1. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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2. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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3. |
- Ramdas, S., et al.
(author)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Journal article (peer-reviewed)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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4. |
- Fenstermacher, M.E., et al.
(author)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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In: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Journal article (peer-reviewed)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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5. |
- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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6. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)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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7. |
- Abbasi, R., et al.
(author)
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Acceptance Tests of more than 10 000 Photomultiplier Tubes for the multi-PMT Digital Optical Modules of the IceCube Upgrade
- 2024
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In: Journal of Instrumentation. - 1748-0221. ; 19:7
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Journal article (peer-reviewed)abstract
- More than 10 000 photomultiplier tubes (PMTs) with a diameter of 80 mm will be installed in multi-PMT Digital Optical Modules (mDOMs) of the IceCube Upgrade. These have been tested and pre-calibrated at two sites. A throughput of more than 1000 PMTs per week with both sites was achieved with a modular design of the testing facilities and highly automated testing procedures. The testing facilities can easily be adapted to other PMTs, such that they can, e.g., be re-used for testing the PMTs for IceCube-Gen2. Single photoelectron response, high voltage dependence, time resolution, prepulse, late pulse, afterpulse probabilities, and dark rates were measured for each PMT. We describe the design of the testing facilities, the testing procedures, and the results of the acceptance tests.
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8. |
- Abbasi, R., et al.
(author)
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Characterization of the astrophysical diffuse neutrino flux using starting track events in IceCube
- 2024
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In: Physical Review D - Particles, Fields, Gravitation and Cosmology. - 2470-0010 .- 2470-0029. ; 110:2
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Journal article (peer-reviewed)abstract
- A measurement of the diffuse astrophysical neutrino spectrum is presented using IceCube data collected from 2011-2022 (10.3 years). We developed novel detection techniques to search for events with a contained vertex and exiting track induced by muon neutrinos undergoing a charged-current interaction. Searching for these starting track events allows us to not only more effectively reject atmospheric muons but also atmospheric neutrino backgrounds in the southern sky, opening a new window to the sub-100 TeV astrophysical neutrino sky. The event selection is constructed using a dynamic starting track veto and machine learning algorithms. We use this data to measure the astrophysical diffuse flux as a single power law flux (SPL) with a best-fit spectral index of γ=2.58-0.09+0.10 and per-flavor normalization of φper-flavorAstro=1.68-0.22+0.19×10-18×GeV-1 cm-2 s-1 sr-1 (at 100 TeV). The sensitive energy range for this dataset is 3-550 TeV under the SPL assumption. This data was also used to measure the flux under a broken power law, however we did not find any evidence of a low energy cutoff.
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9. |
- Abbasi, R., et al.
(author)
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Improved modeling of in-ice particle showers for IceCube event reconstruction
- 2024
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In: Journal of Instrumentation. - 1748-0221. ; 19:6
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Journal article (peer-reviewed)abstract
- The IceCube Neutrino Observatory relies on an array of photomultiplier tubes to detect Cherenkov light produced by charged particles in the South Pole ice. IceCube data analyses depend on an in-depth characterization of the glacial ice, and on novel approaches in event reconstruction that utilize fast approximations of photoelectron yields. Here, a more accurate model is derived for event reconstruction that better captures our current knowledge of ice optical properties. When evaluated on a Monte Carlo simulation set, the median angular resolution for in-ice particle showers improves by over a factor of three compared to a reconstruction based on a simplified model of the ice. The most substantial improvement is obtained when including effects of birefringence due to the polycrystalline structure of the ice. When evaluated on data classified as particle showers in the high-energy starting events sample, a significantly improved description of the events is observed.
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10. |
- Abbasi, R., et al.
(author)
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Citizen science for IceCube: Name that Neutrino
- 2024
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In: European Physical Journal Plus. - 2190-5444. ; 139:6
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Journal article (peer-reviewed)abstract
- Name that Neutrino is a citizen science project where volunteers aid in classification of events for the IceCube Neutrino Observatory, an immense particle detector at the geographic South Pole. From March 2023 to September 2023, volunteers did classifications of videos produced from simulated data of both neutrino signal and background interactions. Name that Neutrino obtained more than 128,000 classifications by over 1800 registered volunteers that were compared to results obtained by a deep neural network machine-learning algorithm. Possible improvements for both Name that Neutrino and the deep neural network are discussed.
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