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- Bucchiarone, Antonio, et al.
(författare)
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Rule-based modeling and static analysis of self-adaptive systems by graph transformation
- 2015
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Ingår i: Lecture Notes in Computer Science. - Cham : Springer International Publishing. - 0302-9743 .- 1611-3349. ; 8950, s. 582-601
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Tidskriftsartikel (refereegranskat)abstract
- Software systems nowadays require continuous operation despite changes both in user needs and in their operational environments. Self-adaptive systems are typically instrumented with tools to autonomously perform adaptation to these changes while maintaining some desired properties. In this paper we model and analyze self-adaptive systems by means of typed, attributed graph grammars. The interplay of different grammars representing the application and the adaptation logic is realized by an adaption manager. Within this formal framework we define consistency and operational properties that are maintained despite adaptations and we give static conditions for their verification. The overall approach is supported by the AGG tool for modeling, simulating, and analyzing graph transformation systems. A case study modeling a business process that adapts to changing environment conditions is used to demonstrate and validate the formal framework.
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| 2. |
- Cohain, AT, et al.
(författare)
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An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 547-
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Tidskriftsartikel (refereegranskat)abstract
- Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.
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| 3. |
- Crawford, A. A., et al.
(författare)
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Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease
- 2021
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 66:6, s. 625-636
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Tidskriftsartikel (refereegranskat)abstract
- The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from similar to 2.2 M to similar to 7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and alpha 1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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| 4. |
- Dawson, Lucas, et al.
(författare)
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Why don't we go outside? - Perceived constraints for users of urban greenspace in Sweden
- 2023
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Ingår i: Urban Forestry & Urban Greening. - : Elsevier BV. - 1618-8667 .- 1610-8167. ; 82
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Tidskriftsartikel (refereegranskat)abstract
- Urban greenspace (UGS) is important for human wellbeing, particularly physical and mental health, and is claimed to support social cohesion. However, the expansion and densification of urban centres in recent decades has occurred largely at the expense of UGS. This risks its attractiveness for users. Although recent research has identified various factors that influence the use of UGS in different contexts, few studies have taken an explicit, bottom-up approach to understand which factors constrain willingness to use it. This study analyses responses from an online survey in Sweden (N = 2806) to identify the main constraints to UGS usage, and for whom these are constraints. Respondents could select from 22 different types of constraints – relating to incivilities, management, accessibility and availability, safety, and personal issues. Respondents could also provide comments to identify additional constraints. Incivilities were the most perceived problem. For example, litter was selected by 53% of respondents, while vandalism was selected by 24%. At the same time, many respondents perceived few or no constraints – 59% stated that nothing prevented them from using UGS, while 35% stated that they saw no problems. Safety-related and accessibility/availability constraints were not strongly identified although many respondents commented that UGS in Sweden is inadequate given the large number of users, and that the UGS that people want to use the most is often inaccessible without a car. Multiple binary logistic regression was used to investigate relationships between perceptions of constraints and fourteen predictor variables. Odds ratios were used to determine whether significant (p < 0.05) relationships were meaningful. Our findings show that different groups have starkly divergent perceptions of constraints relating to UGS. Several key factors – including age, self-reported nature-connectedness, distance to UGS, and frequency of use – were associated with a heightened likelihood of perceiving different groups of constraints. However, relationships between constraints and factors relating to environmental justice were not straightforward. These findings indicate the complexity of UGS planning challenges relating to densification, the New Urban Agenda and promotion of societal benefits, and a need to further integrate multiple user perspectives, especially of younger adults and infrequent users.
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| 6. |
- Franzen, Oscar, et al.
(författare)
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Global analysis of A-to-I RNA editing reveals association with common disease variants
- 2018
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Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process.
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| 8. |
- Glicksberg, Benjamin S., et al.
(författare)
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Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
- 2019
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Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
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