冬巴黎最令人兴奋的时尚展览。在巴黎时尚博物馆馆长奥利佛·赛拉德的策划下,法国国家艺术展览馆大皇宫的贵宾厅摇身变为时空列车,讲述路易威登1854年创始至今的品牌传奇故事。展览以历史回顾为主题,... 详细信息

＂飞行、航行、旅行＂可谓是2015年冬巴黎最令人兴奋的时尚展览。在巴黎时尚博物馆馆长奥利佛·赛拉德的策划下,法国国家艺术展览馆大皇宫的贵宾厅摇身变为时空列车,讲述路易威登1854年创始至今的品牌传奇故事。展览以历史回顾为主题,却设计得生动有趣。入口处的路易·威登像无疑来自当代艺术家严培明。另一侧摆放着一只LV标志性古董旅行箱,箱口微启,好像刚刚被主人放下,吸引观众追随他的脚步进行一场发现之旅。

关键词：路易威登大皇宫当代艺术家箱口博物馆馆长 exhibition 旅行箱贵宾厅 exhibitor visitors

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The Xa7 resistance gene guards the rice susceptibility gene SWEET14 against exploitation by the bacterial blight pathogen

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Plant Communications 2021年第3期2卷 82-92页

作者： Dangping Luo Jose C.Huguet-Tapia R.Taylor Raborn frank F.White Volker P.Brendel Bing Yang Division of Plant Sciences Bond Life Sciences CenterUniversity of MissouriColumbiaMO 65211USA Department of Plant Pathology University of FloridaGainesvilleFL 32611USA Department of Biology Department of Computer ScienceIndiana UniversityBloomingtonIN 47405USA Donald Danforth Plant Science Center St.LouisMO 63132USA Biodesign Institute Center for Mechanisms of Evolution Arizona State UniversityTempeAZ 85281USA

Many plant disease resistance(R)genes function specifically in reaction to the presence of cognate effectors from a pathogen.Xanthomonas oryzae pathovar oryzae(Xoo)uses transcription activator-like effectors(TALes)to target specific rice genes for expression,thereby promoting host susceptibility to bacterial blight.Here,we report the molecular characterization of Xa7,the cognate R gene to the TALes AvrXa7 and PthXo3,which target the rice major susceptibility gene SWEET14.Xa7 was mapped to a unique 74-kb region.Gene expression analysis of the region revealed a candidate gene that contained a putative AvrXa7 effector binding element(EBE)in its promoter and encoded a 113-amino-acid peptide of unknown function.Genome editing at the Xa7 locus rendered the plants susceptible to avrXa7-carrying Xoo strains.Both AvrXa7 and PthXo3 activated a GUS reporter gene fused with the EBE-containing Xa7 promoter in Nicotiana benthamiana.The EBE of Xa7 is a close mimic of the EBE of SWEET14 for TALe-induced disease susceptibility.Ectopic expression of Xa7 triggers cell death in N.benthamiana.Xa7 is prevalent in indica rice accessions from 3000 rice genomes.Xa7 appears to be an adaptation that protects against pathogen exploitation of SWEET14 and disease susceptibility.

关键词： Xa7 TAL effector Xanthomonas bacterial blight disease resistance SWEET14

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