| 1. |
- Allentoft, Morten E., et al.
(author)
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Population genomics of post-glacial western Eurasia
- 2024
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In: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Journal article (peer-reviewed)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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| 2. |
- Petersen, Anders Ø., et al.
(author)
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Conjugated C-6 hydroxylated bile acids in serum relate to human metabolic health and gut Clostridia species
- 2021
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.
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| 3. |
- Priskorn, Lærke, et al.
(author)
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RUBIC (ReproUnion Biobank and Infertility Cohort) : A binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility-related morbidity
- 2021
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In: Andrology. - : Wiley. - 2047-2919 .- 2047-2927. ; 9:6, s. 1828-1842
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Journal article (peer-reviewed)abstract
- Background: Infertility affects 15%–25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth. Objectives: Three overall questions will be studied: (1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? (2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And (3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up?. Material and Methods: ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skåne University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of biospecimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem.
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| 4. |
- Allentoft, Morten E., et al.
(author)
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100 ancient genomes show repeated population turnovers in Neolithic Denmark
- 2024
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In: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337
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Journal article (peer-reviewed)abstract
- Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
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| 5. |
- Banasik, Karina, et al.
(author)
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The FOXO3A rs2802292 G-Allele Associates with Improved Peripheral and Hepatic Insulin Sensitivity and Increased Skeletal Muscle-FOXO3A mRNA Expression in Twins.
- 2011
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96, s. 119-124
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Journal article (peer-reviewed)abstract
- Objective: The minor G allele of FOXO3A rs2802292 has been associated with longevity. We aimed to investigate whether a phenotype related to healthy metabolic aging could be identified in individuals carrying the longevity-associated FOXO3A rs2802292 G allele. Research Design and Methods: rs2802292 was genotyped in a phenotypically well-characterized population of young and elderly twins (n = 190) and in the population-based Inter99 cohort (n = 5768). All participants underwent oral glucose tolerance tests, and the twin population was additionally examined with an iv glucose tolerance test and a hyperinsulinemic, euglycemic clamp. Basal and insulin-stimulated FOXO3A mRNA expression was assessed in skeletal muscle biopsies from the twin population. Results: In the twin sample, carriers of the minor G allele of rs2802292 showed reduced fasting plasma insulin [per allele effect (β) = -13% (-24; -1) (95% confidence interval), P = 0.03] and lower incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -14% (-23; -), P = 0.005]. The G allele was associated with increased peripheral insulin action [glucose disposal rate clamp, β = 0.85 mg·kgfat-free mass(-1) · min(-1) (0.049; 1.64), P = 0.04] and lower hepatic insulin resistance index [β = -13% (-25; -1), P = 0.03]. Furthermore, carriers of the G allele had increased basal FOXO3A mRNA expression in skeletal muscle compared with T-allele carriers [β = 16% (0; 33), P = 0.047]. In the Inter99 sample, we found an association with reduced incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -3% (-5; -0.07), P = 0.04], but this association was not significant after adjustment for body mass index. Conclusion: Our data indicate that the minor G allele of FOXO3A rs2802292 is associated with enhanced peripheral and hepatic insulin sensitivity in our small twin cohort, which may be mediated through increased FOXO3A mRNA expression, although no major metabolic impact of rs2802292 was found in the large Inter99 cohort.
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| 6. |
- Bohn, Pernille, et al.
(author)
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Abiotic degradation of antibiotic ionophores
- 2013
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In: Environmental Pollution. - 0269-7491 .- 1873-6424. ; 182, s. 177-183
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Journal article (peer-reviewed)abstract
- Hydrolytic and photolytic degradation were investigated for the ionophore antibiotics lasalocid, monensin, salinomycin, and narasin. The hydrolysis study was carried out by dissolving the ionophores in solutions of pH 4, 7, and 9, followed by incubation at three temperatures of 6, 22, and 28 °C for maximum 34 days. Using LC–MS/MS for chemical analysis, lasalocid was not found to hydrolyse in any of the tested environments. Monensin, salinomycin, and narasin were all stable in neutral or alkaline solution but hydrolysed in the solution with a pH of 4. Half-lives at 25 °C were calculated to be 13, 0.6, and 0.7 days for monensin, salinomycin, and narasin, respectively. Absorbance spectra from each compound indicated that only lasalocid is degraded by photolysis (half-life below 1 h) due to an absorbance maximum around 303 nm, and monensin, salinomycin, and narasin are resistant to direct photolysis because they absorb light of environmentally irrelevant wavelengths.
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| 7. |
- Bohn, Pernille, et al.
(author)
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Abiotic degradation of antibiotic ionophores
- 2013
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In: Environmental Pollution. - : Elsevier Ltd.. - 0269-7491 .- 1873-6424. ; 182, s. 177-183
-
Journal article (peer-reviewed)abstract
- Hydrolytic and photolytic degradation were investigated for the ionophore antibiotics lasalocid, monensin, salinomycin, and narasin. The hydrolysis study was carried out by dissolving the ionophores in solutions of pH 4, 7, and 9, followed by incubation at three temperatures of 6, 22, and 28 °C for maximum 34 days. Using LC–MS/MS for chemical analysis, lasalocid was not found to hydrolyse in any of the tested environments. Monensin, salinomycin, and narasin were all stable in neutral or alkaline solution but hydrolysed in the solution with a pH of 4. Half-lives at 25 °C were calculated to be 13, 0.6, and 0.7 days for monensin, salinomycin, and narasin, respectively. Absorbance spectra from each compound indicated that only lasalocid is degraded by photolysis (half-life below 1 h) due to an absorbance maximum around 303 nm, and monensin, salinomycin, and narasin are resistant to direct photolysis because they absorb light of environmentally irrelevant wavelengths.
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| 8. |
- Christoffersen, Christina, et al.
(author)
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The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles
- 2012
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In: Journal of Lipid Research. - 1539-7262. ; 53:10, s. 2198-2204
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Journal article (peer-reviewed)abstract
- ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptor-mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 +/- 0.13 mu M, P = 0.003, and 1.23 +/- 0.10 mu M, P = 0.02, respectively) as compared with noncarriers (0.93 +/- 0.04 mu M). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-deficient mice (n = 6), the removal of HDL-associated human apoM was delayed in the LDL receptor-deficient mice. After 2 h, 54 +/- 5% versus 90 +/- 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = -0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL receptor-mediated clearance of apoB-containing particles.-Christoffersen, C., M. Benn, P. M. Christensen, P. L. S. M. Gordts, A. J. M. Roebroek, R. Frikke-Schmidt, A. Tybjaerg-Hansen, B. Dahlback, and L. B. Nielsen. The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles. J. Lipid Res. 2012. 53: 2198-2204.
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| 9. |
- Clausen, Bettina Hjelm, et al.
(author)
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Fumarate decreases edema volume and improves functional outcome after experimental stroke
- 2017
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In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 295, s. 144-154
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Journal article (peer-reviewed)abstract
- Background Oxidative stress and inflammation exacerbate tissue damage in the brain after ischemic stroke. Dimethyl-fumarate (DMF) and its metabolite monomethyl-fumarate (MMF) are known to stimulate anti-oxidant pathways and modulate inflammatory responses. Considering these dual effects of fumarates, we examined the effect of MMF treatment after ischemic stroke in mice. Methods Permanent middle cerebral artery occlusion (pMCAO) was performed using adult, male C57BL/6 mice. Thirty minutes after pMCAO, 20 mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48 h after pMCAO. First, we examined whether a bolus of MMF was capable of changing expression of kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor (Nrf)2 in the infarcted brain. Next, we studied the effect of MMF on functional recovery. To explore mechanisms potentially influencing functional changes, we examined infarct volumes, edema formation, the expression of heat shock protein (Hsp)72, hydroxycarboxylic acid receptor 2 (Hcar2), and inducible nitric oxide synthase (iNOS) in the infarcted brain using real-time PCR and Western blotting. Concentrations of a panel of pro- and anti-inflammatory cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, TNF) were examined in both the infarcted brain tissue and plasma samples 6, 24 and 48 h after pMCAO using multiplex electrochemoluminiscence analysis. Results Administration of MMF increased the protein level of Nrf2 6 h after pMCAO, and improved functional outcome at 24 and 48 h after pMCAO. MMF treatment did not influence infarct size, however reduced edema volume at both 24 and 48 h after pMCAO. MMF treatment resulted in increased Hsp72 expression in the brain 6 h after pMCAO. Hcar2 mRNA levels increased significantly 24 h after pMCAO, but were not different between saline- and MMF-treated mice. MMF treatment also increased the level of the anti-inflammatory cytokine IL-10 in the brain and plasma 6 h after pMCAO, and additionally reduced the level of the pro-inflammatory cytokine IL-12p70 in the brain at 24 and 48 h after pMCAO. Conclusions A single intravenous bolus of MMF improved sensory-motor function after ischemic stroke, reduced edema formation, and increased the levels of the neuroprotective protein Hsp72 in the brain. The early increase in IL-10 and reduction in IL-12p70 in the brain combined with changes in systemic cytokine levels may also contribute to the functional recovery after pMCAO.
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| 10. |
- Dahl, Olav, et al.
(author)
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Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version
- 2020
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In: Acta Oncologica. - 0284-186X .- 1651-226X. ; 59:9, s. 1016-1023
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Journal article (peer-reviewed)abstract
- Background: The UICC TNM 7th edition introduced stage groups for anal cancer which in 2019 has not yet come into general use. The new TNM 8th edition from 2016 defines 7 sub-stages. Background data for these changes are lacking. We aimed to investigate whether the new classification for anal cancer reliably predict the prognosis in the different stages.Patients and methods: The Nordic Anal Cancer Group (NOAC) conducted a large retrospective study of all anal cancers in Norway, Sweden and most of Denmark in 2000–2007. From the Nordic cohort 1151 anal cancer patients with follow-up data were classified by the TNM 4th edition which has identical T, N and M definitions as the TNM 7th edition, and therefore also can be classified by the TNM 7th stage groups. We used the Nordic cohort to translate the T, N and M stages into the TNM 8th stages and sub-stages. Overall survival for each stage was assessed.Results: Although the summary stage groups for TNM 8th edition discriminates patients with different prognosis reasonably well, the analyses of the seven sub-stages show overlapping overall survival: HR for stage IIA 1.30 (95%CI 0.80–2.12) is not significantly different from stage I (p = .30) and HR for stage IIB 2.35 (95%CI 1.40–3.95) and IIIA 2.48 (95%CI 1.43–4.31) are also similar as were HRs for stage IIIB 3.41 (95%CI 1.99–5.85) and IIIC 3.22 (95%CI 1.99–5.20). Similar overlapping was shown for local recurrence and distant spread.Conclusion: The results for the sub-stages calls for a revision of the staging system. We propose a modification of the TNM 8th edition for staging of anal cancer into four stages based on the T, N and M definitions of the TNM 8th classification.
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| 11. |
- de Graaff, Anne M., et al.
(author)
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Scalable psychological interventions for Syrian refugees in Europe and the Middle East : STRENGTHS study protocol for a prospective individual participant data meta-analysis
- 2022
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In: BMJ Open. - : BMJ. - 2044-6055. ; 12:4
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Journal article (peer-reviewed)abstract
- Introduction The World Health Organization's (WHO) scalable psychological interventions, such as Problem Management Plus (PM+) and Step-by-Step (SbS) are designed to be cost-effective non-specialist delivered interventions to reduce symptoms of common mental disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD). The STRENGTHS consortium aims to evaluate the effectiveness, cost-effectiveness and implementation of the individual format of PM+ and its group version (gPM+), as well as of the digital SbS intervention among Syrian refugees in seven countries in Europe and the Middle East. This is a study protocol for a prospective individual participant data (IPD) meta-analysis to evaluate (1) overall effectiveness and cost-effectiveness and (2) treatment moderators of PM+, gPM+ and SbS with Syrian refugees. Methods and analysis Five pilot randomised controlled trials (RCTs) and seven fully powered RCTs conducted within STRENGTHS will be combined into one IPD meta-analytic dataset. The RCTs include Syrian refugees of 18 years and above with elevated psychological distress (Kessler Psychological Distress Scale (K10>15)) and impaired daily functioning (WHO Disability Assessment Schedule 2.0 (WHODAS 2.0>16)). Participants are randomised into the intervention or care as usual control group, and complete follow-up assessments at 1-week, 3-month and 12-month follow-up. Primary outcomes are symptoms of depression and anxiety (25-item Hopkins Symptom Checklist). Secondary outcomes include daily functioning (WHODAS 2.0), PTSD symptoms (PTSD Checklist for DSM-5) and self-identified problems (PSYCHLOPS). We will conduct a one-stage IPD meta-analysis using linear mixed models. Quality of evidence will be assessed using the GRADE approach, and the economic evaluation approach will be assessed using the CHEC-list. Ethics and dissemination Local ethical approval has been obtained for each RCT. This IPD meta-analysis does not require ethical approval. The results of this study will be published in international peer-reviewed journals.
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| 12. |
- Due, Pernille, et al.
(author)
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Is victimization from bullying associated with medicine use among adolescents? A nationally representative cross-sectional survey in Denmark
- 2007
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In: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 120:1, s. 110-117
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Journal article (peer-reviewed)abstract
- OBJECTIVE. The goal was to examine whether being a victim of bullying was associated with medicine use, taking into account the increased prevalence of physical and psychological symptoms. METHODS. The study population included all students in grades 5, 7, and 9 (mean ages: 11.6, 13.6, and 15.6 years, respectively) in a random sample of schools in Denmark (participation rate: 88.5%; N = 5205). The students reported health problems, medicine use, bullying, and a range of psychosocial conditions in an anonymous standardized questionnaire. The outcome measure was self-reported medicine use for headache, stomachache, difficulties in getting to sleep, and nervousness. The determinant was frequency of exposure to bullying, measured with 1 item. RESULTS. In multivariate models adjusted for age and social class, we found that adolescent victims of bullying used medicine for pains and psychological problems more often than did adolescents who were not bullied. The increased odds of using medicine were not explained by the higher prevalence of symptoms among the bullied children. CONCLUSIONS. We found victimization from bullying to be associated with medicine use, even when we controlled for the higher prevalence of symptoms among bullied victims. The medications that adolescents use can have adverse effects, in addition to the potentially health-damaging effects of bullying. Policy makers, health care professionals, and school staff should be aware that the adolescent victims of bullying are prone to excess use of medicine, and preventive actions should be taken to decrease the level of bullying as well as the use of medicine among adolescents.
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| 13. |
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| 14. |
- Gaml-Sørensen, Anne, et al.
(author)
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Maternal vitamin D levels and male reproductive health : a population-based follow-up study
- 2023
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In: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 38:5, s. 469-484
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Journal article (peer-reviewed)abstract
- Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels < 25 nmol/L had 11% (95% CI − 19 to − 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI − 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75 nmol/L during pregnancy may be beneficial for testes function in adult sons.
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| 15. |
- Grunnet, Louise G., et al.
(author)
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Regulation and Function of FTO mRNA Expression in Human Skeletal Muscle and Subcutaneous Adipose Tissue
- 2009
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:10, s. 2402-2408
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Journal article (peer-reviewed)abstract
- OBJECTIVE-Common variants in FTO (the fat mass- and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and nongenetic regulation of FTO mRNA in skeletal muscle and adipose tissue and their influence on in vivo glucose and fat metabolism. RESEARCH DESIGN AND METHODS-The FTO rs9939609 polymorphism was genotyped in two twin cohorts: 1) 298 elderly twins aged 62-83 years with glucose tolerance ranging from normal to type 2 diabetes and 2) 196 young (25-32 years) and elderly (58-66 years) nondiabetic twins examined by a hyperinsulinemic-euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n = 226) and skeletal muscle biopsies (n = 158). RESULTS-Heritability of FTO expression in both tissues was low, and FTO expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle, FTO mRNA expression was negatively associated to fat and positively to glucose oxidation rates as well as positively correlated with expression of genes involved in oxidative phosphorylation including PGC1 alpha. CONCLUSIONS-The heritability of FTO expression in adipose tissue and skeletal muscle is low and not influenced by obesity-associated FTO genotype. The age-dependent decline in FTO expression is associated with peripheral defects of glucose and fat metabolism. Diabetes 58:2402-2408, 2009
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| 16. |
- Gunnarsdottir, Maria J., et al.
(author)
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Implementing risk-based approaches to improve drinking water quality in small water supplies in the Nordic region – barriers and solutions
- 2023
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In: Journal of Water and Health. - 1477-8920. ; 21:12, s. 1747-1760
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Journal article (peer-reviewed)abstract
- Small water supplies face similar problems worldwide, regardless of ownership or management type. Non-compliance with water quality regulations is more frequent in small supplies than in large ones, as are waterborne disease outbreaks. The new EU Drinking Water Directive requires risk-based approach (RBA) to secure water safety as is recommended in the WHO's Guidelines for drinking water quality through ‘water safety plans’. This is already in regulation in the Nordic countries, although less used in small supplies. In this research, we explore the challenges, barriers and possible solutions to implementing RBA and improving compliance in small supplies. This was achieved by conducting and analysing interviews with 53 stakeholders from all 8 Nordic countries to produce recommendations for action by the different implicated actors. Our findings suggest the centrality of governmental policy, including support for continuous training, provision of simple RBA guidelines and increasing cooperation in the water sector. The Nordic experience reflects global challenges with small water supplies and the trend towards systematic preventive management epitomized in the framework for drinking water safety advocated by the World Health Organization since 2004.
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| 17. |
- Haman, Ewa, et al.
(author)
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Noun and verb knowledge in monolingual preschool children across 17 languages : Data from Cross-linguistic Lexical Tasks (LITMUS-CLT)
- 2017
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In: Clinical Linguistics & Phonetics. - PHILADELPHIA : Taylor & Francis Group. - 0269-9206 .- 1464-5076. ; 31:11-12, s. 818-843
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Journal article (peer-reviewed)abstract
- This article investigates the cross-linguistic comparability of the newly developed lexical assessment tool Cross-linguistic Lexical Tasks (LITMUS-CLT). LITMUS-CLT is a part the Language Impairment Testing in Multilingual Settings (LITMUS) battery (Armon-Lotem, de Jong & Meir, 2015). Here we analyse results on receptive and expressive word knowledge tasks for nouns and verbs across 17 languages from eight different language families: Baltic (Lithuanian), Bantu (isiXhosa), Finnic (Finnish), Germanic (Afrikaans, British English, South African English, German, Luxembourgish, Norwegian, Swedish), Romance (Catalan, Italian), Semitic (Hebrew), Slavic (Polish, Serbian, Slovak) and Turkic (Turkish). The participants were 639 monolingual children aged 3;0-6;11 living in 15 different countries. Differences in vocabulary size were small between 16 of the languages; but isiXhosa-speaking children knew significantly fewer words than speakers of the other languages. There was a robust effect of word class: accuracy was higher for nouns than verbs. Furthermore, comprehension was more advanced than production. Results are discussed in the context of cross-linguistic comparisons of lexical development in monolingual and bilingual populations.
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| 18. |
- Hansen, Violeta, 1979, et al.
(author)
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Naturally occurring radionuclides assessment in the Arctic
- 2023
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In: The XIX conference of the Nordic Society for Radiation Protection, held at Malmö Live, Malmö, Sweden, June 5-9, 2023. - https://nsfs.org/?lang=en : The Nordic Society for Radiation Protection (NSFS).
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Conference paper (other academic/artistic)abstract
- Naturally occurring radionuclides (NORs), primarily 210Po, accumulates in seafood, marine, and terrestrial mammals, which are an important part of the traditional Arctic diet. Arctic seafood plays an important role in the worldwide seafood industry. NORs were measured in glaciers from Svalbard, the Arctic Ocean, surface seawater and sediments from Norwegian marine areas, seabirds from Greenland, seafood and marine mammals from the Nordic region, Faroe Islands, Greenland, and Canada, terrestrial mammals from Greenland, and lake sediments in northernmost Finland. Outdoor 222Rn was measured in Finland, Canada, and Norway and atmospheric 210Pb, 212Pb, and 7Be were measured in Norway, Sweden, Finland, Iceland, and Canada. Deposited 210Pb and 7Be were measured in Sweden and Finland. Glaciers and marine sediment results show oil and gas, coal combustion, and ore mining as anthropogenic sources. NORs are long-range transported via atmospheric and oceanic currents in the Arctic. 210Pb has a long atmospheric residence time, especially in winter. 228Ra activities in the Transpolar Drift approximately doubled between 2007 and 2015, indicating that climate-driven changes may be increasing the release of shelf-derived elements to the open Arctic Ocean. Results showed no effect of climate change on 210Pb deposition in sediments in Lake Kevojarvi in northernmost Finland. 210Po is the major contributor to the annual effective dose via seafood and marine and terrestrial mammal consumption in the Arctic population, far exceeding dose contributions from 137Cs, 226Ra, 228Ra, and 210Pb. 210Po absorbed dose rates to studied biota are several orders of magnitude lower than the recommended dose rate screening value of 10 µGy h-1. NORs atmospheric results follow an annual cycle, which is mainly driven by seasonal weather and climate changes. Understanding the sources and associated doses from NORs is necessary to assess risks and public perception of risks, support science-based decision-making, and policy development engaging public and Indigenous peoples.
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| 19. |
- Hofherr, Alexis, et al.
(author)
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Targeting inflammation for the treatment of Diabetic Kidney Disease: a five-compartment mechanistic model.
- 2022
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In: BMC nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 23:1
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Journal article (peer-reviewed)abstract
- Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Mortality and morbidity associated with DKD are increasing with the global prevalence of type 2 diabetes. Chronic, sub-clinical, non-resolving inflammation contributes to the pathophysiology of renal and cardiovascular disease associated with diabetes. Inflammatory biomarkers correlate with poor renal outcomes and mortality in patients with DKD. Targeting chronic inflammation may therefore offer a route to novel therapeutics for DKD. However, the DKD patient population is highly heterogeneous, with varying etiology, presentation and disease progression. This heterogeneity is a challenge for clinical trials of novel anti-inflammatory therapies. Here, we present a conceptual model of how chronic inflammation affects kidney function in five compartments: immune cell recruitment and activation; filtration; resorption and secretion; extracellular matrix regulation; and perfusion. We believe that the rigorous alignment of pathophysiological insights, appropriate animal models and pathology-specific biomarkers may facilitate a mechanism-based shift from recruiting 'all comers' with DKD to stratification of patients based on the principal compartments of inflammatory disease activity.
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| 20. |
- Kulakova, Alina, et al.
(author)
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Chemometrics in Protein Formulation : Stability Governed by Repulsion and Protein Unfolding
- 2023
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In: Molecular Pharmaceutics. - 1543-8384. ; 20:6, s. 2951-2965
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Journal article (peer-reviewed)abstract
- Therapeutic proteins can be challenging to develop due to their complexity and the requirement of an acceptable formulation to ensure patient safety and efficacy. To date, there is no universal formulation development strategy that can identify optimal formulation conditions for all types of proteins in a fast and reliable manner. In this work, high-throughput characterization, employing a toolbox of five techniques, was performed on 14 structurally different proteins formulated in 6 different buffer conditions and in the presence of 4 different excipients. Multivariate data analysis and chemometrics were used to analyze the data in an unbiased way. First, observed changes in stability were primarily determined by the individual protein. Second, pH and ionic strength are the two most important factors determining the physical stability of proteins, where there exists a significant statistical interaction between protein and pH/ionic strength. Additionally, we developed prediction methods by partial least-squares regression. Colloidal stability indicators are important for prediction of real-time stability, while conformational stability indicators are important for prediction of stability under accelerated stress conditions at 40 °C. In order to predict real-time storage stability, protein-protein repulsion and the initial monomer fraction are the most important properties to monitor.
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| 21. |
- Ostergaard, Henrik, et al.
(author)
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Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide
- 2011
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:8, s. 2333-2341
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Journal article (peer-reviewed)abstract
- Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency. (Blood. 2011; 118(8): 2333-2341)
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| 22. |
- Ottosen, Lisbeth M., et al.
(author)
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Electrodialytic remediation of soil slurry-removal of Cu, Cr, and As
- 2009
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In: Separation science and technology (Print). - Philadelphia, PA : Taylor & Francis. - 0149-6395 .- 1520-5754. ; 44:10, s. 2245-2268
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Journal article (other academic/artistic)abstract
- Severe soil contamination is often found at old wood preservation sites and a common combination of pollutants is Cu, Cr, and As. In the present work it is tested if simultaneous removal of Cu, Cr, and As can be obtained in an electrodialytic cell where the polluted soil is remediated as a stirred suspension (placed as the desalination compartment in accordance to the position of the ion exchange membranes). The soil for the experiments was sampled at an abandoned wood preservation site and contained 2170mg Cu/kg, 710mg Cr/kg and 3200mg As/kg. SEM-EDX analysis showed that Cu, Cr, As and oxygen formed particles that were cementing soil minerals together. The soil was suspended in distilled water, distilled water with I2 crystals to have an oxidizing environment, or in an acidified environment at pH about 1.0. The experiments lasted from 1 to 3 weeks. Good results were obtained in two experiments; an experiment where the soil was suspended in distilled water and the remediation lasted 3 weeks with 2.5mA and an experiment with acidification of the soil suspension with HNO3 to pH about 1.0 (2 weeks and 5mA). The best separation of pollutants and soil was obtained in the experiment with suspension in distilled water. Based on soil concentrations, good Cu removal (95%) was obtained in both experiments. Removal of Cr was most efficient from the acidified soil suspension (74%). Both Cu and Cr concentrations were below the limiting values after the remediation. The As concentration, however, was not even although 61% was removed. In the soil remained about 1070mg As/kg soil and since the limiting value is 40mg As/kg, the removal was not efficient enough. So simultaneous removal was possible, but the target values were only met in the case of Cu and Cr, and more research is needed to remove As to a sufficiently low concentration, as well.
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| 23. |
- Peleli, Maria, et al.
(author)
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Inhibition of cystathionine-gamma lyase dampens vasoconstriction in mouse and human intracerebral arterioles
- 2023
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In: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 239:1
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Journal article (peer-reviewed)abstract
- AimIn extracerebral vascular beds cystathionine-gamma lyase (CSE) activity plays a vasodilatory role but the role of this hydrogen sulfide (H2S) producing enzyme in the intracerebral arterioles remain poorly understood. We hypothesized a similar function in the intracerebral arterioles. MethodsIntracerebral arterioles were isolated from wild type C57BL/6J mouse (9-12 months old) brains and from human brain biopsies. The function (contractility and secondary dilatation) of the intracerebral arterioles was tested ex vivo by pressure myography using a perfusion set-up. Reverse transcription polymerase chain reaction was used for detecting CSE expression. ResultsCSE is expressed in human and mouse intracerebral arterioles. CSE inhibition with L-propargylglycine (PAG) significantly dampened the K+-induced vasoconstriction in intracerebral arterioles of both species (% of maximum contraction: in human control: 45.4 & PLUSMN; 2.7 versus PAG: 27 & PLUSMN; 5.2 and in mouse control: 50 & PLUSMN; 1.5 versus PAG: 33 & PLUSMN; 5.2) but did not affect the secondary dilatation. This effect of PAG was significantly reversed by the H2S donor sodium hydrosulfide (NaSH) in human (PAG + NaSH: 38.8 & PLUSMN; 7.2) and mouse (PAG + NaSH: 41.7 & PLUSMN; 3.1) arterioles, respectively. The endothelial NO synthase (eNOS) inhibitor, N & omega;-Nitro-l-arginine methyl ester (L-NAME), and the inhibitor of soluble guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reversed the effect of PAG on the K+-induced vasoconstriction in the mouse arterioles and attenuated the K+-induced secondary dilatation significantly. ConclusionCSE contributes to the K+-induced vasoconstriction via a mechanism involving H2S, eNOS, and sGC whereas the secondary dilatation is regulated by eNOS and sGC but not by CSE.
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| 24. |
- Peluso, A. Augusto, et al.
(author)
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Functional assay for assessment of agonistic or antagonistic activity of angiotensin AT2 receptor ligands reveals that EMA401 and PD123319 have agonistic properties
- 2023
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In: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 216
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Journal article (peer-reviewed)abstract
- With the discovery of the protective arm of the renin-angiotensin system (RAS), interest has grown in protective RAS-related receptors such as the angiotensin AT2-receptor [AT2R] as potential new drug targets. While it is known that AT2R couple to Gi, it is also apparent that they do not signal via inhibition of adenylyl cyclase/ decrease in cAMP, as do many Gi-coupled receptors. Thus, standard commercially-available assays cannot be applied to test for agonistic or antagonistic properties of AT2R ligands. This lack of standard assays has hampered the development of new drugs targeting the AT2R.Therefore, we aimed at developing a reliable, technically easy assay for the determination of intrinsic activity of AT2R ligands, primarily for distinguishing between AT2R agonists and antagonists. We found that measure-ment of NO release by DAF-FM fluorescence in primary human aortic endothelial cells (HAEC) or in AT2R-transfected CHO cells is a reliable assay for the characterization of AT2R ligands. While testing the assay, we made several novel findings, including: a) C21 is a full agonist at the AT2R (with the same efficacy as angiotensin II); b) C21 has no intrinsic activity at the receptor Mas; c) AT2R-transfected HEK-293 cells are unresponsive to AT2R stimulation; d) EMA401 and PD123319, which are commonly regarded as AT2R antagonists, are partial agonists at the AT2R.Collectively, we have developed and tested an assay based on the measurement and quantification of NO release in HAEC or in AT2R-CHO cells that is suitable for the characterisation of novel and established AT2R ligands.
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| 25. |
- Ribel-Madsen, Rasmus, et al.
(author)
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Impact of rs361072 in the Phosphoinositide 3-Kinase p110 beta Gene on Whole-Body Glucose Metabolism and Subunit Protein Expression in Skeletal Muscle
- 2010
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:4, s. 1108-1112
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Journal article (peer-reviewed)abstract
- OBJECTIVE-Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110 beta subunit, has previously been found to be associated with homeostasis model assessment for insulin resistance (HOMA-IR) in obese subjects. The aim was to investigate the influence of rs361072 on in vivo glucose metabolism, skeletal muscle PI3K subunit protein levels, and type 2 diabetes. RESEARCH DESIGN AND METHODS-The functional role of rs361072 was studied in 196 Danish healthy adult twins. Peripheral and hepatic insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp. Basal and insulin-stimulated biopsies were taken from the vastus lateralis muscle, and tissue p110 beta and p85 alpha proteins were measured by Western blotting. The genetic association with type 2 diabetes and quantitative metabolic traits was investigated in 9,316 Danes with glucose tolerance ranging from normal to overt type 2 diabetes. RESULTS-While hepatic insulin resistance was similar in the fasting state, carriers of the minor G allele had lower hepatic glucose output (per-allele effect: 16%, P-add = 0.004) during high physiological insulin infusion. rs361072 did not associate with insulin-stimulated peripheral glucose disposal despite a decreased muscle p85 alpha:p110 beta protein ratio (P-add = 0.03) in G allele carriers. No association with HOMA-IR or type 2 diabetes (odds ratio 1.07, P = 0.5) was identified, and obesity did not interact with rs361072 on these traits. CONCLUSIONS-Our study suggests that the minor G allele of PIK3CB rs361072 associates with decreased muscle p85 alpha:p110 beta ratio and lower hepatic glucose production at high plasma insulin levels. However, no impact on type 2 diabetes prevalence was found. Diabetes 59:1108-1112, 2010
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