| 1. |
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| 2. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)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. |
- Abbasi, R., et al.
(författare)
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Search for neutrino lines from dark matter annihilation and decay with IceCube
- 2023
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Ingår i: Physical Review D. - : American Physical Society. - 2470-0010 .- 2470-0029. ; 108:10
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Tidskriftsartikel (refereegranskat)abstract
- Dark matter particles in the Galactic Center and halo can annihilate or decay into a pair of neutrinos producing a monochromatic flux of neutrinos. The spectral feature of this signal is unique and it is not expected from any astrophysical production mechanism. Its observation would constitute a dark matter smoking gun signal. We performed the first dedicated search with a neutrino telescope for such signal, by looking at both the angular and energy information of the neutrino events. To this end, a total of five years of IceCube's DeepCore data has been used to test dark matter masses ranging from 10 GeV to 40 TeV. No significant neutrino excess was found and upper limits on the annihilation cross section, as well as lower limits on the dark matter lifetime, were set. The limits reached are of the order of 10-24 cm3/s for an annihilation and up to 1027 s for decaying dark matter. Using the same data sample we also derive limits for dark matter annihilation or decay into a pair of Standard Model charged particles.
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| 5. |
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| 6. |
- Barucca, G., et al.
(författare)
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The potential of Λ and Ξ- studies with PANDA at FAIR
- 2021
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Ingår i: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 57:4
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Tidskriftsartikel (refereegranskat)abstract
- The antiproton experiment PANDA at FAIR is designed to bring hadron physics to a new level in terms of scope, precision and accuracy. In this work, its unique capability for studies of hyperons is outlined. We discuss ground-state hyperons as diagnostic tools to study non-perturbative aspects of the strong interaction, and fundamental symmetries. New simulation studies have been carried out for two benchmark hyperon-antihyperon production channels: p¯ p→ Λ¯ Λ and p¯ p→ Ξ¯ +Ξ-. The results, presented in detail in this paper, show that hyperon-antihyperon pairs from these reactions can be exclusively reconstructed with high efficiency and very low background contamination. In addition, the polarisation and spin correlations have been studied, exploiting the weak, self-analysing decay of hyperons and antihyperons. Two independent approaches to the finite efficiency have been applied and evaluated: one standard multidimensional efficiency correction approach, and one efficiency independent approach. The applicability of the latter was thoroughly evaluated for all channels, beam momenta and observables. The standard method yields good results in all cases, and shows that spin observables can be studied with high precision and accuracy already in the first phase of data taking with PANDA.
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| 7. |
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| 8. |
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| 9. |
- Barucca, G., et al.
(författare)
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Study of excited Ξ baryons with the P¯ ANDA detector
- 2021
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Ingår i: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 57:4
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Tidskriftsartikel (refereegranskat)abstract
- The study of baryon excitation spectra provides insight into the inner structure of baryons. So far, most of the world-wide efforts have been directed towards N∗ and Δ spectroscopy. Nevertheless, the study of the double and triple strange baryon spectrum provides independent information to the N∗ and Δ spectra. The future antiproton experiment P¯ANDA will provide direct access to final states containing a Ξ¯ Ξ pair, for which production cross sections up to μb are expected in p¯p reactions. With a luminosity of L= 10 31 cm- 2 s- 1 in the first phase of the experiment, the expected cross sections correspond to a production rate of ∼106events/day. With a nearly 4 π detector acceptance, P¯ANDA will thus be a hyperon factory. In this study, reactions of the type p¯p → Ξ¯ +Ξ∗ - as well as p¯p → Ξ¯ ∗ +Ξ- with various decay modes are investigated. For the exclusive reconstruction of the signal events a full decay tree fit is used, resulting in reconstruction efficiencies between 3 and 5%. This allows high statistics data to be collected within a few weeks of data taking.
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| 10. |
- Bosson, J. K., et al.
(författare)
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Psychometric Properties and Correlates of Precarious Manhood Beliefs in 62 Nations
- 2021
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Ingår i: Journal of Cross-Cultural Psychology. - : SAGE Publications. - 0022-0221 .- 1552-5422. ; 52:3
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Tidskriftsartikel (refereegranskat)abstract
- Precarious manhood beliefs portray manhood, relative to womanhood, as a social status that is hard to earn, easy to lose, and proven via public action. Here, we present cross-cultural data on a brief measure of precarious manhood beliefs (the Precarious Manhood Beliefs scale [PMB]) that covaries meaningfully with other cross-culturally validated gender ideologies and with country-level indices of gender equality and human development. Using data from university samples in 62 countries across 13 world regions (N = 33,417), we demonstrate: (1) the psychometric isomorphism of the PMB (i.e., its comparability in meaning and statistical properties across the individual and country levels); (2) the PMB's distinctness from, and associations with, ambivalent sexism and ambivalence toward men; and (3) associations of the PMB with nation-level gender equality and human development. Findings are discussed in terms of their statistical and theoretical implications for understanding widely-held beliefs about the precariousness of the male gender role.
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| 11. |
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| 12. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 13. |
- Strakova, A., et al.
(författare)
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Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby 'selfish' positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells.
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| 14. |
- Abdollahi, S., et al.
(författare)
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Incremental Fermi Large Area Telescope Fourth Source Catalog
- 2022
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 260:2
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Tidskriftsartikel (refereegranskat)abstract
- We present an incremental version (4FGL-DR3, for Data Release 3) of the fourth Fermi Large Area Telescope (LAT) catalog of γ-ray sources. Based on the first 12 years of science data in the energy range from 50 MeV to 1 TeV, it contains 6658 sources. The analysis improves on that used for the 4FGL catalog over eight years of data: more sources are fit with curved spectra, we introduce a more robust spectral parameterization for pulsars, and we extend the spectral points to 1 TeV. The spectral parameters, spectral energy distributions, and associations are updated for all sources. Light curves are rebuilt for all sources with 1 yr intervals (not 2 month intervals). Among the 5064 original 4FGL sources, 16 were deleted, 112 are formally below the detection threshold over 12 yr (but are kept in the list), while 74 are newly associated, 10 have an improved association, and seven associations were withdrawn. Pulsars are split explicitly between young and millisecond pulsars. Pulsars and binaries newly detected in LAT sources, as well as more than 100 newly classified blazars, are reported. We add three extended sources and 1607 new point sources, mostly just above the detection threshold, among which eight are considered identified, and 699 have a plausible counterpart at other wavelengths. We discuss the degree-scale residuals to the global sky model and clusters of soft unassociated point sources close to the Galactic plane, which are possibly related to limitations of the interstellar emission model and missing extended sources.
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| 15. |
- Kristan, M., et al.
(författare)
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The Eighth Visual Object Tracking VOT2020 Challenge Results
- 2020
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Ingår i: Computer Vision. - Cham : Springer International Publishing. - 9783030682378 ; , s. 547-601
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Konferensbidrag (refereegranskat)abstract
- The Visual Object Tracking challenge VOT2020 is the eighth annual tracker benchmarking activity organized by the VOT initiative. Results of 58 trackers are presented; many are state-of-the-art trackers published at major computer vision conferences or in journals in the recent years. The VOT2020 challenge was composed of five sub-challenges focusing on different tracking domains: (i) VOT-ST2020 challenge focused on short-term tracking in RGB, (ii) VOT-RT2020 challenge focused on “real-time” short-term tracking in RGB, (iii) VOT-LT2020 focused on long-term tracking namely coping with target disappearance and reappearance, (iv) VOT-RGBT2020 challenge focused on short-term tracking in RGB and thermal imagery and (v) VOT-RGBD2020 challenge focused on long-term tracking in RGB and depth imagery. Only the VOT-ST2020 datasets were refreshed. A significant novelty is introduction of a new VOT short-term tracking evaluation methodology, and introduction of segmentation ground truth in the VOT-ST2020 challenge – bounding boxes will no longer be used in the VOT-ST challenges. A new VOT Python toolkit that implements all these novelites was introduced. Performance of the tested trackers typically by far exceeds standard baselines. The source code for most of the trackers is publicly available from the VOT page. The dataset, the evaluation kit and the results are publicly available at the challenge website (http://votchallenge.net ).
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| 16. |
- Ajello, M., et al.
(författare)
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Fermi Large Area Telescope Performance after 10 Years of Operation
- 2021
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 256:1
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Tidskriftsartikel (refereegranskat)abstract
- The Large Area Telescope (LAT), the primary instrument for the Fermi Gamma-ray Space Telescope (Fermi) mission, is an imaging, wide field-of-view, high-energy gamma-ray telescope, covering the energy range from 30 MeV to more than 300 GeV. We describe the performance of the instrument at the 10 yr milestone. LAT performance remains well within the specifications defined during the planning phase, validating the design choices and supporting the compelling case to extend the duration of the Fermi mission. The details provided here will be useful when designing the next generation of high-energy gamma-ray observatories.
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| 17. |
- Filippi, F., et al.
(författare)
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Plasma density profile reconstruction of a gas cell for Ionization Induced Laser Wakefield Acceleration
- 2023
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 18:5
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Tidskriftsartikel (refereegranskat)abstract
- Laser-driven plasma wakefields can provide hundreds of MeV electron beam in mm-range distances potentially shrinking the dimension of the actual particle accelerators. The plasma density plays a fundamental role in the control and stability of the acceleration process, which is a key development for the future electron injector proposed by EuPRAXIA. A gas cell was designed by LPGP and LIDYL teams, with variable length and backing pressure, to confine the gas and tailor the gas density profile before the arrival of the laser. This cell was used during an experimental campaign with the multi TW-class laser at the Lund Laser Centre. Ionization assisted injection in a tailored density profile is used to tune the electron beam properties. During the experiment, we filled the gas cell with hydrogen mixed with different concentration of nitrogen. We also varied the backing pressure of the gas and the geometrical length of the gas cell. We used a transverse probe to acquire shadowgraphic images of the plasma and to measure the plasma electron density. Methods and results of the analysis with comparisons between shadowgraphic and interferometric images will be discussed.
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| 18. |
- Gómez, M., et al.
(författare)
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From agroindustries to integrated biomass logistics centres. Agroinlog project : Summary of final results
- 2020
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Ingår i: European Biomass Conference and Exhibition Proceedings. - : ETA-Florence Renewable Energies. ; , s. 941-952
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Konferensbidrag (refereegranskat)abstract
- AGROinLOG project has tested the integrated biomass logistics centres (IBLC) concept in three real agro-industries in Europe. The relevance of the IBLC strategy relies on the fact that it allows agro-industries to create a new activity with lower investment, increasing incomes, stabilizing their annual activity (avoiding idle periods) and maintaining or creating new jobs. The demos’ studies were performed in Spain at a fodder industry, in Greece at an olive oil industry, and in Sweden inside a cereal processing industry. AGROinLOG validated these demos´ business models from a holistic perspective, also studying the replicability of the IBLC business model in other agro-industries from different sectors (vegetable oil extraction, olive oil chain, feed & fodder, wine, grain chain and sugar industry). Sectorial analysis was carried out as well, allowing the identification of opportunities among the targeted sector to replicate the IBLC concept, drawing barriers to overcome in each case. Thus, technical, economic and environmental feasibility of integrated biomass logistics centers (IBLCs) for food and non-food products have been assessed in detail.
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| 19. |
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| 20. |
- Ajello, M., et al.
(författare)
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A gamma-ray pulsar timing array constrains the nanohertz gravitational wave background
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 376:6592, s. 521-523
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Tidskriftsartikel (refereegranskat)abstract
- After large galaxies merge, their central supermassive black holes are expected to form binary systems. Their orbital motion should generate a gravitational wave background (GWB) at nanohertz frequencies. Searches for this background use pulsar timing arrays, which perform long-term monitoring of millisecond pulsars at radio wavelengths. We used 12.5 years of Fermi Large Area Telescope data to form a gamma-ray pulsar timing array. Results from 35 bright gamma-ray pulsars place a 95% credible limit on the GWB characteristic strain of 1.0 x 10(-14) at a frequency of 1 year(-1). The sensitivity is expected to scale with t(obs), the observing time span, as t(obs)(-13/6). This direct measurement provides an independent probe of the GWB while offering a check on radio noise models.
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| 21. |
- Bybrant, M. C., et al.
(författare)
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Celiac disease can be predicted by high levels of tissue transglutaminase antibodies in children and adolescents with type 1 diabetes
- 2021
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 22:3, s. 417-424
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Children with type 1 diabetes (T1D) are not included in guidelines regarding diagnosis criteria for celiac disease (CD) without a diagnostic biopsy, due to lack of data. We explored whether tissue transglutaminase antibodies (anti-tTG) that were >= 10 times the upper limit of normal (10x ULN) predicted CD in T1D. Methods Data from the Swedish prospective Better Diabetes Diagnosis study was used, and 2035 children and adolescents with T1D diagnosed between 2005-2010 were included. Of these, 32 had been diagnosed with CD before T1D. The children without CD were repeatedly screened for CD using anti-tTG antibodies of immunoglobulin type A. In addition, their human leukocyte antigen (HLA) were genotyped. All children with positive anti-tTG were advised to undergo biopsy. Biopsies were performed on 119 children and graded using the Marsh-Oberhuber classification. Results All of the 60 children with anti-tTG >= 10x ULN had CD verified by biopsies. The degree of mucosal damage correlated with anti-tTG levels. Among 2003 screened children, 6.9% had positive anti-tTG and 5.6% were confirmed CD. The overall CD prevalence, when including the 32 children with CD before T1D, was 7.0% (145/2035). All but one of the children diagnosed with CD had HLA-DQ2 and/or DQ8. Conclusions As all screened children and adolescents with T1D with tissue transglutaminase antibodies above 10 times the positive value 10x ULN had CD, we propose that the guidelines for diagnosing CD in screened children, when biopsies can be omitted, should also apply to children and adolescents with T1D as a noninvasive method.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Erdinc, Direnis, et al.
(författare)
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Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
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Ingår i: Embo Molecular Medicine. - 1757-4676. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Topoisomerase 3 alpha (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
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| 28. |
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| 31. |
- Olahova, M., et al.
(författare)
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POLRMT mutations impair mitochondrial transcription causing neurological disease
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase gamma, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
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| 32. |
- Olsson, MIT, et al.
(författare)
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Gender Gap in Parental Leave Intentions : Evidence from 37 Countries
- 2023
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Ingår i: Political Psychology. - : Wiley-Blackwell Publishing Ltd. - 0162-895X .- 1467-9221. ; 44:6, s. 1163-1192
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Tidskriftsartikel (refereegranskat)abstract
- Despite global commitments and efforts, a gender-based division of paid and unpaid work persists. To identify how psychological factors, national policies, and the broader sociocultural context contribute to this inequality, we assessed parental-leave intentions in young adults (18–30 years old) planning to have children (N = 13,942; 8,880 identified as women; 5,062 identified as men) across 37 countries that varied in parental-leave policies and societal gender equality. In all countries, women intended to take longer leave than men. National parental-leave policies and women's political representation partially explained cross-national variations in the gender gap. Gender gaps in leave intentions were paradoxically larger in countries with more gender-egalitarian parental-leave policies (i.e., longer leave available to both fathers and mothers). Interestingly, this cross-national variation in the gender gap was driven by cross-national variations in women's (rather than men's) leave intentions. Financially generous leave and gender-egalitarian policies (linked to men's higher uptake in prior research) were not associated with leave intentions in men. Rather, men's leave intentions were related to their individual gender attitudes. Leave intentions were inversely related to career ambitions. The potential for existing policies to foster gender equality in paid and unpaid work is discussed.
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| 33. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 34. |
- Sønderby, Ida E., et al.
(författare)
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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- 2021
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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| 35. |
- van der Meer, Dennis, et al.
(författare)
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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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| 36. |
- Van Haute, L., et al.
(författare)
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TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.
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| 37. |
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| 38. |
- Alves, C. A., et al.
(författare)
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Physical and chemical properties of non-exhaust particles generated from wear between pavements and tyres
- 2020
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Ingår i: Atmospheric Environment. - : Elsevier Ltd. - 1352-2310 .- 1873-2844. ; 224
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Tidskriftsartikel (refereegranskat)abstract
- A road simulator was used to generate wear particles from the interaction between two tyre brands and a composite pavement. Particle size distributions were monitored using a scanning mobility particle sizer and an aerosol particle sizer. Continuous measurements of particle mass concentrations were also made. Collection of inhalable particles (PM10) was conducted using a high-volume sampler equipped with quartz filters, which were then analysed for organic and elemental carbon, organic constituents and elemental composition. Tyre fragments chopped into tiny chips were also subjected to detailed organic and elemental speciation. The number concentration was dominated by particles <0.5 μm, whereas most of the mass was found in particles >0.5 μm. The emission factor from wear between pavements and tyres was of the order of 2 mg km−1 veh−1. Organic carbon represented about 10% of the PM10 mass, encompassing multiple aliphatic compounds (n-alkanes, alkenes, hopanes, and steranes), PAHs, thiazols, n-alkanols, polyols, some fragrant compounds, sugars, triterpenoids, sterols, phenolic constituents, phthalate plasticisers and several types of acids, among others. The relationship between airborne particulate organic constituents and organic matter in tyre debris is discussed. The detection of compounds that have been extensively used as biomass burning tracers (e.g. retene, dehydroabietic acid and levoglucosan) in both the shredded tiny tyre chips and the wear particles from the interaction between tyres and pavement puts into question their uniqueness as markers of wood combustion. Trace and major elements accounted for about 5% of the mass of the tyre fragments but represented 15–18% of the PM10 from wear, denoting the contribution of mineral elements from the pavement. Sulphur and zinc were abundant constituents in all samples.
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| 39. |
- Berkström, Charlotte, et al.
(författare)
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Thresholds in seascape connectivity : the spatial arrangement of nursery habitats structure fish communities on nearby reefs
- 2020
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Ingår i: Ecography. - : Wiley. - 0906-7590 .- 1600-0587. ; 43:6, s. 882-896
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Tidskriftsartikel (refereegranskat)abstract
- Ecosystems are linked by the movement of organisms across habitat boundaries and the arrangement of habitat patches can affect species abundance and composition. In tropical seascapes many coral reef fishes settle in adjacent habitats and undergo ontogenetic habitat shifts to coral reefs as they grow. Few studies have attempted to measure at what distances from nursery habitats these fish migrations (connectivity) cease to exist and how the abundance, biomass and proportion of nursery species change on coral reefs along distance gradients away from nursery areas. The present study examines seascape spatial arrangement, including distances between habitats, and its consequences on connectivity within a tropical seascape in Mozambique using a seascape ecology approach. Fish and habitat surveys were undertaken in 2016/2017 and a thematic habitat map was created in ArcGIS, where cover and distances between habitat patches were calculated. Distance to mangroves and seagrasses were significant predictors for abundance and biomass of most nursery species. The proportions of nursery species were highest in the south of the archipelago, where mangroves were present and decreased with distance to nurseries (mangroves and seagrasses). Some nursery species were absent on reef sites farthest from nursery habitats, at 80 km from mangroves and at 12 km from seagrass habitats. The proportion of nursery/non-nursery snapper and parrotfish species, as well as abundance and biomass of seagrass nursery species abruptly declined at 8 km from seagrass habitats, indicating a threshold distance at which migrations may cease. Additionally, reefs isolated by large stretches of sand and deep water had very low abundances of several nursery species despite being within moderate distances from nursery habitats. This highlights the importance of considering the matrix (sand and deep water) as barriers for fish migration.
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| 40. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 41. |
- Bonnet, Timothee, et al.
(författare)
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Genetic variance in fitness indicates rapid contemporary adaptive evolution in wild animals
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 376:6596, s. 1012-1016
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Tidskriftsartikel (refereegranskat)abstract
- The rate of adaptive evolution, the contribution of selection to genetic changes that increase mean fitness, is determined by the additive genetic variance in individual relative fitness. To date, there are few robust estimates of this parameter for natural populations, and it is therefore unclear whether adaptive evolution can play a meaningful role in short-term population dynamics. We developed and applied quantitative genetic methods to long-term datasets from 19 wild bird and mammal populations and found that, while estimates vary between populations, additive genetic variance in relative fitness is often substantial and, on average, twice that of previous estimates. We show that these rates of contemporary adaptive evolution can affect population dynamics and hence that natural selection has the potential to partly mitigate effects of current environmental change.
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| 42. |
- Ceberg, S., et al.
(författare)
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FLASH radiotherapy and the associated dosimetric challenges
- 2023
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Ingår i: Journal of Physics: Conference Series. ; 2630
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Konferensbidrag (refereegranskat)abstract
- At Lund University and Skåne University Hospital in Lund, Sweden, we have, as the first clinic, modified a clinical Elekta Precise linear accelerator for convertible delivery of ultrahigh dose rate (FLASH) irradiation. Whereas recently published reviews highlighted the need for standardised protocols for ultra-high dose rate beam dosimetry to be able to determine the true potential of FLASH irradiation, several dosimetry studies as well as in-vitro and in-vivo experiments have been carried out at our unit. Dosimetric procedures for verification of accurate dose delivery of FLASH irradiation to cell cultures, zebrafish embryos and small animals have been established using radiochromic films and thermo-luminescent dosimeters. Also, recently the first experience of electron FLASH radiotherapy (FLASH-RT) in canine patients in our clinical setting was published. Our research facilities also include a laboratory for 3D polymer gel manufacturing. Recently, we started investigating the feasibility of a NIPAM polymer gel dosimeter for ultra-high dose rate dosimetry. Furthermore, in the bunker of the modified Elekta linear accelerator, a Surface Guided Radiotherapy (SGRT) system is accessible. The CatalystTM system (C-Rad Positioning, Uppsala, Sweden) provides optical surface imaging for patient setup, real-time motion monitoring and breathing adapted treatment. Aiming at treating patients using ultra-high dose rates, a real-time validation of the alignment between the beam and the target is crucial as the dose is delivered in a fraction of a second. Our research group has during the last decade investigated and developed SGRT workflows which improved patient setup and breathing adapted treatment for several cancer patient groups. Recently, we also started investigating the feasibility of a real-time motion monitoring system for surface guided FLASH-RT. Both FLASH related studies; 3D polymer gel dosimetry and surface guided FLASH-RT are to our knowledge the first of their kind. Following an introduction to the field of FLASH and the associated dosimetric challenges, we here aim to present the two ongoing studies including some preliminary results.
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| 43. |
- Fussell, Julia C., et al.
(författare)
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A Review of Road Traffic-Derived Non-Exhaust Particles : Emissions, Physicochemical Characteristics, Health Risks, and Mitigation Measures
- 2022
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:11, s. 6813-6835
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Forskningsöversikt (refereegranskat)abstract
- Implementation of regulatory standards has reduced exhaust emissions of particulate matter from road traffic substantially in the developed world. However, nonexhaust particle emissions arising from the wear of brakes, tires, and the road surface, together with the resuspension of road dust, are unregulated and exceed exhaust emissions in many jurisdictions. While knowledge of the sources of nonexhaust particles is fairly good, source-specific measurements of airborne concentrations are few, and studies of the toxicology and epidemiology do not give a clear picture of the health risk posed. This paper reviews the current state of knowledge, with a strong focus on health-related research, highlighting areas where further research is an essential prerequisite for developing focused policy responses to nonexhaust particles.
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| 44. |
- Gonzalez-Perez, V., et al.
(författare)
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Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 118:3
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Tidskriftsartikel (refereegranskat)abstract
- Y Goblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters are thought to impact on MUC2 secretion, the specific cellular mechanisms that regulate GC function remain incompletely understood. Previously, we demonstrated that leucine-rich repeat-containing protein 26 (LRRC26), a known regulatory subunit of the Ca2+-and voltage-activated K+ channel (BK channel), localizes specifically to secretory cells within the intestinal tract. Here, utilizing a mouse model in which MUC2 is fluorescently tagged, thereby allowing visualization of single GCs in intact colonic crypts, we show that murine colonic GCs have functional LRRC26-associated BK channels. In the absence of LRRC26, BK channels are present in GCs, but are not activated at physiological conditions. In contrast, all tested MUC2(-) cells completely lacked BK channels. Moreover, LRRC26-associated BK channels underlie the BK channel contribution to the resting transepithelial current across mouse distal colonic mucosa. Genetic ablation of either LRRC26 or BK pore-forming alpha-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate. These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.
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| 45. |
- Graco-Roza, Caio, et al.
(författare)
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Distance decay 2.0 – A global synthesis of taxonomic and functional turnover in ecological communities
- 2022
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 31:7, s. 1399-1421
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Understanding the variation in community composition and species abundances (i.e., beta-diversity) is at the heart of community ecology. A common approach to examine beta-diversity is to evaluate directional variation in community composition by measuring the decay in the similarity among pairs of communities along spatial or environmental distance. We provide the first global synthesis of taxonomic and functional distance decay along spatial and environmental distance by analysing 148 datasets comprising different types of organisms and environments.Location: Global.Time period: 1990 to present.Major taxa studied: From diatoms to mammals.Method: We measured the strength of the decay using ranked Mantel tests (Mantel r) and the rate of distance decay as the slope of an exponential fit using generalized linear models. We used null models to test whether functional similarity decays faster or slower than expected given the taxonomic decay along the spatial and environmental distance. We also unveiled the factors driving the rate of decay across the datasets, including latitude, spatial extent, realm and organismal features.Results: Taxonomic distance decay was stronger than functional distance decay along both spatial and environmental distance. Functional distance decay was random given the taxonomic distance decay. The rate of taxonomic and functional spatial distance decay was fastest in the datasets from mid-latitudes. Overall, datasets covering larger spatial extents showed a lower rate of decay along spatial distance but a higher rate of decay along environmental distance. Marine ecosystems had the slowest rate of decay along environmental distances.Main conclusions: In general, taxonomic distance decay is a useful tool for biogeographical research because it reflects dispersal-related factors in addition to species responses to climatic and environmental variables. Moreover, functional distance decay might be a cost-effective option for investigating community changes in heterogeneous environments.
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| 46. |
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| 47. |
- Gupta, Dhanu, et al.
(författare)
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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
- 2021
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Ingår i: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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| 48. |
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| 49. |
- Holm Nielsen, S., et al.
(författare)
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The novel collagen matrikine, endotrophin, is associated with mortality and cardiovascular events in patients with atherosclerosis
- 2021
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 290:1, s. 179-189
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO-C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention. Objective: In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO-C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. Methods: Sections from the stenotic human carotid plaques were stained with the PRO-C6 antibody. PRO-C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro- and macrovascular hard end-points for innovative diabetes tools (IMI-SUMMIT, validation cohort, n = 1,378). Median follow-up was 43 months. Kaplan–Meier curves and log-rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. Results: PRO-C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO-C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 −1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 −1.241], p = 0.04) and all-cause death (HR 1.087 [95% CI 1.008 −1.172], p = 0.03). In the validation cohort, PRO-C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 −1.117], p = 0.017). Conclusion: PRO-C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all-cause mortality in two large prospective cohorts.
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| 50. |
- Knoop, K. A., et al.
(författare)
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Synchronization of mothers and offspring promotes tolerance and limits allergy
- 2020
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Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:15
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Tidskriftsartikel (refereegranskat)abstract
- Allergic disorders, characterized by Th2 immune responses to environmental substances, are increasingly common in children in Western societies. Multiple studies indicate that breastfeeding, early complementary introduction of food allergens, and antibiotic avoidance in the first year of life reduces allergic outcomes in at-risk children. Why the benefit of these practices is restricted to early life is largely unknown. We identified a preweaning interval during which dietary antigens are assimilated by the colonic immune system. This interval is under maternal control via temporal changes in breast milk, coincides with an influx of naive T cells into the colon, and is followed by the development of a long-lived population of colonic peripherally derived Tregs (pTregs) that can be specific for dietary antigens encountered during this interval. Desynchronization of mothers and offspring produced durable deficits in these pTregs, impaired tolerance to dietary antigens introduced during and after this preweaning interval, and resulted in spontaneous Th2 responses. These effects could be rescued by pTregs from the periweaning colon or by Tregs generated in vitro using periweaning colonic antigen-presenting cells. These findings demonstrate that mothers and their offspring are synchronized for the development of a balanced immune system.
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