| 1. |
- Klein, C. F., et al.
(författare)
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In-hospital metabolite changes in infective endocarditis-a longitudinal H-1 NMR-based study
- 2019
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Ingår i: European Journal of Clinical Microbiology & Infectious Diseases. - : Springer Science and Business Media LLC. - 0934-9723 .- 1435-4373. ; 38:8, s. 1553-1560
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of infective endocarditis (IE) is a 4-6-week provided course of intravenously administered antibiotics. The aim of this study was to investigate how serum metabolites as measured by proton nuclear magnetic resonance (H-1 NMR) spectroscopy are changing over time during the active phase of IE, and to see whether these metabolite changes might be used to monitor recovery in these patients. Patients hospitalized with first-time IE at Herlev Hospital, Denmark, from September 2015 to June 2017 were included. Longitudinal blood sampling was performed and serum was analyzed using H-1 NMR. Orthogonal projection to latent structures discriminant analysis (OPLS-DA) was used to separate sample groups and analyze differences in metabolite profiles. Thirteen patients were included in the study (77% men, median age 62 years (IQR 53-77)). All patients were cured during the hospitalization without any relapse during 6 months of follow-up. We analyzed 61 serum samples (median 5 samples, range 2-8 per person) drawn in the treatment period after IE diagnosis. The main changes during the in-hospital period were decreased levels of glucose, mannose, leucine, isoleucine, phenylalanine, tyrosine, and signals from polyols and N-acetylated protein. The metabolomic changes could in contrast to the routinely used parameters CRP and leucocyte levels distinguish between the early and late stages of disease treatment. We present the first longitudinal study of H-1 NMR metabolomics in patients with infective endocarditis. The metabolomic changes show a promising strength compared to routinely used clinical parameters.
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| 2. |
- Ekvall, Mikael T., et al.
(författare)
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Adsorption of bio-organic eco-corona molecules reduces the toxic response to metallic nanoparticles in Daphnia magna
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- As the use of engineered nanomaterials increases, so does the risk of them spreading to natural ecosystems. Hitherto, knowledge regarding the toxic properties of nanoparticles (NP's) and their potential interactions with natural bio-organic molecules adsorbed to them, and thereby forming surface coronas, is limited. However, we show here that the toxic effect of NPs of tungsten carbide cobalt (WC-Co) and cobalt (Co) on the crustacean Daphnia magna is postponed in the presence of natural biological degradation products (eco-corona biomolecules). For Daphnia exposed to WC-Co NPs the survival time increased with 20-25% and for Co NPs with 30-47% after mixing the particles with a solution of eco-corona biomolecules before exposure. This suggests that an eco-corona, composed of biomolecules always present in natural ecosystems, reduces the toxic potency of both studied NPs. Further, the eco-coronas did not affect the particle uptake, suggesting that the reduction in toxicity was related to the particle-organism interaction after eco-corona formation. In a broader context, this implies that although the increasing use and production of NPs may constitute a novel, global environmental threat, the acute toxicity and long-term effects of some NPs will, at least under certain conditions, be reduced as they enter natural ecosystems.
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| 3. |
- Mattsson, Karin, et al.
(författare)
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Altered Behavior, Physiology, and Metabolism in Fish Exposed to Polystyrene Nanoparticles
- 2015
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Ingår i: Environmental Science & Technology. - : American Chemical Society (ACS). - 1520-5851 .- 0013-936X. ; 49:1, s. 553-561
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Tidskriftsartikel (refereegranskat)abstract
- The use of nanoparticles in consumer products, for example, cosmetics, sunscreens, and electrical devices, has increased tremendously over the past decade despite insufficient knowledge about their effects on human health and ecosystem function. Moreover, the amount of plastic waste products that enter natural ecosystems, such as oceans and lakes, is increasing, and degradation of the disposed plastics produces smaller particles toward the nano scale. Therefore, it is of utmost importance to gain knowledge about how plastic nanoparticles enter and affect living organisms. Here we have administered 24 and 27 nm polystyrene nanoparticles to fish through an aquatic food chain, from algae through Daphnia, and studied the effects on behavior and metabolism. We found severe effects on feeding and shoaling behavior as well as metabolism of the fish; hence, we conclude that polystyrene nanoparticles have severe effects on both behavior and metabolism in fish and that commonly used nanosized particles may have considerable effects on natural systems and ecosystem services derived from them.
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| 4. |
- Mattsson, Karin, et al.
(författare)
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Brain damage and behavioural disorders in fish induced by plastic nanoparticles delivered through the food chain
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The tremendous increases in production of plastic materials has led to an accumulation of plastic pollution worldwide. Many studies have addressed the physical effects of large-sized plastics on organisms, whereas few have focused on plastic nanoparticles, despite their distinct chemical, physical and mechanical properties. Hence our understanding of their effects on ecosystem function, behaviour and metabolism of organisms remains elusive. Here we demonstrate that plastic nanoparticles reduce survival of aquatic zooplankton and penetrate the blood-to-brain barrier in fish and cause behavioural disorders. Hence, for the first time, we uncover direct interactions between plastic nanoparticles and brain tissue, which is the likely mechanism behind the observed behavioural disorders in the top consumer. In a broader perspective, our findings demonstrate that plastic nanoparticles are transferred up through a food chain, enter the brain of the top consumer and affect its behaviour, thereby severely disrupting the function of natural ecosystems.
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| 5. |
- Arnés, Mercedes, et al.
(författare)
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Amyloid β42 peptide is toxic to non-neural cells in Drosophila yielding a characteristic metabolite profile and the effect can be suppressed by PI3K
- 2017
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Ingår i: Biology Open. - : The Company of Biologists. - 2046-6390. ; 6:11, s. 1664-1671
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Tidskriftsartikel (refereegranskat)abstract
- The human Aβ42 peptide is associated with Alzheimer’s disease through its deleterious effects in neurons. Expressing the human peptide in adult Drosophila in a tissue- and time-controlled manner, we show that Aβ42 is also toxic in non-neural cells, neurosecretory and epithelial cell types in particular. This form of toxicity includes the aberrant signaling by Wingless morphogen leading to the eventual activation of Caspase 3. Preventing Caspase 3 activation by means of p53 keeps epithelial cells from elimination but maintains the Aβ42 toxicity yielding more severe deleterious effects to the organism. Metabolic profiling by nuclear magnetic resonance (NMR) of adult flies at selected ages post Aβ42 expression onset reveals characteristic changes in metabolites as early markers of the pathological process. All morphological and most metabolic features of Aβ42 toxicity can be suppressed by the joint overexpression of PI3K.
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| 6. |
- Evenäs, Johan, et al.
(författare)
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Ca2+ binding and conformational changes in a calmodulin domain
- 1998
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 37:39, s. 13744-13754
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Tidskriftsartikel (refereegranskat)abstract
- Calcium activation of the C-terminal domain of calmodulin was studied using 1H and 15N NMR spectroscopy. The important role played by the conserved bidentate glutmate Ca2+ ligand in the binding loops is emphasized by the striking effects resulting from a mutation of this glutantic acid to a glutamine, i.e. E104Q in loop III and E140Q in loop IV. The study involves determination of Ca2+ binding constants, assignments, and structural characterizations of the apo, (Ca2+)1, and (Ca2+)2 states of the E104Q mutant and comparisons to the wild-type protein and the E140Q mutant [Evenas et al. (1997) Biochemistry 36, 3448-3457]. NMR titration data show sequential Ca2+ binding in the E104Q mutant. The first Ca2+ binds to loop IV and the second to loop III, which is the order reverse to that observed for the E140Q mutant. In both mutants, the major structural changes occur upon Ca2+ binding to loop IV, which implies a different response to Ca2+ binding in the N- and C-terminal EF-hands. Spectral characteristics show that the (Ca2+)1 and (Ca2+)2 states of the E104Q mutant undergo global exchange on a 10-100 μs time scale between conformations seemingly similar to the closed and open structures of this domain in wild-type calmodulin, paralleling earlier observations for the (Ca2+)2 state of the E140Q mutant, indicating that both glutamic acid residues, E104 and E140, are required for stabilization of the open conformation in the (Ca2+)2 state. To verify that the NOE constraints cannot be fulfilled in a single structure, solution structures of the (Ca2+)2 state of the E104Q mutant are calculated. Within the ensemble of structures the precision is good. However, the clearly dynamic nature of the state, a large number of violated distance restraints, ill-defined secondary structural elements, and comparisons to the structures of calmodulin indicate that the ensemble does not provide a good picture of the (Ca2+)2 state of the E104Q mutant but rather represents the distance- averaged structure of at least two distinct different conformations.
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| 7. |
- Evenäs, Johan, et al.
(författare)
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NMR studies of the E140Q mutant of the carboxy-terminal domain of calmodulin reveal global conformational exchange in the Ca2+-saturated state
- 1997
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 36:12, s. 3448-3457
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Tidskriftsartikel (refereegranskat)abstract
- In the present investigation, the Ca2+ activation of the C-terminal domain of bovine calmodulin and the effects of replacing the bidentate Ca2+-coordinating glutamic acid residue in the 12th and last position of loop IV with a glutamine are studied by NMR spectroscopy. The mutation E140Q results in sequential Ca2+ binding in this domain and has far-reaching effects on the structure of (Ca2+)2 TR2C, thereby providing further evidence for the critical role of this glutamic acid residue for the Ca2+- induced conformational change of regulatory EF-hand proteins. Analyses of the NOESY spectra of the mutant under Ca2+-saturated conditions, such that 97% of the protein is in the (Ca2+)2 form, revealed two sets of mutually exclusive NOEs. One set of NOEs is found to be consistent with the closed structure observed in the apo state of the C-terminal domain of the wild- type protein, while the other set supports the open structure observed in the Ca2+-saturated state. In addition, several residues in the hydrophobic core exhibit broadened resonances. We conclude that the (Ca2+)2 form of the mutant experiences a global conformational exchange between states similar to the closed and open conformations of the C-terminal domain of wild-type calmodulin. A population of 65 ± 15% of the open conformation and an exchange rate of (1-7) x 104 s-1 were estimated from the NMR data and the chemical shifts of the wild-type protein. From a Ca2- titration of the 15N-labeled mutant, the macroscopic binding constants (log(K1) = 4.9 ± 0.3 and log(K2) = 3.15 ± 0.10] and the inherent chemical shifts of the intermediate (Ca2+)1 form of the mutant were determined using NMR. Valuable information was also provided on the mechanism of the Ca2+ activation and the roles of the structural elements in the two Ca2+- binding events. Comparison with the wild-type protein indicates that the (Ca2+)1 conformation of the mutant is essentially closed but that some rearrangement of the empty loop IV toward the Ca2+-bound form has occurred.
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| 8. |
- Jensen, Kristine Steen, et al.
(författare)
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Identification of Distinct Soluble States During Fibril Formation Using Multilinear Analysis of NMR Diffusion Data
- 2023
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Ingår i: Methods in Molecular Biology. - New York, NY : Springer US. - 1940-6029 .- 1064-3745. - 9781071625965 - 9781071625972 ; 2551, s. 461-479
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Bokkapitel (refereegranskat)abstract
- Protein misfolding and self-assembling into amyloid structures are associated with a number of diseases. Characterization of protein amyloid formation reactions is a challenging task as transient populations of multiple species are involved. Here we outline a method for identification and characterization of the individual soluble states during protein amyloid formation. The method combines NMR translational diffusion measurements with multilinear data analysis.
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| 9. |
- Jensen, Kristine Steen, et al.
(författare)
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Revealing Well-Defined Soluble States during Amyloid Fibril Formation by Multilinear Analysis of NMR Diffusion Data
- 2019
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 141:47, s. 18649-18652
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid fibril formation is a hallmark of neurodegenerative disease caused by protein aggregation. Oligomeric protein states that arise during the process of fibril formation often coexist with mature fibrils and are known to cause cell death in disease model systems. Progress in this field depends critically on development of analytical methods that can provide information about the mechanisms and species involved in oligomerization and fibril formation. Here, we demonstrate how the powerful combination of diffusion NMR and multilinear data analysis can efficiently disentangle the number of involved species, their kinetic rates of formation or disappearance, spectral contributions, and diffusion coefficients, even without prior knowledge of the time evolution of the process or chemical shift assignments of the various species. Using this method we identify oligomeric species that form transiently during aggregation of human superoxide dismutase 1 (SOD1), which is known to form misfolded aggregates in patients with amyotrophic lateral sclerosis. Specifically, over a time course of 42 days, during which SOD1 fibrils form, we detect the disappearance of the native monomeric species, formation of a partially unfolded intermediate in the dimer to tetramer size range, subsequent formation of a distinct similarly sized species that dominates the final spectrum detected by solution NMR, and concomitant appearance of small peptide fragments.
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| 10. |
- Kelpsiene, Egle, et al.
(författare)
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Metabolomics-based analysis in Daphnia magna after exposure to low environmental concentrations of polystyrene nanoparticles
- 2023
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Ingår i: Environmental Science: Nano. - 2051-8153. ; 10:7, s. 1858-1866
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Tidskriftsartikel (refereegranskat)abstract
- Larger plastic pieces break down into micro- and eventually nano-sized plastics. This makes nanoplastics ubiquitous in the environment, giving rise to great concern for its effect on biota. Many studies use polystyrene nanoparticles (PS-NPs) as a model for nanoplastics, showing a negative impact on various organisms, but the molecular effects are yet not fully explored. Here we applied 1H nuclear magnetic resonance (NMR) metabolomics to characterize the metabolic changes in Daphnia magna during long-term (37 days) exposure to low concentrations of positively and negatively charged (aminated and carboxylated) PS-NPs. We show that exposure to PS-NPs at concentrations down to 3.2 μg L−1 affected amino acid metabolism and the bacterial metabolite isopropanol in D. magna. These effects were largely independent of particle concentration and surface charge. The results highlight the importance of (1) performing chronic exposures under low concentrations and (2) further investigation of particles with different surface charges.
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