| 1. |
- Murari, A., et al.
(författare)
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A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
- 2024
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Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
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| 5. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 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
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 8. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 9. |
- Arellano, Santiago, 1981, et al.
(författare)
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Synoptic analysis of a decade of daily measurements of SO2 emission in the troposphere from volcanoes of the global ground-based Network for Observation of Volcanic and Atmospheric Change
- 2021
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3516 .- 1866-3508. ; 13:3, s. 1167-1188
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Tidskriftsartikel (refereegranskat)abstract
- Volcanic plumes are common and far-reaching manifestations of volcanic activity during and between eruptions. Observations of the rate of emission and composition of volcanic plumes are essential to recognize and, in some cases, predict the state of volcanic activity. Measurements of the size and location of the plumes are important to assess the impact of the emission from sporadic or localized events to persistent or widespread processes of climatic and environmental importance. These observations provide information on volatile budgets on Earth, chemical evolution of magmas, and atmospheric circulation and dynamics. Space-based observations during the last decades have given us a global view of Earth's volcanic emission, particularly of sulfur dioxide (SO2). Although none of the satellite missions were intended to be used for measurement of volcanic gas emission, specially adapted algorithms have produced time-averaged global emission budgets. These have confirmed that tropospheric plumes, produced from persistent degassing of weak sources, dominate the total emission of volcanic SO2. Although space-based observations have provided this global insight into some aspects of Earth's volcanism, it still has important limitations. The magnitude and short-term variability of lower-atmosphere emissions, historically less accessible from space, remain largely uncertain. Operational monitoring of volcanic plumes, at scales relevant for adequate surveillance, has been facilitated through the use of ground-based scanning differential optical absorption spectrometer (ScanDOAS) instruments since the beginning of this century, largely due to the coordinated effort of the Network for Observation of Volcanic and Atmospheric Change (NOVAC). In this study, we present a compilation of results of homogenized post-analysis of measurements of SO2 flux and plume parameters obtained during the period March 2005 to January 2017 of 32 volcanoes in NOVAC. This inventory opens a window into the short-term emission patterns of a diverse set of volcanoes in terms of magma composition, geographical location, magnitude of emission, and style of eruptive activity. We find that passive volcanic degassing is by no means a stationary process in time and that large sub-daily variability is observed in the flux of volcanic gases, which has implications for emission budgets produced using short-term, sporadic observations. The use of a standard evaluation method allows for intercomparison between different volcanoes and between ground- and space-based measurements of the same volcanoes. The emission of several weakly degassing volcanoes, undetected by satellites, is presented for the first time. We also compare our results with those reported in the literature, providing ranges of variability in emission not accessible in the past. The open-access data repository introduced in this article will enable further exploitation of this unique dataset, with a focus on volcanological research, risk assessment, satellite-sensor validation, and improved quantification of the prevalent tropospheric component of global volcanic emission. Datasets for each volcano are made available at https://novac.chalmers.se (last access: 1 October 2020) under the CC-BY 4 license or through the DOI (digital object identifier) links provided in Table 1.
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| 10. |
- Gustavsson, Emil K., et al.
(författare)
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The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1
- 2024
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Ingår i: Science Advances. - 2375-2548. ; 10:26, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson’s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function—yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.
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| 11. |
- Egg, David, et al.
(författare)
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Therapeutic options for CTLA-4 insufficiency
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 149:2, s. 736-746
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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| 12. |
- Espen Yttri, Karl, et al.
(författare)
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Trends, composition, and sources of carbonaceous aerosol at the Birkenes Observatory, northern Europe, 2001-2018
- 2021
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 21:9, s. 7149-7170
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Tidskriftsartikel (refereegranskat)abstract
- We present 18 years (2001-2018) of aerosol measurements, including organic and elemental carbon (OC and EC), organic tracers (levoglucosan, arabitol, mannitol, trehalose, glucose, and 2-methyltetrols), trace elements, and ions, at the Birkenes Observatory (southern Norway) - a site representative of the northern European region. The OC=EC (2001-2018) and the levoglucosan (2008-2018) time series are the longest in Europe, with OC=EC available for the PM10, PM2:5 (fine), and PM10-2:5 (coarse) size fractions, providing the opportunity for a nearly 2-decade-long assessment. Using positive matrix factorization (PMF), we identify seven carbonaceous aerosol sources at Birkenes: mineraldust- dominated aerosol (MIN), traffic/industry-like aerosol (TRA/IND), short-range-transported biogenic secondary organic aerosol (BSOASRT), primary biological aerosol particles (PBAP), biomass burning aerosol (BB), ammoniumnitrate- dominated aerosol (NH4NO3), and (one low carbon fraction) sea salt aerosol (SS). We observed significant (p < 0:05), large decreases in EC in PM10 (-3:9%yr-1) and PM2:5 (-4:2%yr-1) and a smaller decline in levoglucosan (-2:8%yr-1), suggesting that OC=EC from traffic and industry is decreasing, whereas the abatement of OC=EC from biomass burning has been slightly less successful. EC abatement with respect to anthropogenic sources is further supported by decreasing EC fractions in PM2:5 (-3:9%yr-1) and PM10 (-4:5%yr-1). PMF apportioned 72% of EC to fossil fuel sources; this was further supported by PMF applied to absorption photometer data, which yielded a two-factor solution with a low aerosol ngstr m exponent (AAED0.93) fraction, assumed to be equivalent black carbon from fossil fuel combustion (eBCFF), contributing 78% to eBC mass. The higher AAE fraction (AAED2.04) is likely eBC from BB (eBCBB). Source-receptor model calculations (FLEXPART) showed that continental Europe and western Russia were the main source regions of both elevated eBCBB and eBCFF. Dominating biogenic sources explain why there was no downward trend for OC. A relative increase in the OC fraction in PM2:5 (C3:2%yr-1) and PM10 (C2:4%yr-1) underscores the importance of biogenic sources at Birkenes (BSOA and PBAP), which were higher in the vegetative season and dominated both fine (53 %) and coarse (78 %) OC. Furthermore, 77 %-91% of OC in PM2:5, PM10-2:5, and PM10 was attributed to biogenic sources in summer vs. 22 %- 37% in winter. The coarse fraction had the highest share of biogenic sources regardless of season and was dominated by PBAP, except in winter. Our results show a shift in the aerosol composition at Birkenes and, thus, also in the relative source contributions. The need for diverse offline and online carbonaceous aerosol speciation to understand carbonaceous aerosol sources, including their seasonal, annual, and long-term variability, has been demonstrated.
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| 13. |
- Gredal, H., et al.
(författare)
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Diagnosis and long-term outcome in dogs with acute onset intracranial signs
- 2020
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Ingår i: Journal of Small Animal Practice. - : Wiley. - 0022-4510 .- 1748-5827. ; 61:2, s. 101-109
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate dogs with acute onset of intracranial signs suspected of stroke by primary veterinary clinicians, and establish possible differential diagnoses and long-term outcome. In addition, serum C-reactive protein and plasma cytokines were investigated as potential biomarkers of disease. Materials and Methods: All cases were evaluated by neurologic examination, routine haematology and biochemistry and measurement of serum C-reactive protein, plasma cytokine concentrations (interleukin-2, -6, -8, -10, tumour necrosis factor) and low-field MRI. Results: Primary veterinarians contacted the investigators with 85 suspected stroke cases. Only 20 met the inclusion criteria. Of these, two were diagnosed with ischaemic stroke. Other causes were idiopathic vestibular syndrome (n=6), brain tumour (n=5) and inflammatory brain disease (n=2); in five cases a precise diagnosis could not be determined. Median survival times were: brain tumour, 3 days, idiopathic vestibular syndrome, 315 days, ischaemic stroke, 365 days and inflammatory central nervous system (CNS) disease, 468 days. The median plasma concentrations of interleukin-2, -6, -8, -10 or tumour necrosis factor were not significantly increased in any of the diagnosis groups compared to healthy controls. Serum C-reactive protein was higher in dogs with brain tumours and inflammatory brain disease but not above the upper bound of the reference interval. Clinical Significance: Dogs that present with acute onset intracranial disease may have ischaemic stroke but are more likely to have other causes. Many dogs with such acute onset of neurological dysfunction (brain tumours excluded) may recover within a couple of weeks despite their initial severe clinical appearance.
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| 14. |
- Kurzawa-Akanbi, M., et al.
(författare)
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Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina
- 2022
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors atrophy and/or retinal and choroidal angiogenesis. Here we use AMD patient-specific RPE cells with the Complement Factor H Y402H high-risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi-omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co-expressing retinal progenitor cell markers Pax6/Vsx2, suggesting injury-induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells.
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