| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
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| 3. |
- Rahnev, D, et al.
(författare)
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The Confidence Database
- 2020
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Ingår i: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 4:3, s. 317-325
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Waszak, S. M., et al.
(författare)
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Germline Elongator mutations in Sonic Hedgehog medulloblastoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7803
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Tidskriftsartikel (refereegranskat)abstract
- Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
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| 7. |
- Baumeister, S, et al.
(författare)
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Processing of social and monetary rewards in autism spectrum disorders
- 2023
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Ingår i: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 222:3, s. 100-111
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Tidskriftsartikel (refereegranskat)abstract
- Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD.AimsUtilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.MethodFunctional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6–30.6 years of age) and 181 typically developing participants (7.6–30.8 years of age).ResultsAcross social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD.ConclusionsOur results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.
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| 8. |
- Hong, A. C., et al.
(författare)
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Uptake of Hydrogen Peroxide from the Gas Phase to Grain Boundaries: A Source in Snow and Ice
- 2023
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Ingår i: Environmental Science and Technology. - 0013-936X .- 1520-5851. ; 57:31, s. 11626-11633
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Tidskriftsartikel (refereegranskat)abstract
- This work shows that hydrogen peroxidereadily enters grainboundaries in ice and snow directly from the atmosphere. Acceleratedreaction rates in these reservoirs have been described with an impacton air quality and snow composition. Hydrogen peroxide is a primary atmospheric oxidant significantin terminating gas-phase chemistry and sulfate formation in the condensedphase. Laboratory experiments have shown an unexpected oxidation accelerationby hydrogen peroxide in grain boundaries. While grain boundaries arefrequent in natural snow and ice and are known to host impurities,it remains unclear how and to which extent hydrogen peroxide entersthis reservoir. We present the first experimental evidence for thediffusive uptake of hydrogen peroxide into grain boundaries directlyfrom the gas phase. We have machined a novel flow reactor system featuringa drilled ice flow tube that allows us to discern the effect of theice grain boundary content on the uptake. Further, adsorption to theice surface for temperatures from 235 to 258 K was quantified. Disentanglingthe contribution of these two uptake processes shows that the transferof hydrogen peroxide from the atmosphere to snow at temperatures relevantto polar environments is considerably more pronounced than previouslythought. Further, diffusive uptake to grain boundaries appears tobe a novel mechanism for non-acidic trace gases to fill the highlyreactive impurity reservoirs in snow's grain boundaries.
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| 9. |
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| 10. |
- Bartels-Rausch, T., et al.
(författare)
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Interfacial supercooling and the precipitation of hydrohalite in frozen NaCl solutions as seen by X-ray absorption spectroscopy
- 2021
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Ingår i: Cryosphere. - : Copernicus GmbH. - 1994-0416. ; 15:4, s. 2001-2020
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Tidskriftsartikel (refereegranskat)abstract
- Laboratory experiments are presented on the phase change at the surface of sodium chloride-water mixtures at temperatures between 259 and 241 K. Chloride is a ubiquitous component of polar coastal surface snow. The chloride embedded in snow is involved in reactions that modify the chemical composition of snow as well as ultimately impact the budget of trace gases and the oxidative capacity of the overlying atmosphere. Multiphase reactions at the snow-air interface have been of particular interest in atmospheric science. Undoubtedly, chemical reactions proceed faster in liquids than in solids; but it is currently unclear when such phase changes occur at the interface of snow with air. In the experiments reported here, a high selectivity to the upper few nanometres of the frozen solution-air interface is achieved by using electron yield near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy. We find that sodium chloride at the interface of frozen solutions, which mimic sea-salt deposits in snow, remains as supercooled liquid down to 241 K. At this temperature, hydrohalite exclusively precipitates and anhydrous sodium chloride is not detected. In this work, we present the first NEXAFS spectrum of hydrohalite. The hydrohalite is found to be stable while increasing the temperature towards the eutectic temperature of 252 K. Taken together, this study reveals no differences in the phase changes of sodium chloride at the interface as compared to the bulk. That sodium chloride remains liquid at the interface upon cooling down to 241 K, which spans the most common temperature range in Arctic marine environments, has consequences for interfacial chemistry involving chlorine as well as for any other reactant for which the sodium chloride provides a liquid reservoir at the interface of environmental snow. Implications for the role of surface snow in atmospheric chemistry are discussed. © 2021 BMJ Publishing Group. All rights reserved.
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