| 161. |
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| 162. |
- Jonson, Maria
(författare)
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Investigating Amyloid β toxicity in Drosophila melanogaster
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis Drosophila melanogaster (the fruit fly) has been used as a model organism to study the aggregation and toxic properties of the human amyloid β (Aβ) peptide involved in the onset of Alzheimer's disease (AD). AD is one of many misfolding diseases where the important event of a protein to adopt its’ specific three-dimensional structure has failed, leading to aggregation and formation of characteristic amyloid fibrils. AD has a complex pathology and probably reflects a variety of related molecular and cellular abnormalities, however, the most apparent common denominator so far is abnormal Amyloid-β precursor protein (APP) processing, resulting in a pool of various Aβ-peptides. In AD, the Aβ peptide misfolds, aggregates and forms amyloid plaques in the brain of patients, resulting in progressive neurodegeneration that eventually leads to death.By expressing the human Aβ protein in the fly, we have studied the mechanisms and toxicity of the aggregation in detail and how different cell types in the fly are affected. We have also used this model to investigate the effect of potential drugs that can have a positive impact on disease progression. In the first and second work in this thesis, we have, in a systematic way, proved that the length of the Aβ-peptide is essential for its toxicity and propensity to aggregate. If the peptide expressed ends at amino acid 42 it is extremely toxic to the fly nervous system. However, this toxicity can be completely abolished by expressing a variant that is shorter than 42 amino acids (1-37 to 1-41 aa), or be significantly reduced by expressing a longer variant (1-43 aa). Toxicity can be partly mitigated in trans by co-expressing the 1-42 variant with a 1-38 variant. This supports the theory that the disease progression could be inhibited if the formation of Aβ 1-42 is decreased. In the third work we demonstrate that amyloid aggregates can be found in various cell types of Drosophila, however, the toxicity seem to be selective to neurons. Our results indicate that the aggregates of glial expressing flies have a more mature structure, which appear to be less toxic. This also suggests that glial cells might spread Aβ aggregates without being harmed. The last work in this thesis investigates how curcumin (turmeric) can affect Aβ aggregation and toxicity. Curcumin appears to shift the equilibrium between the less stableaggregates and mature fibers toward the final stage resulting in an improved lifespan for treated flies.In summary, this thesis demonstrates that the toxicity of Aβ in Drosophila is highly dependent on the Aβ variant expressed, the structure of the protein aggregates and which cell type that expresses the protein. We have also shed light on the potential of using Drosophila when it comes to examining possible therapeutic substances as a tool for drug discovery.
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| 163. |
- Jonsson, Frida, et al.
(författare)
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Are neighbourhood inequalities in adult health explained by socio-economic and psychosocial determinants in adolescence and the subsequent life course in northern Sweden? : A decomposition analysis
- 2018
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Ingår i: Health and Place. - : Elsevier. - 1353-8292 .- 1873-2054. ; 52, s. 127-134
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Tidskriftsartikel (refereegranskat)abstract
- This study explains neighbourhood deprivation inequalities in adult health for a northern Swedish cohort by examining the contribution of socio-economic and psychosocial determinants from adolescence (age 16), young adulthood (age 21) and midlife (age 42) to the disparity. Self-reported information from 873 participants was drawn from questionnaires, with complementary neighbourhood register data. The concentration index was used to estimate the inequality while decomposition analyses were run to attribute the disparity to its underlying determinants. The results suggest that socio-economic and psychosocial factors in midlife explain a substantial part, but also that the inequality can originate from conditions in adolescence and young adulthood.
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| 164. |
- Jonsson, Frida, et al.
(författare)
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Intragenerational social mobility and functional somatic symptoms in a northern Swedish context : analyses of diagonal reference models
- 2017
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Ingår i: International Journal for Equity in Health. - : Springer Science and Business Media LLC. - 1475-9276. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Research indicate that social class mobility could be potentially important for health, but whether this is due to the movement itself or a result of people having been integrated in different class contexts is, to date, difficult to infer. In addition, although several theories suggest that transitions between classes in the social hierarchy can be stressful experiences, few studies have empirically examined whether such movements may have health effects, over and above the implications of "being" in these classes. In an attempt to investigate whether intragenerational social mobility is associated with functional somatic symptoms in mid-adulthood, the current study tests three partially contrasting theories.METHOD: The dissociative theory suggests that mobility in general and upward mobility in particular may be linked to psychological distress, while the falling from grace theory indicates that downward mobility is especially stressful. In contrast, the acculturation theory holds that the health implications of social mobility is not due to the movement itself but attributed to the class contexts in which people find themselves. Diagonal Reference Models were used on a sample of 924 individuals who in 1981 graduated from 9(th) grade in the municipality of Luleå, Sweden. Social mobility was operationalized as change in occupational class between age 30 and 42 (measured in 1995 and 2007). The health outcome was functional somatic symptoms at age 42, defined as a clustering self-reported physical symptoms, palpitation and sleeping difficulties during the last 12 months.RESULTS: Overall mobility was not associated with higher levels of functional somatic symptoms compared to being immobile (p = 0.653). After controlling for prior and current class, sex, parental social position, general health, civil status, education and unemployment, the association between downward mobility was borderline significant (p = 0.055) while upward mobility was associated with lower levels of functional somatic symptoms (p = 0.03).CONCLUSION: The current study did not find unanimous support for any of the theories. Nevertheless, it sheds light on the possibility that upward mobility may be beneficial to reduce stress-related health problems in mid-life over and above the exposure to prior and current class, while downward mobility can be of less importance for middle-age health complaints.
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| 165. |
- Jonsson, F., et al.
(författare)
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Paths of adversity linking adolescent socioeconomic conditions to adult functional somatic symptoms
- 2016
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Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 26:Suppl 1, s. 227-227
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Tidskriftsartikel (refereegranskat)abstract
- Background: While research examining the health impact of early socioeconomic conditions suggests that effects may exist independently of or jointly with adult socioeconomic position, studies exploring other pathways are few. Following a chain of risk life course model, this study examine if the socioeconomic conditions of the family contributes to an adverse social and material environment across life ultimately affecting functional somatic symptoms in adulthood.Methods: Mediation was examined using path analysis on prospective data from a sample of 987 individuals residing in Luleå, Sweden in 1981 and who answered surveys at age 16, 21, 30 and 42. Early socioeconomic conditions was assessed at age 16 by using the parents occupation. The participant’s own occupation was measured at age 21 and 30. At age 21 and 30, social adversity comprised of items pertaining to stressful life events, while material adversity included items of unfavorable economic conditions. Functional somatic symptoms was examined at age 42 as a summary of self-reported physical symptoms, palpitation and sleeping difficulties occurring during the last 12 months.Results: The results suggested that the association between socioeconomic conditions at age 16 and functional somatic symptoms at age 42 (r = .068) could be explained by two plausible pathways. Through own class at age 21 and then through material (B = .064, 95% CI = .004 – .123) and social adversity (B = .067, 95% CI = .019 – .114) at age 30.Conclusions: Growing up in an unfavorable socioeconomic setting might be a source for later adversities, and these might largely explain the effects of early disadvantage on later health. Thus, improved social and financial living conditions for people from poor backgrounds could avert adult stress-related health problems.Key messages:Chains of life events may be central to understand socioeconomic health effectsBreaking life course chains might avert adult health effects of early disadvantage
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| 166. |
- Jonsson, Frida, et al.
(författare)
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Social capital across the life course and functional somatic symptoms in mid-adulthood
- 2014
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Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 42:7, s. 581-588
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To examine social capital across life and functional somatic symptoms in middle-age, according to life-course models of cumulative risk and sensitive periods.Methods: Data from the 26-year prospective study the Northern Swedish Cohort enabled complete case analyses on 940 individuals (451 women and 489 men) participating in questionnaire surveys at ages 16, 21, 30 and 42. Social capital was operationalized at the individual level, comprising items on social participation, social influence and social support. Functional somatic symptoms were a summary measure of self-reported physical symptoms, palpitation and sleeping difficulties occuring during the 12 months prior to the data collection. Linear regression was used as the main statistical method, examining the relationship between functional somatic symptoms at age 42 and social capital across life.Results: Lower levels of social capital accumulated over the life course were associated with higher levels of functional somatic symptoms at age 42, for both women and men. Social capital was, especially among adolescent men, related to functional somatic symptoms at age 42, independently of social capital later in life and baseline material circumstances.Conclusions: The health impact of poor social capital may be due to accumulation across the life course and to adolescence being a particularly sensitive period. It is relevant for preventive work to acknowledge effects of social capital throughout life.
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| 167. |
- Jonsson, Frida, 1988-
(författare)
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The presence of the past : a life course approach to the social determinants of health and health inequalities in northern Sweden
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Positioned at the intersection between the social and life course epidemiological sub-fields, this thesis builds on the idea that the health implications of life and living conditions can extend over years and decades before becoming expressed in the population patterns of ill-health. The overall purpose was to assess how multiple types of social determinants of health across the life course may contribute to ill-health and health inequalities in midlife. Several gaps in knowledge served as the basis for four research questions that focused on: 1) the intermediate role of socio-economic, material and psychosocial factors in young adulthood, in the long-term association between adolescent socio-economic position and midlife ill-health; 2) the implications of poor social capital in adolescence and accumulated over the life course for midlife ill-health; 3) the consequences of intra-generational social mobility for midlife ill-health and 4) the contribution of socio-economic, material and psychosocial circumstances in adolescence, young adulthood and middle-age to midlife neighbourhood deprivation inequalities in ill-health.Methods: The setting of the thesis is Sweden spanning over nearly three decades, from the early 1980s and until the mid-2010s. With information drawn from the Northern Swedish Cohort the study population consists of 1,083 pupils (506 girls and 577 boys) who attended, or should have attended, the last year of compulsory school in 1981. The data used came from questionnaires answered by the participants in the follow-ups at the ages of 16 (in 1981), 21 (in 1986), 30 (in 1995) and 42 (in 2007). The attrition rate was low with 1,010 out of the 1,071 students who were alive over the 26-years participated in all waves (94.3%). Data was also included from the Swedish registers for the same ages as the surveys on the participants’ neighbourhoods and sociodemographic characteristics on all other residents in these areas. The health outcome was functional somatic symptoms, referring to the occurrence of common physical complaints such as musculoskeletal pain, headache, palpitations and fatigue. To capture various social determinants of health, socio-economic, material and psychosocial factors were operationalised as main exposures. The research questions were analysed using: 1) path analysis, 2) multiple linear regression, 3) diagonal reference models and 4) a decomposition analysis.Results: With regard to the four research questions, the results firstly indicated that the long-term association between adolescent socio-economic position and midlife ill-health was linked by socio-economic position in young adulthood and further via material and psychosocial factors in middle-age. Secondly, that poor social capital in adolescence also could play a role in the development of adult illhealth, but that this influence seem to be largely dependent on recent or current conditions in adulthood. Thirdly, that downward mobility in the socio-economic hierarchy during middle-age may have little to no health implications, while upward movements could have a small positive effect on health. Fourthly, that ill-health was concentrated in more socio-economically deprived neighbourhoods and that this inequality was to a small extent attributed to conditions in earlier life period and mainly to factors in adulthood.Conclusions: Based on patterns cutting across the original research questions, the findings from this thesis indicate broadly that socio-economic, material and psychosocial conditions may be meaningful for midlife ill-health and health disparities, jointly and independently from each other. The results also suggests that determinants in the present on the surface appear to be more important for midlife ill-health and health inequalities than those of the past, but at the same time that life circumstances in the earlier life course may not be irrelevant. Rather than representing permanent or resilient health implications, however, the long-term influence of adolescent conditions seem to reflect mainly social processes that are conditional on recent or concurrent adult factors. In sum, the results indicate that a continuum of various life and living conditions may be a key phenomenon underlying ill-health and health disparities in midlife. Specifically, this thesis illustrates how the past may become part of the present through the accumulation and chains of unfavourable circumstances over the life course and conversely, how the present health reflects and embodies a life-long past.
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| 168. |
- Jonsson, Maria, et al.
(författare)
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Aggregated Aβ1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila
- 2018
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Ingår i: Cell Chemical Biology. - Cambridge, United States : Elsevier BV. - 2451-9456 .- 2451-9448. ; 25:5, s. 595-610.e5
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Tidskriftsartikel (refereegranskat)abstract
- The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human Aβ1-42 associated with Alzheimer's disease. Expression of Aβ1-42 in various neurons resulted in concentration-dependent severe neurodegenerative phenotypes, and intraneuronal ring-tangle-like aggregates with immature fibril properties when analyzed by aggregate-specific ligands. Unexpectedly, expression of Aβ1-42 from a pan-glial driver produced a mild phenotype despite massive brain load of Aβ1-42 aggregates, even higher than in the strongest neuronal driver. Glial cells formed more mature fibrous aggregates, morphologically distinct from aggregates found in neurons, and was mainly extracellular. Our findings implicate that Aβ1-42 cytotoxicity is both cell and aggregate morphotype dependent. Jonson et al. used transgenic Drosophila to understand cell-specific response to protein aggregates in neurodegenerative disease. They demonstrate that the Alzheimer-associated peptide Aβ1-42 form various amyloid structures with different toxic properties when expressed in different cell types of the brain. © 2018 Elsevier Ltd
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| 169. |
- Jonsson, Maria, et al.
(författare)
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Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Brain amyloid plaques are a hallmark of Alzheimers disease (AD), and primarily consist of aggregated A beta peptides. While A beta 1-40 and A beta 1-42 are the most abundant, a number of other A beta peptides have also been identified. Studies have indicated differential toxicity for these various A beta peptides, but in vivo toxicity has not been systematically tested. To address this issue, we generated improved transgenic Drosophila UAS strains expressing 11 pertinent A beta peptides. UAS transgenic flies were generated by identical chromosomal insertion, hence removing any transgenic position effects, and crossed to a novel and robust Gal4 driver line. Using this improved Gal4/UAS set-up, survival and activity assays revealed that A beta 1-42 severely shortens lifespan and reduces activity. N-terminal truncated peptides were quite toxic, with 3-42 similar to 1-42, while 11-42 showed a pronounced but less severe phenotype. N-terminal mutations in 3-42 (E3A) or 11-42 (E11A) resulted in reduced toxicity for 11-42, and reduced aggregation for both variants. Strikingly, C-terminal truncation of A beta (1-41, -40, -39, -38, -37) were non-toxic. In contrast, C-terminal extension to 1-43 resulted in reduced lifespan and activity, but not to the same extent as 1-42. Mutating residue 42 in 1-42 (A42D, A42R and A42W) greatly reduced A beta accumulation and toxicity. Histological and biochemical analysis revealed strong correlation between in vivo toxicity and brain A beta aggregate load, as well as amount of insoluble A beta. This systematic Drosophila in vivo and in vitro analysis reveals crucial N- and C-terminal specificity for A beta neurotoxicity and aggregation, and underscores the importance of residues 1-10 and E11, as well as a pivotal role of A42.
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| 170. |
- Kharezy, Mohammad
(författare)
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A Novel Oil-immersed Medium Frequency Transformer for Offshore HVDC Wind Farms
- 2020
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this project, a design of an oil type medium frequency transformer for offshore wind farm applications is proposed. The design is intended for applications when series coupling of the output of the DC/DC converters of the wind turbine on their secondary side is done to achieve a cost-effective high voltage solution for collecting energy from offshore wind parks. The focus of the work is on the insulation design of the high voltage side of a medium frequency transformer where the magnetic design constraints should also be satisfied.Above all, a proof of concept is made demonstrating a possible solution for the design of the transformer for such a DC/DC converter unit. The transformer suggested is using oil/paper as insulation medium. Furthermore, characterisation of an eco-friendly biodegradable transformer oil for this type of HVDC transformer application is made. Moreover, an introduction of reliable high frequency characterisation test methods to medium frequency transformer designers is made. In addition, the Non-Linear Maxwell Wagner (NLMW) relations are further developed to form a method for the development of an HVDC MFT transformer. All in all, the DC series concept has been further developed one step closer to pre-commercialization, i.e. from TRL 1 to about 2.
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