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Chen, P.-F.; Hsiao, J.S.; Sirois, C.L.; Chamberlain, S.J. |
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Title |
RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing |
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Journal Article |
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Year |
2016 |
Publication |
Scientific Reports |
Abbreviated Journal |
Sci Rep |
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6 |
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25368 |
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Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function of the maternally inherited copy of UBE3A, an imprinted gene expressed biallelically in most tissues, but expressed exclusively from the maternal allele in neurons. Active transcription of the neuron-specific long non-coding RNA (lncRNA), UBE3A-ATS, has been shown to silence paternal UBE3A. We hypothesized that alternative splicing factors RBFOX2 and RBFOX1 might mediate splicing changes and result in the transcription of UBE3A-ATS in neurons. We found that RBFOX2 and RBFOX1 both bind to UBE3A-ATS transcript in neurons, but are not required for gene expression and/or neuron-specific processing in the SNURF/SNRPN-UBE3A region. However, we found that depletion of RBFOX2 causes a proliferation phenotype in immature neural cultures, suggesting that RBFOX2 is involved in division versus differentiation decisions in iPSC-derived neural progenitors. Absence of RBFOX2 also altered the expression of some genes that are important for glutamatergic neocortical development and Wnt-Frizzled signalling in mature neuronal cultures. Our data show that while RBFOX1 and RBFOX2 do not mediate neuron-specific processing of UBE3A-ATS, these proteins play important roles in developing neurons and are not completely functionally redundant. |
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University of Connecticut Stem Cell Institute, University of Connecticut Health Center, Farmington, Connecticut, 06030, USA |
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2045-2322 |
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PMID:27146458; PMCID:PMC4857170 |
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refbase @ user @ |
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16684 |
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Ananiev, G.; Williams, E.C.; Li, H.; Chang, Q. |
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Title |
Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model |
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Journal Article |
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Year |
2011 |
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PloS one |
Abbreviated Journal |
PLoS One |
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6 |
Issue |
9 |
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e25255 |
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Adult; Animals; Cell Differentiation/genetics/physiology; Cell Line; Child; Child, Preschool; Female; Humans; Induced Pluripotent Stem Cells/cytology/*metabolism; Male; Methyl-CpG-Binding Protein 2/*genetics; Mice; Mice, Inbred NOD; Mice, SCID; Neurons/cytology/metabolism; Rett Syndrome/*genetics; Teratoma/metabolism/pathology; X Chromosome Inactivation/genetics |
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Rett syndrome (RTT) is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many MeCP2 target genes, better understanding of the neurobiological consequences of the loss- or mis-function of MeCP2, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5-6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology. |
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Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America |
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1932-6203 |
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PMID:21966470; PMCID:PMC3180386 |
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refbase @ user @ |
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16967 |
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Gillet-Chaulet, F.; Hindmarsh, R.C.A.; Corr, H.F.J.; King, E.C.; Jenkins, A. |
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In-situquantification of ice rheology and direct measurement of the Raymond Effect at Summit, Greenland using a phase-sensitive radar |
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Journal Article |
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2011 |
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Geophysical Research Letters |
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38 |
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24 |
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24503 |
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0724 Ice cores, 0726 Ice sheets, 0776 Glaciology, 0798 Modeling, Ice sheet modelling, Rheology, ice divides, ice sheets |
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The Glen exponent ncharacterizes the stress-dependence of ice deformation, directly influencing the rate at which ice masses respond to external forcing. The slow deformation in large ice-sheets makes laboratory rheometry at representative strain-rates difficult. We develop a new technique to estimaten in-situ, deploying a phase-sensitive radar to measure vertical strain rates of around 10-4 yr-1within the top 1000 m of ice across ice divides at Summit and NEEM, Greenland. A fluid-dynamical feature, the Raymond Effect, predicts strong vertical strain-rate variation across divides over distances of a few ice-thicknesses. We achieve sufficient resolution to show this pattern, enabling us to estimaten= 4.5 by inverting our observations with flow modelling. This is higher than values previously used but consistent with other indirect measurements, implying laboratory measurements do not explore the full range of ice rheology and the consequent possibility of a greater sensitivity and responsiveness in ice-sheet dynamics. |
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1944-8007 |
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refbase @ user @ gillet-chaulet_-situquantification_2011 |
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17447 |
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Freude, K.K.; Penjwini, M.; Davis, J.L.; LaFerla, F.M.; Blurton-Jones, M. |
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Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells |
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Journal Article |
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2011 |
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The Journal of Biological Chemistry |
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J Biol Chem |
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286 |
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27 |
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24264-24274 |
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Alzheimer Disease/metabolism/pathology; Antigens, Differentiation/biosynthesis/genetics; Cell Differentiation; Cell Line; Embryonic Stem Cells/*metabolism/pathology; *Gene Expression Regulation; Humans; Neurons/*metabolism/pathology; Serum Amyloid A Protein/*biosynthesis/genetics; Tubulin/biosynthesis/genetics |
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Human embryonic stem cells (hESCs) offer tremendous potential for not only treating neurological disorders but also for their ability to serve as vital reagents to model and investigate human disease. To further our understanding of a key protein involved in Alzheimer disease pathogenesis, we stably overexpressed amyloid precursor protein (APP) in hESCs. Remarkably, we found that APP overexpression in hESCs caused a rapid and robust differentiation of pluripotent stem cells toward a neural fate. Despite maintenance in standard hESC media, up to 80% of cells expressed the neural stem cell marker nestin, and 65% exhibited the more mature neural marker beta-3 tubulin within just 5 days of passaging. To elucidate the mechanism underlying the effects of APP on neural differentiation, we examined the proteolysis of APP and performed both gain of function and loss of function experiments. Taken together, our results demonstrate that the N-terminal secreted soluble forms of APP (in particular sAPPbeta) robustly drive neural differentiation of hESCs. Our findings not only reveal a novel and intriguing role for APP in neural lineage commitment but also identify a straightforward and rapid approach to generate large numbers of neurons from human embryonic stem cells. These novel APP-hESC lines represent a valuable tool to investigate the potential role of APP in development and neurodegeneration and allow for insights into physiological functions of this protein. |
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Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, USA |
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0021-9258 |
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PMID:21606494; PMCID:PMC3129207 |
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refbase @ user @ |
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16981 |
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Kaempfer, T.U.; Hopkins, M.A.; Perovich, D.K. |
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A three-dimensional microstructure-based photon-tracking model of radiative transfer in snow |
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Journal Article |
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2007 |
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Journal of Geophysical Research-Atmospheres |
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112 |
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D24 |
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24113 |
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[1] Solar radiation is a key component of the energy budget of snow-covered landscapes. Even a thin snow cover reflects most of the incident sunlight and transmits little. An understanding of the interaction of solar radiation with snow is essential to the study of the snow thermodynamics, chemistry, hydrology, ecology, and remote sensing. To investigate this interaction, a microstructure-based photon-tracking algorithm is presented. The three-dimensional snow microstructure is provided either by a discrete element model defined by shape, size, and spatial arrangement of individual ice grains or by an X-ray microtomography image of a snowpack. The model uses refraction, Fresnel reflection, and absorption laws, and the only optical input parameters are the complex index of refraction and absorption coefficient. The model follows individual photons through the microstructure, a porous network of ice and air, applying the fundamental optics laws at the ice-air interfaces and within the ice. By firing tens of thousands of photons a detailed examination of the spectral radiance and irradiance above, below, and within the snowpack is possible. The model was compared to results from a discrete ordinates model, and its sensitivity to the microstructural representation was studied. It was applied to investigate changes in reflected, absorbed, and transmitted light as a function of wavelength, snow depth, grain size, and snow density, used to predict the amount and direction of scattering within the snowpack, and used to explore the interaction of a collimated beam with snow. |
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Kaempfer, T. U. Hopkins, M. A. Perovich, D. K. |
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refbase @ admin @ Kaempfer2007 |
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8072 |
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