| 1. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 2. |
- Cappellini, Francesca, et al.
(författare)
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Mechanistic insight into reactivity and (geno)toxicity of well-characterized nanoparticles of cobalt metal and oxides
- 2018
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Ingår i: Nanotoxicology. - : Taylor & Francis. - 1743-5390 .- 1743-5404. ; 12:6, s. 602-620
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Tidskriftsartikel (refereegranskat)abstract
- An increasing use of cobalt (Co)-based nanoparticles (NPs) in different applications and exposures at occupational settings triggers the need for toxicity assessment. Improved understanding regarding the physiochemical characteristics of Co metal NPs and different oxides in combination with assessment of toxicity and mechanisms may facilitate decisions for grouping during risk assessment. The aim of this study was to gain mechanistic insights in the correlation between NP reactivity and toxicity of three different Co-based NPs (Co, CoO, and Co3O4) by using various tools for characterization, traditional toxicity assays, as well as six reporter cell lines (ToxTracker) for rapid detection of signaling pathways of relevance for carcinogenicity. The results showed cellular uptake of all NPs in lung cells and induction of DNA strand breaks and oxidative damage (comet assay) by Co and CoO NPs. In-depth studies on the ROS generation showed high reactivity of Co, lower for CoO, and no reactivity of Co3O4 NPs. The reactivity depended on the corrosion and transformation/dissolution properties of the particles and the media highlighting the role of the surface oxide and metal speciation as also confirmed by in silico modeling. By using ToxTracker, Co NPs were shown to be highly cytotoxic and induced reporters related to oxidative stress (Nrf2 signaling) and DNA strand breaks. Similar effects were observed for CoO NPs but at higher concentrations, whereas the Co3O4 NPs were inactive at all concentrations tested. In conclusion, our study suggests that Co and CoO NPs, but not Co3O4, may be grouped together for risk assessment.
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| 3. |
- Kessler, Amanda, et al.
(författare)
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Adsorption of Horseradish Peroxidase on Metallic Nanoparticles : Effects on Reactive Oxygen Species Detection Using 2′,7′-Dichlorofluorescin Diacetate
- 2021
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society. - 0893-228X .- 1520-5010. ; 350, s. S215-S216
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Tidskriftsartikel (refereegranskat)abstract
- The fluorescent probe 2′,7′-dichlorofluorescein diacetate (DCFH-DA) together with the enzyme horseradish peroxidase (HRP) is widely used in nanotoxicology to study acellular reactive oxygen species (ROS) production from nanoparticles (NPs). This study examined whether HRP adsorbs onto NPs of Mn, Ni, and Cu and if this surface process influences the extent of metal release and hence the ROS production measurements using the DCFH assay in phosphate buffered saline (PBS), saline, or Dulbecco's modified Eagle's medium (DMEM). Adsorption of HRP was evident onto all NPs and conditions, except for Mn NPs in PBS. The presence of HRP resulted in an increased release of copper from the Cu NPs in PBS and reduced levels of nickel from the Ni NPs in saline. Both metal ions in solution and the adsorption of HRP onto the NPs can change the activity of HRP and thus influence the ROS results. The effect of HRP on the NP reactivity was shown to be solution chemistry dependent. Most notable was the evident affinity/adsorption of phosphate toward the metal NPs, followed by a reduced adsorption of HRP, the concomitant reduction in released manganese from the Mn NPs, and increased levels of released metals from the Cu NPs in PBS. Minor effects were observed for the Ni NPs. The solution pH should be monitored since the release of metals can change the solution pH and the activity of HRP is known to be pH-dependent. It is furthermore essential that solution pH adjustments are made following the addition of NaOH during diacetyl removal of DCFH-DA. Even though not observed for the given exposure conditions of this study, released metal ions could possibly induce agglomeration or partial denaturation of HRP, which in turn could result in steric hindrance for H2O2 to reach the active site of HRP. This study further emphasizes the influence of HRP on the background kinetics, its solution dependence, and effects on measured ROS signals. Different ways of correcting for the background are highlighted, as this can result in different interpretations of generated results. The results show that adsorption of HRP onto the metal NPs influenced the extent of metal release and may, depending on the investigated system, result in either under- or overestimated ROS signals if used together with the DCFH assay. HRP should hence be used with caution when measuring ROS in the presence of reactive metallic NPs. © 2021 The Authors.
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| 4. |
- McCarrick, Heather, et al.
(författare)
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The Simons Observatory Microwave SQUID Multiplexing Detector Module Design
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 922:1
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Tidskriftsartikel (refereegranskat)abstract
- Advances in cosmic microwave background (CMB) science depend on increasing the number of sensitive detectors observing the sky. New instruments deploy large arrays of superconducting transition-edge sensor (TES) bolometers tiled densely into ever larger focal planes. High multiplexing factors reduce the thermal loading on the cryogenic receivers and simplify their design. We present the design of focal-plane modules with an order of magnitude higher multiplexing factor than has previously been achieved with TES bolometers. We focus on the novel cold readout component, which employs microwave SQUID multiplexing (μmux). Simons Observatory will use 49 modules containing 70,000 bolometers to make exquisitely sensitive measurements of the CMB. We validate the focal-plane module design, presenting measurements of the readout component with and without a prototype detector array of 1728 polarization-sensitive bolometers coupled to feedhorns. The readout component achieves a 95% yield and a 910 multiplexing factor. The median white noise of each readout channel is 65 pA √Hz . This impacts the projected SO mapping speed by <8%, which is less than is assumed in the sensitivity projections. The results validate the full functionality of the module. We discuss the measured performance in the context of SO science requirements, which are exceeded.
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| 5. |
- McCarrick, Sarah
(författare)
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Exploring toxicity and fate of metal-based particles in the lung : from mechanistic screening to lung deposition modelling
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We are all exposed to small particles in the air that we breath and some of them will contain metals in a dose and form that may be harmful. In addition, the field of nanotechnology holds great promises, but an increased production of nanoparticles leads to a higher risk of exposure. Metal-based particles are indeed also present in various traditional occupational settings resulting in an exposure to the workers within this field. Welders are one group at risk for exposure to metal containing particles. Despite this, many knowledge gaps remain regarding the possible risks that particles pose on human health. With the emerging use of nanomaterial and the move away from animal-based experiments, there is currently a need to establish approaches of testing particles in efficient and informative ways using alternative test strategies. This thesis aims to gain a deeper understanding of the toxicity and fate of metalbased particles in the lung by employing experimental approaches ranging from mechanistic screening and established in vitro assays to lung deposition modelling. In Paper I and II, the toxicity and associated mechanisms for a wide selection of metalcontaining nanoparticles were investigated using the reporter cell based ToxTracker assay. Reporters related to oxidative stress were most frequently activated in response to the nanoparticles, whereas fewer nanoparticles activated reporters linked to DNA damage. However, the latter ones were suggested to be considered of particular concern. With the variation in activation of various reporters, this suggests that the ToxTracker can be used as a sensitive tool to gain rapid and efficient mechanistic insight into the toxicity of particles. In Paper II, the toxicity and underlying mechanisms of welding fume particles generated by welding of stainless steel were investigated in vitro as a function of welding techniques, settings and materials. Observations revealed a high variation in toxic potential of different welding fumes, primarily depending on choice of welding electrode. Welding fumes generated with flux cored wire (FCW) were most toxic. This was strongly associated with higher metal release, in particular hexavalent chromium (Cr(VI)). In the follow-up Paper III, the released metal fraction was shown to induce similar cytotoxicity and DNA damage as the particles, further emphasizing the importance of released metals in acute toxicity induced by welding fumes. Furthermore, Paper III demonstrated the potential benefit in substituting standard Cr(VI)- generating FCW electrodes with Cr(VI)-reduced electrodes in order to create less hazardous fume particles and a safer working environment for welders. These studies furthermore highlight the beneficial collaboration between academia and industry to improve occupational environments. In Paper IV we wanted to understand the applied in vitro doses of welding fumes in the context of human exposure. Therefore, a review of the literature was performed to obtain information on welding fume exposure at occupational settings. Next, human lung doses were estimated by simulating real-life occupational welding scenarios in the Multiple-Path Particle Dosimetry (MPPD) model. Interestingly, lung doses following both acute and more chronic exposure were found comparable to in vitro doses where we observed toxic effects in Paper III. The lung dose of the tracheobronchial region was found to exceed a cytotoxic in vitro dose already after one working shift. Moreover, this study demonstrates the significant contribution of dosimetry modelling in order to understand the relation between in vitro doses and human exposure, and its potential future importance for risk assessment and study design. In conclusion, the results of the studies within the framework of this thesis demonstrate a variation in toxic potency and mode of action for metal-based particles. Metal release is shown to be an important factor for metal-particle induced toxicity, with results showing metal release, rather than metal content, to be largely responsible for acute toxicity induced by welding fumes. This thesis especially highlights the use of in vitro models for the hazard assessment of particles, identifying both the ToxTracker and lung deposition modelling as important tools for improving the efficiency and regulatory weight of in vitro approaches.
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| 6. |
- McCarrick, Sarah, et al.
(författare)
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Genotoxicity and inflammatory potential of stainless steel welding fume particles : an in vitro study on standard vs Cr(VI)-reduced flux-cored wires and the role of released metals
- 2021
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Ingår i: Archives of Toxicology. - : Springer Nature. - 0340-5761 .- 1432-0738. ; 95:9, s. 2961-2975
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Tidskriftsartikel (refereegranskat)abstract
- Welders are daily exposed to various levels of welding fumes containing several metals. This exposure can lead to an increased risk for different health effects which serves as a driving force to develop new methods that generate less toxic fumes. The aim of this study was to explore the role of released metals for welding particle-induced toxicity and to test the hypothesis that a reduction of Cr(VI) in welding fumes results in less toxicity by comparing the welding fume particles of optimized Cr(VI)-reduced flux-cored wires (FCWs) to standard FCWs. The welding particles were thoroughly characterized, and toxicity (cell viability, DNA damage and inflammation) was assessed following exposure to welding particles as well as their released metal fraction using cultured human bronchial epithelial cells (HBEC-3kt, 5-100 mu g/mL) and human monocyte-derived macrophages (THP-1, 10-50 mu g/mL). The results showed that all Cr was released as Cr(VI) for welding particles generated using standard FCWs whereas only minor levels (< 3% of total Cr) were released from the newly developed FCWs. Furthermore, the new FCWs were considerably less cytotoxic and did not cause any DNA damage in the doses tested. For the standard FCWs, the Cr(VI) released in cell media seemed to explain a large part of the cytotoxicity and DNA damage. In contrast, all particles caused rather similar inflammatory effects suggesting different underlying mechanisms. Taken together, this study suggests a potential benefit of substituting standard FCWs with Cr(VI)-reduced wires to achieve less toxic welding fumes and thus reduced risks for welders.
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| 7. |
- McCarrick, Sarah, et al.
(författare)
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High variability in toxicity of welding fume nanoparticles from stainless steel in lung cells and reporter cell lines : the role of particle reactivity and solubility
- 2019
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Ingår i: Nanotoxicology. - : TAYLOR & FRANCIS LTD. - 1743-5390 .- 1743-5404.
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Tidskriftsartikel (refereegranskat)abstract
- Millions of people in the world perform welding as their primary occupation resulting in exposure to metal-containing nanoparticles in the fumes generated. Even though health effects including airway diseases are well-known, there is currently a lack of studies investigating how different welding set-ups and conditions affect the toxicity of generated nanoparticles of the welding fume. The aim of this study was to investigate the toxicity of nine types of welding fume particles generated via active gas shielded metal arc welding (GMAW) of chromium-containing stainless steel under different conditions and, furthermore, to correlate the toxicity to the particle characteristics. Toxicological endpoints investigated were generation of reactive oxygen species (ROS), cytotoxicity, genotoxicity and activation of ToxTracker reporter cell lines. The results clearly underline that the choice of filler material has a large influence on the toxic potential. Fume particles generated by welding with the tested flux-cored wire (FCW) were found to be more cytotoxic compared to particles generated by welding with solid wire or metal-cored wire (MCW). FCW fume particles were also the most potent in causing ROS and DNA damage and they furthermore activated reporters related to DNA double- strand breaks and p53 signaling. Interestingly, the FCW fume particles were the most soluble in PBS, releasing more chromium in the hexavalent form and manganese compared to the other fumes. These results emphasize the importance of solubility of different metal constituents of the fume particles, rather than the total metal content, for their acute toxic potential.
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| 8. |
- McCarrick, Sarah, et al.
(författare)
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Toxicity of particles derived from combustion of Ethiopian traditional biomass fuels in human bronchial and macrophage-like cells
- 2024
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Ingår i: Archives of Toxicology. - 0340-5761. ; 98:5, s. 1515-1532
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Tidskriftsartikel (refereegranskat)abstract
- The combustion of traditional fuels in low-income countries, including those in sub-Saharan Africa, leads to extensive indoor particle exposure. Yet, the related health consequences in this context are understudied. This study aimed to evaluate the in vitro toxicity of combustion-derived particles relevant for Sub-Saharan household environments. Particles (< 2.5 µm) were collected using a high-volume sampler during combustion of traditional Ethiopian biomass fuels: cow dung, eucalyptus wood and eucalyptus charcoal. Diesel exhaust particles (DEP, NIST 2975) served as reference particles. The highest levels of particle-bound polycyclic aromatic hydrocarbons (PAHs) were found in wood (3219 ng/mg), followed by dung (618 ng/mg), charcoal (136 ng/mg) and DEP (118 ng/mg) (GC–MS). BEAS-2B bronchial epithelial cells and THP-1 derived macrophages were exposed to particle suspensions (1–150 µg/mL) for 24 h. All particles induced concentration-dependent genotoxicity (comet assay) but no pro-inflammatory cytokine release in epithelial cells, whereas dung and wood particles also induced concentration-dependent cytotoxicity (Alamar Blue). Only wood particles induced concentration-dependent cytotoxicity and genotoxicity in macrophage-like cells, while dung particles were unique at increasing secretion of pro-inflammatory cytokines (IL-6, IL-8, TNF-α). In summary, particles derived from combustion of less energy dense fuels like dung and wood had a higher PAH content and were more cytotoxic in epithelial cells. In addition, the least energy dense and cheapest fuel, dung, also induced pro-inflammatory effects in macrophage-like cells. These findings highlight the influence of fuel type on the toxic profile of the emitted particles and warrant further research to understand and mitigate health effects of indoor air pollution.
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| 9. |
- Thörnqvist, Per-Ove, et al.
(författare)
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Bold zebrafish (Danio rerio) express higher levels of delta opioid and dopamine D2 receptors in the brain compared to shy fish
- 2019
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Ingår i: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 359, s. 927-934
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Tidskriftsartikel (refereegranskat)abstract
- Individual variation in coping with environmental challenges is a well-known phenomenon across vertebrates, including teleost fish. Dopamine is the major transmitter in the brain reward networks, and important for motivational processes and stress coping. Functions of the endogenous opioid system are not well studied in teleosts. However, in mammals the activity in the brain reward networks is regulated by the endogenous opioid system. This study aimed at investigating if there was a correlation between risk-taking behavior and the expression of dopamine and opioid receptors in the zebrafish (Danio rerio) brain. Risk-taking behavior was assessed in a novel tank diving test, and the most extreme high risk taking, i.e. bold, and low risk taking, i.e. shy, fish were sampled for qPCR analysis of whole brain gene expression. The expression analysis showed a significantly higher expression of the dopamine D2 receptors (drd2a and drd2b) and the delta opioid receptor (DOR; oprd1b) in bold compared to shy fish. Besides reward and reinforcing properties, DORs are also involved in emotional responses. Dopamine D2 receptors are believed to be important for active stress coping in rodents, and taken together the results of the current study suggest similar functions in zebrafish. However, additional experiments are required to clarify how dopamine and opioid receptor activation affect behavior and stress coping in this species.
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| 10. |
- Åkerlund, Emma, et al.
(författare)
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Inflammation and (secondary) genotoxicity of Ni and NiO nanoparticles
- 2019
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Ingår i: Nanotoxicology. - : Taylor & Francis. - 1743-5390 .- 1743-5404. ; 13:8, s. 1060-1072
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticle-induced genotoxicity can arise through different mechanisms, and generally, primary and secondary genotoxicity can be distinguished where the secondary is driven by an inflammatory response. It is, however, yet unclear how a secondary genotoxicity can be detected using in vitro methods. The aim of this study was to investigate inflammation and genotoxicity caused by agglomerated nickel (Ni) and nickel oxide (NiO) nanoparticles and, furthermore, to explore the possibility to test secondary (inflammation-driven) genotoxicity in vitro. As a benchmark particle to compare with, we used crystalline silica (quartz). A proteome profiler antibody array was used to screen for changes in release of 105 different cytokines and the results showed an increased secretion of various cytokines including vascular endothelial growth factor (VEGF) following exposure of macrophages (differentiated THP-1 cells). Both Ni and NiO caused DNA damage (comet assay) following exposure of human bronchial epithelial cells (HBEC) and interestingly conditioned media (CM) from exposed macrophages also resulted in DNA damage (2- and 3-fold increase for Ni and NiO, respectively). Similar results were also found when using a co-culture system of macrophages and epithelial cells. In conclusion, this study shows that it is possible to detect a secondary genotoxicity in lung epithelial cells by using in vitro methods based on conditioned media or co-cultures. Further investigation is needed in order to find out what factors that are causing this secondary genotoxicity and whether such effects are caused by numerous nanoparticles.
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