| 1. |
- 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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| 2. |
- Fisher, Jane, et al.
(författare)
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Is heparin-binding protein inhibition a mechanism of albumin's efficacy in human septic shock?
- 2018
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Ingår i: Critical Care Medicine. - 0090-3493. ; 46:5, s. 364-374
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Our objectives were to determine first whether albumin prevents heparin-binding protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma heparin-binding protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. Design: In vitro human endothelial and renal cell model and observation cohort of septic shock. Settings: Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). Patients: Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr). Interventions: In vitro: heparin-binding protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. Measurements and Main Results: Transendothelial electrical resistance - a marker of permeability - of human endothelial cells was measured using a voltohmmeter. We measured plasma heparin-binding protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an heparin-binding protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited heparin-binding protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher heparin-binding protein-to-albumin ratio (1.6 vs 0.89; p < 0.001) and heparin-binding protein (38.2 vs 20.8 ng/mL; p < 0.001) than patients without acute kidney injury. The highest heparin-binding protein-to-albumin ratio (> 3.05), heparin-binding protein quartiles (> 69.8), and heparin-binding protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-binding protein and heparin-binding protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of heparin-binding protein-to-albumin ratio and heparin-binding protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. Conclusions: Albumin inhibits heparin-binding protein-induced increased human endothelial cell permeability and heparin-binding protein greater than 30 ng/mL and heparin-binding protein-to-albumin ratio greater than 3.01 - but not serum albumin - identified patients at increased risk for acute kidney injury in septic shock.
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| 3. |
- Kim, Ye-Jin, et al.
(författare)
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Femtosecond-resolved imaging of a single-particle phase transition in energy-filtered ultrafast electron microscopy
- 2023
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Using an energy filter in transmission electron microscopy has enabled elemental mapping at the atomic scale and improved the precision of structural determination by gating inelastic and elastic imaging electrons, respec-tively. Here, we use an energy filter in ultrafast electron microscopy to enhance the temporal resolution toward the domain of atomic motion. Visualizing transient structures with femtosecond temporal precision was achieved by selecting imaging electrons in a narrow energy distribution from dense chirped photoelectron packets with broad longitudinal momentum distributions and thus typically exhibiting picosecond durations. In this study, the heterogeneous ultrafast phase transitions of vanadium dioxide (VO2) nanoparticles, a repre-sentative strongly correlated system, were filmed and attributed to the emergence of a transient, low-symmetry metallic phase caused by different local strains. Our approach enables electron microscopy to access the time scale of elementary nuclear motion to visualize the onset of the structural dynamics of matter at the nanoscale.
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| 4. |
- Kraft, Andrew W, et al.
(författare)
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Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.
- 2013
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 27:1, s. 187-98
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation-glial fibrillary acid protein (Gfap) and vimentin (Vim)-in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap(-/-)Vim(-/-) mice had twice the plaque load of APP/PS1 Gfap(+/+)Vim(+/+) mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation. Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap(-/-)Vim(-/-) astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2- to 3-fold higher than APP/PS1 Gfap(+/+)Vim(+/+) mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque-related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque.-Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., Lee, J.-M. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.
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| 5. |
- Lee, Hyejin, et al.
(författare)
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Characteristics of road users’ safety behavior and attitude in Korea : findings from ESRA survey
- 2018
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Konferensbidrag (refereegranskat)abstract
- While the risky behaviors to traffic and road safety attitude have been advocated as necessary contributors for road safety policies, a few studies have examined the behavioral and attitudinal characteristics of road users in Korea. This paper conducted a questionnaire survey to road users, as the part of E-survey of road users’ attitudes (ESRA-Project), in Korea (N=1000) comparing 24 western countries (N=1000 for each country) to understand the behaviors and attitudinal characteristics of road users. The survey consists of four main parts: (Q1) safe feeling, (Q2) involvement in road crash, (Q3) road user behaviors and (Q4) personal acceptability toward risky behaviors. The survey asked responses about 8 items, which are (I-1) speeding in urban area, (I-2) speeding in freeway, (I-3) driving while drowsy, (I-4) typing text message or email while driving, (I-5) talking on hand-held mobile phone while driving, (I-6) wearing seat belt in front seat, (I-7) wearing seat belt in back seat and (I-8) installing child restraint systems. This paper aims to answer two questions: How do Korean road users perceive the importance of several risky road behaviors comparing Western road users? Are there important differences in road safety attitude and behaviors between Korea and Western countries? By ANOVA analysis and Discriminant Analysis between two groups, statistically significant differences and discriminant loadings are revealed. Results shows that road users in Korea are more lenient with several risky behaviors, such as (I-8) using child restraint systems, (I-4) typing text message or e-mails while driving and (I-6) not wearing a seatbelt in the front seat of the car. This result should be applied to road safety campaign, promotion and education for safer road in Korea. In addition, Korean road safety observatory system should be improved to tract the risky behaviors for development of road safety policies.
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| 6. |
- Lee, Ji-Eun, et al.
(författare)
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Structure-Property Relationship of Perylene Bisimide Macrocycles Probed by Atomic Force Microscopy and Single-Molecule Fluorescence Spectroscopy
- 2013
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-086X .- 1936-0851. ; 7:6, s. 5064-5076
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Tidskriftsartikel (refereegranskat)abstract
- Properties of a series of acetylene-linked perylene bisimide (PBI) macrocycles with different ring size composed of three to six PBI dyes were investigated by atomic force microscopy (AFM) and single-molecule fluorescence spectroscopy in a condensed phase. it was demonstrated that the structures of PBI cyclic arrays (CNs, N = 3, 4,5, and 6) become distorted with increasing the ring size through molecular dynamic (MD) simulations (PM6-DH2 method) and AFM height images of CNs on highly ordered pyrolytic graphite (HOPG) surface. The MD simulations showed that only C5 and C6 rings are highly flexible molecules whose planarization goes along with a significant energetic penalty. Accordingly, both molecules did not show ordered adlayers on a HOPG surface. In contrast, C3 and C4 are far more rigid molecules leading to well-ordered hexagonal (C3) and rectangular (C4) 20 lattices. At the single-molecule level, we showed that the fluorescence properties of single CNs are affected by the structural changes. The fluorescence lifetimes of CNs became shorter and their distributions became broader due to the structural distortions with increasing the ring size. Furthermore, the CNs of smaller ring size exhibit a higher photostability and an efficient excitation energy transfer (EET) due to the more well-defined and planar structures compared to the larger CNs. Consequently, these observations provide evidence that not only PBI macrocycles are promising candidates for artificial light-harvesting systems, but also the photophysical properties of CNs are strongly related to the structural rigidity of CNs.
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