| 1. |
- Thomassen, Mads, et al.
(författare)
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Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach
- 2022
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 43:12, s. 1921-1944
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Tidskriftsartikel (refereegranskat)abstract
- Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.
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| 2. |
- Tilmes, Simone, et al.
(författare)
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The hydrological impact of geoengineering in the Geoengineering Model Intercomparison Project (GeoMIP)
- 2013
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Ingår i: Journal of Geophysical Research. - : American Geophysical Union (AGU). - 0148-0227 .- 2156-2202 .- 2169-897X. ; 118:19, s. 11036-11058
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Tidskriftsartikel (refereegranskat)abstract
- The hydrological impact of enhancing Earth's albedo by solar radiation management is investigated using simulations from 12 Earth System models contributing to the Geoengineering Model Intercomparison Project (GeoMIP). We contrast an idealized experiment, G1, where the global mean radiative forcing is kept at preindustrial conditions by reducing insolation while the CO2 concentration is quadrupled to a 4×CO2 experiment. The reduction of evapotranspiration over land with instantaneously increasing CO2 concentrations in both experiments largely contributes to an initial reduction in evaporation. A warming surface associated with the transient adjustment in 4×CO2 generates an increase of global precipitation by around 6.9% with large zonal and regional changes in both directions, including a precipitation increase of 10% over Asia and a reduction of 7% for the North American summer monsoon. Reduced global evaporation persists in G1 with temperatures close to preindustrial conditions. Global precipitation is reduced by around 4.5%, and significant reductions occur over monsoonal land regions: East Asia (6%), South Africa (5%), North America (7%), and South America (6%). The general precipitation performance in models is discussed in comparison to observations. In contrast to the 4×CO2 experiment, where the frequency of months with heavy precipitation intensity is increased by over 50% in comparison to the control, a reduction of up to 20% is simulated in G1. These changes in precipitation in both total amount and frequency of extremes point to a considerable weakening of the hydrological cycle in a geoengineered world.
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