| 1. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 2. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 3. |
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| 4. |
- Andersson, Jan, 1965-, et al.
(författare)
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Regeringsuppdrag synfält : utredning om förutsättningar för undantag från de medicinska kraven för individer med synfältsbortfall
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I regeringsuppdraget (I2021/ 02412) framgår att VTI, i samarbete med Trafikverket och Transportstyrelsen, ska utreda förutsättningarna för undantagshantering från de medicinska föreskrifterna med avseende på synfältsbortfall (B-körkort). Vidare ska tre aspekter beaktas: hur andra länder gör, konsekvenser för den enskilde samt samhällsekonomiska konsekvenser. Slutrapporten påvisar att Sverige med gällande rättsligt ramverk inte kan genomföra de förslag som slutrapporten föreslår. Det innebär att det kommer att krävas juridiska förändringar. Givet att dessa förändringar genomförs och att ett nytt förfaringssätt nyttjas visar slutrapporten på att a) positiva effekter för den enskilde individen uppstår, b) samhällsekonomiska vinster uppstår och c) en rättssäker och rättvis prövning är möjlig. Slutrapporten redovisar dessutom hur ett urval av andra länder har hanterat handläggningen av individer med synfältsbortfall givet samma EU-direktiv som Sverige regleras av. Det framgår också av undersökningen att samtliga länder, som en förutsättning för undantag från de föreskrivna kraven avseende synfält, tillämpar krav eller rekommendationer om att ett praktiskt körprov ska utgöra del i underlaget för bedömning av körförmågan. Kunskapsläget med avseende på körförmågebedömningar för individer med synfältsbortfall redovisas och där framgår med tydlighet att perimetrin som Sverige utnyttjar som underlag för återkallelse av körkort inte kan predicera individers körförmåga. Perimetrin är dock viktig eftersom individer med synfältsbortfall som grupp kan vara olämpliga förare. Slutsatsen som forskningslitteraturen enstämmigt lyfter är att det behövs förarprov (på väg eller i en simulator) för att kunna genomföra en valid bedömning. Slutligen innehåller slutrapporten vilka problem (aktiviteter) som kvarstår för att skapa en lämplig och kvalitetssäkrad process. Dessutom presenteras den kronologiska ordning på aktiviteter som behöver genomföras. Kronologin krävs eftersom resultatet av lämplig metod och aktör påverkar det vidare arbetet med avseende på utformning av körprov och rättsligt ramverk. Slutrapportens slutsats är att Sverige har möjligheten att genomföra en förändring med avsevärda nyttor. Detta eftersom de valda aktörerna och de valda metoderna existerar idag och därför endast behöver utvecklas i viss mån för att säkerställa att individer med synfältsbortfall erbjuds en kvalitetssäkrad, rättssäker och rättvis process som dessutom bedöms vara samhällsekonomiskt lönsam.
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| 5. |
- Dupont, Daniel M, et al.
(författare)
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Protein-binding RNA aptamers affect molecular interactions distantly from their binding sites.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Nucleic acid aptamer selection is a powerful strategy for the development of regulatory agents for molecular intervention. Accordingly, aptamers have proven their diligence in the intervention with serine protease activities, which play important roles in physiology and pathophysiology. Nonetheless, there are only a few studies on the molecular basis underlying aptamer-protease interactions and the associated mechanisms of inhibition. In the present study, we use site-directed mutagenesis to delineate the binding sites of two 2´-fluoropyrimidine RNA aptamers (upanap-12 and upanap-126) with therapeutic potential, both binding to the serine protease urokinase-type plasminogen activator (uPA). We determine the subsequent impact of aptamer binding on the well-established molecular interactions (plasmin, PAI-1, uPAR, and LRP-1A) controlling uPA activities. One of the aptamers (upanap-126) binds to the area around the C-terminal α-helix in pro-uPA, while the other aptamer (upanap-12) binds to both the β-hairpin of the growth factor domain and the kringle domain of uPA. Based on the mapping studies, combined with data from small-angle X-ray scattering analysis, we construct a model for the upanap-12:pro-uPA complex. The results suggest and highlight that the size and shape of an aptamer as well as the domain organization of a multi-domain protein such as uPA, may provide the basis for extensive sterical interference with protein ligand interactions considered distant from the aptamer binding site.
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| 6. |
- Kalso, Eija, et al.
(författare)
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Do strong opioids have a role in the early management of back pain? Recommendations from a European expert panel
- 2005
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Ingår i: Current Medical Research and Opinion. - : Taylor & Francis. - 0300-7995 .- 1473-4877. ; 21:11, s. 1819-1828
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Since chronic low back pain (CLBP) is a complex biopsychosocial problem the ideal treatment is multimodal and multidisciplinary. However, in many countries, primary-care physicians care for many people with CLBP and have a pivotal role in selecting patients for more intensive treatments when these are available. Guidelines on the general use of strong opioids in chronic non-cancer pain have been published but, until now, no specific guidelines were available on their use in chronic low back pain. Given the prevalence of CLBP, and the complex nature of this multifactorial condition, it was felt that specific, evidence-based recommendations, with a focus on primary-care treatment, would be helpful. Methods: An expert panel drawn from across Europe including pain specialists, anaesthetists, neurologists, rheumatologists, a general practitioner, an epidemiologist and the chairman of a pain charity was therefore convened. The aim of the group was to develop evidence-based recommendations that could be used as a framework for more specific guidelines to reflect local differences in the availability of specialist pain services and in the legal status and availability of strong opioids. Statements were based on published evidence (identified by a literature search) wherever possible, and supported by clinical experience when suitable evidence was lacking. Recommendations: Strong opioids have a role in the treatment of low back pain when other treatments have failed. They should be prescribed as part of a multimodal, and ideally interdisciplinary, treatment plan. The aim of treatment should be to relieve pain and facilitate rehabilitation.
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| 7. |
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| 8. |
- Lilja, Mirjam, 1981-, et al.
(författare)
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Impact of Biomechanical Forces on Antibiotics Release Kinetics from Hydroxyapatite Coated Surgical Fixation Pins
- 2013
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Ingår i: Journal of Biomaterials and Nanobiotechnology. - : Scientific Research Publishing, Inc.. - 2158-7027 .- 2158-7043. ; 4:4, s. 343-350
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Tidskriftsartikel (refereegranskat)abstract
- This work investigates the impact of biomechanical wear and abrasion on the antibiotic release profiles of hydroxyapa-tite (HA) coated fixation pins during their insertion into synthetic bone. Stainless steel fixation pins are coated with crystalline TiO2 by cathodic arc evaporation forming the bioactive layer for biomimetic deposition of Tobramycin con-taining HA. Tobramycin is either introduced by co-precipitation during HA formation or by adsorption-loading after HA deposition. The samples containing antibiotics are inserted into bone mimicking polyethylene foam after which the drug release is monitored using high performance liquid chromatography. This analysis shows that HA coating wear and delamination significantly decrease the amount of drug released during initial burst, but only marginally influence the sustained release period. Spalled coating fragments are found to remain within the synthetic bone material structure. The presence of HA within this structure supports the assumption that the local release of Tobramycin is not only ex-pected to eliminate bacteria growth directly at the pin interface but as well at some distance from the implant. Further-more, no negative effect of gamma sterilization could be observed on the drug release profile. Overall, the observed results demonstrate the feasibility of a multifunctional implant coating that is simultaneously able to locally deliver clinically relevant doses of antibiotics and an HA coating capable of promoting osteoconduction. This is a potentially promising step toward orthopaedic devices that combine good fixation with the ability to treat and prevent post-surgical infections.
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| 9. |
- Nielsen, Steffen, et al.
(författare)
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Comparison of Coding Transcriptomes in Fibroblasts Irradiated With Low and High LET Proton Beams and Cobalt-60 Photons
- 2019
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 103:5, s. 1203-1211
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To identify differential cellular responses after proton and photon irradiation by comparing transcriptomes of primary fibroblasts irradiated with either radiation type. Methods and Materials: A panel of primary dermal fibroblast cultures was irradiated with low and higher linear energy transfer (LET) proton beams. Cobalt-60 photon irradiation was used as reference. Dose was delivered in 3 fractions of 3.5 Gy (relative biological effectiveness) using a relative biological effectiveness of 1.1 for proton doses. Cells were harvested 2 hours after the final fraction was delivered, and RNA was purified. RNA sequencing was performed using Illumina NextSeq 500 with high-output kit. The edgeR package in R was used for differential gene expression analysis. Results: Pairwise comparisons of the transcriptomes in the 3 treatment groups showed that there were 84 and 56 differentially expressed genes in the low LET group compared with the Cobalt-60 group and the higher LET group, respectively. The higher LET proton group and the Cobalt-60 group had the most distinct transcriptome profiles, with 725 differentially regulated genes. Differentially regulated canonical pathways and various regulatory factors involved in regulation of biological mechanisms such as inflammation, carcinogenesis, and cell cycle control were identified. Conclusions: Inflammatory regulators associated with the development of normal tissue complications and malignant transformation factors seem to be differentially regulated by higher LET proton and Cobalt-60 photon irradiation. The reported transcriptome differences could therefore influence the progression of adverse effects and the risk of developing secondary cancers.
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| 10. |
- Nielsen, Steffen, et al.
(författare)
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Differential gene expression in primary fibroblasts induced by proton and cobalt-60 beam irradiation
- 2017
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 56:11, s. 1406-1412
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Proton beam therapy delivers a more conformal dose distribution than conventional radiotherapy, thus improving normal tissue sparring. Increasing linear energy transfer (LET) along the proton track increases the relative biological effectiveness (RBE) near the distal edge of the Spread-out Bragg peak (SOBP). The severity of normal tissue side effects following photon beam radiotherapy vary considerably between patients.Aim: The dual study aim was to identify gene expression patterns specific to radiation type and proton beam position, and to assess whether individual radiation sensitivity influences gene expression levels in fibroblast cultures irradiated in vitro.Methods: The study includes 30 primary fibroblast cell cultures from patients previously classified as either radiosensitive or radioresistant. Cells were irradiated at three different positions in the proton beam profile: entrance, mid-SOBP and at the SOBP distal edge. Dose was delivered in three fractions × 3.5 Gy(RBE) (RBE 1.1). Cobalt-60 (Co-60) irradiation was used as reference. Real-time qPCR was performed to determine gene expression levels for 17 genes associated with inflammation response, fibrosis and angiogenesis.Results: Differences in median gene expression levels were observed for multiple genes such as IL6, IL8 and CXCL12. Median IL6 expression was 30%, 24% and 47% lower in entrance, mid-SOBP and SOBP distal edge groups than in Co-60 irradiated cells. No genes were found to be oppositely regulated by different radiation qualities. Radiosensitive patient samples had the strongest regulation of gene expression; irrespective of radiation type.Conclusions: Our findings indicate that the increased LET at the SOBP distal edge position did not generally lead to increased transcriptive response in primary fibroblast cultures. Inflammatory factors were generally less extensively upregulated by proton irradiation compared with Co-60 photon irradiation. These effects may possibly influence the development of normal tissue damage in patients treated with proton beam therapy.
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