| 1. |
- Hallström, Hadar, et al.
(författare)
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Probiotic supplements and debridement of peri-implant mucositis : a randomized controlled trial
- 2015
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Ingår i: Acta Odontologica Scandinavica. - : Taylor & Francis. - 0001-6357 .- 1502-3850. ; 74:1, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this double-blind randomized placebo-controlled trial was to evaluate the effects of probiotic supplements in adjunct to conventional management of peri-implant mucositis.Materials and methods.Forty-nine adult patients with peri-implant mucositis were consecutively recruited after informed consent. After initial mechanical debridement and oral hygiene instructions, the patients received a topical oil application (active or placebo) followed by twice-daily intake of lozenges (active or placebo) for 3 months. The active products contained a mix of two strains of Lactobacillus reuteri. Patients were clinically monitored and sampled at baseline and after 1, 2, 4, 12 and 26 weeks. The clinical end-points were pocket-probing depth (PPD), plaque index (PI) and bleeding on probing (BOP). In addition, the subgingival microbiota was processed with checkerboard DNA-DNA hybridization and samples of gingival crevicular fluid (GCF) were analyzed for selected cytokines with the aid of multiplex immunoassays.Results.After 4 and 12 weeks, all clinical parameters were improved in both the test and the placebo group. PPD and BOP were significantly reduced compared with baseline (p < 0.05), but no significant differences were displayed between the groups. The clinical improvements persisted 3 months after the intervention. No major alterations of the subgingival microflora were disclosed and the levels of inflammatory mediators in GCF did not differ between the groups.Conclusions.Mechanical debridement and oral hygiene reinforcement resulted in clinical improvement of peri-implant mucositis and a reduction in cytokine levels. Probiotic supplements did not provide added benefit to placebo.
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| 2. |
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| 3. |
- Knutsson, Sofie, et al.
(författare)
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Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:23, s. 10545-10557
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Tidskriftsartikel (refereegranskat)abstract
- Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.
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| 4. |
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| 5. |
- Willems, S. M., et al.
(författare)
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Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
- 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
- Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality. © The Author(s) 2017.
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| 6. |
- Agnér, Ulf, et al.
(författare)
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Bredäng : Miljonprogrammets föregångare
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna publikation är ett resultat av läsåret 2017-2018 i kursen Restaureringskonst vid Kungl. Konsthögskolan, arkitekturavdelningen. Årets tema var bostadsarkitektur. Förvalta, förädla, förvanska? Under läsåret undersöktes bostadsarkitekturen som kulturarv, hur bostadshus och bostadsområden förvaltas, förädlas alternativt förvanskas genom restaureringsåtgärder, förtätningar och omvandlingar. II läsårets projektstudie ingick fem bostadsområden i södra Stockholm, utvalda för att representera varsin epok i 1900-talets bostadsutveckling. En projektgrupp för varje bostadsområde gjorde studier i olika skalor, från den utvalda lägenhetens detaljer, trapphuset och bostadshuset, gården och gatan till stadsdelsnivån.
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| 7. |
- Andersson, C. David, et al.
(författare)
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Benefits of statistical molecular design, covariance analysis, and reference models in QSAR : a case study on acetylcholinesterase
- 2015
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Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 29:3, s. 199-215
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Tidskriftsartikel (refereegranskat)abstract
- Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.
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| 8. |
- Chu, Audrey Y, et al.
(författare)
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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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| 9. |
- Corbin, Laura J., et al.
(författare)
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Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.
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| 10. |
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| 11. |
- Dumanski, Jan P., et al.
(författare)
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Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 98:6, s. 1208-1219
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Tidskriftsartikel (refereegranskat)abstract
- Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
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| 12. |
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| 13. |
- Dumanski, Jan P., et al.
(författare)
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Smoking is associated with mosaic loss of chromosome Y
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6217, s. 81-83
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Tidskriftsartikel (refereegranskat)abstract
- Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.
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| 14. |
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| 15. |
- Ek, Weronica E, et al.
(författare)
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Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:4, s. 817-827
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Tidskriftsartikel (refereegranskat)abstract
- Growth-differentiation factor 15 (GDF-15) is expressed in low to moderate levels in most healthy tissues and increases in response to inflammation. GDF-15 is associated with cardiovascular dysfunction and over-expressed in the myocardium of patients with myocardial infarction (MI). However, little is known about the function of GDF-15 in cardiovascular disease, and the underlying regulatory network of GDF-15 is not known. To investigate a possible association between GDF-15 levels and DNA methylation, we performed a genome-wide DNA methylation study of white blood cells in a population-based study (N = 717). Significant loci where replicated in an independent cohort (N = 963). We also performed a gene ontology (GO) enrichment analysis. We identified and replicated 16 CpG-sites (false discovery rate [FDR] < 0.05), at 11 independent loci including MIR21. MIR21 encodes a microRNA (miR-21) that has previously been shown to be associated with the development of heart disease. Interestingly, GDF15 mRNA contains a binding site for miR-21. Four sites were also differentially methylated in blood from participants previously diagnosed with MI and 14 enriched GO terms (FDR < 0.05, enrichment > 2) were identified, including 'cardiac muscle cell differentiation'. This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease.
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| 16. |
- Engström, Elisabet, et al.
(författare)
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Computer-assisted reading intervention for children with sensorineural hearing loss using hearing aids : Effects on auditory event-related potentials and mismatch negativity
- 2019
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Ingår i: International Journal of Pediatric Otorhinolaryngology. - : Elsevier. - 0165-5876 .- 1872-8464. ; 117, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The primary aim was to investigate whether computer-assisted reading intervention somehow can affect event-related potentials (ERP) and mismatch negativity (MMN) in hearing impaired (HI) children with hearing aids (HAs) and normal hearing (NH) children.METHODS: The study included 15 HI children with sensorineural hearing loss (SNHL) using bilateral HAs and 14 NH children as a reference group; all children between the ages of 5 and 8. A multi-feature MMN-paradigm, Optimum-1, with a standard stimulus alternating with 5 different deviants was used. ERPs were recorded pre and post intervention, i.e. one month of repeatedly computer-assisted training (GraphoGame). MMN was calculated from the average ERP of each deviant minus standard. Data were based on samples within a specific time interval, 80-224 ms, and repeated measures ANOVA was used to analyze possible interactions.RESULTS: There was a significant difference between groups before training, though, the mean obligatory responses or MMN was not statistically significantly different before versus after training, neither among the NH nor the HI children. Further, the HI children did generally achieve lower levels in GraphoGame compared to the NH children. Altogether, our findings indicate differences between the groups and that training may affect the neurophysiological processing in the brain, gaining the HI children. Both MMN and positive mismatch response (pMMR) were seen among both the HA and NH children, irrespective to deviant type. Individually, changes of the MMN and pMMR after training seem unpredictable.CONCLUSION: There are statistically significant differences in both the obligatory responses in ERP and the MMNs between the NH and HI groups before the computer-assisted training. Though, these differences disappear after the intervention. This suggests possible training effects regarding the central auditory processing among the HI children.
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| 17. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 18. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 19. |
- Folkersen, Lasse, et al.
(författare)
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Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
- 2017
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
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| 20. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 21. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 22. |
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| 23. |
- Hallberg, Mathilda
(författare)
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Barn till beskådan : Familj, välfärdsstat och nation i fototävlingar och fotoböcker 1930-1944
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- I fokus för den här avhandlingen står åskådningskulturen under 1930- och 40-talen, närmare bestämt fototävlingar och fotoböcker med bilder på barn som bärande element. Den här studien granskar hur fototävlingar och fotoböcker var en del i förhandlingen om välfärdens organisering rörande barn och familj. I studien undersöks hur familj, välfärdsstat och nation konstruerades genom representationer av barn, vilka budskap som därigenom etablerades och vilka politiska visioner som kommunicerades. Analyser av bilder och texter visar att fototävlingar och fotoböcker presenterade ett enhetligt budskap om att det behövdes fler och bättre barn, men också hur fototävlingar och fotoböcker förmedlade skilda visioner om hur detta skulle uppnås. Studien bidrar till att synliggöra hur användbara representationer av barn var i bygget av välfärden. De hade potential att förmedla både skilda och gemensamma visioner om välfärdssamhället.
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| 24. |
- Hallström, Hadar, et al.
(författare)
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Probiotic supplements and debridement of peri-implant mucositis : A randomized controlled trial
- 2016
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Ingår i: Acta Odontologica Scandinavica. - : Informa Healthcare. - 0001-6357 .- 1502-3850. ; 74:1, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this double-blind randomized placebo-controlled trial was to evaluate the effects of probiotic supplements in adjunct to conventional management of peri-implant mucositis. Materials and methods. Forty-nine adult patients with peri-implant mucositis were consecutively recruited after informed consent. After initial mechanical debridement and oral hygiene instructions, the patients received a topical oil application (active or placebo) followed by twice-daily intake of lozenges (active or placebo) for 3 months. The active products contained a mix of two strains of Lactobacillus reuteri. Patients were clinically monitored and sampled at baseline and after 1, 2, 4, 12 and 26 weeks. The clinical end-points were pocket-probing depth (PPD), plaque index (PI) and bleeding on probing (BOP). In addition, the subgingival microbiota was processed with checkerboard DNA-DNA hybridization and samples of gingival crevicular fluid (GCF) were analyzed for selected cytokines with the aid of multiplex immunoassays. Results. After 4 and 12 weeks, all clinical parameters were improved in both the test and the placebo group. PPD and BOP were significantly reduced compared with baseline (p < 0.05), but no significant differences were displayed between the groups. The clinical improvements persisted 3 months after the intervention. No major alterations of the subgingival microflora were disclosed and the levels of inflammatory mediators in GCF did not differ between the groups. Conclusions. Mechanical debridement and oral hygiene reinforcement resulted in clinical improvement of peri-implant mucositis and a reduction in cytokine levels. Probiotic supplements did not provide added benefit to placebo.
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| 25. |
- Horikoshi, Momoko, et al.
(författare)
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Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
- 2015
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
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| 26. |
- Hubrich, Martin, et al.
(författare)
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Feasibility and Functions of Central Venous Catheters versus Peripherally Inserted Central Venous Catheter
- 2019
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Ingår i: Open Journal of Surgery. - 2689-0593. ; 3:2, s. 028-033
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Tidskriftsartikel (refereegranskat)abstract
- Safety, risk of complications and the functional feasibility among diff erent kinds of central venous access are still a matter of debate. Not many clinical trials have reported a comparison of complications and patency of CVCs versus Peripherally Inserted Catheters (PICC) as central venous access for indoor patients with advanced gastrointestinal disorder. The aim of the present study was to compare CVCs and PICCs regarding function, complications and convenience in a controlled clinical study on patients aimed for oncology surgery aimed for cure. Distributions of patients were comparable. Malignant diagnoses were signifi cantly higher among CVC-patients. CVCs and PICCs were used for treatment during equal number of days, without any signifi cant complication rates and with comparable number of days on antibiotics and other potent drugs. The overall cumulative hazard (risk) for treatment interruptions, due to either full-fi lled clinical indications or due to any complication among the subgroups of patients did not diff er. Central Venous Catheter and Peripheral Inserted Central Venous Catheter, for central venous access, did not diff er among consecutive unselected patients with serious gastro-intestinal disorders.
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| 27. |
- Imsland, Freyja, et al.
(författare)
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Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation underlying Dun camouflage colour in horses
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:2, s. 152-158
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Tidskriftsartikel (refereegranskat)abstract
- Dun is a wild-type coat color in horses characterized by pigment dilution with a striking pattern of dark areas termed primitive markings. Here we show that pigment dilution in Dun horses is due to radially asymmetric deposition of pigment in the growing hair caused by localized expression of the T-box 3 (TBX3) transcription factor in hair follicles, which in turn determines the distribution of hair follicle melanocytes. Most domestic horses are non-dun, a more intensely pigmented phenotype caused by regulatory mutations impairing TBX3 expression in the hair follicle, resulting in a more circumferential distribution of melanocytes and pigment granules in individual hairs. We identified two different alleles (non-dun1 and non-dun2) causing non-dun color. non-dun2 is a recently derived allele, whereas the Dun and non-dun1 alleles are found in ancient horse DNA, demonstrating that this polymorphism predates horse domestication. These findings uncover a new developmental role for T-box genes and new aspects of hair follicle biology and pigmentation.
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| 28. |
- Jeppsson, Cecilia, 1967-, et al.
(författare)
-
Exploring equal opportunities : Children’s experiences of the Swedish Community School of Music and Arts
- 2018
-
Ingår i: Research Studies in Music Education. - : Sage Publications. - 1321-103X .- 1834-5530. ; 40:2, s. 191-210
-
Tidskriftsartikel (refereegranskat)abstract
- This article explores the social stratification of the Swedish Community School of Music and Arts, which offers voluntary extra-curricular arts education to children in Sweden, and children’s experiences of attending the school. A survey was executed where sixth-graders in Sweden were asked about their experiences of the school and about background factors such as their gender, country of birth, parents’ level of education and family involvement in the music and arts. The results show that the typical Swedish Community School of Music and Arts student is a Swedish-born girl with well-educated parents. Children of parents who play an instrument or sing are more likely to find their way to the school, and the level of support that parents provide contributes to the children’s persistence in their studies. In sum, the results largely conform to cultural reproduction theory.
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| 29. |
- Jeppsson, Cecilia, 1967-, et al.
(författare)
-
Exploring equal opportunities : Children’s experiences of the Swedish Community School of Music and Arts
- 2018
-
Ingår i: Research Studies in Music Education. - London : Sage Publications. - 1321-103X .- 1834-5530. ; 40:2, s. 191-210
-
Tidskriftsartikel (refereegranskat)abstract
- This article explores the social stratification of the Swedish Community School of Music and Arts, which offers voluntary extra-curricular arts education to children in Sweden, and children’s experiences of attending the school. A survey was executed where sixth-graders in Sweden were asked about their experiences of the school and about background factors such as their gender, country of birth, parents’ level of education and family involvement in the music and arts. The results show that the typical Swedish Community School of Music and Arts student is a Swedish-born girl with well-educated parents. Children of parents who play an instrument or sing are more likely to find their way to the school, and the level of support that parents provide contributes to the children’s persistence in their studies. In sum, the results largely conform to cultural reproduction theory. © The Author(s) 2018
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| 30. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
-
Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 31. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
-
Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 32. |
- Kallioinen, Petter, et al.
(författare)
-
Semantic Processing in Deaf and Hard-of-Hearing Children : Large N400 Mismatch Effects in Brain Responses, Despite Poor Semantic Ability
- 2016
-
Ingår i: Frontiers in Psychology. - London : Frontiers Media SA. - 1664-1078. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Difficulties in auditory and phonological processing affect semantic processing in speech comprehension for deaf and hard-of-hearing (DHH) children. However, little is known about brain responses related to semantic processing in this group. We investigated event-related potentials (ERPs) in DHH children with cochlear implants (CIs) and/or hearing aids (HAs), and in normally hearing controls (NH). We used a semantic priming task with spoken word primes followed by picture targets. In both DHH children and controls, cortical response differences between matching and mismatching targets revealed a typical N400 effect associated with semantic processing. Children with CI had the largest mismatch response despite poor semantic abilities overall; Children with CI also had the largest ERP differentiation between mismatch types, with small effects in within-category mismatch trials (target from same category as prime) and large effects in between-category mismatch trials (where target is from a different category than prime), compared to matching trials. Children with NH and HA had similar responses to both mismatch types. While the large and differentiated ERP responses in the CI group were unexpected and should be interpreted with caution, the results could reflect less precision in semantic processing among children with CI, or a stronger reliance on predictive processing.
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| 33. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 34. |
- Knowles, Joshua W., et al.
(författare)
-
Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
- 2015
-
Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:4, s. 1739-1751
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Tidskriftsartikel (refereegranskat)abstract
- Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
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| 35. |
- Kraja, Aldi T., et al.
(författare)
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New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals
- 2017
-
Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 1942-325X .- 1942-3268. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Methods and Results - Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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| 36. |
- Lagging, Cecilia, et al.
(författare)
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APOE ε4 is associated with younger age at ischemic stroke onset but not with stroke outcome
- 2019
-
Ingår i: Neurology. - 1526-632X. ; 93:19, s. 849-853
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Tidskriftsartikel (refereegranskat)abstract
- Stroke outcome is determined by a complex interplay, where age and stroke severity are predominant predictors. Studies on hemorrhagic stroke indicate that APOE genotype is a predictor of poststroke outcomes,1,2 but results from studies on ischemic stroke are more conflicting.1,3 There is 1 study suggesting an influence of APOE genotype on age at ischemic stroke onset,4 and sex-specific effects on outcome have been reported.5 Taken together, there is a need for larger studies on APOE and ischemic stroke outcomes with integrated information on age, severity, and sex.The 3 common APOE alleles ε2, ε3, and ε4 can be separated by a combination of 2 single nucleotide polymorphisms (SNPs), rs429358 and rs7412. Thus, associations with APOE alleles are not directly captured in a regular genome-wide association study (GWAS), where each SNP is investigated separately. We derived the 3 common APOE alleles and investigated the interplay between APOE, age at ischemic stroke onset, severity, sex, and outcome within a large international collaboration, the Genetics of Ischaemic Stroke Functional Outcome (GISCOME) network.
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| 37. |
- Lind, Judith, 1971-, et al.
(författare)
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Displays of parent suitability in adoption assessment reports
- 2017
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Ingår i: Child & Family Social Work. - : John Wiley & Sons. - 1356-7500 .- 1365-2206. ; 22:S1, s. 53-63
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Tidskriftsartikel (refereegranskat)abstract
- Through adoption, the state actively contributes to creating families. It therefore also assumes the role of guarantor of the child’s best interests in the adoption process, which entails assessing the suitability of presumptive adoptive parents. In the present article, we use the concluding sections of assessment reports on applicants for intercountry adoption in Sweden to answer the following question: What must be said about an individual or a couple in order for her/them to be seen as a suitable adoptive parent? We thus assume that report conclusions serve to display parent suitability to their audiences. The assessment aligns with Swedish national adoption guidelines, and the study shows how the assessment handbook comes to serve as a catalogue of arguments that not only define good parenthood, but also outline a way of life that is suitable for parenthood. The analysis illustrates how valid arguments for granting consent to adopt refer to three layers of suitability. They include not only the applicants’ insights into and knowledge about adoption in particular and children in general, but also their conventional and orderly life, i.e. a life free from distractions that could hinder a wholehearted focus on children and family life.
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| 38. |
- Lind, Lars, et al.
(författare)
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Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p '-dde levels in a population-based sample
- 2017
-
Ingår i: Environment International. - Oxford, United Kingdom : Elsevier. - 0160-4120 .- 1873-6750. ; 98, s. 212-218
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p, p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.Results: Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472 ng/g lipid, while the corresponding level for those being homozygote for the T allelewas 192 ng/g lipid (p= 1.5x10(-31)). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19: 41520351; p= 2.2 x 10(-8)). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p= 6.2 x 10(-9)) located 7 kb downstreamthe CYP2B6 gene (cg27089200, position chr19: 41531976). This CpG-sitewas also related to the lead SNP (p = 3.8 x 10(-35)), but mediated only 4% of the effect of the lead SNP on p, p'-DDE levels.Conclusion: Circulating levels of p, p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p, p'-DDE levels.
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| 39. |
- Lindgren, Cecilia, et al.
(författare)
-
Cerebrospinal fluid lactate and neurological outcome after subarachnoid haemorrhage
- 2019
-
Ingår i: Journal of Clinical Neuroscience. - : Elsevier BV. - 0967-5868 .- 1532-2653. ; 60, s. 63-67
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Increased lactate in cerebrospinal fluid (CSF) has been regarded as a marker for cerebral ischemia and damage in the central nervous system. The aim of this study was to evaluate if CSF-lactate was associated with; impaired cerebral circulation, outcome, sex, age, clinical condition or treatment after subarachnoid haemorrhage (SAH). Methods: This study consists of 33 patients (22 females, 11 males) with aneurysmal SAH treated at Umea university hospital 2008-2009. Samples were obtained from external ventricular catheters 0-240 h after SAH. Normal CFS-lactate was defined as 1.2-2-1 mmol/L. Hunt & Hess scale assessed clinical condition. Impaired cerebral circulation was evaluated by clinical examination, transcranial doppler, CT-scan, and cerebral angiography. Glasgow outcome scale (GOS) evaluated outcome. Results: Seventy-nine CSF-lactate samples were analysed. CSF-lactate >2.1 mmol/L was found in 25/33 (76%) patients and in 50/79 (63%) samples. No difference in CSF-lactate levels was found over time. No association was found between patients with CSF-lactate >2.1 mmol/L and; sex, severity of clinical condition, impaired cerebral circulation or outcome. CSF-lactate >2.1 mmol/L was more common in patients >= 61 years of age (p = 0.04) and in patients treated with endovascular coiling compared to surgical clipping (p = 0.0001). Conclusion: In patients with SAH, no association was found between increased CSF-lactate (>2.1 mmol/L) and severe clinical condition, impaired cerebral circulation or unfavourable outcome. Endovascular coiling and age >= 61 years was associated with CSF-lactate above >2.1 mmol/L. (C) 2018 Published by Elsevier Ltd.
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| 40. |
- Lindgren, Cecilia, 1988-
(författare)
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Design strategies for new drugs targeting multicomponent systems : focusing on class II MHC proteins and acetylcholinesterase
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The field of medicinal chemistry is constantly evolving. Aided by advances within techniques as well as knowledge of biological systems, increasingly complex targets and drugs can be considered. This thesis includes two projects focusing on the design of drugs targeting multicomponent systems, referring to systems for which multiple components must be considered during the drug design process.In the first project, the long-term goal is to develop a vaccine against the autoimmune disease rheumatoid arthritis (RA). The cause of RA is unknown, but it is genetically linked to expression of class II MHC proteins that present antigens to T-cell receptors (TCRs), responsible for initiating an immune response. A glycopeptide fragment, CII259–273, from type II collagen has shown promising results as a vaccine against arthritis resembling RA in mice. CII259–273 binds to the class II MHC protein followed by presentation to the TCR, forming a multicomponent system.We have used molecular dynamics (MD) simulations to study the effect that modifications of CII259–273 have on the multicomponent system. Non-native amino acids and amide bond isosteres have been introduced. This has demonstrated the importance of retaining the backbone conformation of CII259–273, as well as the hydrogen bonds formed to the backbone. The ability to introduce such modifications would be of value to affect the potency towards the MHC protein, and prevent degradation of the glycopeptide. The studies have revealed a multicomponent system that is highly sensitive to even small modifications that can affect the dynamics of the entire complex.In the second project, the long-term goal is to develop a broad-spectrum antidote against nerve agents. Nerve agents are extremely toxic compounds that act by covalently inhibiting the enzyme acetylcholinesterase (AChE), which is essential for termination of nerve signalling. A major limitation of current antidotes is that their efficiency is dependent on the type of nerve agent. A broad-spectrum antidote must be able to bind to the multicomponent system consisting of AChE covalently inhibited by different nerve agents. It will then act by performing a nucleophilic attack on the nerve agent adduct, thus breaking the covalent bond to AChE.We have used statistical molecular design (SMD) and quantitative structure-activity relationship (QSAR) modelling to identify a fragment with a potency for AChE inhibited by different nerve agents. A nucleophilic component able to restore the enzyme to the active form was thereafter introduced. This resulted in a functional reactivator, efficient for multiple nerve agents. Furthermore, the mechanism of reactivation has been investigated through structural studies, enabled by a combination of X-ray crystallography and molecular modelling. A high flexibility of the reactivator, as well as the ability to bind to AChE in multiple conformations, are defined as important properties for a broad-spectrum antidote.
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| 41. |
- Lindgren, Cecilia, et al.
(författare)
-
Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis
- 2018
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:11, s. 4774-4790
-
Tidskriftsartikel (refereegranskat)abstract
- Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CI1259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CI1259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CI1259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CI1259-273, together with the positioning of the galactose moiety of CI1259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CI1259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.
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| 42. |
- Lindgren, Cecilia, et al.
(författare)
-
Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A(q)/glycopeptide complexes
- 2015
-
Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 13:22, s. 6203-6216
-
Tidskriftsartikel (refereegranskat)abstract
- Class II major histocompatibility complex (MHC) proteins are involved in initiation of immune responses to foreign antigens via presentation of peptides to receptors of CD4(+) T-cells. An analogous presentation of self-peptides may lead to autoimmune diseases, such as rheumatoid arthritis (RA). The glycopeptide fragment CII259-273, derived from type II collagen, is presented by A(q) MHCII molecules in the mouse and has a key role in development of collagen induced arthritis (CIA), a validated model for RA. We have introduced hydroxyethylene amide bond isosteres at the Ala(261)-Gly(262) position of CII259-273. Biological evaluation showed that A(q) binding and T cell recognition were dramatically reduced for the modified glycopeptides, although static models predicted similar binding modes as the native type II collagen fragment. Molecular dynamics (MD) simulations demonstrated that introduction of the hydroxyethylene isosteres disturbed the entire hydrogen bond network between the glycopeptides and A(q). As a consequence the hydroxyethylene isosteric glycopeptides were prone to dissociation from A(q) and unfolding of the beta(1)-helix. Thus, the isostere induced adjustment of the hydrogen bond network altered the structure and dynamics of A(q)/glycopeptide complexes leading to the loss of A(q) affinity and subsequent T cell response.
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| 43. |
- Lindgren, Cecilia, 1969-
(författare)
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Ideals of parenting and childhood in the contact zone of intercountry adoption : Assessment of second-time adoption applicants in Sweden
- 2015
-
Ingår i: Childhood. - : Sage Publications. - 0907-5682 .- 1461-7013. ; 22:4, s. 474-489
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Tidskriftsartikel (refereegranskat)abstract
- Intercountry adoption is a global phenomenon, a contact zone in which notions of ‘good parents’ and ‘the child’s best interest’ are negotiated. This article explores what norms of parenthood and childhood Sweden, as a receiving country, communicates in the global flow of children and ideas. Adoption assessment reports are examined, with a focus on how adoption applicants are portrayed and how ‘good parents’ are thereby construed. The analysis demonstrates how certain qualities, for example, being loving, self-sacrificing and child-centred, are ascribed to applicants, and how the presentation of ‘good parents’ also defines a proper childhood.
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| 44. |
- Lindgren, Cecilia, et al.
(författare)
-
Leptin levels after subarachnoid haemorrhage are gender dependent
- 2016
-
Ingår i: Springerplus. - : Springer Science and Business Media LLC. - 2193-1801. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Subarachnoid hemorrhage (SAH) is a neurological disease where the majority of the patients are critically ill. The adipokine leptin has in cerebral emergencies been related to severity of disease and to adverse outcome. The aim of this study was to examine leptin levels over time after SAH and associations to gender, age, body mass index, severity of disease, parenteral lipids, systemic organ failure and outcome. Methods: Prospective observational study in 56 patients. Leptin was obtained 0-240 h after SAH, in 48 h intervals. Severity of disease was assessed with the Hunt and Hess score, organ failure with the sequential organ failure assessment score, and outcome with Glasgow outcome scale. Leptin levels in the SAH group were compared with controls from the same geographical area. Results: At admission, Leptin was significantly higher in SAH patients compared to controls, both in female (28.6 +/- 25.6 vs 13.0 +/- 2.3 ng/mL, p = 0.001) and male patients (13.3 +/- 8.4 vs 4.3 +/- 0.7 ng/mL, p = 0.001). Leptin levels remained stable over time. Female patients had significantly higher leptin levels than male patients, and deceased female patients had higher leptin levels than female survivors (85.5 +/- 20.5 vs 50.5 +/- 34.6, n = 4/35, p < 0.05). Leptin levels did not differ between male survivors and non-survivors. Leptin levels were not associated with severity of disease, organ failure or parenteral lipids. Conclusion: Leptin levels were significantly higher in both male and female patients compared to controls. Higher leptin levels were related to outcome and organ failure in women but not in men. When analysing leptin levels gender-related differences should be considered.
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| 45. |
- Lindgren, Cecilia, et al.
(författare)
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Long-term subarachnoid haemorrhage survivors still die due to cerebrovascular causes
- 2015
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Ingår i: Acta Neurologica Scandinavica. - : John Wiley & Sons. - 0001-6314 .- 1600-0404. ; 132:6, s. 410-416
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Subarachnoid haemorrhage (SAH) is associated with sympathetic nervous activation and inflammation. SAH could therefore theoretically be a risk factor for development of cardiovascular disease. The aim of this study was to investigate whether long-term (>/=1 year) SAH survivors had an increased risk of death due to cardiovascular causes. MATERIAL & METHODS: SAH patients >/=18 years treated at Umea University Hospital between 1986 and 2006 were eligible for inclusion. Deceased patients were identified in the Swedish population register. Death certificates from long-term SAH survivors and causes of death in the general population were obtained from the National Board of Health and Welfare, Sweden. The prevalence of comorbidities at the time of SAH was compared with the distribution of cardiovascular risk factors in the northern Sweden MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) health survey. Analyses were stratified for age and sex. RESULTS: In the SAH patients, the median year of SAH was 1992 and the median year of death was 2001. The MONICA survey in 1994 and the distribution of deaths in the general population in 2001 were used for comparison. Long-term SAH survivors had, compared to the general population, a significantly increased risk for death due to cerebrovascular disease (P < 0.0001), but not for death due to cardiovascular disease. Hypertension was more common in SAH patients compared to survey participants (P < 0.01). CONCLUSION: Cerebrovascular causes of death were significantly more common in long-term survivors after SAH compared to the general population.
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| 46. |
- Lindgren, Cecilia, 1969-, et al.
(författare)
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Sustaining and transgressing borders : The relationship between children and the elderly in Mad Men
- 2018
-
Ingår i: Connecting childhood and old age in popular media. - Jackson, MS : University Press of Mississippi. - 9781496815163 ; , s. 184-206
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Bokkapitel (refereegranskat)abstract
- Children and the elderly are, in various contexts, portrayed as ideal companions, and positioned as “others” in relation to the more powerful generation in between (Joosen 128, 136-138; Hockey and James 2-5). In children’s literature, for example, the relationship between the two age groups tends to be romanticized, featuring their mutual interests in nature, animals, fantasy and storytelling. In this chapter, we explore how the two categories meet in the award-winning drama TV series Mad Men. The aim is to scrutinize the link between childhood and old age, by analyzing how the relationships between a young girl, Sally Draper, and her elderly relatives are played out. Exploring key scenes, we show how the companionship between children and the elderly is constructed as rewarding for both parties, yet as provocative and challenging rather than romantic and harmless...
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| 47. |
- Lindgren, Cecilia
(författare)
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Time for good parenthood : a study of intercountry adoption assessment
- 2016
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Ingår i: Doing good parenthood. - Cham : Palgrave Macmillan. - 9783319467733 ; , s. 17-27
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this study is to explore how parents’ opinions and actions related to time are presented in intercountry adoption assessment reports concerning applicants who have been granted consent to adopt. As these reports establish what is required for someone to be categorised as a suitable parent, they construct and display the moral order of parenthood. An analysis of statements about time, as it relates to parental leave, working hours, preschool hours, family activities, leisure time and hobbies, illustrates how meanings of good parenthood are discursively produced. Good parents make time for, and spend time with, their children. They invest in togetherness by exchanging time of lesser value for time of greater value. This officially sanctioned understanding of good parenthood corresponds with the cultural norm of involved, devoted and child-centred parents, and reinforces the romanticised image of quality time and togetherness in the lives of nuclear families.
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| 48. |
- Lindgren, Monica, 1958, et al.
(författare)
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Explorativ design för lärande i doktorandseminarier
- 2017
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Ingår i: Högskolepedagogisk konferens i Göteborg (HKG 2017).
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Bakgrund Forskarskolan CUL vid Göteborgs universitet är indelad i fem forskningsteman som spänner över olika ämnesdiscipliner och vetenskapsområden. Idén med forskningstema är att ge möjligheter till utveckling av en kreativ forskningsmiljö över fakultetsgränserna. Varje tema leds av två forskare vars uppgift är att stödja doktoranderna i deras utveckling samt lägga grunden till ett långsiktigt fakultetsövergripande samarbete kring utbildningsvetenskapliga frågor. Inom temat Utbildning, undervisning och lärande med inriktning mot kultur och estetik studeras estetiska och praktiknära ämnen och läroprocesser i förskola, grundskola och gymnasieskola, men även barns och ungas vardagskulturella uttryck i en alltmer globaliserad och digitaliserad värld. Doktorander och forskare från konstnärliga, utbildningsvetenskapliga och humanistiska fakulteten är aktiva i temat. Verksamheten inriktas mot reguljära doktorandseminarier men även öppna seminarier och konferenser arrangeras inom ramen för temat utifrån aktuella frågor och texter inom ramen för forskningsintresset. Under år 2016 och 2017 har temat experimenterat med seminarieform. Seminarier och öppna minikonferenser har designats utifrån en explorativ design, där seminarieform har designats och gestaltats på skilda sätt. Syftet har varit att skapa en kreativ forskningsmiljö och samtidigt utveckla och studera design för undervisning i högre utbildning generellt. Tidigare forskning har bland annat pekat på makthierarkier i forskningsseminarier (Cronqvist & Maurits, 2016), något som kan motverka den kreativa miljö som eftersträvas inom temat. Syfte och frågeställningar Konferensbidraget syftar till att diskutera frågan om formens betydelse för utveckling och lärande i högskolepedagogisk undervisningskontext, i detta fall forskarutbildning. Med ett antal exempel, hämtade från CUL-temat Kultur och estetiks verksamhet under år 2016 och 2017, ställs följande specifika frågeställning för bidraget: Hur kan formen för doktorandseminarier designas explorativt? Metod och teori Teoretiskt och metodologiskt tas avstamp i teorier om design för lärande (Rostwall & Selander, 2010) samt Levines (2014) teori om sociala arrangemang och ”affordances”. Metodologiskt bygger studien på självkritisk reflexiv etnografi. Som temaledare är vi själva en del i den sociala praktik som CUL-temat utgör, och konstruerar således också själva denna praktik i produktionen av data. Därigenom ställs stora krav på en hög grad av självprövning, och i summering och analys av fältanteckningar, observationer, samtal och doktorandreflektioner har vi försökt att utveckla ett självkritiskt förhållningssätt kring egna förgivettagna föreställningar (Alvesson, 2003) genom att tillsammans pröva olika typer av tolkningar. Vid konferenspresentationen kommer analysen av tre case från temaverksamheten att presenteras och det preliminära resultatet lyftas till diskussion kring såväl forskarutbildning som högre utbildning generellt.
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| 49. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 50. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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