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- Fälth, Billy, 1968-
(författare)
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Simulating Earthquake Rupture and Near-Fault Fracture Response
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sweden is presently a low seismicity area where most earthquakes are small and pose no serious threat to constructions. For the long-term perspectives of safety assessments of geological repositories for spent nuclear fuel, however, the effects of large earthquakes have to be considered. For the Swedish nuclear waste storage concept, seismically induced secondary fracture shear displacements across waste canister positions could pose a long-term seismic risk to the repository.In this thesis, I present earthquake simulations with which I study the potential for near-fault secondary fracture shear displacements. As a measure I use the Coulomb Failure Stress (CFS), but also calculate explicit fracture displacements. I account for both the dynamic and quasi-static stress perturbations generated during the earthquake. As numerical tool I use the 3DEC code, whose performance I validate using Stokes closed-form solution and the Compsyn code as benchmarks. In a model of a Mw 6.4 earthquake, I investigate how fault roughness, the fault rupture propagation model and rupture velocity may impact the near-fault CFS evolution. I find that fault roughness can reduce the amount of fault slip by tens of percent, but also increase the near-fault CFS with similar amounts locally. Furthermore, different fault rupture models generate similar CFS levels. I also find that the secondary stresses scale with rupture velocity.In a model based on data from the Forsmark nuclear waste repository site, and assuming stress conditions prevailing at the end of a glaciation, I simulate several high stress drop ~Mw 5.6 earthquake scenarios on the gently dipping fault zone ZFMA2 and calculate secondary fracture displacements on 300 m diameter planar fractures. Less than 1% of the fractures at the shortest distance from ZFMA2 generate displacements exceeding the 50 mm criterion established by the Swedish Nuclear Fuel and Waste Management Co. Given the high stress drops and the assumption of fracture planarity, I consider the calculated displacements to represent upper bound estimates of possible secondary displacements at Forsmark. Hence, the results should strengthen the confidence in the safety assessment of the nuclear waste repository at the Forsmark site.
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| 3. |
- Fälth, Billy, et al.
(författare)
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Simulating earthquake rupture and off-fault fracture response : Application to the safety assessment of the Swedish nuclear waste repository
- 2015
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Ingår i: Bulletin of The Seismological Society of America (BSSA). - : Seismological Society of America (SSA). - 0037-1106 .- 1943-3573. ; 105:1, s. 134-151
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Tidskriftsartikel (refereegranskat)abstract
- To assess the long‐term safety of a deep repository of spent nuclear fuel, upper bound estimates of seismically induced secondary fracture shear displacements are needed. For this purpose, we analyze a model including an earthquake fault, which is surrounded by a number of smaller discontinuities representing fractures on which secondary displacements may be induced. Initial stresses are applied and a rupture is initiated at a predefined hypocenter and propagated at a specified rupture speed. During rupture we monitor shear displacements taking place on the nearby fracture planes in response to static as well as dynamic effects. As a numerical tool, we use the 3Dimensional Distinct Element Code (3DEC) because it has the capability to handle numerous discontinuities with different orientations and at different locations simultaneously. In tests performed to benchmark the capability of our method to generate and propagate seismic waves, 3DEC generates results in good agreement with results from both Stokes solution and the Compsyn code package. In a preliminary application of our method to the nuclear waste repository site at Forsmark, southern Sweden, we assume end‐glacial stress conditions and rupture on a shallow, gently dipping, highly prestressed fault with low residual strength. The rupture generates nearly complete stress drop and an Mw 5.6 event on the 12 km2 rupture area. Of the 1584 secondary fractures (150 m radius), with a wide range of orientations and locations relative to the fault, a majority move less than 5 mm. The maximum shear displacement is some tens of millimeters at 200 m fault‐fracture distance.
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| 5. |
- Lund, Harald, et al.
(författare)
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Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a– microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.
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| 6. |
- Lund, Harald
(författare)
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Regulation of microglia and monocyte function by the cytokine TGF-beta
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It has been almost a century since Pío del Río-Hortega described the microglial cell, proposing it to be primarily occupied with phagocytosis of waste products. While this makes up one of its functions, we know today that microglia participate in numerous tasks and can interact with and regulate all other cell types of the brain. Given this knowledge, it is perhaps not surprising that microglia dysfunction has been implicated in a wide range of neurological disorders, including diseases of neuroinflammatory (multiple sclerosis), neurodevelopmental (schizophrenia) and neurodegenerative (amyotrophic lateral sclerosis and Alzheimer’s disease) character. Monocytes are produced in the bone marrow and are released into the bloodstream from where they can infiltrate virtually any tissue, either as a homeostatic process to replace the local macrophage pool, or as an inflammatory response to tissue damage. Monocytes can engraft the central nervous system under various conditions and are historically recognized as the main drivers of the demyelinating process that clinically manifests as multiple sclerosis. However, given the right signals, monocytes can also integrate into the neural network and become permanent residents of the brain. The work presented in this thesis explores how these distinct processes are regulated by the cytokine TGF-β. Using conditional gene targeting approaches we investigated the role of TGF-β signaling in monocytes during autoimmune neuroinflammation as well as during homeostatic replacement of microglia after experimental depletion. We demonstrate that, when autoimmune paralysis is established, TGF-β suppresses monocyte effector functions including pro-inflammatory cytokine production and oxidative damage, which initiates remission of disease. Subsequently, in a setting of microglia loss, monocytes required TGF-β to colonize the microglial niche and to maintain microglia-like phenotype and function. Abrogation of TGF-β signaling in monocytederived microglial replacements resulted in the spontaneous initiation of demyelination and neuronal damage that clinically presented as a progressive and fatal motor disease. In summary, our studies provide novel mechanisms by which TGF-β regulates brain homeostasis, which are likely deregulated during disease and that could be pharmacologically targeted.
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| 7. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 8. |
- Sackmann, Valerie, et al.
(författare)
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Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells
- 2017
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Ingår i: Neurobiology of Aging. - : ELSEVIER SCIENCE INC. - 0197-4580 .- 1558-1497. ; 60, s. 173-182
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation plays an influential role in Alzheimers disease (AD), although the mechanisms underlying this phenomenon remain largely unknown. Microglia are thought to be responsible for the majority of these effects and can be characterized into resting (M0), proinflammatory (M1), or anti-inflammatory (M2) functional phenotypes. We investigated the effects of conditioned macrophage media, as an analogue to microglia, on the transfer of oligomeric amyloid beta (oA beta) between differentiated SH-SY5Y cells. We also investigated how the different inflammatory environments related to intercellular and intracellular changes. We demonstrate that M2 products decrease interneuronal transfer of oA beta, while recombinant interleukin (IL)-4, IL-10, and IL-13 increase transfer. There were no alterations to the mRNA of a number of AD-related genes in response to the combination of oA beta and M0, M1, or M2, but several intracellular proteins, some relating to protein trafficking and the endosomal/lysosomal system, were altered. Stimulating microglia to an M2 phenotype may thus slow down the progression of AD and could be a target for future therapies. (C) 2017 Elsevier Inc. All rights reserved.
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