| 1. |
- Sundström, Elisabeth, et al.
(author)
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Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses
- 2012
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In: Pigment Cell & Melanoma Research. - 1755-1471 .- 1755-148X. ; 25:1, s. 28-36
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Journal article (peer-reviewed)abstract
- Greying with age in horses is an autosomal dominant trait, characterized by hair greying, high incidence of melanoma and vitiligo-like depigmentation. Previous studies have revealed that the causative mutation for this phenotype is a 4.6-kb intronic duplication in STX17 (Syntaxin 17). By using reporter constructs in transgenic zebrafish, we show that a construct containing two copies of the duplicated sequence acts as a strong enhancer in neural crest cells and has subsequent melanophore-specific activity during zebrafish embryonic development whereas a single copy of the duplicated sequence acts as a weak enhancer, consistent with the phenotypic manifestation of the mutation in horses. We further used luciferase assays to investigate regulatory regions in the duplication, to reveal tissue-specific activities of these elements. One region upregulated the reporter gene expression in a melanocyte-specific manner and contained two microphthalmia-associated transcription factor (MITF) binding sites, essential for the activity. Microphthalmia-associated transcription factor regulates melanocyte development, and these binding sites are outstanding candidates for mediating the melanocyte-specific activity of the element. These results provide strong support for the causative nature of the duplication and constitute an explanation for the melanocyte-specific effects of the Grey allele.
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| 2. |
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| 3. |
- Golovko, Anna, et al.
(author)
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Exon resequencing of PMEL in Swedish melanoma patients
- 2012
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In: The melanocyte and its environment. - Bologna, Italy : Medimond. - 9788875876784 ; , s. 15-18
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Conference paper (other academic/artistic)abstract
- Interplay between ultraviolet radiation and skin pigmentation appears to be one of the major risk factors for melanoma development. Allelic variants in a number of pigmentation genes have been associated with increased melanoma susceptibility. PMEL is a melanosomal membrane protein primarily involved in eumelanin synthesis. PMEL functional mutations resulting in hypopigmentation have been identified in a number of vertebrate species, including Dominant white in chickens, Silver in horses, and Merle in dogs. A complete loss of PMEL in transgenic mice had a dramatic effect on the morphology of the melanosomes in skin, hair, and eye, and led to a substantial reduction in the content of eumelanin. No human PMEL mutation associated with any phenotypic effects or disorders has yet been reported. In this study we have investigated the possibility that PMEL mutations may be associated with an increased susceptibility to melanoma in a Nordic polulation by sequencing all 11 exons of PMEL in a cohort of 60 Swedish melanoma patients with a history of familial melanoma. No mutations, apart from the two synonymous SNPs common in general European populations, were found, demonstrating that PMEL mutations do not appear to be a common cause for melanoma susceptibility.
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| 4. |
- Golovko, Oksana, et al.
(author)
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Organic micropollutants in water and sediment from Lake Malaren, Sweden
- 2020
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 258
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Journal article (peer-reviewed)abstract
- The occurrence and distribution of 111 organic micropollutants (OMPs) were evaluated in water and sediment samples from Lake Malaren, Sweden, using a liquid chromatography-tandem mass spectrometry method. The partitioning of contaminants between lake compartments was estimated using solid water distribution coefficients (K-d) and organic carbon-water partitioning coefficients (K-OC). In total, 30 and 24 OMPs were detected in lake water and sediment, respectively. Concentrations ranged from low ng/L to 89 ng/L (lamotrigine) in lake water and from low ng/g dry weight (dw) to 28 ng/g dw (citalopram) in sediment. Carbamazepine, lamotrigine, caffeine, and tolyltriazole were the dominant compounds in Lake Malaren samples (both water and sediment). Seventeen OMPs were detected in both water and sediment samples, including carbamazepine, DEET, tolyltriazole, bicalutamide, caffeine, lamotrigine, and cetirizine. Log K-d values varied between 0.84 for lamotrigine and 4.4 for citalopram, while log K-OC values varied between 2.1 for lamotrigine and 5.9 for citalopram. These results indicate that sorption to sediment plays a minor role in removal of all OMPs analyzed in the aqueous phase except for citalopram and cetirizine, which showed high sorption potential. The environmental risks of OMPs were assessed based on the RQ values. The worst-case scenario for environmental risk assessment was conducted using the maximum measured environment concentration. For most of the target OMPs, including tolyltriazole, bicalutamide, fexofenadine, oxazepam, cetirizine, and diclofenac, the RQ values were below 0.01, indicating low or no risk to lake ecosystems. (C) 2020 Elsevier Ltd. All rights reserved.
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| 5. |
- Golovko, Oksana, et al.
(author)
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Spridning av mikroföroreningar och per- och polyfluoralkyl substanser (PFAS) till jordbruk vid bevattning med kommunalt avloppsvatten
- 2022
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Reports (other academic/artistic)abstract
- Återanvändning av avloppsvatten för jordbruksbevattning är ett sätt att minska efterfrågan på sötvatten, men det kan också introducera läkemedel, personliga hygienprodukter och andra kemikalier i jordbrukets ekosystem och livsmedelskedja. Syftet med denna studie var att mäta förekomsten av en rad potentiellt skadliga organiska mikroföroreningar (OMP), såsom läkemedel, personliga hygienprodukter, industrikemikalier, bekämpningsmedel och per- och polyfluoralkylsubstanser (PFAS) i avloppsvatten som används för bevattning och i den mottagande jordbruksmarken. Bevattningsvatten bestående av renat avloppsvatten vid två anläggningar på Gotland provtogs vid fyra tillfällen under juli och augusti 2021. Dessutom togs prover på jord och daggmaskar i september 2021 efter skörd från två åkrar bevattnade med avloppsvattnet samt från en åker som inte hade bevattnats alls. Potatis som fortfarande var i marken togs från ett av de bevattnade fälten.Ett brett spektrum av OMP-koncentrationer (ng/l till ug/l) hittades i bevattningsvattnet, och totalt upptäcktes 35 av 77 analyserade OMP. Totalt 19 av 24 olika PFAS detekterades i bevattningsvattnet i intervallet 0,1-1000 ng/l. Extraherbart organiskt fluor (EOF) och totala oxiderbara prekursorer (TOP) mättes även i vattenproverna. Intervallet för EOF var 366-507 ng/l och endast två av totalt åtta bevattningsvattenprover visade en liten ökning av perfluoroktansyra (PFOA) och perfluorhexansyra (PFHxA) efter oxidation.Ingen av OMP:erna i denna studie upptäcktes i något av jordproverna. Perfluoroktansulfonsyra (PFOS) hittades över detektionsgränsen i jord från båda bevattnade fälten (0,14-0,17 ng/ d.w.) men låg under detektionsgränsen i jord från referensplatsen. Perfluorbutansyra (PFBA) hittades i låga nivåer men över detektionsgränsen i ett av de bevattnade fälten (0,22 ng/g d.w.) och den närliggande referensplatsen (0,27 ng/g d.w.). EOF-analysen av jord resulterade inte i någon ytterligare information då detektionsgränsen var relativt hög (280 ng/g).Av 77 analyserade OMP:er hittades endast fem OMP:er (sotalol, oxazepam, metformin, etylparaben och venlafaxin) i daggmaskar i koncentrationsintervallet 8,4-160 ng/g d.w. Mellan fem och tio PFAS upptäcktes i daggmaskar från de två bevattnade fälten (19-35 ng/g d.w. för summan PFAS) och sju PFAS hittades i maskar från referensplatsen med en summakoncentration på 69 ng/g d.w. Endast två OMP-föreningar (6,6 ng/g d.w. för metformin och 340 ng/g d.w. för BAM) hittades i potatis som samlats in från en bevattnad åker, och ingen av de analyserade PFAS kunde detekteras.Den aktuella studien kunde bara upptäcka ett fåtal PFAS och andra OMP i jord och potatis från marken som bevattnats med avloppsvatten. Bioackumulering av fem OMP och upp till tio PFAS påvisades i daggmaskar på den bevattnade jordbruksmarken men även på referensplatsen. Således kunde ingen påverkan av avloppsvatten på marken eller daggmask påvisas. Detta var dock en begränsad studie och det kan inte uteslutas upptag av OMP till ätbara växter eller läckage till grundvatten.
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| 6. |
- Guerriera, Gea, et al.
(author)
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The RY/Sph element mediates transcriptional repression of MAT genes from late maturation to early seedling growth
- 2009
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In: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 184:3, s. 552-565
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Journal article (peer-reviewed)abstract
- P>In orthodox seeds, the transcriptional activator ABI3 regulates two major stages in embryo maturation: a mid-maturation (MAT) stage leading to accumulation of storage compounds, and a late maturation (LEA) stage leading to quiescence and desiccation tolerance. Our aim was to elucidate mechanisms for transcriptional shutdown of MAT genes during late maturation, to better understand phase transition between MAT and LEA stages. Using transgenic and transient approaches in Nicotiana, we examined activities of two ABI3-dependent reporter genes driven by multimeric RY and abscisic acid response elements (ABREs) from a Brassica napus napin gene, termed RY and ABRE, where the RY reporter requires ABI3 DNA binding. Expression of RY peaks during mid-maturation and drops during late maturation, mimicking the MAT gene program, and in Arabidopsis thaliana RY elements are over-represented in MAT, but not in LEA, genes. The ABI3 transactivation of RY is inhibited by staurosporine, by a PP2C phosphatase, and by a repressor of maturation genes, VAL1/HSI2. The RY element mediates repression of MAT genes, and we propose that transcriptional shutdown of the MAT program during late maturation involves inhibition of ABI3 DNA binding by dephosphorylation. Later, during seedling growth, VAL1/HSI2 family repressors silence MAT genes by binding RY elements.
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| 7. |
- Guerriero, Gea, et al.
(author)
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The RY/Sph element mediates transcriptional repression of maturation genes from late maturation to early seedling growth
- 2009
-
In: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 184:3, s. 552-565
-
Journal article (peer-reviewed)abstract
- P>In orthodox seeds, the transcriptional activator ABI3 regulates two major stages in embryo maturation: a mid-maturation (MAT) stage leading to accumulation of storage compounds, and a late maturation (LEA) stage leading to quiescence and desiccation tolerance. Our aim was to elucidate mechanisms for transcriptional shutdown of MAT genes during late maturation, to better understand phase transition between MAT and LEA stages. Using transgenic and transient approaches in Nicotiana, we examined activities of two ABI3-dependent reporter genes driven by multimeric RY and abscisic acid response elements (ABREs) from a Brassica napus napin gene, termed RY and ABRE, where the RY reporter requires ABI3 DNA binding. Expression of RY peaks during mid-maturation and drops during late maturation, mimicking the MAT gene program, and in Arabidopsis thaliana RY elements are over-represented in MAT, but not in LEA, genes. The ABI3 transactivation of RY is inhibited by staurosporine, by a PP2C phosphatase, and by a repressor of maturation genes, VAL1/HSI2. The RY element mediates repression of MAT genes, and we propose that transcriptional shutdown of the MAT program during late maturation involves inhibition of ABI3 DNA binding by dephosphorylation. Later, during seedling growth, VAL1/HSI2 family repressors silence MAT genes by binding RY elements. New Phytologist (2009)doi: 10.1111/j.1469-8137.2009.02977.x.
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| 8. |
- Jiang, Lin, et al.
(author)
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Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses
- 2014
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14, s. 857-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses.METHODS: Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting.RESULTS: We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses.CONCLUSIONS: These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this pathway during melanomagenesis. These findings are consistent with the universal importance of the ERK pathway in melanomagenesis and may have valuable implications for human melanoma research.
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| 9. |
- Pielberg, Gerli Rosengren, et al.
(author)
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A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse
- 2008
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:8, s. 1004-1009
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Journal article (peer-reviewed)abstract
- In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.
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| 10. |
- Rehrl, Anna-Lena, et al.
(author)
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Spatial and seasonal trends of organic micropollutants in Sweden's most important drinking water reservoir
- 2020
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 249
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Journal article (peer-reviewed)abstract
- The main objective of this study was to comprehensively investigate the occurrence of organic micropollutants (OMPs) in the surface water in Lake Mälaren over a period of one year and assess the spatial (horizontal and vertical) distribution and seasonal trends of OMPs. The applied multi-residue method comprised 111 OMPs covering compounds with wide range of physicalal–chemical properties. In total, 46 OMPs were detected at least once above limit of quantification (LOQ). DEET (diethyltoluamide), lamotrigine, bicalutamide, tolyltriazole, caffeine, carbamazepine, metoprolol, oxazepam, cetirizine, fexofenadine, lidocaine and tramadol were detected in more than 75% of the sampling points. The highest detected concentration was found for lamotrigine with 140 ng/L. The locations Ekoln and Västeråsfjärden were identified to be most affected by OMPs pollution. In the surface water (0.5 m depth) most highest concentrations of OMPs were observed in spring and lower concentrations in summer. Antihistamine demonstrated a seasonal trend that can be related to seasonal consumption patterns. The investigation of the vertical distribution of OMPs demonstrated that thermal lake stratification can lead to different concentrations within the water column. For instance, in February the highest concentration for most OMPs was observed in the deepest sampled water depth (30 m). Two industrial chemicals, tolyltriazole and tris(2-butoxylethyl)phosphate were detected frequently and it is recommended to incorporate these compounds more regularly in future analysis. To the best of our knowledge, this study is the first one to report the occurrence and distribution of OMPs representing such wide physico-chemical properties, including industrial chemicals, in a Swedish lake. © 2020 Elsevier Ltd
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