| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 11. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 12. |
- Wang, QBS, et al.
(författare)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
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| 18. |
- Andreasson, K. I., et al.
(författare)
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Targeting innate immunity for neurodegenerative disorders of the central nervous system
- 2016
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; , s. 653-693
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. (Figure presented.) Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. © 2016 International Society for Neurochemistry
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| 22. |
- Vilardell, A. M., et al.
(författare)
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B2-structured Fe3Al alloy manufactured by laser powder bed fusion : Processing, microstructure and mechanical performance
- 2023
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Ingår i: Intermetallics (Barking). - : Elsevier. - 0966-9795 .- 1879-0216. ; 156
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Tidskriftsartikel (refereegranskat)abstract
- Prealloyed Fe3Al was successfully manufactured by laser powder bed fusion. The best set of process parameters led to parts with a relative density of 99.5 %, a surface roughness, Sa, of 31.5 ± 5.6 μm and a hardness of 319 ± 14 HV0.1. Its microstructure as well as its mechanical properties at room and high temperatures were analyzed. The results of the chemical composition showed minor variations in aluminum content oscillating between 21 and 28 at.% along the melt pool. Additionally, elongated grains were observed to grow parallel to the building direction, as well as the development of a weak 001 texture along the building direction. The mechanical properties were influenced by the temperature. Compression tests showed a loss in strength with the increase in temperature, from a yield strength of 621 ± 40 MPa at room temperature to 89 ± 20 MPa at 650 °C. Reciprocating sliding wear tests showed that fragmentation of the intermetallic at room temperature occurs, whereas plastic deformation dominated at higher temperatures. For all temperatures, tribochemical wear was also present due to the oxidation of wear debris.
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| 23. |
- Vilardell, Anna M., et al.
(författare)
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Manufacturing and characterization of in-situ alloyed Ti6Al4V(ELI)-3 at.% Cu by laser powder bed fusion
- 2020
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Ingår i: Additive Manufacturing. - : Elsevier. - 2214-8604 .- 2214-7810. ; 36, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Biofunctionalization of Ti6Al4V alloy with metallic agents like Ag or Cu is a promising approach to add antibacterial properties and thus to reduce the risk of implant failure. This research investigates the in-situ alloying of Ti6Al4V(ELI) with 3 at.% Cu powders using Laser Powder Bed Fusion (L-PBF). The morphology and geometrical characteristics of the single tracks and layers were studied. Laser powers of 170 W and 340 W, and scanning speeds ranging from 0.4 to 1.4 m/s and 0.8-2.8 m/s were implemented. Single track results showed balling effect and humping at high scanning speeds, 1.4 m/s and 1.6 m/s, for each laser powder respectively. Conversely, keyhole formation occurred at lower scanning speeds of 0.4-0.6 m/s for 170 W laser power, and below and 0.8 m/s for 340 W laser power. For both laser powers, single layers resulted in smoother surfaces at lower scanning speeds. These results were used for the development of optimal process parameters for 3D cubes with 99.9 % density. Optimal process parameters were found for 170 W and 340W laser powders at 0.7-0.9 and 1.0-1.2 m/s scanning speeds, respectively.In-situ alloying by L-PBF was challenging and a homogeneous distribution of Cu within the alloy was hard to achieve. The increase in laser power from 170 to 340 W resulted in small increase in homogenization. Microstructural analyses after stress-relieving treatment showed the presence of alpha' and beta phases, as well as CuTi2 intermetallic precipitates. The finer microstructure together with CuTi2 intermetallic precipitates resulted in an increase in hardness. This study demonstrates the potential for printing in-situ alloyed Ti6Al4V(ELI)- 3 at.% Cu for biomedical applications. However, further studies are required to determine the effectiveness of antibacterial properties.
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| 24. |
- Vilardell, Anna M., et al.
(författare)
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Mechanical behavior of in-situ alloyed Ti6Al4V(ELI)-3 at.% Cu lattice structures manufactured by laser powder bed fusion and designed for implant applications
- 2021
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Ingår i: Journal of The Mechanical Behavior of Biomedical Materials. - : Elsevier. - 1751-6161 .- 1878-0180. ; 113, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, cellular lattice structures for implant applications are reported for the first-time incorporating copper directly by in-situ alloying in the laser powder bed fusion process. The aim to incorporate 3 at.% Cu into Ti6Al4V(ELI) is selected for improved antibacterial properties while maintaining appropriate mechanical properties. Previously, topologically optimized Ti6Al4V(ELI) lattice structures were successfully designed, manufactured and studied for implant applications. The development of a new alloy produced by in-situ alloying of elemental powder mixture of Ti6Al4V(ELI) and pure Cu powders was used here for the production of identical lattice structures with improved antibacterial properties. One of the same as-designed CAD models was used for the manufacturing of these lattices compared to previous work on pure Ti6Al4V(ELI) lattices, making direct comparison of mechanical properties possible. Similar manufacturability highlights the applicability of this alloying technique to other lattice designs. Microstructural characterization was performed by optical and electron microscopies, as well as microCT. Mechanical characterization was performed by means of compression tests and hardness measurements. Results showed that in-situ alloying with copper leads to the formation of localized Cu-rich regions, refinement of martensitic phase and the formation of CuTi2 intermetallic precipitates, which increased the hardness and strength of the material. Deviations in wall thickness between the as-designed and as-manufactured lattices led to anisotropy of the mechanical properties of the lattices. Higher compressive strength values were obtained when thicker walls were oriented along the loading direction. Nevertheless, alloying with Cu had a higher impact on the compressive strength of lattice structure than the wall thickness deviations. The direct in-situ alloying of copper in Ti6Al4V(ELI) is a promising mute for direct manufacturing of antibacterial implants.
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| 25. |
- Pälike, Heiko, et al.
(författare)
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A Cenozoic record of the equatorial Pacific carbonate compensation depth
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 488:7413, s. 609-614
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.
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