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| 2. |
- 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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| 3. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 4. |
- Ackley, K., et al.
(författare)
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Observational constraints on the optical and near-infrared emission from the neutron star-black hole binary merger candidate S190814bv
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 643
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Tidskriftsartikel (refereegranskat)abstract
- Context. Gravitational wave (GW) astronomy has rapidly reached maturity, becoming a fundamental observing window for modern astrophysics. The coalescences of a few tens of black hole (BH) binaries have been detected, while the number of events possibly including a neutron star (NS) is still limited to a few. On 2019 August 14, the LIGO and Virgo interferometers detected a high-significance event labelled S190814bv. A preliminary analysis of the GW data suggests that the event was likely due to the merger of a compact binary system formed by a BH and a NS.Aims. In this paper, we present our extensive search campaign aimed at uncovering the potential optical and near infrared electromagnetic counterpart of S190814bv. We found no convincing electromagnetic counterpart in our data. We therefore use our non-detection to place limits on the properties of the putative outflows that could have been produced by the binary during and after the merger.Methods. Thanks to the three-detector observation of S190814bv, and given the characteristics of the signal, the LIGO and Virgo Collaborations delivered a relatively narrow localisation in low latency - a 50% (90%) credible area of 5 deg(2) (23 deg(2)) - despite the relatively large distance of 26752 Mpc. ElectromagNetic counterparts of GRAvitational wave sources at the VEry Large Telescope collaboration members carried out an intensive multi-epoch, multi-instrument observational campaign to identify the possible optical and near infrared counterpart of the event. In addition, the ATLAS, GOTO, GRAWITA-VST, Pan-STARRS, and VINROUGE projects also carried out a search on this event. In this paper, we describe the combined observational campaign of these groups.Results. Our observations allow us to place limits on the presence of any counterpart and discuss the implications for the kilonova (KN), which was possibly generated by this NS-BH merger, and for the strategy of future searches. The typical depth of our wide-field observations, which cover most of the projected sky localisation probability (up to 99.8%, depending on the night and filter considered), is r similar to 22 (resp. K similar to 21) in the optical (resp. near infrared). We reach deeper limits in a subset of our galaxy-targeted observations, which cover a total similar to 50% of the galaxy-mass-weighted localisation probability. Altogether, our observations allow us to exclude a KN with large ejecta mass M greater than or similar to 0.1 M-circle dot to a high (> 90%) confidence, and we can exclude much smaller masses in a sub-sample of our observations. This disfavours the tidal disruption of the neutron star during the merger.Conclusions. Despite the sensitive instruments involved in the campaign, given the distance of S190814bv, we could not reach sufficiently deep limits to constrain a KN comparable in luminosity to AT 2017gfo on a large fraction of the localisation probability. This suggests that future (likely common) events at a few hundred megaparsecs will be detected only by large facilities with both a high sensitivity and large field of view. Galaxy-targeted observations can reach the needed depth over a relevant portion of the localisation probability with a smaller investment of resources, but the number of galaxies to be targeted in order to get a fairly complete coverage is large, even in the case of a localisation as good as that of this event.
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| 5. |
- Kennedy, S. A., et al.
(författare)
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Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
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| 7. |
- Launhardt, R., et al.
(författare)
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ISPY-NACO Imaging Survey for Planets around Young stars : Survey description and results from the first 2.5 years of observations
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635
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Tidskriftsartikel (refereegranskat)abstract
- Context. The occurrence rate of long-period (a greater than or similar to 50 au) giant planets around young stars is highly uncertain since it is not only governed by the protoplanetary disc structure and planet formation process, but also reflects both dynamical re-structuring processes after planet formation as well as possible capture of planets not formed in situ. Direct imaging is currently the only feasible method to detect such wide-orbit planets and constrain their occurrence rate.Aims. We aim to detect and characterise wide-orbit giant planets during and shortly after their formation phase within protoplanetary and debris discs around nearby young stars.Methods. We carry out a large L-band high-contrast direct imaging survey for giant planets around 200 young stars with protoplanetary or debris discs using the NACO instrument at the ESO Very Large Telescope on Cerro Paranal in Chile. We use very deep angular differential imaging observations with typically >60 degrees field rotation, and employ a vector vortex coronagraph where feasible to achieve the best possible point source sensitivity down to an inner working angle of about 100 mas. This paper introduces the NACO Imaging Survey for Planets around Young stars (NACO-ISPY), its goals and strategy, the target list, and data reduction scheme, and presents preliminary results from the first 2.5 survey years.Results. We achieve a mean 5 sigma contrast of Delta L ' = 6.4 +/- 0.1 mag at 150 mas and a background limit of L ' (bg) = 16.5 +/- 0.2 textual-form L bg ' =16.5 +/- 0.2 mag at 1.' ' 5. Our detection probability is 50% for companions with greater than or similar to 8 M-Jup at semi-major axes of 80-200 au and >13 M-Jup at 30-250 au. It thus compares well to the detection space of other state-of-the-art high-contrast imaging surveys. We have already contributed to the characterisation of two new planets originally discovered by VLT/SPHERE, but we have not yet independently discovered new planets around any of our target stars. We have discovered two new close-in low-mass stellar companions around R CrA and HD 193571 and report in this paper the discovery of close co-moving low-mass stellar companions around HD 72660 and HD 92536. Furthermore, we report L ' -band scattered light images of the discs around eleven stars, six of which have never been imaged at L ' -band before.Conclusions. The first 2.5 yr of the NACO-ISPY survey have already demonstrated that VLT/NACO combined with our survey strategy can achieve the anticipated sensitivity to detect giant planets and reveal new close stellar companions around our target stars.
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| 8. |
- Rice, H. J., et al.
(författare)
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Design of a Kelvin cell acoustic metamaterial
- 2020
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Ingår i: Journal of Sound and Vibration. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 0022-460X .- 1095-8568. ; 472
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Tidskriftsartikel (refereegranskat)abstract
- Advancements in 3D print technology now allow the printing of structured acoustic absorptive materials at appropriate microscopic scales and sample sizes. Optimisation of parameter sets associated with a Kelvin Cell structure have the potential to develop various metabehaviours in the associated acoustic responses. The repeatability of the fundamental cell unit also provide a route for the development of viable macro models to simulate built up structures based on detailed models of the individual cell units. This paper describes a process to model, print and test such a sample. Manufacturing restraints will initially guide the optimised design and introduce response uncertainties associated with surface finishes and critical geometric dimensions. A "micro to macro" model is developed using a full visco thermal acoustic model of a single cell to develop a frequency dependent cell transfer matrix. The transfer matrices for the repeated cells may then be combined until sufficient material depth is achieved and efficiently generate an absorptivity for the material layer. Two prints using different processes (digital light processing (DLP) and selective laser melting (SLM)) of nominally the same kelvin cell structure. For the metal print the model predicts the absorptivity well once an allowance is made for the surface roughness. The DLP has a smoother finish with a lower geometric fidelity; however the DLP sample is still well modelled by the process.
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| 9. |
- Heap, Michael J., et al.
(författare)
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The thermal properties of porous andesite
- 2020
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Ingår i: Journal of Volcanology and Geothermal Research. - : ELSEVIER. - 0377-0273 .- 1872-6097. ; 398
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Tidskriftsartikel (refereegranskat)abstract
- The thermal properties of volcanic rocks are crucial to accurately model heat transfer in volcanoes and in geothermal systems located within volcanic deposits. Here we provide laboratory measurements of thermal conductivity and thermal diffusivity for variably porous andesites from Mt. Ruapehu (New Zealand) and variably altered basaltic-andesites from Merapi volcano (Indonesia) measured at ambient laboratory pressure and temperature using the transient hot-strip method. The specific heat capacity of each sample was then calculated using these measured values and the bulk sample density. Thermal conductivity and thermal diffusivity decrease as a function of increasing porosity, but specific heat capacity does not vary systematically with porosity. For a given porosity, saturation with water increases thermal conductivity and specific heat capacity, but decreases thermal diffusivity. Measurements on samples from Merapi volcano show that, compared to the unaltered samples from Mt. Ruapehu, hydrothermal alteration deceases thermal conductivity and thermal diffusivity, and increases specific heat capacity. We use an effective medium approach to parameterise these data, showing that when the porosity and pore-fluid properties are scaled for, the measured values agree well with theoretical predictions. We find that despite the microstructural complexity of the studied andesites, porosity is the principal parameter dictating their thermal properties. To understand whether the measured changes in thermal properties are sufficient to influence natural processes, we model heat transfer from magma to the surrounding host-rock by solving Fick's second law cast in 1D Cartesian (dyke geometry) and cylindrical (conduit geometry) coordinates. We provide models for different host-rock porosities (0-0.6), different initial magmatic temperatures (800-1200 degrees C), and different levels of host-rock alteration. Our modelling shows how the cooling of a dyke and conduit is slowed by a higher host-rock porosity and by increased hydrothermal alteration. The thermal properties provided herein can help improve modelling designed to inform on volcanic and geothermal processes. (C) 2020 Elsevier B.V. All rights reserved.
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