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- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 4. |
- North, R. L., et al.
(författare)
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The state of Lake Simcoe (Ontario, Canada) : the effects of multiple stressors on phosphorus and oxygen dynamics
- 2013
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Ingår i: Inland Waters. - 2044-2041 .- 2044-205X. ; 3:1, s. 51-74
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Tidskriftsartikel (refereegranskat)abstract
- Lake Simcoe, the largest lake in southern Ontario outside of the Laurentian Great Lakes, is affected by numerous stressors including eutrophication resulting from total phosphorus (TP) loading, climate change, and invasions of exotic species. We synthesized the long-term responses of Lake Simcoe to these stressors by assessing trends in water quality and biological composition over multiple trophic levels. Evidence for climate change included increasing thermal stability of the lake and changes in subfossil diatom communities over time. Although the deep water dissolved oxygen (O-2) minimum has increased significantly since TP load reductions, it is still below estimated historical values and the Lake Simcoe Protection Plan end-of-summer target level of 7 mg O-2 L-1. Low deep water O-2 concentrations corresponded with a decline in coldwater fish abundance. Since 1980, some nutrient concentrations have decreased (spring TP) while others have increased (silica), but many show no obvious changes (ice-free TP, nitrate, ammonium). Increases in water clarity, combined with declines in chlorophyll a and phytoplankton biovolumes in Cook's Bay, were temporally consistent with declines in TP loading and the lake-wide establishment of dreissenid mussels as a major component of the Lake Simcoe ecosystem. Using an investigative tool, we identified 2 periods when abrupt shifts potentially occurred in multiple parameters: 1986 and 1995-1997. Additional ecosystem level changes such as declines in zooplankton, declines in offshore benthic invertebrate abundance, and increased nearshore invertebrate abundance likely reflect the effects of invasive species. The interaction of these multiple stressors have significantly altered the Lake Simcoe ecosystem.
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- Forsgård, Richard A., 1987-, et al.
(författare)
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Limosilactobacillus reuteri DSM 17938 supplementation and SARS-CoV-2 specific antibody response in healthy adults : a randomized, triple-blinded, placebo-controlled trial
- 2023
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Ingår i: Gut microbes. - : Taylor & Francis. - 1949-0976 .- 1949-0984. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Studies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108 colony-forming units of Limosilactobacillus reuteri DSM 17938 + 10 μg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 μg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n = 6) tended to have higher serum anti-spike IgG (609 [168-1480] BAU/ml vs 111 [36.1-1210] BAU/ml, p = 0.080) and anti-receptor binding domain (RBD) IgG (928 [212-3449] BAU/ml vs (83.7 [22.8-2094] BAU/ml, p = 0.066) levels than individuals in the placebo arm (n = 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n = 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9-976] BAU/ml vs 61.3 [26.7-97.1] BAU/ml, p = 0.036) than the placebo arm (n = 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.
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| 7. |
- Imaz-Rosshandler, Ivan, et al.
(författare)
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Tracking early mammalian organogenesis - prediction and validation of differentiation trajectories at whole organism scale
- 2024
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Ingår i: DEVELOPMENT. - 0950-1991 .- 1477-9129. ; 151:3
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Tidskriftsartikel (refereegranskat)abstract
- Early organogenesis represents a key step in animal development, during which pluripotent cells diversify to initiate organ formation. Here, we sampled 300,000 single-cell transcriptomes from mouse embryos between E8.5 and E9.5 in 6-h intervals and combined this new dataset with our previous atlas (E6.5-E8.5) to produce a densely sampled timecourse of >400,000 cells from early gastrulation to organogenesis. Computational lineage reconstruction identified complex waves of blood and endothelial development, including a new programme for somite-derived endothelium. We also dissected the E7.5 primitive streak into four adjacent regions, performed scRNA-seq and predicted cell fates computationally. Finally, we defined developmental state/ fate relationships by combining orthotopic grafting, microscopic analysis and scRNA-seq to transcriptionally determine cell fates of grafted primitive streak regions after 24 h of in vitro embryo culture. Experimentally determined fate outcomes were in good agreement with computationally predicted fates, demonstrating how classical grafting experiments can be revisited to establish high-resolution cell state/fate relationships. Such interdisciplinary approaches will benefit future studies in developmental biology and guide the in vitro production of cells for organ regeneration and repair.
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| 8. |
- Roeder, SS, et al.
(författare)
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Evidence for postnatal neurogenesis in the human amygdala
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 366-
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Tidskriftsartikel (refereegranskat)abstract
- The human amygdala is involved in processing of memory, decision-making, and emotional responses. Previous studies suggested that the amygdala may represent a neurogenic niche in mammals. By combining two distinct methodological approaches, lipofuscin quantification and 14C-based retrospective birth dating of neurons, along with mathematical modelling, we here explored whether postnatal neurogenesis exists in the human amygdala. We investigated post-mortem samples of twelve neurologically healthy subjects. The average rate of lipofuscin-negative neurons was 3.4%, representing a substantial proportion of cells substantially younger than the individual. Mass spectrometry analysis of genomic 14C-concentrations in amygdala neurons compared with atmospheric 14C-levels provided evidence for postnatal neuronal exchange. Mathematical modelling identified a best-fitting scenario comprising of a quiescent and a renewing neuronal population with an overall renewal rate of >2.7% per year. In conclusion, we provide evidence for postnatal neurogenesis in the human amygdala with cell turnover rates comparable to the hippocampus.
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| 9. |
- Sobolev, Egor, et al.
(författare)
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Megahertz single-particle imaging at the European XFEL
- 2020
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Ingår i: Communications Physics. - : Springer Science and Business Media LLC. - 2399-3650. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- The emergence of high repetition-rate X-ray free-electron lasers (XFELs) powered by superconducting accelerator technology enables the measurement of significantly more experimental data per day than was previously possible. The European XFEL is expected to provide 27,000 pulses per second, over two orders of magnitude more than any other XFEL. The increased pulse rate is a key enabling factor for single-particle X-ray diffractive imaging, which relies on averaging the weak diffraction signal from single biological particles. Taking full advantage of this new capability requires that all experimental steps, from sample preparation and delivery to the acquisition of diffraction patterns, are compatible with the increased pulse repetition rate. Here, we show that single-particle imaging can be performed using X-ray pulses at megahertz repetition rates. The results obtained pave the way towards exploiting high repetition-rate X-ray free-electron lasers for single-particle imaging at their full repetition rate.
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