| 1. |
- Wang, Z., et al.
(författare)
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Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
- 2022
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:9
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Tidskriftsartikel (refereegranskat)abstract
- Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.
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| 2. |
- Johansson, Karin C, et al.
(författare)
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Microarray analysis of immune challenged Drosophila hemocytes
- 2005
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 305:1, s. 145-155
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Tidskriftsartikel (refereegranskat)abstract
- nsect hemocytes play multiple roles in immunity and carry out cellular responses like phagocytosis, encapsulation and melanization as well as producing humoral effector proteins in the first line of defense after injury and invasion of microorganisms. In this work, we used the Drosophila melanogaster hemocyte-like cell line mbn-2 and Affymetrix Drosophila GeneChips to investigate the transcriptome of a single type of immune competent tissue exposed to Gram-negative cell wall components (crude LPS) or high dose infection with live Escherichia coli. We found that gene expression profiles of both treatments overlap but show important differences in expression levels of several genes involved in immunity. In addition, cell morphology during infection was monitored and revealed distinct alterations in cell shape and adhesion. Presence of large numbers of bacteria also increased the number of cells taking on crystal cell fate. Taken together, our results indicate that hemocytes sense and respond differently to purified bacterial surface molecules and infection with live and actively growing bacteria both at the level of gene expression and in cell behavior.
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| 3. |
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| 4. |
- Llorens, Jose V., et al.
(författare)
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Mitochondrial iron supply is required for the developmental pulse of ecdysone biosynthesis that initiates metamorphosis in Drosophila melanogaster
- 2015
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Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 20:8, s. 1229-1238
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Tidskriftsartikel (refereegranskat)abstract
- Synthesis of ecdysone, the key hormone that signals the termination of larval growth and the initiation of metamorphosis in insects, is carried out in the prothoracic gland by an array of iron-containing cytochrome P450s, encoded by the halloween genes. Interference, either with iron-sulfur cluster biogenesis in the prothoracic gland or with the ferredoxins that supply electrons for steroidogenesis, causes a block in ecdysone synthesis and developmental arrest in the third instar larval stage. Here we show that mutants in Drosophila mitoferrin (dmfrn), the gene encoding a mitochondrial carrier protein implicated in mitochondrial iron import, fail to grow and initiate metamorphosis under dietary iron depletion or when ferritin function is partially compromised. In mutant dmfrn larvae reared under iron replete conditions, the expression of halloween genes is increased and 20-hydroxyecdysone (20E), the active form of ecdysone, is synthesized. In contrast, addition of an iron chelator to the diet of mutant dmfrn larvae disrupts 20E synthesis. Dietary addition of 20E has little effect on the growth defects, but enables approximately one-third of the iron-deprived dmfrn larvae to successfully turn into pupae and, in a smaller percentage, into adults. This partial rescue is not observed with dietary supply of ecdysone's precursor 7-dehydrocholesterol, a precursor in the ecdysone biosynthetic pathway. The findings reported here support the notion that a physiological supply of mitochondrial iron for the synthesis of iron-sulfur clusters and heme is required in the prothoracic glands of insect larvae for steroidogenesis. Furthermore, mitochondrial iron is also essential for normal larval growth.
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| 5. |
- Mattis, Katia K, et al.
(författare)
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Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression
- 2023
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Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 66:4, s. 674-694
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.METHODS: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles.RESULTS: CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function.CONCLUSIONS/INTERPRETATION: Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.
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| 6. |
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| 7. |
- Metzendorf, Christoph, et al.
(författare)
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Characterization of Drosophila mitoferrin and CG18317 mutants
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Mitochondria are the site of iron-sulfur cluster synthesis and insertion of iron into heme, two essential prosthetic groups. Mrs3/4/mitoferrins are mitochondrial carrier proteins, which are involved in the mitochondrial iron transport. Yeast mutants suggest that a low-affinity iron transport system exists. Previous analysis of Drosophila mitoferrin P element mutants revealed an involvement of dmfrn in spermatogenesis. The ubiquitous expression of dmfrn in several adult male tissues, did however suggest a more general role. Results: Here we analyzed stocks with deletions in dmfrn and find that on low iron food dmfrn deletion inhibits development to adulthood, whereas on normal and high iron food some escapers do eclose. RNAi of dmfrn driven by the ubiquitous Actin5C-Gal4 driver recapitulates the phenotype on low iron food, but not on normal or high iron food. Overexpression of dmfrn from an UAS-dmfrn transgenic construct that contains only the coding region of dmfrn also resulted in the failure to develop to adulthood on low iron food. We identified CG18317 as putative Drosophila homolog of yeast Rim2p/Mrs12p, a mitochondrial pyrimidine carrier that is implicated in low affinity iron transport. CG18317 is ubiquitously expressed in several tissues of the male fly and the second exon is alternatively spliced resulting in a 21 nucleotides shorter transcript. An initial study of transposon mutants and deletion mutants of this gene showed sensitivity of one transposon mutant to low iron food conditions. Preliminary results indicate that increased expression of CG18317 might rescue development of dmfrn deletion mutants to at least pupal stage. Conclusions: In contrast to yeast MRS3/4, Drosophila mitoferrin is an essential gene, necessary for development of Drosophila to adulthood. The presence of escapers does however suggest, that dmfrn is either not the only mitochondrial iron carrier or that dmfrn modulates activity of a mitochondrial iron transport system. The sensitivity to low iron conditions of one CG18317 mutant and the partial rescue of dmfrn mutants indicates that this gene could indeed mediate mitochondrial iron uptake in the fly.
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| 8. |
- Metzendorf, Christoph, et al.
(författare)
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Drosophila mitoferrin is essential for male fertility : Evidence for a role of mitochondrial iron metabolism during spermatogenesis
- 2010
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Ingår i: BMC Developmental Biology. - 1471-213X. ; 10, s. 68-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mammals and Drosophila melanogaster share some striking similarities in spermatogenesis. Mitochondria in spermatids undergo dramatic morphological changes and syncytial spermatids are stripped from their cytoplasm and then individually wrapped by single membranes in an individualization process. In mammalian and fruit fly testis, components of the mitochondrial iron metabolism are expressed, but so far their function during spermatogenesis is unknown. Here we investigate the role of Drosophila mitoferrin (dmfrn), which is a mitochondrial carrier protein with an established role in the mitochondrial iron metabolism, during spermatogenesis.Results: We found that P-element insertions into the 5'-untranslated region of the dmfrn gene cause recessive male sterility, which was rescued by a fluorescently tagged transgenic dmfrn genomic construct (dmfrn(venus)). Testes of mutant homozygous dmfrn(SH115) flies were either small with unorganized content or contained some partially elongated spermatids, or testes were of normal size but lacked mature sperm. Testis squashes indicated that spermatid elongation was defective and electron micrographs showed mitochondrial defects in elongated spermatids and indicated failed individualization. Using a LacZ reporter and the dmfrn(venus) transgene, we found that dmfrn expression in testes was highest in spermatids, coinciding with the stages that showed defects in the mutants. Dmfrn-venus protein accumulated in mitochondrial derivatives of spermatids, where it remained until most of it was stripped off during individualization and disposed of in waste bags. Male sterility in flies with the hypomorph alleles dmfrn(BG00456) and dmfrn(EY01302) over the deletion Df(3R)ED6277 was increased by dietary iron chelation and suppressed by iron supplementation of the food, while male sterility of dmfrn(SH115)/Df(3R)ED6277 flies was not affected by food iron levels.Conclusions: In this work, we show that mutations in the Drosophila mitoferrin gene result in male sterility caused by developmental defects. From the sensitivity of the hypomorph mutants to low food iron levels we conclude that mitochondrial iron is essential for spermatogenesis. This is the first time that a link between the mitochondrial iron metabolism and spermatogenesis has been shown. Furthermore, due to the similar expression patterns of some mitochondrial iron metabolism genes in Drosophila and mammals, it is likely that our results are applicable for mammals as well.
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| 9. |
- Metzendorf, Christoph, 1977-
(författare)
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Mitochondrial Iron Metabolism : Study of mitoferrin in Drosophila melanogaster
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Iron has a dualistic character. On the one hand it is essential for the life of most organisms, on the other hand it is involved in the generation of reactive oxygen species that are implicated in diseases and aging. During evolution efficient mechanisms for uptake, handling and storage of iron in a safe way have developed to keep the balance between iron availability and minimizing the hazards. In eukaryotes, mitochondria are the central organelle for “metabolizing” iron and consequently play an important role in cellular iron homeostasis. Mitoferrins are mitochondrial carrier proteins, which are involved in iron transport into mitochondria. In vertebrates two mitoferrins exist, one (mitoferrin1) of which is essential for heme synthesis during erythropoiesis, while the function of the other (mitoferrin2) is not well defined. In the fruit fly we found only one mitoferrin gene (dmfrn), which codes most likely for a functional homologueof vertebrate mitoferrin2. In Drosophila cell culture, dmfrn overexpression resulted in an overestimation of cell sensed iron levels. The signal responsible for this, is most likely a yet unidentified compound of ISC synthesis. In the cell culture system we also showed that iron chelation blocks the progression of the cell cycle in a reversible and therefore most likely controlled way. Study of different dmfrn mutants indicates a role of dmfrn during spermatogenesis and development to adulthood. As dmfrn deletion mutants are not lethal, it is likely that other lower affinity iron transporters exist. A similar conclusion has been drawn by others from the study of yeast mitoferrin homologuemutants. Rim2p/Mrs12p has recently been implicated in mitochondrial iron transport, and might be an alternative metal carrier. We identified a putative homologuein the fruit fly and found a possible link between mutants in this gene and iron. Our results emphasize the importance of the mitochondrial iron metabolism in cellular iron homeostasis. We also show for the first time, a direct connection between the mitochondrial iron metabolism and spermatogenesis. Mutants characterized and developed by us will help to study these processes in further detail and reveal the underlying mechanisms.
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