| 1. |
- Arja, Katriann, et al.
(författare)
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Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
- 2013
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Ingår i: Macromolecular rapid communications. - : Wiley-VCH Verlag. - 1022-1336 .- 1521-3927. ; 34:9, s. 723-730
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Tidskriftsartikel (refereegranskat)abstract
- Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.
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| 2. |
- Berg, Ina, 1982-, et al.
(författare)
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Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses
- 2010
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Ingår i: Nature Protocols. - : Macmillan Publishers Ltd.. - 1754-2189 .- 1750-2799. ; 5:5, s. 935-944
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Tidskriftsartikel (refereegranskat)abstract
- Drosophila melanogaster is emerging as an important model system for neurodegenerative disease research. In this protocol, we describe an efficient method for imaging amyloid deposits in the Drosophila brain, by the use of a luminescent-conjugated oligothiophene (lco), p-Ftaa polymer probe. We also demonstrate the feasibility of co-staining with antibodies and compare the lco staining with standard amyloid-specific probes. the lco protocol enables high-resolution imaging of several different protein aggregates, such as aβ1-42, aβ1-42e22G, transthyretin V30M and human tau, in the Drosophila brain. aβ and tau aggregates could also be distinguished from each other because of distinct lco emission spectra. Furthermore, this protocol enables threedimensional brain mapping of amyloid distribution in whole-mount Drosophila brains. the use of p-Ftaa combined with other probes, antibodies and/or dyes will aid the rapid characterization of various amyloid deposits in the rapidly growing number of Drosophila models of neurodegenerative diseases.
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| 3. |
- Bett, Cyrus, et al.
(författare)
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Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions
- 2013
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Ingår i: PLoS Pathogens. - : Public Library of Science. - 1553-7366 .- 1553-7374. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion.
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| 4. |
- Bett, Cyrus, et al.
(författare)
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Structure of the beta 2-alpha 2 loop and interspecies prion transmission
- 2012
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Ingår i: The FASEB Journal. - : Federation of American Society of Experimental Biology (FASEB). - 0892-6638 .- 1530-6860. ; 26:7, s. 2868-2876
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Tidskriftsartikel (refereegranskat)abstract
- Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The beta 2-alpha 2 loop region of endogenous prion protein, PrPC, has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar beta 2-alpha 2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the beta 2-alpha 2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered beta 2-alpha 2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrPC from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.
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| 5. |
- Bodegard, J, et al.
(författare)
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Changes in body mass index following newly diagnosed type 2 diabetes and risk of cardiovascular mortality: A cohort study of 8486 primary-care patients
- 2013
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Ingår i: Diabetes & Metabolism. - : MASSON EDITEUR, 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE. - 1262-3636 .- 1878-1780. ; 39:4, s. 306-313
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Tidskriftsartikel (refereegranskat)abstract
- Aims. - Elevated body mass index (BMI) is associated with an increased risk of type 2 diabetes and cardiovascular disease (CVD). This study explored the association between BMI changes in the first 18 months of newly diagnosed type 2 diabetes and the risk of long-term CVD mortality. less thanbrgreater than less thanbrgreater thanMethods. - A total of 8486 patients with newly diagnosed type 2 diabetes and no previous history of CVD or cancer were identified from 84 primary-care centres in Sweden. During the first year after diagnosis, patients were grouped according to BMI change: Increase, or andgt;= +1 BMI unit; unchanged, or between +1 and-1 BMI unit; and decrease, or andlt;=-1 BMI unit. Associations between BMI change and CVD mortality, defined as death from stroke, myocardial infarction or sudden death, were estimated using adjusted Cox proportional hazards models (NCT 01121315). less thanbrgreater than less thanbrgreater thanResults. - Baseline mean age was 60.0 years and mean BMI was 30.2 kg/m(2). Patients were followed for up to 9 years (median: 4.6 years). During the first 18 months, 53.4% had no change in their BMI, while 32.2% decreased and 14.4% increased. Compared with patients with unchanged BMI, those with an increased BMI had higher risks of CVD mortality (hazard ratio: 1.63, 95% CI: 1.11-2.39) and all-cause mortality (1.33, 1.01-1.76). BMI decreases had no association with these risks compared with unchanged BMI: 1.06 (0.76-1.48) and 1.06 (0.85-1.33), respectively. less thanbrgreater than less thanbrgreater thanConclusion. - Increased BMI within the first 18 months of type 2 diabetes diagnosis was associated with an increased long-term risk of CVD mortality. However, BMI decrease did not lower the long-term risk of mortality.
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| 6. |
- 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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| 7. |
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| 8. |
- Drevenhorn, Eva, et al.
(författare)
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Consultation training of nurses for cardiovascular prevention - A randomized study of 2 years duration
- 2012
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Ingår i: Blood Pressure. - : Informa Healthcare. - 0803-7051 .- 1651-1999. ; 21:5, s. 293-299
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to increase patients adherence to the treatment of hypertension through the consultation training of nurses. Thirty-three nurses were included in the study. In the intervention group (IG), 19 nurses took part in a 3-day residential training course on the Stages of Change model, Motivational Interviewing and guidelines for cardiovascular prevention, and recruited 153 patients. Sixteen nurses in the control group (CG) recruited 59 patients. A decrease in systolic and diastolic blood pressure and total cholesterol was noticed in both groups over the 2 years. Heart rate (p = 0.027), body mass index (p = 0.019), weight (p = 0.0001), waist (p = 0.041), low-density lipoprotein-cholesterol (p = 0.0001), the waist-hip ratio (p = 0.024), and perceived stress (p = 0.001) decreased to any great extent only in the IG. After 2 years, 52.6% of the patients in the IG (p = 0.13) reached the target of andlt;= 140/90 mmHg in blood pressure compared with 39.2% in the CG. For self-reported physical activity, there was a significant (p = 0.021) difference between the groups. The beneficial effects of the consultation training on patients weight parameters, physical activity, perceived stress and the proportion of patients who achieved blood pressure control emphasize consultation training and the use of behavioural models in motivating patients to adhere to treatment.
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| 9. |
- 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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| 10. |
- 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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