| 11. |
- Berg, Ina, 1982-
(författare)
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Modeling Amyloid Disease in Drosophila melanogaster
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloid diseases are caused by protein misfolding and aggregation. To date there are 27 known proteins causing amyloid disorders involving brain and peripheral protein deposition. The proteins involved in this mechanism do not share sequence homology, but the amyloid fibrils share biophysical properties and possibly a common pathogenic mechanism. Amyloid deposits are known to be involved in a broad range of neurodegenerative diseases, such as Alzheimer’s disease and Creutzfeldt-Jakob disease, as well as in non-neuropathic diseases, such as senile systemic amyloidosis and type II diabetes.During the last decade the fruit fly, Drosophila melanogaster (Drosophila), have increasingly been used as a model for neurodegenerative disease, such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and familial amyloidotic polyneuropathy. The advantages of using the Drosophila model are the well-defined genetic characteristics, the quantity, short life span, simplicity in genetic manipulation and the powerful binary UAS-Gal4 transgenic system. The UAS-Gal4 system allows for rapid generation of individual strains in which expression of a specific gene of interest can be directed to different tissues or cell types. The system allows the target gene to be activated in different cell- and tissue-types by altering the activator-expressing lines.This thesis has been focused on modeling amyloid diseases in Drosophila. This has been performed by:Creating new model systems of senile systemic amyloidosis and familial amyloidotic polyneuropathy in DrosophilaDeveloping a new staining protocol for detection of amyloid in DrosophilaInitiate a compound screen of Alzheimer’s disease modeled in Drosophila
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| 12. |
- Bohlin, Anna, et al.
(författare)
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Perceived gender inequality in the couple relationship and musculoskeletal pain in middle-aged women and men
- 2013
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Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 41:8, s. 825-831
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Musculoskeletal pain is a major health problem, especially in women, and is partially determined by psychosocial factors. The aim of the present study was to investigate whether gender inequality in the couple relationship was related to musculoskeletal pain. Methods: Participants (n=721; 364 women and 357 men) were all individuals living in a couple relationship in the Northern Swedish Cohort, a 26-year Swedish cohort study. Self-administered questionnaire data at age 42 years comprised perceived gender inequality in the couple relationship and musculoskeletal pain (in three locations, summarised into one score and median-split), concurrent demographic factors, psychological distress, and previous musculoskeletal pain at age 30 years. Associations were examined using logistic regression. Results: Gender inequality was positively associated with symptoms of musculoskeletal pain in the total sample, remaining significant after addition of possible confounders and of previous musculoskeletal pain. Separate adjustment for concurrent psychological distress attenuated the association but not below significance. The association was present and of comparable strength in both women and men. Conclusions: Gender inequality in the couple relationship might contribute to the experience of musculoskeletal pain in both women and men. The results highlight the potential adverse bodily consequences of living in unequal relationships.
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| 13. |
- Ceasar (Berg), Ina, et al.
(författare)
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Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- The pathology of Alzheimers disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-beta (A beta) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic A beta amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate A beta toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of A beta deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to A beta deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of A beta(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant A beta(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of A beta, resulting in a reduced neurotoxicity in Drosophila.
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| 14. |
- Ekstrand-Hammarström, Barbro, et al.
(författare)
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Human Primary Bronchial Epithelial Cells are more Responsive to Titanium Dioxide Nanoparticles than the Lung Epithelial Cell Lines A549 and BEAS-2B
- 2012
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Ingår i: Nanotoxicology. - : Informa Healthcare. - 1743-5390 .- 1743-5404. ; 6:6, s. 623-634
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Tidskriftsartikel (refereegranskat)abstract
- We have compared the cellular uptake and responses of fivepreparations of nanocrystalline titanium dioxide (TiO2) betweennormal human bronchial epithelial (NHBE) cells and epithelialcell lines (A549 and BEAS-2B). The P25 nanoparticles, containingboth anatase and rutile modifications, induced reactive oxygenspecies (ROS) and secretion of the neutrophil chemoattractantIL-8 in all three cell types used. Pure anatase and rutile particlesprovoked differential IL-8 response in A549 and no response inBEAS-2B cells despite similar formation of ROS. The pure TiO2modifications also provoked release of the inflammatorymediators: IL-6, G-CSF and VEGF, in NHBE cells but not in the twocell lines. We conclude that the responsiveness of lung epithelialcells is strongly dependent on both the physicochemicalproperties of TiO2 nanoparticles and the type of responder cells.The differential pro-inflammatory responsiveness of primarylung epithelial cells compared with immortalized cell linesshould be considered in the assessment of adverse reactions toinhaled nanoparticles.
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| 15. |
- Ekstrand-Hammarström, Barbro, et al.
(författare)
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Human primary bronchial epithelial cells respond differently to titanium dioxide nanoparticles than the lung epithelial cell lines A549 and BEAS-2B
- 2012
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Ingår i: Nanotoxicology. - : Informa UK Limited. - 1743-5390 .- 1743-5404. ; 6:6, s. 623-634
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Tidskriftsartikel (refereegranskat)abstract
- We have compared the cellular uptake and responses of five preparations of nanocrystalline titanium dioxide (TiO(2)) between normal human bronchial epithelial (NHBE) cells and epithelial cell lines (A549 and BEAS-2B). The P25 nanoparticles, containing both anatase and rutile modifications, induced reactive oxygen species (ROS) and secretion of the neutrophil chemoattractant IL-8 in all three cell types used. Pure anatase and rutile particles provoked differential IL-8 response in A549 and no response in BEAS-2B cells despite similar formation of ROS. The pure TiO(2) modifications also provoked release of the inflammatory mediators: IL-6, G-CSF and VEGF, in NHBE cells but not in the two cell lines. We conclude that the responsiveness of lung epithelial cells is strongly dependent on both the physicochemical properties of TiO(2) nanoparticles and the type of responder cells. The differential pro-inflammatory responsiveness of primary lung epithelial cells compared with immortalized cell lines should be considered in the assessment of adverse reactions to inhaled nanoparticles.
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| 16. |
- Fritschi, Sarah K., et al.
(författare)
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A beta seeds resist inactivation by formaldehyde
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Verlag (Germany). - 0001-6322 .- 1432-0533. ; 128:4, s. 477-484
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral beta-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated beta-amyloid (A beta) into young, pre-depositing A beta precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated A beta itself. Here we report that the beta-amyloid-inducing activity of Alzheimers disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analysis with amyloid conformation-sensitive luminescent conjugated oligothiophene dyes reveals that the strain-like properties of aggregated A beta are maintained in fixed tissues. The resistance of A beta seeds to inactivation and structural modification by formaldehyde underscores their remarkable durability, which in turn may contribute to their persistence and spread within the body. The present findings can be exploited to establish the relationship between the molecular structure of A beta aggregates and the variable clinical features and disease progression of AD even in archived, formalin-fixed autopsy material.
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| 17. |
- Fyrner, Timmy, et al.
(författare)
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Derivatization of a bioorthogonal protected trisaccharide linker : towards multimodal tools for chemical biology
- 2012
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 23:6, s. 1333-1340
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Tidskriftsartikel (refereegranskat)abstract
- When cross-linking biomolecules to surfaces or to other biomolecules, the use of appropriate spacer molecules is of great importance. Mimicking the naturally occurring spacer molecules will give further insight into their role and function, possibly unveil important issues regarding the importance of the specificity of carbohydrate-based anchor moieties, in e.g., glycoproteins and glycosylphosphatidylinositols. Herein, we present the synthesis of a lactoside-based trisaccharide, potentially suitable as a heterobifunctional bioorthogonal linker molecule whereon valuable chemical handles have been conjugated. An amino-derivative having thiol functionality shows promise as novel SPR-surfaces. Furthermore, the trisaccharide has been conjugated to a cholesterol moiety in combination with a fluorophore which successfully assemble on the cell surface in lipid microdomains, possibly lipid-rafts. Finally, a CuI-catalyzed azide-alkyne cycloaddition reaction (CuAAC) confirms the potential use of oligosaccharides as bioorthogonal linkers in chemical biology.
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| 18. |
- Gabrielsson, Erik O, et al.
(författare)
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Spatially Controlled Amyloid Reactions Using Organic Electronics
- 2010
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Ingår i: SMALL. - : John Wiley and Sons, Ltd. - 1613-6810. ; 6:19, s. 2153-2161
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal protein aggregates, so called amyloid fibrils, are mainly known as pathological hallmarks of a wide range of diseases, but in addition these robust well-ordered self-assembled natural nanostructures can also be utilized for creating distinct nanomaterials for bioelectronic devices. However, current methods for producing amyloid fibrils in vitro offer no spatial control. Herein, we demonstrate a new way to produce and spatially control the assembly of amyloid-like structures using an organic electronic ion pump (OEIP) to pump distinct cations to a reservoir containing a negatively charged polypeptide. The morphology and kinetics of the created proteinaceous nanomaterials depends on the ion and current used, which we leveraged to create layers incorporating different conjugated thiophene derivatives, one fluorescent (p-FTAA) and one conducting (PEDOT-S). We anticipate that this new application for the OEIP will be useful for both biological studies of amyloid assembly and fibrillogenesis as well as for creating new bioelectronic nanomaterials and devices.
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| 19. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 20. |
- Groenning, Minna, et al.
(författare)
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Thermodynamic stability and denaturation kinetics of a benign natural transthyretin mutant identified in a Danish kindred
- 2011
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Ingår i: AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS. - : Informa Healthcare. - 1350-6129. ; 18:2, s. 35-46
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Tidskriftsartikel (refereegranskat)abstract
- The disease phenotype of transthyretin (TTR) is dramatically influenced by single point mutations in the TTR gene. Herein, we report on a novel mutation D99N (Asp99Asn) in TTR found in a Danish kindred. None of the family members carrying this mutation have so far shown any clinical signs of amyloidosis. One carrier found compound heterozygous for TTR D99N and L111M (Leu111Met) associated with cardiac amyloid is asymptomatic (42 years). Disease severity can often be linked to both the kinetics of fibril formation and the degree of destabilisation of the native state. In this study, we show that the thermodynamic stability and rate of tetramer dissociation of the variant TTR D99N is unchanged or slightly more stable than wild type (WT) TTR. Furthermore, the in vitro fibrillation kinetics of the variant reveals an unchanged or slightly suppressed tendency to form fibrils compared to WT. Thus, the in vitro experiments support the lack of clinical symptoms observed so far for the TTR D99N carriers. In line with this, studies on kinetic stability and fibrillation kinetics reveal indistinguishable stability of TTR heterotetramers D99N/L111M compared to the heterotetramers WT/L111M. In conclusion, TTR D99N is predicted to be a non-pathogenic benign mutation with WT properties.andlt;/.
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