| 11. |
- Byhamre, Marja Lisa, et al.
(författare)
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Snus use during the life-course and risk of the metabolic syndrome and its components
- 2017
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Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 45:8, s. 733-740
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We aimed to investigate the association between life-course exposure to snus and prevalence of the metabolic syndrome and its components in adulthood.Design and method: Tobacco habits at baseline (age 16) and three follow-ups (ages 21, 30 and 43) were assessed among 880 participants in a population-based cohort in Northern Sweden. Presence of the metabolic syndrome at age 43 was ascertained using the International Diabetes Federation criteria. Odds ratios and CIs for risk of the metabolic syndrome and its components by snus use at 16, 21, 30 and 43 years were calculated using logistic regression. Cumulative snus use was defined as number of life periods (1-4) with current snus use.Results: At age 43, 164 participants (18.6%) were current snus users. We found no association between exclusive snus use at the ages of 16, 21, 30 and 43 years and the metabolic syndrome at age 43 years. Snus use (among non-smokers) was associated with raised triglycerides and high blood pressure in crude analysis, but not in multivariable models. There was no association between cumulative snus use and risk of the metabolic syndrome. Cumulative snus use was associated with central obesity, raised triglycerides and impaired fasting glucose/diabetes mellitus type 2 in crude analyses, but not after adjustments.Conclusion: The health consequences of snus exposure from adolescence to mid-adulthood do not seem to include increased risk of the metabolic syndrome or its components. The cardio-metabolic risk of dual exposure to snus and cigarettes may warrant further attention.
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| 12. |
- Campos Melo, Raúl Ivan, et al.
(författare)
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Novel Trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin
- 2016
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:7, s. 924-940
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Tidskriftsartikel (refereegranskat)abstract
- Accumulation of misfolded transthyretin (TTR) as amyloid fibrils causes various human disorders. Native transthyretin is a neurotrophic protein and is a putative extracellular molecular chaperone. Several fluorophores have been shown in vitro to bind selectively to native TTR. Other compounds, such as thioflavin T, bind TTR amyloid fibrils. The probe 1-anilinonaphthalene-8-sulfonate (ANS) binds to both native and fibrillar TTR, becoming highly fluorescent, but with indistinguishable emission spectra for native and fibrillar TTR. Herein we report our efforts to develop a fluorescent small molecule capable of binding both native and misfolded protofibrillar TTR, providing distinguishable emission spectra. We used microwave synthesis for efficient production of a small library of trans-stilbenes and fluorescence spectral screening of their binding properties. We synthesized and tested 22 trans-stilbenes displaying a variety of functional groups. We successfully developed two naphthyl-based trans-stilbenes probes that detect both TTR states at physiological concentrations. The compounds bound with nanomolar to micromolar affinities and displayed distinct emission maxima upon binding native or misfolded protofibrillar TTR (>100 nm difference). The probes were mainly responsive to environment polarity providing evidence for the divergent hydrophobic structure of the binding sites of these protein conformational states. Furthermore, we were able to successfully use one of these probes to quantify the relative amounts of native and protofibrillar TTR in a dynamic equilibrium. In conclusion, we identified two trans-stilbene-based fluorescent probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (11) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (14), that bind native and protofibrillar TTR, providing a wide difference in emission maxima allowing conformational discrimination by fluorescence spectroscopy. We expect these novel molecules to serve as important chemical biology research tools in studies of TTR folding and misfolding.
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| 13. |
- Elgland, Mathias, 1987-
(författare)
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Synthesis and application of β-configured [18/19F]FDGs : Novel prosthetic CuAAC click chemistry fluoroglycosylation tools for amyloid PET imaging and cancer theranostics
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Positron emission tomography (PET) is a non-invasive imaging method that renders three-dimensional images of tissue that selectively has taken up a radiolabelled organic compound, referred to as a radiotracer. This excellent technique provides clinicians with a tool to monitor disease progression and to evaluate how the patient respond to treatment. The by far most widely employed radiotracer in PET is called 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), which is often referred to as the golden standard in PET. From a molecular perspective, [18F]FDG is an analogue of glucose where a hydroxyl group has been replaced with a radioactive fluorine atom (18F). It is well known that covalent attachment of carbohydrates (i.e., glycosylation) to biomolecules tend to improve their properties in the body, in terms of; improved pharmacokinetics, increased metabolic stability and faster clearance from blood and other non-specific tissue. It is therefore natural to pursuit the development of a [18F]fluoroglycosylation method where [18F]FDG is chemically conjugated to a ligand with high affinity for a given biological target (e.g., tumors or disease-associated protein aggregates).This thesis describes a novel [18F]fluoroglycosylation method that in a simple and general manner facilitate the conjugation of [18F]FDG to biological ligands using click chemistry. The utility of the developed [18F]fluoroglycosylation method is demonstrated by radiolabelling of curcumin, thus forming a tracer that may be employed for diagnosis of Alzheimer’s disease. Moreover, a set of oligothiophenes were fluoroglycosylated for potential diagnosis of Alzheimer’s disease but also for other much rarer protein misfolding diseases (e.g., Creutzfeldt-Jakob disease and systemic amyloidosis). In addition, the synthesis of a series of 19F-fluoroglycosylated porphyrins is described which exhibited promising properties not only to detect but also to treat melanoma cancer. Lastly, the synthesis of a set of 19F-fluorinated E-stilbenes, structurally based on the antioxidant resveratrol is presented. The E-stilbenes were evaluated for their capacity to spectrally distinguish between native and protofibrillar transthyretin in the pursuit of finding diagnostic markers for the rare but severe disease, transthyretin amyloidosis.
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| 14. |
- Elwér, Sofia, et al.
(författare)
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Life course models of economic stress and poor mental health in mid-adulthood : Results from the prospective Northern Swedish Cohort
- 2015
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 43:8, s. 833-840
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim was to analyse the association between economic stress during youth and adulthood, and poor mental health through life course models of (1) accumulation of risk and (2) sensitive period. Methods: The study was based on the Northern Sweden Cohort, a 26-year prospective cohort (N = 1010 in 2007; 94% of those participating in 1981 still alive) ranging from adolescence to middle age. Economic stress was measured at age 16, 21, 30 and 42 years. Two life course models of accumulation of risk and sensitive period were analysed using ordinal regression with internalized symptoms of mental health as outcome. Results: Exposure of economic stress at several life course periods was associated with higher odds of internalized mental health symptoms for both women and men, which supports the accumulated risk model. No support for a sensitive period was found for the whole sample. For men, however, adolescence appears to be a sensitive period during which the exposure to economic stress has negative mental health consequences later in life independently of economic stress at other ages. Conclusion: This study confirms that the duration of economic stress between adolescence and middle age is important for mental health. In addition, the results give some indication of a sensitive period of exposure to economic stress during adolescence for men, although more research is needed to confirm possible gender differences.
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| 15. |
- Fändrich, M., et al.
(författare)
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Amyloid fibril polymorphism: a challenge for molecular imaging and therapy
- 2018
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 283:3, s. 218-237
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimers disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimers or Parkinsons diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.
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| 16. |
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| 17. |
- Gabrielsson, Erik, et al.
(författare)
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Spatiotemporal Control of Amyloid-Like A Plaque Formation Using a Multichannel Organic Electronic Device
- 2016
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Ingår i: Macromolecular materials and engineering. - : WILEY-V C H VERLAG GMBH. - 1438-7492 .- 1439-2054. ; 301:4, s. 359-363
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Tidskriftsartikel (refereegranskat)abstract
- We herein report on an iontronic device to drive and control A1-40 and A1-42 fibril formation. This system allows kinetic control of A aggregation by regulation of H+ flows. The formed aggregates show both nanometer-sized fibril structure and microscopic growth, thus mimicking senile plaques, at the H+-outlet. Mechanistically we observed initial accumulation of A1-40 likely driven by electrophoretic migration which preceded nucleation of amyloid structures in the accumulated peptide cluster.
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| 18. |
- Gallardo, Rodrigo, et al.
(författare)
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De novo design of a biologically active amyloid
- 2016
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Ingår i: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 354:6313, s. 720-
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Tidskriftsartikel (refereegranskat)abstract
- Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional-determined by VEGFR2 loss of function in a biological context in which target protein function is essential.
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| 19. |
- Groenning, Minna, et al.
(författare)
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Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils
- 2015
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Ingår i: Scientific Reports. - : Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group. - 2045-2322. ; 5:11443
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Tidskriftsartikel (refereegranskat)abstract
- Despite numerous studies, a detailed description of the transthyretin (TTR) self-assembly mechanism and fibril structure in TTR amyloidoses remains unresolved. Here, using a combination of primarily small -angle X-ray scattering (SAXS) and hydrogen exchange mass spectrometry (HXMS) analysis, we describe an unexpectedly dynamic TTR protofibril structure which exchanges protomers with highly unfolded monomers in solution. The protofibrils only grow to an approximate final size of 2,900 kDa and a length of 70 nm and a comparative HXMS analysis of native and aggregated samples revealed a much higher average solvent exposure of TTR upon fibrillation. With SAXS, we reveal the continuous presence of a considerably unfolded TTR monomer throughout the fibrillation process, and show that a considerable fraction of the fibrillating protein remains in solution even at a late maturation state. Together, these data reveal that the fibrillar state interchanges with the solution state. Accordingly, we suggest that TTR fibrillation proceeds via addition of considerably unfolded monomers, and the continuous presence of amyloidogenic structures near the protofibril surface offers a plausible explanation for secondary nucleation. We argue that the presence of such dynamic structural equilibria must impact future therapeutic development strategies.
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| 20. |
- Gustafsson, Per, 1981-, et al.
(författare)
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Cumulative contextual and individual disadvantages over the life course and adult functional somatic symptoms in Sweden
- 2015
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Ingår i: European Journal of Public Health. - : Oxford University Press (OUP). - 1101-1262 .- 1464-360X. ; 25:4, s. 592-597
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Disadvantage, originating in one's residential context or in one's past life course, has been shown to impact on health in adulthood. There is however little research on the accumulated health impact of both neighbourhood and individual conditions over the life course. This study aims to examine whether the accumulation of contextual and individual disadvantages from adolescence to middle-age predicts functional somatic symptoms (FSS) in middle-age, taking baseline health into account.METHODS:: The sample is the age 16, 21, 30 and 42 surveys of the prospective Northern Swedish Cohort, with analytical sample size n = 910 (85% of the original cohort). FSS at age 16 and 42, and cumulative socioeconomic disadvantage, social adversity and material adversity between 16 and 42 years were operationalized from questionnaires, and cumulative neighbourhood disadvantage between 16 and 42 years from register data.RESULTS:: Results showed accumulation of disadvantages jointly explained 9-12% of FSS variance. In the total sample, cumulative neighbourhood and socioeconomic disadvantage significantly predicted FSS at age 42 in the total sample. In women, neighbourhood disadvantage but not socioeconomic disadvantage contributed significantly, whereas in men, socioeconomic but not neighbourhood disadvantage contributed significantly. In all analyses, associations were largely explained by the parallel accumulation of social and material adversities, but not by symptoms at baseline.CONCLUSION:: In conclusion, the accumulation of diverse forms of disadvantages together plays an important role for somatic complaints in adulthood, independently of baseline health.
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