| 1. |
- Björkman, Andrea, et al.
(författare)
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Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells.
- 2015
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 112:7, s. 2157-2162
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1's function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- Hammarström, Per, et al.
(författare)
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Porcine prion protein amyloid
- 2015
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Ingår i: Prion. - : Taylor andamp; Francis: STM, Behavioural Science and Public Health Titles. - 1933-6896 .- 1933-690X. ; 9:4, s. 266-277
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.
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| 6. |
- Herrmann, Uli S., et al.
(författare)
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Structure-based drug design identifies polythiophenes as antiprion compounds
- 2015
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 7:299, s. 299ra123-
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Tidskriftsartikel (refereegranskat)abstract
- Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by greater than80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.
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| 7. |
- Johansson, Klara, et al.
(författare)
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Neighbourhood disadvantage and individual adversities in adolescence and total alcohol consumption up to mid-life : Results from the Northern Swedish Cohort
- 2015
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Ingår i: Health and Place. - : Elsevier BV. - 1353-8292 .- 1873-2054. ; 33, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- This study tests if neighbourhood socioeconomic disadvantage and family social and material adversities during adolescence are independently related to total alcohol consumption from adolescence through to mid-life. Self-reports from the Northern Swedish Cohort (effective sample=950) at ages 16, 18, 21, 30 and 42 was combined with register data on the socioeconomic composition of neighbourhoods at age 16. Total volume of alcohol consumed between age 16-42 was estimated based on the five survey waves, and self-reported social and material adversities were computed as composite variables. Neighbourhood socioeconomic disadvantage at age 16 was associated with alcohol consumption age 16-42 for men but not for women. Social adversities at age 16 were associated with alcohol consumption age 16-42 for both women and men, but material adversity or parental class was not. In conclusion, neighbourhood socioeconomic disadvantage in adolescence has a significant relationship with later alcohol consumption among men, even independently from individual factors. On family level, social factors but not socioeconomic factors in adolescence independently predict later alcohol consumption.
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| 8. |
- 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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| 9. |
- Magnusson, Karin, 1981-
(författare)
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Poly-and oligothiophenes : Optical probes for multimodal fluorescent assessment of biological processes
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One interesting class of molecules in the research field of imaging biological processes is luminescent conjugated polythiophenes, LCPs. These fluorescent probes have a flexible backbone consisting of repetitive thiophene units. Due to this backbone, the probes possess unique abilities to give rise to different spectral signatures depending on their target and environment. LCPs are a polydispersed material meaning there is an uneven distribution of lengths of the probe. Recently, monodispersed chemically well-defined material denoted luminescent conjugated oligothiophenes, LCOs, with an exact number of repetitive units and distinct sidechain functionalities along the backbone has been developed. LCOs have the advantages of being smaller which leads to higher ability to cross the blood brain barrier. The synthesis of minor chemical alterations is also more simplified due to the well-defined materials.During my doctoral studies I have used both LCPs and LCOs to study biological processes such as conformational variation of protein aggregates in prion diseases and cellular uptake in normal cells and cancer cells. The research has generally been based on the probes capability to emit light upon irradiation and the interaction with their targets has mainly been assessed through variations in fluorescence intensity, emission-and excitation profiles and fluorescence lifetime decay. These studies verified the utility of LCPs and LCOs for staining and discrimination of both prion strains and cell phenotypes. The results also demonstrated the pronounced influence minor chemical modifications have on the LCO´s staining capacity.
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| 10. |
- Nyström, Sofie, et al.
(författare)
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Generic amyloidogenicity of mammalian prion proteins from species susceptible and resistant to prions
- 2015
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Ingår i: Scientific Reports. - : Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group. - 2045-2322. ; 5:10101
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Tidskriftsartikel (refereegranskat)abstract
- Prion diseases are lethal, infectious diseases associated with prion protein (PrP) misfolding. A large number of mammals are susceptible to both sporadic and acquired prion diseases. Although PrP is highly conserved and ubiquitously expressed in all mammals, not all species exhibit prion disease. By employing full length recombinant PrP from five known prion susceptible species (human, cattle, cat, mouse and hamster) and two species considered to be prion resistant (pig and dog) the amyloidogenicity of these PrPs has been delineated. All the mammalian PrPs, even from resistant species, were swiftly converted from the native state to amyloid-like structure when subjected to a native condition conversion assay. The PrPs displayed amyloidotypic tinctorial and ultrastructural hallmarks. Self-seeded conversion of the PrPs displayed significantly decreased lag phases demonstrating that nucleation dependent polymerization is a dominating mechanism in the fibrillation process. Fibrils from A beta 1-40, A beta 1-42, Lysozyme, Insulin and Transthyretin did not accelerate conversion of HuPrP whereas fibrils from HuPrP90-231 and HuPrP121-231 as well as full length PrPs of all PrPs efficiently seeded conversion showing specificity of the assay requiring the C-terminal PrP sequence. Our findings have implications for PrP misfolding and could have ramifications in the context of prion resistant species and silent carriers.
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