| 1. |
- Abdellah, Tebani, et al.
(författare)
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Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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| 2. |
- Abelein, A, et al.
(författare)
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High-yield Production of Amyloid-β Peptide Enabled by a Customized Spider Silk Domain
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 235-
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Tidskriftsartikel (refereegranskat)abstract
- During storage in the silk gland, the N-terminal domain (NT) of spider silk proteins (spidroins) keeps the aggregation-prone repetitive region in solution at extreme concentrations. We observe that NTs from different spidroins have co-evolved with their respective repeat region, and now use an NT that is distantly related to previously used NTs, for efficient recombinant production of the amyloid-β peptide (Aβ) implicated in Alzheimer’s disease. A designed variant of NT from Nephila clavipes flagelliform spidroin, which in nature allows production and storage of β-hairpin repeat segments, gives exceptionally high yields of different human Aβ variants as a solubility tag. This tool enables efficient production of target peptides also in minimal medium and gives up to 10 times more isotope-labeled monomeric Aβ peptides per liter bacterial culture than previously reported.
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| 3. |
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| 4. |
- Agback, Peter, et al.
(författare)
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H-1, C-13 and N-15 resonance assignment of backbone and IVL-methyl side chain of the S135A mutant NS3pro/NS2B protein of Dengue II virus reveals unique secondary structure features in solution
- 2022
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Ingår i: Biomolecular Nmr Assignments. - : Springer Science and Business Media LLC. - 1874-2718 .- 1874-270X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- The serotype II Dengue (DENV 2) virus is the most prevalent of all four known serotypes. Herein, we present nearly complete H-1, N-15, and C-13 backbone and H-1, C-13 isoleucine, valine, and leucine methyl resonance assignment of the apo S135A catalytically inactive variant of the DENV 2 protease enzyme folded as a tandem formed between the serine protease domain NS3pro and the cofactor NS2B, as well as the secondary structure prediction of this complex based on the assigned chemical shifts using the TALOS-N software. Our results provide a solid ground for future elucidation of the structure and dynamic of the apo NS3pro/NS2B complex, key for adequate development of inhibitors, and a thorough molecular understanding of their function(s).
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| 5. |
- Agback, Tatiana, et al.
(författare)
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Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro
- 2023
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Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The dengue protease NS2B/NS3pro has been reported to adopt either an 'open' or a 'closed' conformation. We have developed a conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution. Experimental values derived from relaxation parameters for the backbone and methyl side chains were compared with the corresponding back-calculated relaxation parameters of different conformational ensembles obtained from free MD simulations. Our results demonstrate a high prevalence for the 'closed' conformational ensemble while the 'open' conformation is absent, indicating that the latter conformation is most probably due to crystal contacts. Conversely, conformational ensembles in which the positioning of the co-factor NS2B results in a 'partially' open conformation, previously described in both MD simulations and X-ray studies, were identified by our conformational filter. Altogether, we believe that our approach allows for unambiguous identification of true conformational ensembles, an essential step for reliable drug discovery. A conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution suggests dengue protease NS2B/NS3pro predominantly exists in a "closed" conformation.
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| 6. |
- Ahlgren, Kerstin M, et al.
(författare)
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Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e105473-
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS:Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.METHODS:Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.RESULTS:None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.CONCLUSIONS/INTERPRETATIONS:Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.
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| 7. |
- Ahlström, J. Zebialowicz, et al.
(författare)
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Synthetic surfactant with a recombinant surfactant protein C analogue improves lung function and attenuates inflammation in a model of acute respiratory distress syndrome in adult rabbits
- 2019
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Ingår i: Respiratory Research. - : BMC. - 1465-9921 .- 1465-993X. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- AimIn acute respiratory distress syndrome (ARDS) damaged alveolar epithelium, leakage of plasma proteins into the alveolar space and inactivation of pulmonary surfactant lead to respiratory dysfunction. Lung function could potentially be restored with exogenous surfactant therapy, but clinical trials have so far been disappointing. These negative results may be explained by inactivation and/or too low doses of the administered surfactant. Surfactant based on a recombinant surfactant protein C analogue (rSP-C33Leu) is easy to produce and in this study we compared its effects on lung function and inflammation with a commercial surfactant preparation in an adult rabbit model of ARDS.MethodsARDS was induced in adult New Zealand rabbits by mild lung-lavages followed by injurious ventilation (V-T 20m/kg body weight) until P/F ratio<26.7kPa. The animals were treated with two intratracheal boluses of 2.5mL/kg of 2% rSP-C33Leu in DPPC/egg PC/POPG, 50:40:10 or poractant alfa (Curosurf (R)), both surfactants containing 80mg phospholipids/mL, or air as control. The animals were subsequently ventilated (V-T 8-9m/kg body weight) for an additional 3h and lung function parameters were recorded. Histological appearance of the lungs, degree of lung oedema and levels of the cytokines TNF alpha IL-6 and IL-8 in lung homogenates were evaluated.ResultsBoth surfactant preparations improved lung function vs. the control group and also reduced inflammation scores, production of pro-inflammatory cytokines, and formation of lung oedema to similar degrees. Poractant alfa improved compliance at 1h, P/F ratio and PaO2 at 1.5h compared to rSP-C33Leu surfactant.ConclusionThis study indicates that treatment of experimental ARDS with synthetic lung surfactant based on rSP-C33Leu improves lung function and attenuates inflammation.
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| 8. |
- Ahsan, Muhammad, et al.
(författare)
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Identification of candidate genes and mutations in QTL regions for chicken growth using bioinformatic analysis of NGS and SNP-chip data.
- 2013
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Mapping of chromosomal regions harboring genetic polymorphisms that regulate complex traits is usually followed by a search for the causative mutations underlying the observed effects. This is often a challenging task even after fine mapping, as millions of base pairs including many genes will typically need to be investigated. Thus to trace the causative mutation(s) there is a great need for efficient bioinformatic strategies. Here, we searched for genes and mutations regulating growth in the Virginia chicken lines - an experimental population comprising two lines that have been divergently selected for body weight at 56 days for more than 50 generations. Several quantitative trait loci (QTL) have been mapped in an F2 intercross between the lines, and the regions have subsequently been replicated and fine mapped using an Advanced Intercross Line. We have further analyzed the QTL regions where the largest genetic divergence between the High-Weight selected (HWS) and Low-Weight selected (LWS) lines was observed. Such regions, covering about 37% of the actual QTL regions, were identified by comparing the allele frequencies of the HWS and LWS lines using both individual 60K SNP chip genotyping of birds and analysis of read proportions from genome resequencing of DNA pools. Based on a combination of criteria including significance of the QTL, allele frequency difference of identified mutations between the selected lines, gene information on relevance for growth, and the predicted functional effects of identified mutations we propose here a subset of candidate mutations of highest priority for further evaluation in functional studies. The candidate mutations were identified within the GCG, IGFBP2, GRB14, CRIM1, FGF16, VEGFR-2, ALG11, EDN1, SNX6, and BIRC7 genes. We believe that the proposed method of combining different types of genomic information increases the probability that the genes underlying the observed QTL effects are represented among the candidate mutations identified.
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| 9. |
- Akesson, Agneta, et al.
(författare)
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Dietary exposure to polychlorinated biphenyls and risk of heart failure - A population-based prospective cohort study
- 2019
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Ingår i: Environment International. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0160-4120 .- 1873-6750. ; 126, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Beneficial effects of fish consumption on heart failure (HF) may be modified by contaminants in fish. Polychlorinated biphenyls (PCBs) are of particular concern as they have been associated with well-established risk factors of HF, but current data are limited. Objectives: We aimed to assess the association between dietary PCB exposure and risk of HF, accounting for dietary intake of long-chain omega-3 fish fatty acids. Design: We used the prospective population-based research structure SIMPLER (previously the Swedish Mammography Cohort and Cohort of Swedish Men) comprising 32,952 women and 36,546 men, free from cancer, cardiovascular disease and diabetes at baseline in 1997. Validated estimates of dietary PCBs and long-chain omega-3 fish fatty acids [eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] were obtained via a food frequency questionnaire at baseline. Incident cases of HF were ascertained through register linkage. Results: During an average of 12 years of follow-up, we ascertained 2736 and 3128 incident cases of HF in women and men, respectively. In multivariable-adjusted models, mutually adjusted for PCBs and EPA-DHA, the relative risk (RR) for dietary PCB exposure was 1.48 (95% CI 1.12-1.96) in women and 1.42 (95% CI 1.08-1.86) in men, comparing extreme quintiles. Corresponding RRs for EPA-DHA intake were 0.71 (95% CI 0.54-0.93) and 0.82 (95% CI 0.63-1.07), respectively. Conclusions: Dietary exposure to PCBs was associated with an increased risk of HF in both women and men. EPA-DHA intake was associated with a lower risk of HF in women, with a similar tendency in men.
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