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  • 1
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    Dystrophin rescue by trans-splicing: a strategy for DMD genotypes not eligible for exon skipping approaches (2013)
    Oxford University Press
    Details
    Publication Date: 2013-09-26
    Description: RNA-based therapeutic approaches using splice-switching oligonucleotides have been successfully applied to rescue dystrophin in Duchenne muscular dystrophy (DMD) preclinical models and are currently being evaluated in DMD patients. Although the modular structure of dystrophin protein tolerates internal deletions, many mutations that affect nondispensable domains of the protein require further strategies. Among these, trans -splicing technology is particularly attractive, as it allows the replacement of any mutated exon by its normal version as well as introducing missing exons or correcting duplication mutations. We have applied such a strategy in vitro by using cotransfection of pre– trans -splicing molecule (PTM) constructs along with a reporter minigene containing part of the dystrophin gene harboring the stop-codon mutation found in the mdx mouse model of DMD. Optimization of the different functional domains of the PTMs allowed achieving accurate and efficient trans -splicing of up to 30% of the transcript encoded by the cotransfected minigene. Optimized parameters included mRNA stabilization, choice of splice site sequence, inclusion of exon splice enhancers and artificial intronic sequence. Intramuscular delivery of adeno-associated virus vectors expressing PTMs allowed detectable levels of dystrophin in mdx and mdx4Cv , illustrating that a given PTM can be suitable for a variety of mutations.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Robust elements of Snowball Earth atmospheric circulation and oases for life (2013)
    Wiley
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    Publication Date: 2013-06-06
    Description: [1]  Atmospheric circulation in a Snowball Earth is critical for determining cloud behavior, heat export from the tropics, regions of bare ice, and sea glacier flow. These processes strongly affect Snowball Earth deglaciation and the ability of oases to support photosynthetic marine life throughout a Snowball Earth. Here we establish robust aspects of the Snowball Earth atmospheric circulation by running six general circulation models with consistent Snowball Earth boundary conditions. The models produce qualitatively similar patterns of atmospheric circulation and precipitation minus evaporation. The strength of the Snowball Hadley circulation is roughly double modern at low CO 2 and greatly increases as CO 2 is increased. We force a 1D axisymmetric sea glacier model with GCM output and show that, neglecting zonal asymmetry, sea glaciers would limit ice thickness variations to O (10%). Global mean ice thickness in the 1D sea glacier model is well-approximated by a 0D ice thickness model with global mean surface temperature as the upper boundary condition. We then show that a thin-ice Snowball solution is possible in the axysymmetric sea glacier model when forced by output from all the GCMs if we use ice optical properties that favor the thin-ice solution. Finally, we examine Snowball oases for life using analytical models forced by the GCM output and find that conditions become more favorable for oases as the Snowball warms, so that the most critical time for the survival of life would be near the beginning of a Snowball Earth episode.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 3
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    Glacial onset predated Late Ordovician climate cooling (2016)
    Wiley
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    Publication Date: 2016-05-29
    Description: The Ordovician glaciation represents the acme of one of only three major icehouse periods in Earth's Phanerozoic history, and is notorious for setting the scene for one of the “big 5" mass extinction events. Nevertheless, the mechanisms that drove ice-sheet growth remain poorly understood, and the final extent of the ice sheet crudely constrained. Here, using an Earth system model with an innovative coupling method between ocean, atmosphere and land-ice accounting for climate and ice-sheet feedback processes, we report simulations portraying for the first time the detailed evolution of the Ordovician ice sheet. We show that the emergence of the ice sheet happened in two discrete phases. In a counter-intuitive sequence of events, the continental ice sheet appeared suddenly in a warm climate. Only during the second act, and set against a background of decreasing atmospheric CO 2 , followed steeply dropping temperatures and extending sea-ice. The comparison with abundant sedimentological, geochemical and micropaleontological data suggests that glacial onset may have occurred as early as the Mid Ordovician Darriwilian, in agreement with recent studies reporting third-order glacio-eustatic cycles during the same period. The second step in ice-sheet growth, typified by a sudden drop in tropical sea-surface temperatures by ∼ 8 ∘ C and the further extension of a single, continental-scale ice sheet over Gondwana, marked the onset of the Hirnantian glacial maximum. By suggesting the presence of an ice sheet over Gondwana throughout most of the Mid and Late Ordovician, our models embrace the emerging paradigm of an “Early Paleozoic Ice Age”.
    Print ISSN: 0883-8305
    Electronic ISSN: 1944-9186
    Topics: Geosciences
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 4
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    Becker muscular dystrophy severity is linked to the structure of dystrophin (2015)
    Oxford University Press
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    Publication Date: 2015-02-10
    Description: In-frame exon deletions of the Duchenne muscular dystrophy ( DMD ) gene produce internally truncated proteins that typically lead to Becker muscular dystrophy (BMD), a milder allelic disorder of DMD. We hypothesized that differences in the structure of mutant dystrophin may be responsible for the clinical heterogeneity observed in Becker patients and we studied four prevalent in-frame exon deletions, i.e. 45–47, 45–48, 45–49 and 45–51. Molecular homology modelling revealed that the proteins corresponding to deletions 45–48 and 45–51 displayed a similar structure (hybrid repeat) than the wild-type dystrophin, whereas deletions 45–47 and 45–49 lead to proteins with an unrelated structure (fractional repeat). All four proteins in vitro expressed in a fragment encoding repeats 16–21 were folded in α-helices and remained highly stable. Refolding dynamics were slowed and molecular surface hydrophobicity were higher in fractional repeat containing 45–47 and 45–49 deletions compared with hybrid repeat containing 45–48 and 45–51 deletions. By retrospectively collecting data for a series of French BMD patients, we showed that the age of dilated cardiomyopathy (DCM) onset was delayed by 11 and 14 years in 45–48 and 45–49 compared with 45–47 patients, respectively. A clear trend toward earlier wheelchair dependency (minimum of 11 years) was also observed in 45–47 and 45–49 patients compared with 45–48 patients. Muscle dystrophin levels were moderately reduced in most patients without clear correlation with the deletion type. Disease progression in BMD patients appears to be dependent on the deletion itself and associated with a specific structure of dystrophin at the deletion site.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    Clouds and Snowball Earth deglaciation (2012)
    Wiley
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    Publication Date: 2012-10-25
    Description: Neoproterozoic, and possibly Paleoproterozoic, glaciations represent the most extreme climate events in post-Hadean Earth, and may link closely with the evolution of the atmosphere and life. According to the Snowball Earth hypothesis, the entire ocean was covered with ice during these events for a few million years, during which time volcanic CO2 increased enough to cause deglaciation. Geochemical proxy data and model calculations suggest that the maximum CO2 was 0.01–0.1 by volume, but early climate modeling suggested that deglaciation was not possible at CO2 = 0.2. We use results from six different general circulation models (GCMs) to show that clouds could warm a Snowball enough to reduce the CO2 required for deglaciation by a factor of 10–100. Although more work is required to rigorously validate cloud schemes in Snowball-like conditions, our results suggest that Snowball deglaciation is consistent with observations.
    Print ISSN: 0094-8276
    Electronic ISSN: 1944-8007
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 6
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    Suspended Sediment Dynamics in the Macrotidal Seine Estuary (France) - Part 1: Numerical Modeling of Turbidity Maximum Dynamics (2017)
    Wiley
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    Publication Date: 2017-12-29
    Description: Tidal pumping, baroclinic circulation and vertical mixing are known to be the main mechanisms responsible for the estuarine turbidity maximum (ETM) formation. However, the influence of hydro-meteorological conditions on ETM dynamics is still not properly grasped and requires further investigation to be quantified. Based on a realistic 3-dimensional numerical model of the macrotidal Seine Estuary (France) that accounts for mud and sand transport processes, the objective of this study is to quantify the influence of the main forcing (river flow, tides, waves) on the ETM location and mass changes. As expected, the ETM location is strongly modulated by semidiurnal tidal cycles and fortnightly timescales with a high sensitivity to river flow variations. The ETM mass is clearly driven by the tidal range, characteristic of the tidal pumping mechanism. However, it is not significantly affected by the river flow. Energetic wave conditions substantially influence the ETM mass by contributing up to 44% of the maximum mass observed during spring tides and by increasing the mass by a factor of three during mean tides compared to calm wave conditions. This means that neglecting wave forcing can result in significantly underestimating the ETM mass in estuarine environments. In addition, neap-to-spring phasing has a strong influence on ETM location and mass through a hysteresis response associated with the delay for tidal pumping and stratification to fully develop. Finally, simulations show that the uppermost limit of the Seine ETM location did not change notably during the last 35 years; however, the seaward limit migrated few kilometers upstream.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 7
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    Suspended Sediment Dynamics in the Macrotidal Seine Estuary (France) - Part 2: Numerical Modeling of Sediment Fluxes and Budgets Under Typical Hydrological and Meteorological Conditions (2017)
    Wiley
    Details
    Publication Date: 2017-12-29
    Description: Understanding the sediment dynamics in an estuary is important for its morphodynamic and ecological assessment as well as, in case of an anthropogenically controlled system, for its maintenance. However, the quantification of sediment fluxes and budgets is extremely difficult from in-situ data and requires thoroughly validated numerical models. In the study presented here, sediment fluxes and budgets in the lower Seine Estuary were quantified and investigated from seasonal to annual time scales with respect to realistic hydro- and meteorological conditions. A realistic three-dimensional process-based hydro- and sediment-dynamic model was used to quantify mud and sand fluxes through characteristic estuarine cross-sections. In addition to a reference experiment with typical forcing, three experiments were carried out and analysed, each differing from the reference experiment in either river discharge or wind and waves so that the effects of these forcings could be separated. Hydro- and meteorological conditions affect the sediment fluxes and budgets in different ways and at different locations. Single storm events induce strong erosion in the lower estuary and can have a significant effect on the sediment fluxes offshore of the Seine Estuary mouth, with the flux direction depending on the wind direction. Spring tides cause significant up-estuary fluxes at the mouth. A high river discharge drives barotropic down-estuary fluxes at the upper cross-sections, but baroclinic up-estuary fluxes at the mouth and offshore so that the lower estuary gains sediment during wet years. This behaviour is likely to be observed worldwide in estuaries affected by density gradients and turbidity maximum dynamics.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 8
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    Tight intramolecular regulation of the human Upf1 helicase by its N- and C-terminal domains (2013)
    Oxford University Press
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    Publication Date: 2013-02-20
    Description: The RNA helicase Upf1 is a multifaceted eukaryotic enzyme involved in DNA replication, telomere metabolism and several mRNA degradation pathways. Upf1 plays a central role in nonsense-mediated mRNA decay (NMD), a surveillance process in which it links premature translation termination to mRNA degradation with its conserved partners Upf2 and Upf3. In human, both the ATP-dependent RNA helicase activity and the phosphorylation of Upf1 are essential for NMD. Upf1 activation occurs when Upf2 binds its N-terminal domain, switching the enzyme to the active form. Here, we uncovered that the C-terminal domain of Upf1, conserved in higher eukaryotes and containing several essential phosphorylation sites, also inhibits the flanking helicase domain. With different biochemical approaches we show that this domain, named SQ, directly interacts with the helicase domain to impede ATP hydrolysis and RNA unwinding. The phosphorylation sites in the distal half of the SQ domain are not directly involved in this inhibition. Therefore, in the absence of multiple binding partners, Upf1 is securely maintained in an inactive state by two intramolecular inhibition mechanisms. This study underlines the tight and intricate regulation pathways required to activate multifunctional RNA helicases like Upf1.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    The climatic significance of Late Ordovician-early Silurian black shales (2017)
    Wiley
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    Publication Date: 2017-04-14
    Description: The Ordovician-Silurian transition (∼ 455-430 Ma) is characterized by repeated climatic perturbations, concomitant with major changes in the global oceanic redox state best exemplified by the periodic deposition of black shales. The relationship between the climatic evolution and the oceanic redox cycles, however, remains largely debated. Here, using an ocean-atmosphere general circulation model accounting for ocean biogeochemistry (MITgcm), we investigate the mechanisms responsible for the burial of organic carbon immediately before, during and right after the latest Ordovician Hirnantian (445-444 Ma) glacial peak. Our results are compared with recent sedimentological and geochemical data. We show that the late Katian time slice (∼ 445 Ma), typified by the deposition of black shales at tropical latitudes, represents an unperturbed oceanic state, with regional organic carbon burial driven by the surface primary productivity. During the Hirnantian, our experiments predict a global oxygenation event, in agreement with the disappearance of the black shales in the sedimentary record. This suggests that deep-water burial of organic matter may not be a tenable triggering factor for the positive carbon excursion reported at that time. Our simulations indicate that the perturbation of the ocean circulation induced by the release of freshwater, in the context of the post-Hirnantian deglaciation, does not sustain over sufficiently long geological periods to cause the Rhuddanian (∼ 444 Ma) oceanic anoxic event. Input of nutrients to the ocean, through increased continental weathering and the leaching of newly-exposed glaciogenic sediments, may instead constitute the dominant control on the spread of anoxia in the early Silurian.
    Print ISSN: 0883-8305
    Electronic ISSN: 1944-9186
    Topics: Geosciences
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 10
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    Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles (2016)
    Oxford University Press
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    Publication Date: 2016-07-04
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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