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- 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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| 2. |
- Hassila Karlsson, Carl Johan, et al.
(författare)
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Influence of carbon content on microstructure and mechanical properties of Inconel 718 processed with Powder Bed Fusion – Laser Beam
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Additive manufacturing of alloys belonging to the Inconel family is today a hot research topic. Given that these alloys were developed with casting and forging as the main manufacturing route, the possibilities of adjusting their composition to make them better suited for the additive manufacturing processes should be investigated. In this work we study two different versions of Alloy 718 with different carbon content; one having a normal carbon content and one having a very low carbon content. Test pieces from these alloys were produced using the Powder Bed Fusion – Laser Beam process. TEM and SEM with EDS/EBSD was used to study the resulting microstructures both in the as-built and after heat treatment. Mechanical properties were evaluated for samples printed in different build directions using tensile and impact testing. The achieved materials in the as-built condition were very similar to one another in both the microstructure and the displayed mechanical properties. After heat treatment, differences in the microstructures could be identified as secondary carbides were found to precipitate exclusively in the alloy with a normal carbon content. Additionally, the different carbon contents affected the number of annealing twins that formed in the respective alloys, where more twins formed in the alloy with a low carbon content. This was attributed to the alloy’s lower stacking-fault energy. As annealing twins facilitate the transformation of the anisotropic as-built grain structure, effectively making the materials more isotropic, only the low carbon content alloy showed isotropic material properties after heat treatment.
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| 4. |
- Åberg-Bengtsson, Lisbeth, et al.
(författare)
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När Agnes fick va solen så fattade man ju precis : Om illustrationer i undervisning av yngre elever
- 2014
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Ingår i: Resultatdialog. - Stockholm : Vetenskapsrådet. - 9789173072472 ; , s. 246-254
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Att göra adekvata tolkningar av bilder och modeller kan vara verkliga stötestenar för många barn. Särskilt besvärligt förefaller det vara att tolka bilder av processer och förlopp i tryckta läromedel. Även enk-lare bilder och vanliga symboler kan dock leda till icke avsedda tolkningar. Barnen i studien föreföll i många fall betrakta illustrationerna som enbart dekoration och förbigick dem ofta om de inte direkt uppmärksammades på dem. Å andra sidan kunde illustrationer också, särskilt sådana som visade på extremer av något slag, väcka förundran och intresse.
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| 5. |
- Åsberg, Dennis, 1988-, et al.
(författare)
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A quality control method enhancement concept : Continual improvement of regulatory approved QC methods
- 2016
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier. - 0731-7085 .- 1873-264X. ; 129, s. 273-281
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Tidskriftsartikel (refereegranskat)abstract
- Quality Control methods (QC-methods) play an important role in the overall control strategy for drug manufacturing. However, efficient life-cycle management and continual improvement are hindered due to a variety of post-approval variation legislations across territories and a lack of harmonization of the requirements. As a result, many QC-methods fall behind the technical development. Developing the QC-method in accordance with the Quality by Design guidelines gives the possibility to do continual improvements inside the original Method Operable Design Region (MODR). However, often it is necessary to do changes outside the MODR, e.g. to incorporate new technology that was not available at the time the original method was development. Here, we present a method enhancement concept which allows minor adjustments, within the same measuring principle, outside the original MODR without interaction with regulatory agencies. The feasibility of the concept is illustrated by a case study of a QC-method based on HPLC, assumed to be developed before the introduction of UHPLC, where the switch from HPLC to UHPLC is necessary as a continual improvement strategy. The concept relies on the assumption that the System Suitability Test (SST) and failure modes are relevant for other conditions outside the MODR as well when the same measuring principle is used. It follows that it should be possible to move outside the MODR as long as the SST has passed. All minor modifications of the original, approved QC-method must be re-validated according to a template given in the original submission and a statistical equivalence should be shown between the original and modified QC-methods. To summarize, revalidation is handled within the pharmaceutical quality control system according to internal change control procedures, but without interaction with regulating agencies.
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| 8. |
- Aguilar, Helena, et al.
(författare)
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VAV3 mediates resistance to breast cancer endocrine therapy
- 2014
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 16:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
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