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- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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- Ortiz Rios, Rodomiro Octavio, et al.
(författare)
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Oil crops for the future
- 2020
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Ingår i: Current Opinion in Plant Biology. - : Elsevier BV. - 1369-5266 .- 1879-0356. ; 56, s. 181-189
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Forskningsöversikt (refereegranskat)abstract
- Agriculture faces enormous challenges including the need to substantially increase productivity, reduce environmental footprint, and deliver renewable alternatives that are being addressed by developing new oil crops for the future. The efforts include domestication of Lepidium spp. using genomics-aided breeding as a cold hardy perennial high-yielding oil crop that provides substantial environmental benefits, expands the geography for oil crops, and improves farmers’ economy. In addition, genetic engineering in Crambe abyssinica may lead to a dedicated industrial oil crop to replace fossil oil. Redirection of photosynthates from starch to oil in plant tubers and cereal endosperm also provides a path for enhancing oil production to meet the growing demands for food, fuel, and biomaterials. Insect pheromone components are produced in seed oil plants in a cost-effective and environmentally friendly pest management replacing synthetically produced pheromones. Autophagy is explored for increasing crop fitness and oil accumulation using genetic engineering in Arabidopsis.
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- Scheffler, Julia M., et al.
(författare)
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ER alpha Signaling in a Subset of CXCL12-Abundant Reticular Cells Regulates Trabecular Bone in Mice
- 2022
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Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen has pronounced effects on the immune system, which also influences bone homeostasis. In recent years, stromal cells in lymphoid organs have gained increasing attention as they not only support the regulation of immune responses but also affect bone remodeling. A conditional knockout mouse model where estrogen receptor alpha (ER alpha) is deleted in CCL19-expressing stromal cells (Ccl19-Cre ER alpha(fl/fl) mice) was generated and bone densitometry was performed to analyze the importance of stromal cell-specific ER alpha signaling on the skeleton. Results showed that female Ccl19-Cre ER alpha(fl/fl) mice display reduced total bone mineral density and detailed X-ray analyses revealed that ER alpha expression in CCL19-expressing stromal cells is important for trabecular but not cortical bone homeostasis. Further analysis showed that the trabecular bone loss is caused by increased osteoclastogenesis. Additionally, the bone formation rate was reduced; however, the expression of osteoprogenitor genes was not altered. Analysis of the bone marrow stromal cell compartment revealed a deletion of ER alpha in a subgroup of CXCL12-abundant reticular (CAR) cells resulting in increased secretion of the pro-osteoclastogenic chemokine CXCL12. In conclusion, this study reveals the importance of ER alpha signaling in CAR cells for bone health. (c) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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- Strawbridge, Rona J., et al.
(författare)
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Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
- 2017
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 266, s. 196-204
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
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- Akselsson, Cecilia, et al.
(författare)
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Weathering rates in Swedish forest soils
- 2019
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 16:22, s. 4429-4450
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Forskningsöversikt (refereegranskat)abstract
- Soil and water acidification was internationally recognised as a severe environmental problem in the late 1960s. The interest in establishing “critical loads” led to a peak in weathering research in the 1980s and 1990s, since base cation weathering is the long-term counterbalance to acidification pressure. Assessments of weathering rates and associated uncertainties have recently become an area of renewed research interest, this time due to demand for forest residues to provide renewable bioenergy. Increased demand for forest fuels increases the risk of depleting the soils of base cations produced in situ by weathering. This is the background to the research programme Quantifying Weathering Rates for Sustainable Forestry (QWARTS), which ran from 2012 to 2019. The programme involved research groups working at different scales, from laboratory experiments to modelling. The aims of this study were to (1) investigate the variation in published weathering rates of base cations from different approaches in Sweden, with consideration of the key uncertainties for each method; (2) assess the robustness of the results in relation to sustainable forestry; and (3) discuss the results in relation to new insights from the QWARTS programme and propose ways to further reduce uncertainties. In the study we found that the variation in estimated weathering rates at single-site level was large, but still most sites could be placed reliably in broader classes of weathering rates. At the regional level, the results from the different approaches were in general agreement. Comparisons with base cation losses after stem-only and whole-tree harvesting showed sites where whole-tree harvesting was clearly not sustainable and other sites where variation in weathering rates from different approaches obscured the overall balance. Clear imbalances appeared mainly after whole-tree harvesting in spruce forests in southern and central Sweden. Based on the research findings in the QWARTS programme, it was concluded that the PROFILE/ForSAFE family of models provides the most important fundamental understanding of the contribution of weathering to long-term availability of base cations to support forest growth. However, these approaches should be continually assessed against other approaches. Uncertainties in the model approaches can be further reduced, mainly by finding ways to reduce uncertainties in input data on soil texture and associated hydrological parameters but also by developing the models, e.g. to better represent biological feedbacks under the influence of climate change.
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- Anter, Karin Fridell, et al.
(författare)
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SYN-TES INTERDISCIPLINARY RESEARCH ON COLOUR AND LIGHT
- 2012
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Ingår i: Proceedings for Interim Meeting of the International Colour Association (AIC); AIC 2012 “In Color We Live: Color and Environment”, 22 – 25 September 2012, Taipei, Taiwan. - : The International Colour Association. ; , s. 80-83, s. 80-83
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Konferensbidrag (refereegranskat)abstract
- Colour and light have largely been considered as belonging to two different fields of knowledge, having disparate theoretical, terminological and methodological traditions. This creates a ground for misunderstandings and obstructs a fruitful interdisciplinary and interprofessional collaboration. A survey over international research literature from 2006 -2011 shows that there has been only little research on the spatial interaction between colour and light, but that the interest for this area has recently increased. The interdisciplinary Nordic research project SYN-TES: Human colour and light synthesis. Towards a coherent field of knowledge was carried out during 2010-11. Colour and light experts from Nordic universities and companies investigated different aspects of the spatial interaction between colour and light and its importance for human beings. This paper deals with the general learnings from the process. Specific results are presented in other papers at this conference.
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| 10. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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