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- Gaulton, Kyle J, et al.
(author)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Journal article (peer-reviewed)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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| 4. |
- Lewin, Susanne, et al.
(author)
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Bone Volume Assessment Around Dental Implants After Open Maxillary Sinus Elevation Surgery : A Quantitative Approach to CBCT Images
- 2019
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In: International Journal of Oral & Maxillofacial Implants. - : QUINTESSENCE PUBLISHING CO INC. - 0882-2786 .- 1942-4434. ; 34:2, s. 489-498
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Journal article (peer-reviewed)abstract
- Purpose: Cone beam computed tomography (CBCT) is an important imaging technique in maxillofacial evaluations. However, application-specific image analysis methods aimed at extracting quantitative information from these images need to be further developed. The aim of this study was to provide a robust and objective method that could assess radiologic changes around dental implants after sinus elevation surgery with simultaneous implant placement.Materials and Methods: The study was performed retrospectively on patients fulfilling the inclusion criteria. The included patients had been CBCT scanned preoperatively, at baseline (early after surgery), and 6 months postoperatively. In order to quantify the radiologic changes, an image analysis workflow was developed based on the postoperative baseline and 6-month scans. The workflow included metal artifact reduction, registration, and a standardized protocol for semiautomatic segmentation. Validation of different steps of the method was conducted by comparing scans from all time points. Comparison of constant volumes (eg, screws and bony parts not subjected to change) was used. Additionally, the Dice similarity coefficient (DSC) was used to measure the overlap of the segmentations.Results: The study included nine maxillary sinuses from six patients. The bone formation was quantified and visualized in 3D. In the validation, no significant differences were found for the constant volumes at the different scanning time points. The DSC showed accurate results with values > 0.92.Conclusion: The method presented in this study provides an objective and robust evaluation of bone formation around dental implants. The same methodologies can be applied in other studies of dental CBCT images, eg, for comparison of grafting materials or surgical strategies.
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| 6. |
- Lewin, Susanne, et al.
(author)
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Evaluation of bone formation in calcium phosphate scaffolds with μCT-method validation using SEM
- 2017
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In: Biomedical Materials. - : Institute of Physics (IOP). - 1748-6041 .- 1748-605X. ; 12:6
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Journal article (peer-reviewed)abstract
- There is a plethora of calcium phosphate (CaP) scaffolds used as synthetic substitutes to bone grafts. The scaffold performance is often evaluated from the quantity of bone formed within or in direct contact with the scaffold. Micro-computed tomography (mu CT) allows three-dimensional evaluation of bone formation inside scaffolds. However, the almost identical x-ray attenuation of CaP and bone obtrude the separation of these phases in mu CT images. Commonly, segmentation of bone in mu CT images is based on gray scale intensity, with manually determined global thresholds. However, image analysis methods, and methods for manual thresholding in particular, lack standardization and may consequently suffer from subjectivity. The aim of the present study was to provide a methodological framework for addressing these issues. Bone formation in two types of CaP scaffold architectures (foamed and robocast), obtained from a larger animal study (a 12 week canine animal model) was evaluated by mu CT. In addition, cross-sectional scanning electron microscopy (SEM) images were acquired as references to determine thresholds and to validate the result. mu CT datasets were registered to the corresponding SEM reference. Global thresholds were then determined by quantitatively correlating the different area fractions in the mu CT image, towards the area fractions in the corresponding SEM image. For comparison, area fractions were also quantified using global thresholds determined manually by two different approaches. In the validation the manually determined thresholds resulted in large average errors in area fraction (up to 17%), whereas for the evaluation using SEM references, the errors were estimated to be less than 3%. Furthermore, it was found that basing the thresholds on one single SEM reference gave lower errors than determining them manually. This study provides an objective, robust and less error prone method to determine global thresholds for the evaluation of bone formation in CaP scaffolds.
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- Murtada, S.-I., et al.
(author)
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Adaptation of active tone in the mouse descending thoracic aorta under acute changes in loading
- 2015
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In: Biomechanics and Modeling in Mechanobiology. - : Springer Berlin/Heidelberg. - 1617-7959 .- 1617-7940. ; 15, s. 579-592
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Journal article (peer-reviewed)abstract
- Arteries can adapt to sustained changes in blood pressure and flow, and it is thought that these adaptive processes often begin with an altered smooth muscle cell activity that precedes any detectable changes in the passive wall components. Yet, due to the intrinsic coupling between the active and passive properties of the arterial wall, it has been difficult to delineate the adaptive contributions of active smooth muscle. To address this need, we used a novel experimental–computational approach to quantify adaptive functions of active smooth muscle in arterial rings excised from the proximal descending thoracic aorta of mice and subjected to short-term sustained circumferential stretches while stimulated with various agonists. A new mathematical model of the adaptive processes was derived and fit to data to describe and predict the effects of active tone adaptation. It was found that active tone was maintained when the artery was adapted close to the optimal stretch for maximal active force production, but it was reduced when adapted below the optimal stretch; there was no significant change in passive behavior in either case. Such active adaptations occurred only upon smooth muscle stimulation with phenylephrine, however, not stimulation with KCl or angiotensin II. Numerical simulations using the proposed model suggested further that active tone adaptation in vascular smooth muscle could play a stabilizing role for wall stress in large elastic arteries.
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| 11. |
- Scott, Robert A., et al.
(author)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Journal article (peer-reviewed)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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