| 1. |
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| 2. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 3. |
- Ruiz-Ramos, Miguel, et al.
(författare)
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Adaptation response surfaces for managing wheat under perturbed climate and CO2 in a Mediterranean environment
- 2018
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Ingår i: Agricultural Systems. - : Elsevier BV. - 0308-521X. ; 159, s. 260-274
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Tidskriftsartikel (refereegranskat)abstract
- Adaptation of crops to climate change has to be addressed locally due to the variability of soil, climate and the specific socio-economic settings influencing farm management decisions. Adaptation of rainfed cropping systems in the Mediterranean is especially challenging due to the projected decline in precipitation in the coming decades, which will increase the risk of droughts. Methods that can help explore uncertainties in climate projections and crop modelling, such as impact response surfaces (IRSs) and ensemble modelling, can then be valuable for identifying effective adaptations. Here, an ensemble of 17 crop models was used to simulate a total of 54 adaptation options for rainfed winter wheat (Triticum aestivum) at Lleida (NE Spain). To support the ensemble building, an ex post quality check of model simulations based on several criteria was performed. Those criteria were based on the "According to Our Current Knowledge" (AOCK) concept, which has been formalized here. Adaptations were based on changes in cultivars and management regarding phenology, vernalization, sowing date and irrigation. The effects of adaptation options under changed precipitation (P), temperature (T), [CO2] and soil type were analysed by constructing response surfaces, which we termed, in accordance with their specific purpose, adaptation response surfaces (ARSs). These were created to assess the effect of adaptations through a range of plausible P, T and [CO2] perturbations. The results indicated that impacts of altered climate were predominantly negative. No single adaptation was capable of overcoming the detrimental effect of the complex interactions imposed by the P, T and [CO2] perturbations except for supplementary irrigation (sI), which reduced the potential impacts under most of the perturbations. Yet, a combination of adaptations for dealing with climate change demonstrated that effective adaptation is possible at Lleida. Combinations based on a cultivar without vernalization requirements showed good and wide adaptation potential. Few combined adaptation options performed well under rainfed conditions. However, a single sI was sufficient to develop a high adaptation potential, including options mainly based on spring wheat, current cycle duration and early sowing date. Depending on local environment (e.g. soil type), many of these adaptations can maintain current yield levels under moderate changes in T and P, and some also under strong changes. We conclude that ARSs can offer a useful tool for supporting planning of field level adaptation under conditions of high uncertainty.
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| 4. |
- Sakornsakolpat, Phuwanat, et al.
(författare)
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Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 494-505
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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| 5. |
- Rodríguez, A., et al.
(författare)
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Implications of crop model ensemble size and composition for estimates of adaptation effects and agreement of recommendations
- 2019
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Ingår i: Agricultural and Forest Meteorology. - : Elsevier BV. - 0168-1923 .- 1873-2240. ; 264, s. 351-362
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Tidskriftsartikel (refereegranskat)abstract
- Climate change is expected to severely affect cropping systems and food production in many parts of the world unless local adaptation can ameliorate these impacts. Ensembles of crop simulation models can be useful tools for assessing if proposed adaptation options are capable of achieving target yields, whilst also quantifying the share of uncertainty in the simulated crop impact resulting from the crop models themselves. Although some studies have analysed the influence of ensemble size on model outcomes, the effect of ensemble composition has not yet been properly appraised. Moreover, results and derived recommendations typically rely on averaged ensemble simulation results without accounting sufficiently for the spread of model outcomes. Therefore, we developed an Ensemble Outcome Agreement (EOA) index, which analyses the effect of changes in composition and size of a multi-model ensemble (MME) to evaluate the level of agreement between MME outcomes with respect to a given hypothesis (e.g. that adaptation measures result in positive crop responses). We analysed the recommendations of a previous study performed with an ensemble of 17 crop models and testing 54 adaptation options for rainfed winter wheat (Triticum aestivum L.) at Lleida (NE Spain) under perturbed conditions of temperature, precipitation and atmospheric CO2 concentration. Our results confirmed that most adaptations recommended in the previous study have a positive effect. However, we also showed that some options did not remain recommendable in specific conditions if different ensembles were considered. Using EOA, we were able to identify the adaptation options for which there is high confidence in their effectiveness at enhancing yields, even under severe climate perturbations. These include substituting spring wheat for winter wheat combined with earlier sowing dates and standard or longer duration cultivars, or introducing supplementary irrigation, the latter increasing EOA values in all cases. There is low confidence in recovering yields to baseline levels, although this target could be attained for some adaptation options under moderate climate perturbations. Recommendations derived from such robust results may provide crucial information for stakeholders seeking to implement adaptation measures.
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| 6. |
- Chandran, P. S., et al.
(författare)
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Cluster detection in cytology images using the cellgraph method
- 2012
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Ingår i: Information Technology in Medicine and Education (ITME), 2012 International Symposium. - 9781467321099 ; , s. 923-927
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Konferensbidrag (refereegranskat)abstract
- Automated cervical cancer detection system is primarily based on delineating the cell nuclei and analyzing their textural and morphometric features for malignant characteristics. The presence of cell clusters in the slides have diagnostic value, since malignant cells have a greater tendency to stick together forming clusters than normal cells. However, cell clusters pose difficulty in delineating nucleus and extracting features reliably for malignancy detection in comparison to free lying cells. LBC slide preparation techniques remove biological artifacts and clustering to some extent but not completely. Hence cluster detection in automated cervical cancer screening becomes significant. In this work, a graph theoretical technique is adopted which can identify and compute quantitative metrics for this purpose. This method constructs a cell graph of the image in accordance with the Waxman model, using the positional coordinates of cells. The computed graph metrics from the cell graphs are used as the feature set for the classifier to deal with cell clusters. It is a preliminary exploration of using the topological analysis of the cellgraph to cytological images and the accuracy of classification using SVM showed that the results are well suited for cluster detection.
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| 7. |
- Shrine, Nick, et al.
(författare)
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New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 481-493
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Tidskriftsartikel (refereegranskat)abstract
- Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
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| 8. |
- Broman, Marcus Ewert, et al.
(författare)
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Malignant hyperthermia, a Scandinavian update.
- 2015
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 59:8, s. 951-961
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Forskningsöversikt (refereegranskat)abstract
- Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can activate an explosive life threatening clinical reaction. Leading symptoms are hypercarbia, muscle rigidity, and metabolic acidosis. MH is inherited in an autosomal-dominant manner and linked to mutations in the large ryanodine 1 gene (RYR1) gene in the majority of cases. Very few MH patients have been found to carry mutations in the CACNA1S gene.
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| 9. |
- Fronzek, Stefan, et al.
(författare)
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Classifying multi-model wheat yield impact response surfaces showing sensitivity to temperature and precipitation change
- 2018
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Ingår i: Agricultural Systems. - : Elsevier BV. - 0308-521X. ; 159, s. 209-224
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Tidskriftsartikel (refereegranskat)abstract
- Crop growth simulation models can differ greatly in their treatment of key processes and hence in their response to environmental conditions. Here, we used an ensemble of 26 process-based wheat models applied at sites across a European transect to compare their sensitivity to changes in temperature (-2 to +9°C) and precipitation (-50 to +50%). Model results were analysed by plotting them as impact response surfaces (IRSs), classifying the IRS patterns of individual model simulations, describing these classes and analysing factors that may explain the major differences in model responses.The model ensemble was used to simulate yields of winter and spring wheat at four sites in Finland, Germany and Spain. Results were plotted as IRSs that show changes in yields relative to the baseline with respect to temperature and precipitation. IRSs of 30-year means and selected extreme years were classified using two approaches describing their pattern.The expert diagnostic approach (EDA) combines two aspects of IRS patterns: location of the maximum yield (nine classes) and strength of the yield response with respect to climate (four classes), resulting in a total of 36 combined classes defined using criteria pre-specified by experts. The statistical diagnostic approach (SDA) groups IRSs by comparing their pattern and magnitude, without attempting to interpret these features. It applies a hierarchical clustering method, grouping response patterns using a distance metric that combines the spatial correlation and Euclidian distance between IRS pairs. The two approaches were used to investigate whether different patterns of yield response could be related to different properties of the crop models, specifically their genealogy, calibration and process description.Although no single model property across a large model ensemble was found to explain the integrated yield response to temperature and precipitation perturbations, the application of the EDA and SDA approaches revealed their capability to distinguish: (i) stronger yield responses to precipitation for winter wheat than spring wheat; (ii) differing strengths of response to climate changes for years with anomalous weather conditions compared to period-average conditions; (iii) the influence of site conditions on yield patterns; (iv) similarities in IRS patterns among models with related genealogy; (v) similarities in IRS patterns for models with simpler process descriptions of root growth and water uptake compared to those with more complex descriptions; and (vi) a closer correspondence of IRS patterns in models using partitioning schemes to represent yield formation than in those using a harvest index.Such results can inform future crop modelling studies that seek to exploit the diversity of multi-model ensembles, by distinguishing ensemble members that span a wide range of responses as well as those that display implausible behaviour or strong mutual similarities.
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| 10. |
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| 11. |
- Janssen, S., et al.
(författare)
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Defining assessment projects and scenarios for policy support: Use of ontology in Integrated Assessment and Modelling
- 2009
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Ingår i: Environmental Modelling & Software. - : Elsevier BV. - 1873-6726 .- 1364-8152. ; 24:12, s. 1491-1500
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Konferensbidrag (refereegranskat)abstract
- Integrated Assessment and Modelling (IAM) provides an interdisciplinary approach to support ex-ante decision-making by combining quantitative models representing different systems and scales into a framework for integrated assessment. Scenarios in IAM are developed in the interaction between scientists and stakeholders to explore possible pathways of future development. As IAM typically combines models from different disciplines, there is a clear need for a consistent definition and implementation of scenarios across models, policy problems and scales. This paper presents such a unified conceptualization for scenario and assessment projects. We demonstrate the use of common ontologies in building this unified conceptualization, e.g. a common ontology on assessment projects and scenarios. The common ontology and the process of ontology engineering are used in a case study, which refers to the development of SEAMLESS-IF, an integrated modelling framework to assess agricultural and environmental policy options as to their contribution to sustainable development. The presented common ontology on assessment projects and scenarios can be reused by IAM consortia and if required, adapted by using the process of ontology engineering as proposed in this paper. (C) 2009 Elsevier Ltd. All rights reserved.
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| 12. |
- Majzoub, Ramsey N, et al.
(författare)
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Fluorescence microscopy colocalization of lipid-nucleic acid nanoparticles with wildtype and mutant Rab5-GFP: A platform for investigating early endosomal events.
- 2015
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 0005-2736. ; 1848:6, s. 1308-1318
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Tidskriftsartikel (refereegranskat)abstract
- Endosomal entrapment is known to be a major bottleneck to successful cytoplasmic delivery of nucleic acids (NAs) using cationic liposome-NA nanoparticles (NPs). Quantitative measurements of distributions of NPs within early endosomes (EEs) have proven difficult due to the sub-resolution size and short lifetime of wildtype EEs. In this study we used Rab5-GFP, a member of the large family of GTPases which cycles between the plasma membrane and early endosomes, to fluorescently label early endosomes. Using fluorescence microscopy and quantitative image analysis of cells expressing Rab5-GFP, we found that at early time points (t<1h), only a fraction (≈35%) of RGD-tagged NPs (which target cell surface integrins) colocalize with wildtype EEs, independent of the NP's membrane charge density. In comparison, a GTP-hydrolysis deficient mutant, Rab5-Q79L, which extends the size and lifetime of EEs yielding giant early endosomes (GEEs), enabled us to resolve and localize individual NPs found within the GEE lumen. Remarkably, nearly all intracellular NPs are found to be trapped within GEEs implying little or no escape at early time points. The observed small degree of colocalization of NPs and wildtype Rab5 is consistent with recycling of Rab5-GDP to the plasma membrane and not indicative of NP escape from EEs. Taken together, our results show that endosomal escape of PEGylated nanoparticles occurs downstream of EEs i.e., from late endosomes/lysosomes. Our studies also suggest that Rab5-Q79L could be used in a robust imaging assay which allows for direct visualization of NP interactions with the luminal membrane of early endosomes.
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| 13. |
- Majzoub, Ramsey N, et al.
(författare)
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Uptake and transfection efficiency of PEGylated cationic liposome-DNA complexes with and without RGD-tagging.
- 2014
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Ingår i: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 35:18, s. 4996-5005
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Tidskriftsartikel (refereegranskat)abstract
- Steric stabilization of cationic liposome-DNA (CL-DNA) complexes is required for in vivo applications such as gene therapy. PEGylation (PEG: poly(ethylene glycol)) of CL-DNA complexes by addition of PEG2000-lipids yields sterically stabilized nanoparticles but strongly reduces their gene delivery efficacy. PEGylation-induced weakening of the electrostatic binding of CL-DNA nanoparticles to cells (leading to reduced uptake) has been considered as a possible cause, but experimental results have been ambiguous. Using quantitative live-cell imaging in vitro, we have investigated cell attachment and uptake of PEGylated CL-DNA nanoparticles with and without a custom synthesized RGD-peptide grafted to the distal ends of PEG2000-lipids. The RGD-tagged nanoparticles exhibit strongly increased cellular attachment as well as uptake compared to nanoparticles without grafted peptide. Transfection efficiency of RGD-tagged PEGylated CL-DNA NPs increases by about an order of magnitude between NPs with low and high membrane charge density (σM; the average charge per unit area of the membrane; controlled by the molar ratio of cationic to neutral lipid), even though imaging data show that uptake of RGD-tagged particles is only slightly enhanced by high σM. This suggests that endosomal escape and, as a result, transfection efficiency of RGD-tagged NPs is facilitated by high σM. We present a model describing the interactions between PEGylated CL-DNA nanoparticles and the anionic cell membrane which shows how the PEG grafting density and membrane charge density affect adhesion of nanoparticles to the cell surface.
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| 14. |
- Niazi, Muhammad Khalid Khan, 1978-, et al.
(författare)
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Fully Automatic Heart Beat Rate Determination in Digital Video Recordings of Rat Embryos
- 2009
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Ingår i: Transactions on Mass-Data Analysis of Images and Signals. - Leipzig, Germany : IBAI Publishing. - 1868-6451. ; 1:2, s. 132-146
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Tidskriftsartikel (refereegranskat)abstract
- Embryo cultures of rodents is an established technique for monitoring adverse effects of chemicals on embryonic development. The assessment involves determination of the heart rate of the embryo which is usually done visually, a technique which is tedious and error prone. We present a new method for fully automatic heart detection in digital videos of rat embryos. First it detects the heart location by using decimation free directional filter bank along with first absolute moment, and then it counts the number of heart beats for a predetermined period of time. Using this automated method many more embryos can be evaluated at reasonable cost.
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| 15. |
- Niazi, Muhammad Khalid Khan, 1978-, et al.
(författare)
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Fully Automatic Heart Beat Rate Determination in Digital Video Recordings of Rat Embryos
- 2008
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Ingår i: ADVANCES IN MASS DATA ANALYSIS OF IMAGES AND SIGNALS IN MEDICINE, BIOTECHNOLOGY, CHEMISTRY AND FOOD INDUSTRY, PRCEEDINGS. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783540707141 ; , s. 27-37
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Konferensbidrag (refereegranskat)abstract
- Embryo cultures of rodents is an established technique for monitoring adverse effects of chemicals on embryonic development. The assessment involves determination of the heart rate of the embryo which is usually done visually, a technique which is tedious and error prone. We present a new method for fully automatic heart detection in digital videos of rat embryos. First it detects the heart location, and then it counts the number of heart beats for a predetermined period of time. Using this automated method many more embryos can be evaluated at reasonable cost.
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| 16. |
- Nilsson, Mats F., et al.
(författare)
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Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs
- 2010
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Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 29:2, s. 156-163
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Tidskriftsartikel (refereegranskat)abstract
- Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20nM, and arrhythmias at 200-400nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.
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| 17. |
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| 18. |
- Schroter, D, et al.
(författare)
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Ecosystem service supply and vulnerability to global change in Europe
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 310:5752, s. 1333-1337
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Tidskriftsartikel (refereegranskat)abstract
- Global change will alter the supply of ecosystem services that are vital for human well-being. To investigate ecosystem service supply during the 21st century, we used a range of ecosystem models and scenarios of climate and land-use change to conduct a Europe-wide assessment. Large changes in climate and land use typically resulted in large changes in ecosystem service supply. Some of these trends may be positive (for example, increases in forest area and productivity) or offer opportunities (for example, "surplus land" for agricultural extensification and bioenergy production). However, many changes increase vulnerability as a result of a decreasing supply of ecosystem services (for example, declining soil fertility, declining water availability, increasing risk of forest fires), especially in the Mediterranean and mountain regions.
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| 19. |
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