22 research outputs found
SRSF1-dependent nuclear export of C9ORF72 repeat-transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection
Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including
ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates
of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the
production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in
the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared
between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and
RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving
the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be
manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat
transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of
SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the
survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in
Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review,
we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a
summary of the published research and highlight the significance of these findings as a novel therapeutic
strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often
thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic
gain-of-functions
Knockdown of zebrafish Nav1.6 sodium channel impairs embryonic locomotor activities
[[abstract]]Although multiple subtypes of sodium channels are expressed in most neurons, the specific contributions of the individual sodium channels remain to be studied. The role of zebrafish Nav1.6 sodium channels in the embryonic locomotor movements has been investigated by the antisense morpholino (MO) knockdown. MO1 and MO2 are targeted at the regions surrounding the translation start site of zebrafish Nav1.6 mRNA. MO3 is targeted at the RNA splicing donor site of exon 2. The correctly spliced Nav1.6 mRNA of MO3 morphants is 6% relative to that of the wild-type embryos. Nav1.6-targeted MO1, MO2 and MO3 attenuate the spontaneous contraction, tactile sensitivity, and swimming in comparison with a scrambled morpholino and mutated MO3 morpholino. No significant defect is observed in the development of slow muscles, the axonal projection of primary motoneurons, and neuromuscular junctions. The movement impairments caused by MO1, MO2, and MO3 suggest that the function of Nav1.6 sodium channels is essential on the normal early embryonic locomotor activities.[[notice]]補正完畢[[journaltype]]國
Associations between birth size and later height from infancy through adulthood:an individual based pooled analysis of 28 twin cohorts participating in the CODATwins project
Background: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment.
Aim: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors.
Methods: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses.
Results: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14-4.25 cm and 0.18-0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length.
Conclusion: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight.This work was supported by the Academy of Finland (grant number #266592). The Australian Twin Registry is supported by a Centre of Research Excellence (grant ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. The CATSS-Study is supported by the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Swedish Heart-Lung Foundation and the Swedish Asthma and Allergy Association's Research Foundation. Colorado Twin Registry is funded by NIDA funded center grant DA011015, & Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637 and 5T32AG052371. Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), Centre of Excellence in Research on Mitochondria, Metabolism and Disease (FinMIT, grant 272376), the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J Kaprio and grant 266286 and 314383 to K Pietilainen), the Finnish Diabetes Research Foundation, Novo Nordisk Foundation, Helsinki University Central Hospital and University of Helsinki. K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health. PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to JC, and RS), the Bonnie Babes Foundation (grant number BBF20704 to JMC), the Financial Markets Foundation for Children (grant no.
r 032-2007 to JMC), and by the Victorian Governments Operational Infrastructure Support Program. The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (Michel Boivin). The Twins Early Development Study (TEDS) is supported by a program grant (MR/M021475/1) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO +); the European Research Council (ERC - 230374), the Avera Institute, Sioux Falls, South Dakota (USA)
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In situ beam analysis of radiation damage kinetics in MgTiO{sub 3} single crystals at 170-470 K
Radiation damage kinetics in synthetic MgTiO{sub 3} (geikielite) single crystals have been studied using the in situ ion beam facility at Los Alamos National Laboratory. The geikielite samples were irradiated at temperatures of 170, 300, and 470 K with 400 keV xenon ions and the radiation damage was sequentially measured with Rutherford backscattering using a 2 MeV He ion beam along a channeling direction. Threshold doses of I and 5x l0{sup 15} Xe/cm{sup 2} were determined for the crystalline-to-amorphous transformation induced by Xe ion irradiation at 170 and 300 K, respectively. However, geikielite retained its crystallinity up to a dose of 2.5xl0{sup 16}Xe/cm{sup 2} at the irradiation temperature of 470 K. This study has shown that MgTiO{sub 3}, which has a corundum derivative structure, is another radiation resistant material that has the potential for use in radiation environments
Burn and Bury Option for Plutonium.
Cubic-stabilized zirconia (ZrO2 doped with, for instance, MgO, CaO, Y2O3) is a fluorite-structure oxide that exhibits high chemical stability and durability. It is an actinide-host phase in which actinides have high solubility (over 10 wt.% for uranium and plutonium). In fact, cubic zirconia is isostructural with actinide oxides such as urania (UO2), plutonia (PuO2), and thoria (ThO2). Cubic zirconia exhibits good radiation damage resistance and so it is attractive as an actinide-bearing nuclear fuel-form and as an actinide-host waste form. We propose that cubic zirconia be used as a material to assist with the dispositioning of the global surplus plutonium inventory (both weapons- and reactor-derived plutonium). Plutonium can be incorporated in a cubic zirconia matrix and destroyed by burning in an existing light-water reactor and then buried in a geologic repository (perhaps without further processing); alternatively, the plutonium-bearing zirconia can be sent directly to a repository.JRC.E-Institute for Transuranium Elements (Karlsruhe
Associations between birth size and later height from infancy through adulthood: An individual based pooled analysis of 28 twin cohorts participating in the CODATwins project
Background: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. Aim: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. Methods: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses. Results: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14-4.25 cm and 0.18-0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length. Conclusion: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight.Peer reviewe
Dyadic approach to supervised community rehabilitation participation in an Asian setting post-stroke: Exploring the role of caregiver and patient characteristics in a prospective cohort study
10.1136/bmjopen-2019-036631BMJ Open104e03663
Healthcare utilization and cost trajectories post-stroke: role of caregiver and stroke factors
10.1186/s12913-018-3696-3BMC health services research18188
Can caregivers report their care recipients' post-stroke hospitalizations and outpatient visits accurately? Findings of an Asian prospective stroke cohort 11 Medical and Health Sciences 1117 Public Health and Health Services
10.1186/s12913-018-3634-4BMC Health Services Research18181