| 41. |
- Bergström, Petra, et al.
(författare)
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Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) and its cleavage product amyloid beta (A beta) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. alpha-Cleaved soluble APP (sAPP alpha) was secreted early during differentiation, from neuronal progenitors, while beta-cleaved soluble APP (sAPP beta) was first secreted after deep-layer neurons had formed. Short A beta peptides, including A beta 1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as A beta 1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by A beta 1-40/42, is associated with mature neuronal phenotypes.
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| 42. |
- Boomsma, Wouter, et al.
(författare)
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PHAISTOS: A framework for Markov chain Monte Carlo simulation and inference of protein structure.
- 2013
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 1096-987X .- 0192-8651. ; 34:19, s. 1697-1705
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Tidskriftsartikel (refereegranskat)abstract
- We present a new software framework for Markov chain Monte Carlo sampling for simulation, prediction, and inference of protein structure. The software package contains implementations of recent advances in Monte Carlo methodology, such as efficient local updates and sampling from probabilistic models of local protein structure. These models form a probabilistic alternative to the widely used fragment and rotamer libraries. Combined with an easily extendible software architecture, this makes PHAISTOS well suited for Bayesian inference of protein structure from sequence and/or experimental data. Currently, two force-fields are available within the framework: PROFASI and OPLS-AA/L, the latter including the generalized Born surface area solvent model. A flexible command-line and configuration-file interface allows users quickly to set up simulations with the desired configuration. PHAISTOS is released under the GNU General Public License v3.0. Source code and documentation are freely available from http://phaistos.sourceforge.net. The software is implemented in C++ and has been tested on Linux and OSX platforms. © 2013 Wiley Periodicals, Inc.
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| 43. |
- Brandt, P. H., et al.
(författare)
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"Profitability is sustainability:" framing of forest management practices by the Swedish forest industry
- 2023
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Ingår i: Scandinavian Journal of Forest Research. - : Taylor & Francis. - 0282-7581 .- 1651-1891. ; 38:7/8, s. 429-441
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Tidskriftsartikel (refereegranskat)abstract
- This article investigates how the Swedish forest industry, as represented by the three largest Swedish private forest companies (Svenska Cellulosa AB, Stora Enso, and Holmen), through their main public relations (PR) channels frame the current dominant Swedish forestry model and alternative models that are promoted by the European Union (EU). The content analysis of the three companies' trade magazines published between 2019 and 2022 explores the patterns in the PR framing of the forest management models with respect to economic, environmental, and social aspects. The time interval is centered by the July 2021 announcement of the EU's new Forest Strategy for 2030. The magazines' target audience is private forest owners, from whom Svenska Cellulosa AB, Stora Enso, and Holmen buy 40-50% of the timber used in production. The main finding of the study is that these corporations did not present alternative methods as viable options to replace the Swedish forestry model. The magazines, with some individual variations, respond to the alternative methods promoted by the EU and environmental associations by an increased emphasis on the benefits, mainly environmental, of the Swedish forestry model - framing the model as not only the most profitable but also the most ecologically sustainable.
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| 44. |
- Bratteby Tollerz, Linda U, et al.
(författare)
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Reliability of energy cost calculations in children with cerebral palsy, cystic fibrosis and healthy controls
- 2011
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 100:12, s. 1616-1620
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To study test-retest reliability of physiological cost index (PCI) and total cost index (TCI) in three groups of children. TCI modified PCI by excluding rest heart rate in calculation. Methods: Energy cost was evaluated from two consecutive walking tests, and results were compared between methods, tests and groups. Thirty-nine children, eight with cerebral palsy, 11 with cystic fibrosis and 20 healthy controls, aged 5-16 years participated in the study conducted at the Clinical Nutrition and Metabolism laboratory, University Hospital, Uppsala, Sweden. Heart rate was recorded during sitting and walking at self-selected speed. PCI and TCI were calculated using both non-steady-state and steady-state work heart rates. Test-retest reliability was analysed by mean of differences, pooled SD, coefficient of variation (CV%) and correlation coefficients. Results: Reliability was high for PCI and TCI. TCI showed consistently lower variation between tests than PCI for all groups. In the group with cerebral palsy, using non-steady-state showed highest reliability. Conclusion: Both PCI and TCI were reliable methods when calculating energy cost in children with cerebral palsy, cystic fibrosis and controls. TCI seemed to be a suitable alternative in the evaluation of gait efficiency in children.
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| 45. |
- Broholm, Christa, et al.
(författare)
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Epigenetic programming of adipose-derived stem cells in low birthweight individuals
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:12, s. 2664-2673
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Low birthweight (LBW) is associated with dysfunctions of adipose tissue and metabolic disease in adult life. We hypothesised that altered epigenetic and transcriptional regulation of adipose-derived stem cells (ADSCs) could play a role in programming adipose tissue dysfunction in LBW individuals. Methods: ADSCs were isolated from the subcutaneous adipose tissue of 13 normal birthweight (NBW) and 13 LBW adult men. The adipocytes were cultured in vitro, and genome-wide differences in RNA expression and DNA methylation profiles were analysed in ADSCs and differentiated adipocytes. Results: We demonstrated that ADSCs from LBW individuals exhibit multiple expression changes as well as genome-wide alterations in methylation pattern. Reduced expression of the transcription factor cyclin T2 encoded by CCNT2 may play a key role in orchestrating several of the gene expression changes in ADSCs from LBW individuals. Indeed, silencing of CCNT2 in human adipocytes decreased leptin secretion as well as the mRNA expression of several genes involved in adipogenesis, including MGLL, LIPE, PPARG, LEP and ADIPOQ. Only subtle genome-wide mRNA expression and DNA methylation changes were seen in mature cultured adipocytes from LBW individuals. Conclusions/interpretation: Epigenetic and transcriptional changes in LBW individuals are most pronounced in immature ADSCs that in turn may programme physiological characteristics of the mature adipocytes that influence the risk of metabolic diseases. Reduced expression of CCNT2 may play a key role in the developmental programming of adipose tissue.
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| 46. |
- Cirenajwis, Helena, et al.
(författare)
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NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics
- 2017
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 11:4, s. 438-451
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Tidskriftsartikel (refereegranskat)abstract
- In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
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| 47. |
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| 48. |
- Dayeh, Tasnim, et al.
(författare)
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Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Impaired insulin secretion is a hallmark of type 2 diabetes (T2D). Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3'UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea) were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼7%) and overrepresented in the open sea (∼60%). 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These results highlight the importance of epigenetics in the pathogenesis of T2D.
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| 49. |
- Dayeh, Tasnim, et al.
(författare)
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Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets.
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 56:5, s. 1036-1046
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: To date, the molecular function of most of the reported type 2 diabetes-associated loci remains unknown. The introduction or removal of cytosine-phosphate-guanine (CpG) dinucleotides, which are possible sites of DNA methylation, has been suggested as a potential mechanism through which single-nucleotide polymorphisms (SNPs) can affect gene function via epigenetics. The aim of this study was to examine if any of 40 SNPs previously associated with type 2 diabetes introduce or remove a CpG site and if these CpG-SNPs are associated with differential DNA methylation in pancreatic islets of 84 human donors. METHODS: DNA methylation was analysed using pyrosequencing. RESULTS: We found that 19 of 40 (48%) type 2 diabetes-associated SNPs introduce or remove a CpG site. Successful DNA methylation data were generated for 16 of these 19 CpG-SNP loci, representing the candidate genes TCF7L2, KCNQ1, PPARG, HHEX, CDKN2A, SLC30A8, DUSP9, CDKAL1, ADCY5, SRR, WFS1, IRS1, DUSP8, HMGA2, TSPAN8 and CHCHD9. All analysed CpG-SNPs were associated with differential DNA methylation of the CpG-SNP site in human islets. Moreover, six CpG-SNPs, representing TCF7L2, KCNQ1, CDKN2A, ADCY5, WFS1 and HMGA2, were also associated with DNA methylation of surrounding CpG sites. Some of the type 2 diabetes CpG-SNP sites that exhibit differential DNA methylation were further associated with gene expression, alternative splicing events determined by splice index, and hormone secretion in the human islets. The 19 type 2 diabetes-associated CpG-SNPs are in strong linkage disequilibrium (r (2) > 0.8) with a total of 295 SNPs, including 91 CpG-SNPs. CONCLUSIONS/INTERPRETATION: Our results suggest that the introduction or removal of a CpG site may be a molecular mechanism through which some of the type 2 diabetes SNPs affect gene function via differential DNA methylation and consequently contributes to the phenotype of the disease.
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| 50. |
- Drachmann, Fie F., et al.
(författare)
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Sire breed has a larger impact on sensory and technological meat quality than dam breed in beef-on-dairy heifers reared on forage and semi-natural grasslands
- 2024
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Ingår i: Livestock Science. - : Elsevier. - 1871-1413 .- 1878-0490. ; 282
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the meat quality of beef-on-dairy heifers from Holstein or Swedish Red-and-White dams sired by Angus or Charolais bulls reared on forage and semi-natural grasslands. Production systems with moderately high and low feeding intensities were compared, where animals grazed for one or two summers and were slaughtered at 20 or 27 months of age, respectively. Meat quality of crossbred heifers from Holstein and Swedish Red-and-White dams was comparable in M. longissimus lumborum (LL) and differed in pH, yellowness and Warner-Bratzler shear force (WBSF) in M. semimembranosus (SM) with Swedish Red-and-White being less tough. Compared with LL from Charolais crossbreeds, LL from Angus was redder and had lower WBSF, higher intramuscular fat concentration (IMF%), a more pronounced metallic flavour and a more pronounced umami taste. Meat quality of SM did not differ between Angus and Charolais crossbreeds. Generally, the production system with moderately high feeding intensity resulted in less tough beef that was lighter and less red and had higher IMF%. Consequently, beef from Charolais crossbreeds reared at a low feeding intensity exhibited the poorest meat quality with the lowest IMF% in LL (2.80 and 3.77 % for Holstein and Swedish Red-and-White, respectively). Nevertheless, crossbreeds did not differ in sensory meat quality. Generally, meat quality of beef-on-dairy heifers reared on forage and semi-natural grasslands was high, and while Angus crossbreeds delivered high-quality beef from both feeding intensities, Charolais crossbreeds are better suited for the moderately high feeding intensity, when aiming for high meat quality.
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