| 1. |
- Donis, Daphne, et al.
(författare)
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Stratification strength and light climate explain variation in chlorophyll a at the continental scale in a European multilake survey in a heatwave summer
- 2021
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Ingår i: Limnology and Oceanography. - : John Wiley & Sons. - 0024-3590 .- 1939-5590. ; 66:12, s. 4314-4333
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Tidskriftsartikel (refereegranskat)abstract
- To determine the drivers of phytoplankton biomass, we collected standardized morphometric, physical, and biological data in 230 lakes across the Mediterranean, Continental, and Boreal climatic zones of the European continent. Multilinear regression models tested on this snapshot of mostly eutrophic lakes (median total phosphorus [TP] = 0.06 and total nitrogen [TN] = 0.7 mg L-1), and its subsets (2 depth types and 3 climatic zones), show that light climate and stratification strength were the most significant explanatory variables for chlorophyll a (Chl a) variance. TN was a significant predictor for phytoplankton biomass for shallow and continental lakes, while TP never appeared as an explanatory variable, suggesting that under high TP, light, which partially controls stratification strength, becomes limiting for phytoplankton development. Mediterranean lakes were the warmest yet most weakly stratified and had significantly less Chl a than Boreal lakes, where the temperature anomaly from the long-term average, during a summer heatwave was the highest (+4 degrees C) and showed a significant, exponential relationship with stratification strength. This European survey represents a summer snapshot of phytoplankton biomass and its drivers, and lends support that light and stratification metrics, which are both affected by climate change, are better predictors for phytoplankton biomass in nutrient-rich lakes than nutrient concentrations and surface temperature.
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| 2. |
- Mantzouki, Evanthia, et al.
(författare)
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Temperature Effects Explain Continental Scale Distribution of Cyanobacterial Toxins
- 2018
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Ingår i: Toxins. - : MDPI. - 2072-6651. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Insight into how environmental change determines the production and distribution of cyanobacterial toxins is necessary for risk assessment. Management guidelines currently focus on hepatotoxins (microcystins). Increasing attention is given to other classes, such as neurotoxins (e.g., anatoxin-a) and cytotoxins (e.g., cylindrospermopsin) due to their potency. Most studies examine the relationship between individual toxin variants and environmental factors, such as nutrients, temperature and light. In summer 2015, we collected samples across Europe to investigate the effect of nutrient and temperature gradients on the variability of toxin production at a continental scale. Direct and indirect effects of temperature were the main drivers of the spatial distribution in the toxins produced by the cyanobacterial community, the toxin concentrations and toxin quota. Generalized linear models showed that a Toxin Diversity Index (TDI) increased with latitude, while it decreased with water stability. Increases in TDI were explained through a significant increase in toxin variants such as MC-YR, anatoxin and cylindrospermopsin, accompanied by a decreasing presence of MC-LR. While global warming continues, the direct and indirect effects of increased lake temperatures will drive changes in the distribution of cyanobacterial toxins in Europe, potentially promoting selection of a few highly toxic species or strains.
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| 3. |
- Arregi, Igor, et al.
(författare)
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Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signaling
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 157:12, s. 4615-4631
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagonβ and insulinβ cells. During the secondary transition, the reduction of Neurogenin3β endocrine progenitors in the mutant dorsal pancreas accounted for fewer β-and α-cells. Changes in the expression of β-and α-cellspecific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal andepithelialRdh10forpancreogenesisandthefirstwaveofendocrinecell differentiation.Wefurther propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source ofRAsignals in the second wave of endocrine cell differentiation.
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| 4. |
- Artner, Isabella, et al.
(författare)
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MafA and MafB Regulate Genes Critical to beta-Cells in a Unique Temporal Manner
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:10, s. 2530-2539
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Several transcription factors are essential to pancreatic islet beta-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with beta-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the beta-cell. RESEARCH DESIGN AND METHODS-The distribution of MafA and MafB in the beta-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB(-/-) pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafA(Delta Panc)). RESULTS-MafB was produced in a larger fraction of beta-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafA(Delta Panc) islets, suggesting that MafA is required to sustain expression in adults. CONCLUSIONS-Our results provide insight into the sequential manner by which MafA and MafB regulate islet beta-cell formation and maturation. Diabetes 59:2530-2539, 2010
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| 5. |
- de Vries, Paul S., et al.
(författare)
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Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10(-8) is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5x10(-8)), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
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| 6. |
- Hermann-Kleiter, Natascha, et al.
(författare)
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Lasp1 misexpression influences chondrocyte differentiation in the vertebral column
- 2009
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Ingår i: International Journal of Developmental Biology. - : UPV/EHU Press. - 1696-3547 .- 0214-6282. ; 53:7, s. 983-991
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Tidskriftsartikel (refereegranskat)abstract
- The mouse mutant wavy tail Tg(Col1a1-lacZ)304ng was created through transgene insertion and exhibits defects of the vertebral column. Homozygous mutant animals have compressed tail vertebrae and wedge-shaped intervertebral discs, resulting in a meandering tail. Delayed closure of lumbar neural arches and lack of processus spinosi have been observed; these defects become most prominent during the transition from cartilage to bone. The spina bifida was resistant to folic acid treatment, while retinoic acid administration caused severe skeletal defects in the mutant, but none in wild type control animals. The transgene integrated at chromosome 11 band D, in an area of high gene density. The insertion site was located between the transcription start sites of the RpI23 and Lasp1 genes. LASP1 (an actin binding protein involved in cell migration and survival) was found to be produced in resting and hypertrophic chondrocytes in the vertebrae. In mutant vertebrae, temporal and spatial misexpression of Lasp1 was observed, indicating that alterations in Lasp1 transcription are most likely responsible for the observed phenotype. These data reveal a yet unappreciated role of Lasp1 in chondrocyte differentiation during cartilage to bone transition.
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| 7. |
- Mazur, Magdalena
(författare)
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Maf and Mitf transcription factors regulate pancreatic endocrine cell differentiation and function
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes - the imbalance in glucose homeostasis is partially caused by loss or dysfunction of pancreatic insulin producing β cells or development of insulin resistance. In Type 1 diabetes β cells are destroyed in the process of an autoimmune attack, whereas in Type 2 diabetes, islets produce insufficient amounts of insulin or the insulin cannot be used adequately. So far, the most promising therapy to treat Type 1 diabetes is pancreatic islet transplantation. However, this method cannot be used in a larger scale because of the severe scarcity of donors. Therefore, there is a great and urgent need to develop new methods and therapies. One of the potential sources of obtaining functional insulin cells are human embryonic stem cells (ESC) or inducible pluripotent stem cells (iPS). Hence, differentiating stem cells into functional β-cells requires a detailed understanding of pancreas development with the focus on molecular programs underlying β-cells formation and function. Pancreas development and differentiation of insulin and glucagon secreting cells is a complex process controlled by a variety of transcription factors. Two of these factors, MafA and MafB, have been shown to play a major role in the regulation of several genes critical to pancreas development and endocrine cell formation. MafB is essential for both α- and β-cell differentiation, as mice lacking MafB have fewer insulin+ and glucagon+ cells during pancreas development. In contrast, in mouse embryos lacking MafA, the development of β-cells is normal, but adult animals develop diabetes. In adult animals these two transcription factors have a distinct expression pattern, with MafB being expressed in α-cells, whereas MafA is exclusively found in β-cells. We have performed gene expression profiling of wild type and MafA/B mutant pancreata to identify genes important for β-cell maturation and function. In these microarray studies several known (insulin, glucagon, Glut2, PC2) but also novel genes were shown to be differentially expressed in MafB and MafA/MafB compound mutant embryos. Gene ontology analysis revealed that the differentially expressed genes were mainly associated with mature β-cell function. Our findings show that Neuronatin (Nnat), islet-specific zinc transporter (Slc30a8), islet-specific glucose-6-phosphatase catalytic subunit-2 protein (G6pc2) and Microphthalmia associated transcription factor (Mitf) are downregulated in embryonic and adult mutant pancreata. In contrast, the mRNA level of Retinol Binding Protein-4 (Rbp4) was upregulated in mutant tissue. Given the differences in spatio-temporal expression pattern of MafA and MafB in developing and adult pancreas, we propose that these two factors regulate islet β-cell formation and maturation in a unique and sequential manner. In MafA deficient models studied so far pancreas development is unaffected, most likely due to compensatory functions of MafB. Therefore, to be able to study the actual role of MafA in β-cell function we developed a β-cell-specific deletion of MafA. Our MafAΔβcell mutant animals lack expression of MafA and MafB in adult β-cells. In contrast to other MafA mutants, our animals have normal islet architecture, β-cells mass, β- to α-cell ratio, and MafB expression is restricted to α-cells. Thus we have created a system suitable for studying the true contribution of MafA to adult β-cell function. Our gene expression experiments have shown that in MafA and MafB mutant embryonic pancreata levels of Mitf expression are reduced comparing to levels found in wild type animals. We also show that Mitf loss of function mutation alters functionality of islet β-cell. In response to an intraperitoneal glucose challenge, but also during non-fasted conditions, Mitf mutant mice have lower blood glucose levels than wild type animals. Mutant islets secrete more insulin upon exposure to high glucose concentrations and Mitf mutant animals have higher circulating insulin levels in fasted conditions. Additionally, Mitf directly regulates the expression of genes regulating blood glucose levels and β-cell formation, which is significantly higher in Mitf mutant than in wild type animals. Thereby, we demonstrate that Mitf is an important factor in modulation of β-cell function.
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| 8. |
- Mazur, Magdalena, et al.
(författare)
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Microphthalmia transcription factor regulates pancreatic β-cell function
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:8, s. 2834-2842
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Tidskriftsartikel (refereegranskat)abstract
- Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-cell-specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and β-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved β-cell function observed in Mitf mutant animals, as it activates insulin and Glut2 transcription. Chromatin immunoprecipitation analysis shows that Mitf binds to Pax4 and Pax6 regulatory regions, suggesting that Mitf represses their transcription in wild-type β-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls β-cell function.
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| 9. |
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