| 121. |
- Robinson-Cohen, Cassianne, et al.
(författare)
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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23
- 2018
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Ingår i: Journal of the American Society of Nephrology. - : AMER SOC NEPHROLOGY. - 1046-6673 .- 1533-3450. ; 29:10, s. 2583-2592
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.Methods: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m(2) to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.Results: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0x10(-24)), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.Conclusions: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
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| 122. |
- Robinson-Cohen, Cassianne, et al.
(författare)
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Genetic Variants Associated with Circulating Parathyroid Hormone.
- 2017
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Ingår i: Journal of the American Society of Nephrology : JASN. - 1533-3450. ; 28:5, s. 1553-1565
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Tidskriftsartikel (refereegranskat)abstract
- Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10(-53)), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10(-17)), rs219779 adjacent to CLDN14 (P=3.5 × 10(-16)), rs4443100 near RTDR1 (P=8.7 × 10(-9)), and rs73186030 near CASR (P=4.8 × 10(-8)). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
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| 123. |
- Rosqvist, Fredrik, 1985-, et al.
(författare)
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Overeating saturated fat promotes fatty liver and ceramides compared to polyunsaturated fat : a randomized trial
- 2019
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 104:12, s. 6207-6219
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Saturated fat (SFA) versus polyunsaturated fat (PUFA) may promote non-alcoholic fatty liver disease (NAFLD) by yet unclear mechanisms.OBJECTIVE: To investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans.DESIGN: Double-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction.SETTING: General community.Participants: n=61 overweight or obese men and women.INTERVENTION: Muffins high in either palm (SFA)- or sunflower oil (PUFA) were added to the habitual diet.MAIN OUTCOME MEASURE: Lean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots.RESULTS: By design, body weight gain was similar in SFA (2.31±1.38 kg) and PUFA (2.01±1.90 kg) groups, P=0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat or total body fat compared with PUFA. SFA consistently increased, while PUFA reduced circulating ceramides; changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction.CONCLUSIONS: Saturated fat markedly induces liver fat and serum ceramides whereas dietary polyunsaturated fat prevent liver fat accumulation, reduce ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.
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| 124. |
- Rääf, Christopher, et al.
(författare)
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Restoring areas after a radioactive fallout : A multidisciplinary study on decontamination
- 2023
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Ingår i: Journal of Environmental Radioactivity. - : Elsevier. - 0265-931X .- 1879-1700. ; 270
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Tidskriftsartikel (refereegranskat)abstract
- Land remediation is an important part of restoration measures after a radioactive fallout containing long-lived fission products such as 137Cs. In this multidisciplinary study, we focused on three main issues related to remediation of contaminated urban areas. First, we assessed how much decontamination contributes to reducing resident radiation exposure and how much this reduction depends on the timing of implemented measures. Second, we calculated direct and indirect costs of decontamination in an industrialized country such as Sweden. Finally, in a survey study, we considered reactions of Swedish citizens to being given the hypothetical option of moving to a site decontaminated after radioactive fallout and how this predicted response might influence the design of contingency plans. The main findings are that clean-up operations must be done within the first few years after a fallout to contribute significantly to reducing residual dose. If conducted within 1-2 years, large-scale decontamination can, on average, avert 20-200 manSv per km2 residential area and unit ground deposition of 137Cs (1 MBq). The estimated direct costs (in 2020 purchasing power) would amount to 100 million Euro per km2 decontaminated residential area (comparable to Japanese estimates after the Fukushima accident), generating 39,000 m3 of radioactive waste on average, mainly in the form of 137Cs-contaminated topsoil. In our survey study of 2291 Swedish respondents about their willingness to return to decontaminated homes, women, families with resident children, and high-income earners exhibited more skepticism about returning, even if authorities were to deem it safe. The demographic pattern in attitudes was similar to that found among evacuees in the Fukushima prefecture after 2011. We conclude that predefined ranges of measured 137Cs ground deposition can be used as guidance for rescue leaders in the early post-accident phase in long-term planning for affected areas. This planning should include timing and intensity of decontamination measures, duration of evacuation, and risk communication to citizens. Because some citizens expressed both high risk perception and risk aversion, however, timely and dialogic communication is unlikely to limit a shift after the incident to an older and more male-dominated population composition. There is a risk that those who can afford to do so will move away, whereas people whose wealth is locked in property (houses or businesses) will feel stuck. Perceptions of unfairness may fray the social fabric and complicate resettlement, which in some cases may mean inefficient outlay of decontamination costs. We believe that the issue of monetary compensation to affected residents requires priority in future work.
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| 125. |
- Shankar, Suma P., et al.
(författare)
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A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder
- 2022
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 24:7, s. 1567-1582
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). Methods: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate–ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. Results: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate–ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. Conclusion: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
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| 126. |
- Shitahun, Alachew, et al.
(författare)
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Model-Based Dynamic Optimization with OpenModelica and CasADi
- 2013
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Ingår i: IFAC-AAC 2013. - 9783902823434 ; , s. 446-451
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Konferensbidrag (refereegranskat)abstract
- This paper demonstrates model-based dynamic optimization through the coupling of two open source tools: OpenModelica, which is a Modelica-based modeling and simulation platform, and CasADi, a framework for numerical optimization. The coupling uses a standardized XML format for exchange of differential-algebraic equations (DAE) models. OpenModelica supports export of models written in Modelica and the optimization language extension using this XML format, while CasADi supports import of models represented in this format. This allows users to define optimal control problems (OCP) using Modelica and optimization language specification, and solve the underlying model formulation using a range of optimization methods, including direct collocation and direct multiple shooting. The proposed solution has been tested on several industrially relevant optimal control problems, including a diesel-electric power train.
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| 127. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 128. |
- Sudarshan Rao, Mayur, et al.
(författare)
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High frequency mechanical impact treatment to improve fatigue life of welds
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- High frequency mechanical impact (HFMI) is a post-weld peening process which is carried out to improve the fatigue life of welded geometries. The increase in fatigue strength is attributed to the combination of inducing compressive residual stresses at the weld toe, a change in the weld toe geometry from the peening, as well as an increased surface hardness in the treated region. To further investigate the benficial effects of HFMI, a benchmark exercise has been developed in the Specialist Committee V.3 Materials and Fabrication Technology of the International Ship and Offshore Structures Congress (ISSC 2018). The eventual expectation is the development of design guidelines for the use of HFMI in cyclically loaded components found, for example, in the ship building industry. The benchmark exercise specifies the use of S355, a structural steel with a minimum yield strength of 355MPa, and a particular coupon geometry, which consists of a stiffener, fillet welded to a membrane loaded plate. This geometry, provided as a finite element model by the benchmark exercise committee, is known to be sensitive to fatigue as it has a high stress concentration at the weld toe. Material and mechanical properties for the simulation of HFMI and the cyclic analysis are also specified. Chalmers University of Technology contributes to the benchmark exercise through the course TME131 – Project in applied mechanics. In this year’s project, an efficient way of simulating HFMI treatment is investigated and studies on how cyclic loading affects the induced beneficial compressive residual stresses are carried out. The project is executed in three different stages. Stage 1 mainly concentrates on evaluating methods to simplify the modelling of the HFMI treatment. The goal is to reduce the computational effort without compromising the accuracy of the results. Simulations are performed on a simple cuboid geometry, also provided by the benchmark exercise, with varying parameters such as the constitutive hardening model, e.g. isotropic or kinematic or Chaboche, the analysis type, e.g dynamic or quasi-static, and the indenter tool model, e.g., a single tool or several tools applied in sequence. It is concluded that the choice of analysis type impacts the residual stress state to a minor extent, while it greatly affects the computational effort. A clear trend shows that with an increasing number of indenter parts, greater computational effort is required. Using a single indenter proved to give comparable results to previous work and a uniform residual stress profile. Since it is also computationally effective, it is concluded that this method is the most suitable. The simplifications are then carried over into Stage 2, where the HFMI treatment is applied to the welded coupon geometry. In this stage, the indenter tool models from Stage 1 are redesigned to fit the coupon and simulations are performed to further evaluate the models. Simulations are performed with a variety of indenter tool models. The simulations with several indenters moving in sequence show a greater variation in the residual stress profile, suggesting some unreliability in this method. It is determined that a five-part single impact model was the the most suitable. Finally, in Stage 3 the coupon model with induced residual stresses from a single impact HFMI simulation is subjected to cyclic membrane loading. The residual stress state is found to not be significantly impacted by constant amplitude loading. However, after variable amplitude loading the beneficial residual compressive stresses are found to be redistributed. Furthermore, the beneficial residual compressive stresses are removed to a greater extent when increasing the maximum applied nominal stress. When applying nominal stress with a peak load of 75% of the yield limit, the beneficial residual compressive stresses are reduced by almost 100%. However, when applying a nominal stress with a peak load of 63% of the yield limit, they are only reduced by 50%. For simulating HFMI, the results suggest using the Chaboche mixed hardening model with quasi-static analysis using a single impact indenter tool model. For future work it is recommended to perform further investigation of the single impact dynamic simulations using kinematic hardening since it showed promising results. Furthermore, to achieve better understanding of the effects of cyclic loading, simulations with a wider range of load amplitudes, and closer investigations of the stress-strain development during loading, are recommended.
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| 129. |
- Svensson, Maria K., et al.
(författare)
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Alterations in heart rate variability during everyday life are linked to insulin resistance. A role of dominating sympathetic over parasympathetic nerve activity?
- 2016
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Ingår i: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To evaluate the role of the autonomic nervous system (ANS) in the development of insulin resistance (IR) and assess the relationship between IR and activity of ANS using power spectrum analysis of heart rate variability (HRV).Subjects and methods: Twenty-three healthy first-degree relatives of patients with type 2 diabetes (R) and 24 control subjects without family history of diabetes (C) group-matched for age, BMI and sex were included. Insulin sensitivity (M value) was assessed by hyperinsulinemic (56 mU/m2/min) euglycemic clamp. Activity of the ANS was assessed using power spectrum analysis of HRV in long-term recordings, i.e., 24-h ECG monitoring, and in short-term recordings during manoeuvres activating the ANS. Computed tomography was performed to estimate the amount and distribution of abdominal adipose tissue.Results: Insulin sensitivity (M value, mg/kg lbm/min) did not differ significantly between the R and C groups. Total spectral power (Ptot) and very low-frequency (PVLF) power was lower in R than C during 24 h ECG-recordings (p = 0.02 and p = 0.03). The best fit multiple variable linear regression model (r2 = 0.37, p < 0.001 for model) indicated that body composition (BMI) and long-term low to high frequency (LF/HF) power ratio (std β = −0.46, p = 0.001 and std β = −0.28, p = 0.003, respectively) were significantly and independently associated with the M value.Conclusion: Altered heart rate variability, assessed by power spectrum analysis, during everyday life is linked to insulin resistance. The data suggest that an increased ratio of sympathetic to parasympathetic nerve activity, occurring via both inherited and acquired mechanisms, could potentially contribute to the development of type 2 diabetes.
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| 130. |
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