| 1. |
- Axelsson, Annika, et al.
(författare)
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Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca 2+-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.
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| 2. |
- Axelsson, Annika, 1969-, et al.
(författare)
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Axelsson, A., Lundqvist, J., & Sandberg, G. (2018, March). Influential factors on children’s reading and writing development: The perspective of parents. : Poster session presented at the NERA 2018
- 2018
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Ingår i: NERA 2018: Boundaries, Breaches and Bridges, Oslo, Norway..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Axelsson, Annika
(författare)
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Identification of new disease mechanisms and treatments for type 2 diabetes based on genetic variants and gene expression networks
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Improved understanding of the disease mechanisms underlying type 2 diabetes (T2D) is needed, and so are new treatments.A new T2D risk variant was recently identified in ADRA2A, which encodes the α2A-adrenergic receptor. The risk allele leads to receptor overexpression in β-cells that causes increased adrenergic signaling and impaired insulin secretion. We showed that the α2A-adrenergic receptor antagonist yohimbine normalized insulin secretion in risk allele carriers with T2D, whereas it was without effect in non-risk allele carriers. These findings suggest that individualized, genotype-based treatment for T2D is possible. Next, in an attempt to identify new genes relevant for the pathogenesis of T2D and to identify new drugs for the treatment of T2D, we utilized microarray gene expression data to gain information about gene coexpression networks. Gene expression in human islets from T2D and non-diabetic donors, and gene expression in liver tissue from hyperglycemic and normoglycemic mice, was analyzed to find groups of coexpressed genes (modules) with disturbed expression in diabetes. “Disease signatures” derived from these modules were used to interrogate publically available microarray data sets. These data sets included gene expression profiles induced by a wide range of drugs and treatments. Data sets with an expression pattern similar to our islet disease signature gave clues to the underlying pathogenic process in β-cell failure, and data sets with a reverse expression pattern to our liver disease signature helped identify drug candidates for treatment of excessive hepatic glucose production. The islet disease signature was associated with β-cell dedifferentiation and loss of a mature β-cell state. We identified the transcription factor SOX5 as a regulator of the T2D-associated islet module. Overexpression of SOX5 increased the expression of β-cell specific genes in human islets and improved secretory function in islets from donors with T2D.The liver disease signature was used to rate compounds based on reverse expression compared with the disease signature. The rationale was that compounds with potential to reverse the disease signature mightaffect the pathophysiology. Sulforaphane, a sulfur-containing compound found naturally in e.g. broccoli, was identified as the top-rated compound. Sulforaphane reduced glucose production from hepatoma cells via amechanism that involves reduced expression of gluconeogenic enzymes. Sulforaphane improved glucose tolerance in animal models of diabetes. Moreover, in a small clinical study, sulforaphane-rich broccoli sproutextract reduced fasting blood glucose and HbA1c levels in obese T2D patients with poor glycemic control. Taken together, the data presented in this thesis demonstrate the opportunities of genotype-based treatment for T2D, and show the usefulness of gene network analysis to identify pathophysiological mechanisms and new potential therapies for T2D. By this approach, we have identified Sox5 as a new regulator of β-cell function, and sulforaphane as a liver-targeting therapy for T2D patients with poor glycemic control.
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| 4. |
- Axelsson, Anton, 1981-
(författare)
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Knowledge elicitation as abstraction of purposive behaviour
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Researchers use knowledge elicitation methods to document expert knowledge for the primary purpose of understanding cognitive processes and with this understanding, technical solutions to resolve human factors issues can be produced. This dissertation offers a novel perspective on knowledge elicitation as an abstraction process. Such a theoretical framework has emerged by consolidating the ecological approach of Brunswikian psychology with the ideas of tacit and personal knowledge of Polanyian epistemology. Traditionally, knowledge elicitation has been considered an extraction process in which knowledge can be readily transferred from one individual to another. Here, this traditional position is rejected in favour of Polanyi’s premise that much of the knowledge individuals possess is tacit in nature, which implies that it cannot be documented easily, expressed in explicit form or explained. In this dissertation, knowledge is characterised as a personal process of knowing, highlighting context as a subjective knowledge structure of personal experiences that is formulated implicitly and indirectly over time through a dynamic interaction with the environment. Therefore, tacit knowledge cannot be articulated or shared; however, learners can be inspired by observing other individuals' purposive (i.e., goal-directed) behaviours and thus shape their own tacit knowledge once they practise the observed skills and develop conceptual understanding through reasoning about the learning process. Knowledge elicitation thereby makes use of observations, questions, or more structured process tracing methods in environments familiar to the observed individuals to elicit purposive behaviour from them. Accordingly, functional descriptions can be produced in this process that further conceptual understanding of a particular domain. Knowledge elicitation procedures are a powerful set of methods for reaching such functional descriptions. Moreover, by understanding the resulting knowledge elicitation data as an abstraction derived from multiple collection points in the same environment, the focus shifts from purely subjective mental constructs to the impact of environmental constraints.
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| 5. |
- Axelsson, Annika, et al.
(författare)
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Parents in Sweden describe influential factors in children’s reading and writing development
- 2019
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Ingår i: CPH, 2019, Conference on Literacy..
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Konferensbidrag (refereegranskat)abstract
- The aim of this study was to shed light on influential factors on children’s reading and writing development from the perspective of parents. Retrospective interviews with 27 parents of preschoolers obtained from a research project were used. Bronfenbrenner’s bioecological model for human development and the PPCT-model were adopted as a theoretical framework. Extracts about children’s reading and writing development were obtained from the interviews. A thematic analysis was used and generated nine themes (preliminary results): Children’s abilities and engagement; Genetics and parents abilities; More able siblings and peers; Involved parents and grandparents; Teacher competence, attitude and collaborations; Social climate in preschool and preschool class; Free play and child-initiated reading and writing activities; Toys and books; Extra support provisions and stimulation. This study shows that factors related to the child, processes at home, in preschool and in preschool class and time can influence children’s reading and writing development. It also showed that parents can be a valuable knowledge source in Nordic (special) education research.
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| 6. |
- Axelsson, Annika S., et al.
(författare)
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Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes
- 2017
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 9:394
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Tidskriftsartikel (refereegranskat)abstract
- A potentially useful approach for drug discovery is to connect gene expression profiles of disease-affected tissues ("disease signatures") to drug signatures, but it remains to be shown whether it can be used to identify clinically relevant treatment options. We analyzed coexpression networks and genetic data to identify a disease signature for type 2 diabetes in liver tissue. By interrogating a library of 3800 drug signatures, we identified sulforaphane as a compound that may reverse the disease signature. Sulforaphane suppressed glucose production from hepatic cells by nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and decreased expression of key enzymes in gluconeogenesis. Moreover, sulforaphane reversed the disease signature in the livers from diabetic animals and attenuated exaggerated glucose production and glucose intolerance by a magnitude similar to that of metformin. Finally, sulforaphane, provided as concentrated broccoli sprout extract, reduced fasting blood glucose and glycated hemoglobin (HbA1c) in obese patients with dysregulated type 2 diabetes.
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| 7. |
- Axelsson, Annika, et al.
(författare)
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Tre mammor berättar om sina barns tid i förskola och förskoleklass samt övergången däremellan
- 2017. - 31
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Ingår i: Barn och unga i skola och samhälle. - Västerås : Mälardalen University Sweden. - 9789174853261
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Bokkapitel (refereegranskat)abstract
- Syftet med den studie som ligger till grund för detta bokkapitel var att belysa tre mammors upplevelser av sina barns väg från förskola till förskoleklass. En kvalitativ forskningsansats, livsberättelser och en bioekologisk innehållsanalys användes. Studien visade att barns tid i förskola och förskoleklass samt övergången däremellan kan se olika ut. Den visade också att mammor kan känna oro för att deras barn inte ska få det stöd som de behöver för att kunna delta, lära sig och utvecklas i förskola och förskoleklass. Dessutom visade studien att mammor kan ta en aktiv del i arbetet med att förebygga och lösa problem i förskola och förskoleklass. De tre mammorna ville sina barns bästa och inriktade sina krafter på att de skulle få en så trygg och harmonisk tid i förskola och förskoleklass som möjligt. De ville också att deras barn skulle få intellektuell stimulans och nödvändiga behov tillgodosedda.
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| 8. |
- Claesson, Andreas, et al.
(författare)
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Medical versus non medical etiology in out-of-hospital cardiac arrest-Changes in outcome in relation to the revised Utstein template.
- 2016
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Ingår i: Resuscitation. - : Elsevier. - 0300-9572 .- 1873-1570. ; 110, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION:The Utstein-style recommendations for reporting etiology and outcome in out-of-hospital cardiac arrest (OHCA) from 2004 have recently been revised. Among other etiologies a medical category is now introduced, replacing the cardiac category from Utstein template 2004.AIM:The aim of this study is to describe characteristics and temporal trends from reporting OHCA etiology according to the revised Utstein template 2014 in regards to patient characteristics and 30-day survival rates.METHODS:This registry study is based on consecutive OHCA cases reported from the Emergency medical services (EMS) to the Swedish Registry of Cardiopulmonary Resuscitation (SRCR) 1992-2014. Characteristics, including a presumed cardiac etiology in Utstein template 2004, were transcribed to a medical etiology in Utstein template 2014.RESULTS:Of a total of n=70,846 cases, 92% were categorized as having a medical etiology and 8% as having a non-medical cause. Using the new classifications, the 30-day survival rate has significantly increased over a 20-year period from 4.7% to 11.0% in the medical group and from 3% to 9.9% in the non-medical group (p≤0.001). Trauma was the most common cause in OHCA of a non-medical etiology (26%) with a 30-day survival rate of 3.4% whilst drowning and drug overdose had the highest survival rates (14% and 10% respectively).CONCLUSION:Based on Utstein 2014 categories of etiology, overall survival after OHCA with a medical etiology has more than doubled in a 20-year period and tripled for non-medical cases. Patients with a medical etiology found in a shockable rhythm have the highest chance of survival. There is great variability in characteristics among non-medical cases.
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| 9. |
- Engen, Karin, et al.
(författare)
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Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening
- 2016
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Ingår i: Assay and drug development technologies. - : Mary Ann Liebert Inc. - 1540-658X .- 1557-8127. ; 14:3, s. 180-193
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Tidskriftsartikel (refereegranskat)abstract
- Intracerebroventricular injection of angiotensin IV, a ligand of insulin-regulated aminopeptidase (IRAP), has been shown to improve cognitive functions in several animal models. Consequently, IRAP is considered a potential target for treatment of cognitive disorders. To identify nonpeptidic IRAP inhibitors, we adapted an established enzymatic assay based on membrane preparations from Chinese hamster ovary cells and a synthetic peptide-like substrate for high-throughput screening purposes. The 384-well microplate-based absorbance assay was used to screen a diverse set of 10,500 compounds for their inhibitory capacity of IRAP. The assay performance was robust with Z-values ranging from 0.81 to 0.91, and the screen resulted in 23 compounds that displayed greater than 60% inhibition at a compound concentration of 10M. After hit confirmation experiments, purity analysis, and promiscuity investigations, three structurally different compounds were considered particularly interesting as starting points for the development of small-molecule-based IRAP inhibitors. After resynthesis, all three compounds confirmed low M activity and were shown to be rapidly reversible. Additional characterization included activity in a fluorescence-based orthogonal assay and in the presence of a nonionic detergent and a reducing agent, respectively. Importantly, the characterized compounds also showed inhibition of the human ortholog, prompting our further interest in these novel IRAP inhibitors.
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| 10. |
- Falkevall, Annelie, et al.
(författare)
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Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease
- 2017
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 25:3, s. 713-726
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.
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