| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
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| 3. |
- 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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| 6. |
- Frassinetti, Lorenzo, et al.
(författare)
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Role of the separatrix density in the pedestal performance in deuterium low triangularity JET-ILW plasmas and comparison with JET-C
- 2021
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Ingår i: Nuclear Fusion. - : IOP Publishing Ltd. - 0029-5515 .- 1741-4326. ; 61:12
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Tidskriftsartikel (refereegranskat)abstract
- A reduction of the pedestal pressure with increasing separatrix density over pedestal density (n (e) (sep)/n (e) (ped)) has been observed in JET. The physics behind this correlation is investigated. The correlation is due to two distinct mechanisms. The increase of n (e) (sep)/n (e) (ped) till approximate to 0.4 shifts the pedestal pressure radially outwards, decreasing the peeling-balloning stability and reducing the pressure height. The effect of the position saturates above n (e) (sep)/n (e) (ped) approximate to 0.4. For higher values, the reduction of the pedestal pressure is ascribed to increased turbulent transport and, likely, to resistive MHD effects. The increase of n (e) (sep)/n (e) (ped) above approximate to 0.4 reduces backward difference n (e) /n (e), increasing eta (e) and the pedestal turbulent transport. This reduces the pressure gradient and the pedestal temperature, producing an increase in the pedestal resistivity. The work suggests that the increase in resistivity might destabilize resistive balloning modes, further reducing the pedestal stability.
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| 7. |
- Horvath, L., et al.
(författare)
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Isotope dependence of the type I ELMy H-mode pedestal in JET-ILW hydrogen and deuterium plasmas
- 2021
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 61:4
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Tidskriftsartikel (refereegranskat)abstract
- The pedestal structure, edge transport and linear MHD stability have been analyzed in a series of JET with the ITER-like wall hydrogen (H) and deuterium (D) type I ELMy H-mode plasmas. The pedestal pressure is typically higher in D than in H at the same input power and gas rate, with the difference mainly due to lower density in H than in D (Maggi et al (JET Contributors) 2018 Plasma Phys. Control. Fusion 60 014045). A power balance analysis of the pedestal has shown that higher inter-ELM separatrix loss power is required in H than in D to maintain a similar pedestal top pressure. This is qualitatively consistent with a set of interpretative EDGE2D-EIRENE simulations for H and D plasmas, showing that higher edge particle and heat transport coefficients are needed in H than in D to match the experimental profiles. It has also been concluded that the difference in neutral penetration between H and D leads only to minor changes in the upstream density profiles and with trends opposite to experimental observations. This implies that neutral penetration has a minor role in setting the difference between H and D pedestals, but higher ELM and/or inter-ELM transport are likely to be the main players. The interpretative EDGE2D-EIRENE simulations, with simultaneous upstream and outer divertor target profile constraints, have indicated higher separatrix electron temperature in H than in D for a pair of discharges at low fueling gas rate and similar stored energy (which required higher input power in H than in D at the same gas rate). The isotope dependence of linear MHD pedestal stability has been found to be small, but if a higher separatrix temperature is considered in H than in D, this could lead to destabilization of peeling-ballooning modes and shrinking of the stability boundary, qualitatively consistent with the reduced pedestal confinement in H.
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| 8. |
- Koszorús, Agota, et al.
(författare)
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Charge radii of exotic potassium isotopes challenge nuclear theory and the magic character of N = 32
- 2021
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Ingår i: Nature Physics. - : Springer Science and Business Media LLC. - 1745-2481 .- 1745-2473. ; 17:4, s. 439-443
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear charge radii are sensitive probes of different aspects of the nucleon–nucleon interaction and the bulk properties of nuclear matter, providing a stringent test and challenge for nuclear theory. Experimental evidence suggested a new magic neutron number at N = 32 (refs. 1–3) in the calcium region, whereas the unexpectedly large increases in the charge radii4,5 open new questions about the evolution of nuclear size in neutron-rich systems. By combining the collinear resonance ionization spectroscopy method with β-decay detection, we were able to extend charge radii measurements of potassium isotopes beyond N = 32. Here we provide a charge radius measurement of 52K. It does not show a signature of magic behaviour at N = 32 in potassium. The results are interpreted with two state-of-the-art nuclear theories. The coupled cluster theory reproduces the odd–even variations in charge radii but not the notable increase beyond N = 28. This rise is well captured by Fayans nuclear density functional theory, which, however, overestimates the odd–even staggering effect in charge radii. These findings highlight our limited understanding of the nuclear size of neutron-rich systems, and expose problems that are present in some of the best current models of nuclear theory.
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| 9. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 10. |
- Berglund, Jennie, et al.
(författare)
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Wood hemicelluloses exert distinct biomechanical contributions to cellulose fibrillar networks
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Hemicelluloses, a family of heterogeneous polysaccharides with complex molecular structures, constitute a fundamental component of lignocellulosic biomass. However, the contribution of each hemicellulose type to the mechanical properties of secondary plant cell walls remains elusive. Here we homogeneously incorporate different combinations of extracted and purified hemicelluloses (xylans and glucomannans) from softwood and hardwood species into self-assembled networks during cellulose biosynthesis in a bacterial model, without altering the morphology and the crystallinity of the cellulose bundles. These composite hydrogels can be therefore envisioned as models of secondary plant cell walls prior to lignification. The incorporated hemicelluloses exhibit both a rigid phase having close interactions with cellulose, together with a flexible phase contributing to the multiscale architecture of the bacterial cellulose hydrogels. The wood hemicelluloses exhibit distinct biomechanical contributions, with glucomannans increasing the elastic modulus in compression, and xylans contributing to a dramatic increase of the elongation at break under tension. These diverging effects cannot be explained solely from the nature of their direct interactions with cellulose, but can be related to the distinct molecular structure of wood xylans and mannans, the multiphase architecture of the hydrogels and the aggregative effects amongst hemicellulose-coated fibrils. Our study contributes to understanding the specific roles of wood xylans and glucomannans in the biomechanical integrity of secondary cell walls in tension and compression and has significance for the development of lignocellulosic materials with controlled assembly and tailored mechanical properties.
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