| 1. |
- Muhar, Matthias, et al.
(författare)
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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 360:6390, s. 800-805
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Tidskriftsartikel (refereegranskat)abstract
- Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway.
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| 2. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 3. |
- Waltenberger, Johannes, et al.
(författare)
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Five-Year Results of the Bioflow-III Registry : Real-World Experience with a Biodegradable Polymer Sirolimus-Eluting Stent
- 2020
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Ingår i: Cardiovascular Revascularization Medicine. - : Elsevier. - 1553-8389 .- 1878-0938. ; 21:1, s. 63-69
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We aimed to assess long-term safety and performance of the Orsiro sirolimus-eluting coronary stent with biodegradable polymer in a large unselected population and in pre-specified subgroups.Methods: BIOFLOW-III is a prospective, multicenter, international, observational registry with follow-up visits scheduled at 6 and 12 months, and at 3 and 5 years (NCT01553526).Results: 1356 patients with 1738 lesions were enrolled. Of those, 392 (28.9%) declined to participate in the study extension from 18 months to 5 years, 37 (2.7%) withdrew consent, and 89 (6.6%) were lost to follow-up. At 5-years, Kaplan-Meier estimates of target lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, coronary artery bypass grafting and clinically driven target lesion revascularization was 10.0% [95% confidence interval (CI): 8.4; 12.0] in the overall population, and 14.0% [95% CI: 10.5; 18.6], 10.3% [95% CI: 7.8; 13.5], 1.8% [95% CI: 0.3; 12.0], and 11.3% [95% CI: 8.5; 15.1] in the pre-defined risk groups of patients with diabetes mellitus, small vessels <= 2.75 mm, chronic total occlusion, and acute myocardial infarction. Definite stent thrombosis was observed in 0.3% [95% CI: 0.1; 0.9] of patients.Conclusion: These long-term outcomes provide further evidence on the safety and performance of a sirolimus-eluting biodegradable polymer stent within daily clinical practice. The very lowdefinite stent thrombosis rate affirms biodegradable polymer safety and performance.
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| 4. |
- Aardal-Eriksson, Elisabeth, et al.
(författare)
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Iron depletion in blood donors - Have extended erythrocyte and reticulocyte parameters diagnostic utility?
- 2015
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Ingår i: Transfusion and apheresis science. - : PERGAMON-ELSEVIER SCIENCE LTD. - 1473-0502 .- 1878-1683. ; 53:1, s. 76-81
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Tidskriftsartikel (refereegranskat)abstract
- Background: Blood donation is associated with iron depletion, but donor iron status is not usually investigated, as such tests are cumbersome and costly. It would therefore be desirable to have simple, fast and inexpensive tests that give information on a donors risk of developing iron depletion. In a pilot study we investigated whether novel erythrocyte and reticulocyte parameters can serve this goal. Methods: In regular blood donors extended red cell parameters were measured using the Abbott CELL-DYN Sapphire hematology analyzer and conventional biochemical tests of iron status. Donors were compared with a regionally matched group of non-donating controls. Results: In the controls, the reference ranges of extended RBC parameters were well comparable to published data. Donors had significantly more microcytic RBC than controls (median 0.9 vs 0.6%), lower serum ferritin concentration (median 43 vs 91 mg/L) and higher soluble transferrin receptor/ferritin index (median 1.60 vs 1.27). Overall 18-28% of the donors were iron depleted. Moreover, 3.3% of donors had iron-restricted erythropoiesis. Microcytic RBC and reticulocyte mean cell hemoglobin content predicted iron depletion with 70% and 64% sensitivities and specificities of 72% and 78%, respectively. When combined these two parameters increased the sensitivity to 82%. Conclusions: Our results in Swedish blood donors confirm a high prevalence of iron depletion, despite iron supplementation used by about half of the donors. Microcytic RBC and MCHr appeared to be helpful in identifying iron-depleted donors, who might benefit from iron supplementation. We recommend larger prospective investigations in order to confirm and extend the findings of this pilot study. (C) 2015 Elsevier Ltd. All rights reserved.
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| 5. |
- Achilles, Silvio, et al.
(författare)
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GPU-Accelerated Coupled Ptychographic Tomography
- 2022
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Ingår i: Developments in X-Ray Tomography XIV. - : SPIE. - 1996-756X .- 0277-786X. - 9781510654686 ; 12242
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Konferensbidrag (refereegranskat)abstract
- Scanning coherent X-ray microscopy (ptychography) has gained considerable interest during the last decade since the performance of this indirect imaging technique does not necessarily rely on the quality of the X-ray optics and, in principle, can achieve highest spatial resolution in X-ray imaging. The method can be easily extended to 3D by adding standard tomographic reconstruction schemes. However, the tomographic reconstruction is often applied in a subsequent step using a sequence of aligned ptychographic 2D projections. In this contribution, we outline current developments of a GPU-accelerated framework for direct 3D ptychography, coupling 2D ptychography and tomography. The program utilizes a custom GPU-accelerated framework for ptychography that offers three distinct ptychographic reconstruction algorithms. The tomographic reconstruction runs simultaneously and uses numerical routines of the ASTRA Toolbox. This parallel-computing approach results in a high performance increase considerably reducing the reconstruction time of 3D ptychographic datasets.
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| 6. |
- Altewischer, Andrea, et al.
(författare)
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Habitat preferences of male Corn Buntings Emberiza calandra in north-eastern Germany
- 2015
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Ingår i: Acta Ornithologica. - 0001-6454 .- 1734-8471. ; 50:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Agricultural ecosystems have faced dramatic changes during past decades, resulting in a dramatic loss of farmland biodiversity. The Corn Bunting Emberiza calandra is considered a suitable indicator for the conservation value of farmland habitats, and has recently suffered strong declines throughout much of its European range. As a basis for targeted conservation measures, we investigated the habitat preferences of this species in north-eastern Germany by comparing the composition of male territories with randomly chosen control sites. A territory was defined as the area within a radius of 150 meters around the assumed centre of the territory, as the majority of nests is found within this radius. To assess food availability for nestlings, arthropod abundance within the most abundant land use types i.e. crop fields, fallows, grassland as well as within unploughed strips was investigated. In total we found 102 male Corn Bunting territories, which were mainly composed of crop fields (50%), grassland (28%), and fallows (12%). Territories compared with control sites were characterized by a lower proportion of crop fields, a higher proportion of fallows, more diverse land use types, more abundant field boundaries, unploughed strips, and tracks, and a higher availability of song posts. However, neither the number of larger (≥ 1 cm), smaller (< 1 cm) or all arthropods differed significantly among analysed land use types i.e. crop fields, fallows, grassland, unploughed strips. Our study confirms the significance of habitat heterogeneity and especially of sites with sparse vegetation (fallows > 10%) and song posts (> 70 m ‘linear song posts’ or > 1 solitary post per ha) for the habitat selection of male Corn Buntings. We conclude that measures to halt population declines of Corn Buntings seem to be relatively easy to implement, provided that farmers are granted a fair compensation.
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| 7. |
- Anthoni, Heidi, et al.
(författare)
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A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:6, s. 667-77
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Tidskriftsartikel (refereegranskat)abstract
- DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium (LD) mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long-distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong LD and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several non-synonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared with non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates when compared with the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.
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| 8. |
- Beyersdorff, Olaf, et al.
(författare)
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The Relative Strength of #SAT Proof Systems
- 2024
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Ingår i: Proceedings of the 27th International Conference on Theory and Applications of Satisfiability Testing (SAT'24).
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Konferensbidrag (refereegranskat)abstract
- The propositional model counting problem #SAT asks to compute the number of satisfying as- signments for a given propositional formula. Recently, three #SAT proof systems kcps (knowledge compilation proof system), MICE (model counting induction by claim extension), and CPOG (certified partitioned-operation graphs) have been introduced with the aim to model #SAT solving and enable proof logging for solvers.Prior to this paper, the relations between these proof systems have been unclear and very few proof complexity results are known. We completely determine the simulation order of the three systems, establishing that CPOG simulates both MICE and kcps, while MICE and kcps are exponentially incomparable. This implies that CPOG is strictly stronger than the other two systems.
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| 9. |
- Brink, Ebba, et al.
(författare)
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Cascades of green: A review of ecosystem-based adaptation in urban areas
- 2016
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Ingår i: Global Environmental Change. - : Elsevier BV. - 0959-3780. ; 36, s. 111-123
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Tidskriftsartikel (refereegranskat)abstract
- Climate change impacts increase pressure on challenges to sustainability and the developmental needs of cities. Conventional, “hard” adaptation measures are often associated with high costs, inflexibility and conflicting interests related to the dense urban fabric, and ecosystem-based adaptation (EbA) has emerged as a potentially cost-efficient, comprehensive, and multifunctional approach. This paper reviews and systematises research on urban EbA. We propose an analytical framework that draws on theory from ecosystem services, climate change adaptation and sustainability science. It conceptualises EbA in terms of five linked components: ecological structures, ecological functions, adaptation benefits, valuation, and ecosystem management practices. Our review identified 110 articles, reporting on 112 cities, and analysed them using both quantitative statistical and qualitative content analysis. We found that EbA research in an urban context is fragmented due to different disciplinary approaches and concepts. Most articles focus on heat or flooding, and the most studied ecological structures for reducing the risk of such hazards are green space, wetlands, trees and parks. EbA is usually evaluated in bio-geophysical terms and the use of economic or social valuations are rare. While most articles do not mention specific practices for managing ecological structures, those that do imply that urban EbA strategies are increasingly being integrated into institutional structures. Few articles considered issues of equity or stakeholder participation in EbA. We identified the following challenges for future EbA research. First, while the large amount of data generated by isolated case studies contributes to systems knowledge, there is a lack of systems perspectives that position EbA in relation to the wider socio-economic and bio-geophysical context. Second, normative and ethical aspects of EbA require more thought, such as who are the winners and losers, especially in relation to processes that put people at risk from climate-related hazards. Third, there is room for more forward-looking EbA research, including consideration of future scenarios, experimentation in the creation of new ecological structures and the role of EbA in transformative adaptation.
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| 10. |
- Christerson, Linus, et al.
(författare)
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Typing of Lymphogranuloma Venereum Chlamydia trachomatis Strains
- 2010
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Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 16:11, s. 1777-1779
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed by multilocus sequence typing 77 lymphogranuloma venereum Chlamydia trachomatis strains from men who have sex with men in Europe and the United States. Specimens from an outbreak in 2003 in Europe were monoclonal. In contrast, several strains were in the United States in the 1980s, including a variant from Europe.
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| 11. |
- Dobbins, Sara E., et al.
(författare)
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Common variation at 10p12.31 near MLLT10 influences meningioma risk
- 2011
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Ingår i: Nature Genetics. - London : Nature America, Inc.. - 1061-4036 .- 1546-1718. ; 43:9, s. 825-827
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Tidskriftsartikel (refereegranskat)abstract
- To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 x 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.
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| 12. |
- Flory, Stephan, et al.
(författare)
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How to hit the allergy target: A critical appraisal of intralymphatic immunotherapy with practical recommendations on ultrasound-guided injections
- 2024
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : WILEY. - 0105-4538 .- 1398-9995.
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIntralymphatic immunotherapy (ILIT) represents a promising novel approach treating allergic diseases. However, no standardized procedures or recommendations have been established or reported, despite the recognized fact that treatment efficacy relies on the ability to inject the allergen intranodally.ObjectiveWe aim to provide a critical appraisal of ILIT as a method of allergen immunotherapy and to deliver practical recommendations for accurate ILIT.MethodsOne hundred and seventy-three ILIT injections were performed in 28 (47%) women and 32 (53%) men with median age of 29 years (21-59). The injections were ultrasound-guided and recorded for retrospective analysis with respect to injection location, needle visibility, medication release, and patient characteristics.ResultsThe results show that the correct positioning of the needle within the lymph node (LN) was most critical. If the whole length of the needle bevel was not inserted into the LN, substance backflush into the interstitium was observed. Selecting a more superficial LN and inserting the needle at a smaller angle towards the LN significantly improved needle visibility in the ultrasound. Longitudinal results showed that continuous practice significantly correlated with improved needle visibility and more accurate ILIT injections.ConclusionBased on our results and practical experience, we propose several recommendations for LN selection and the correct handling of ultrasound probe and needle. We are confident that ILIT standardization and training will be important as to meet the goals of good safety and efficacy of ILIT. Ultrasound-guided ILIT holds promise for treatment of allergy. Correct positioning of the needle within the lymph node is critical for efficacy and safety, and practice correlate with improved needle visibility and more accurate ILIT injections. A guideline is proposed for effective ILIT. Abbreviations: ILIT, intralymphatic immunotherapy; LN, lymph node; SCIT, subcutaneous immunotherapy.image
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| 13. |
- Grünberg, John, 1985, et al.
(författare)
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Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance.
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity.
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| 14. |
- Hess, Timo, et al.
(författare)
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Dissecting the genetic heterogeneity of gastric cancer
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
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| 15. |
- Hoffmann, Gesa, et al.
(författare)
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Arabidopsis RNA processing body components LSM1 and DCP5 aid in the evasion of translational repression during Cauliflower mosaic virus infection
- 2022
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Ingår i: The Plant Cell. - : Oxford University Press. - 1040-4651 .- 1532-298X. ; 34:8, s. 3128-3147
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections impose extraordinary RNA stress, triggering cellular RNA surveillance pathways such as RNA decapping, nonsense-mediated decay, and RNA silencing. Viruses need to maneuver among these pathways to establish infection and succeed in producing high amounts of viral proteins. Processing bodies (PBs) are integral to RNA triage in eukaryotic cells, with several distinct RNA quality control pathways converging for selective RNA regulation. In this study, we investigated the role of Arabidopsis thaliana PBs during Cauliflower mosaic virus (CaMV) infection. We found that several PB components are co-opted into viral factories that support virus multiplication. This pro-viral role was not associated with RNA decay pathways but instead, we established that PB components are helpers in viral RNA translation. While CaMV is normally resilient to RNA silencing, dysfunctions in PB components expose the virus to this pathway, which is similar to previous observations for transgenes. Transgenes, however, undergo RNA quality control-dependent RNA degradation and transcriptional silencing, whereas CaMV RNA remains stable but becomes translationally repressed through decreased ribosome association, revealing a unique dependence among PBs, RNA silencing, and translational repression. Together, our study shows that PB components are co-opted by the virus to maintain efficient translation, a mechanism not associated with canonical PB functions.
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| 16. |
- Hoffmann, Gesa, et al.
(författare)
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Cauliflower mosaic virus protein P6 is a multivalent node for RNA granule proteins and interferes with stress granule responses during plant infection
- 2023
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Ingår i: The Plant Cell. - : Oxford University Press. - 1040-4651 .- 1532-298X. ; 35:9, s. 3363-3382
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Tidskriftsartikel (refereegranskat)abstract
- Biomolecular condensation is a multipurpose cellular process that viruses use ubiquitously during their multiplication. Cauliflower mosaic virus replication complexes are condensates that differ from those of most viruses, as they are nonmembranous assemblies that consist of RNA and protein, mainly the viral protein P6. Although these viral factories (VFs) were described half a century ago, with many observations that followed since, functional details of the condensation process and the properties and relevance of VFs have remained enigmatic. Here, we studied these issues in Arabidopsis thaliana and Nicotiana benthamiana. We observed a large dynamic mobility range of host proteins within VFs, while the viral matrix protein P6 is immobile, as it represents the central node of these condensates. We identified the stress granule (SG) nucleating factors G3BP7 and UBP1 family members as components of VFs. Similarly, as SG components localize to VFs during infection, ectopic P6 localizes to SGs and reduces their assembly after stress. Intriguingly, it appears that soluble rather than condensed P6 suppresses SG formation and mediates other essential P6 functions, suggesting that the increased condensation over the infection time-course may accompany a progressive shift in selected P6 functions. Together, this study highlights VFs as dynamic condensates and P6 as a complex modulator of SG responses.
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| 17. |
- Hou, Liping, et al.
(författare)
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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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| 18. |
- Jäger, Susanne, et al.
(författare)
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Blood copper and risk of cardiometabolic diseases : a Mendelian randomization study
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:5, s. 783-791
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Tidskriftsartikel (refereegranskat)abstract
- Observational evidence links higher blood levels of copper with higher risk of cardiovascular diseases. However, whether those associations reflect causal links or can be attributed to confounding is still not fully clear. We investigated causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease [CAD] and type 2 diabetes) and cardiometabolic risk factors in two-sample Mendelian randomization (MR) studies. The selection of genetic instruments for blood copper levels relied on meta-analysis of genome-wide association studies in three independent studies (European Prospective Investigation into Cancer and Nutrition-Potsdam study, Prospective investigation of the Vasculature in Uppsala Seniors study, Queensland Institute of Medical Research studies). For the selected instruments, outcome associations were drawn from large public genetic consortia on the respective disease endpoints (MEGASTROKE, Cardiogram, DIAGRAM) and cardiometabolic risk factors. MR results indicate an inverse association for genetically higher copper levels with risk of CAD (odds ratio [95% confidence interval] = 0.92 [0.86-0.99], P = 0.022) and systolic blood pressure (beta [standard error (SE)] = -0.238 [0.121]; P = 0.049). Multivariable MR incorporating copper and systolic blood pressure into one model suggested systolic blood pressure as mediating factor between copper and CAD risk. In contrast to previous observational evidence establishing higher blood copper levels as risk-increasing factor for cardiometabolic diseases, this study suggests that higher levels of genetically predicted copper might play a protective role for the development of CAD and systolic blood pressure.
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| 19. |
- Krüger, Nadine, et al.
(författare)
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The upper respiratory tract of felids is highly susceptible to sars‐cov‐2 infection
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:19
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Tidskriftsartikel (refereegranskat)abstract
- Natural or experimental infection of domestic cats and virus transmission from humans to captive predatory cats suggest that felids are highly susceptible to SARS‐CoV‐2 infection. However, it is unclear which cells and compartments of the respiratory tract are infected. To address this question, primary cell cultures derived from the nose, trachea, and lungs of cat and lion were inoculated with SARS‐CoV‐2. Strong viral replication was observed for nasal mucosa explants and tracheal air–liquid interface cultures, whereas replication in lung slices was less efficient. Infection was mainly restricted to epithelial cells and did not cause major pathological changes. Detection of high ACE2 levels in the nose and trachea but not lung further suggests that susceptibility of feline tissues to SARS‐CoV‐2 correlates with ACE2 expression. Collectively, this study demonstrates that SARS‐ CoV‐2 can efficiently replicate in the feline upper respiratory tract ex vivo and thus highlights the risk of SARS‐CoV‐2 spillover from humans to felids.
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| 20. |
- Palmberg, Lars Johan, 1713-1804
(författare)
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Specimen exegetico-dogmaticum, sistens theologiam Jobi, cujus partem tertiam ... suffragante maxime venerando theologorum ordine, in illustri academia Upsaliensi, ad publicum bonorum examen deferunt auctor, m. Laur. Jo. Palmberg ... & respondens, stipendiarius regius, Johannes Hoffmann. Gothlandus. In audit. Carol. maj. d. XXVI maji, anno MDCCLXXIII., P. 3
- 1773
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
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| 21. |
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| 22. |
- Schmid, Johannes M., et al.
(författare)
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Basophil sensitivity reflects long-term clinical outcome of subcutaneous immunotherapy in grass pollen-allergic patients
- 2021
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Ingår i: Allergy: European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538. ; 76:5, s. 1528-1538
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Tidskriftsartikel (refereegranskat)abstract
- Background: Allergic rhinoconjunctivitis is a public health problem. Allergen Immunotherapy is an effective and safe treatment, that modifies the natural course of allergic disease and induces long-term tolerance. Objective: To correlate basophil and antibody biomarkers of subcutaneous immunotherapy to clinical outcomes and cellular changes in target tissue. Methods: Adults suffering from allergic rhinoconjunctivitis due to grass pollen allergy were randomized to receive subcutaneous immunotherapy (n = 18) or to an open control group (n = 6). Patients reported daily symptom and medication scores and weekly rhinitis related quality of life scores during four pollen seasons. Biomarkers were measured every 3 months for three years treatment and every 6 months in the follow-up year. Nasal and cutaneous allergen challenge tests were performed annually. Leukocyte subsets were assessed in nasal mucosa biopsies at baseline and after treatment. Results: Subcutaneous immunotherapy led to a 447-fold decrease in basophil sensitivity during the first treatment year. This remained 100-fold lower than baseline during the 3 year-treatment period and 10-fold lower during the follow-up year (n = 18, P =.03). Decrease in basophil sensitivity after three weeks of treatment predicted long-term improvement in seasonal combined symptom and medication scores (ῥ=−0.69, P =.0027) during three years of treatment. AUC of IgE-blocking factor correlated to nasal allergen challenge (ῥ = 0.63, P =.0012) and SPT (ῥ = 0.45, P =.03). Plasma cell numbers in the nasal mucosa increased during treatment (P =.02). Conclusion: Decrease in basophil sensitivity after three weeks of subcutaneous allergen immunotherapy predicted the clinical outcome of this treatment.
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| 23. |
- Schuette, Moritz, et al.
(författare)
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Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
- 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
- Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling 44,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
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| 24. |
- Senti, Gabriela, et al.
(författare)
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Intralymphatic Immunotherapy : Update and Unmet Needs.
- 2019
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger. - 1018-2438 .- 1423-0097. ; 178:2, s. 141-149
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Forskningsöversikt (refereegranskat)abstract
- Allergen-specific immunotherapy (AIT) is the only allergy treatment that confers long-term symptom amelioration for patients suffering from allergy. The most frequently used allergen application route is subcutaneous injection (SCIT), commonly taken as the gold standard, followed by sublingual (SLIT) or oral (OIT) application of allergen preparations. This is an up-to-date review of the clinical evidence for a novel route of allergen application, i.e., directly into lymph nodes - intralymphatic immunotherapy (ILIT). The major advantages of ILIT over the current AIT approaches are its short duration and the low allergen doses administered. The whole treatment consists of merely 3 ultrasound-guided injections into inguinal lymph nodes 1 month apart. While the number of patients included in randomised controlled trials is still limited, the clinical results for ILIT are encouraging, but more clinical trials are needed, as well as more preclinical work for optimising formulations.
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| 25. |
- Sprafke, Johannes K., et al.
(författare)
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Belt-Shaped π-Systems: Relating Geometry to Electronic Structure in a Six-Porphyrin Nanoring
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 133:43, s. 17262-17273
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Tidskriftsartikel (refereegranskat)abstract
- Linear pi-conjugated oligomers have been widely investigated, but the behavior of the corresponding cyclic oligomers is poorly understood, despite the recent synthesis of pi-conjugated macrocycles such as [n]cycloparaphenylenes and cyclo[n]thiophenes. Here we present an efficient template-directed synthesis of a pi-conjugated butadiyne-linked cyclic porphyrin hexamer directly from the monomer. Small-angle X-ray scattering data show that this nanoring is shape-persistent in solution, even without its template, whereas the linear porphyrin hexamer is relatively flexible. The crystal structure of the nanoring-template complex shows that most of the strain is localized in the acetylenes; the porphyrin units are slightly curved, but the zinc coordination sphere is undistorted. The electrochemistry, absorption, and fluorescence spectra indicate that the HOMO-LUMO gap of the nanoring is less than that of the linear hexamer and less than that of the corresponding polymer. The nanoring exhibits six one-electron reductions and six one-electron oxidations, most of which are well resolved. Ultrafast fluorescence anisotropy measurements show that absorption of light generates an excited state that is delocalized over the whole pi-system within a time of less than 0.5 ps. The fluorescence spectrum is amazingly structured and red-shifted. A similar, but less dramatic, red-shift has been reported in the fluorescence spectra of cycloparaphenylenes and was attributed to a high exciton binding energy; however the exciton binding energy of the porphyrin nanoring is similar to those of linear oligomers. Quantum-chemical excited state calculations show that the fluorescence spectrum of the nanoring can be fully explained in terms of vibronic Herzberg-Teller (HT) intensity borrowing.
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| 26. |
- Stauffer, Flurin, et al.
(författare)
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Soft Electronic Strain Sensor with Chipless Wireless Readout: Toward Real-Time Monitoring of Bladder Volume
- 2018
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Ingår i: Advanced Materials Technologies. - : WILEY. - 2365-709X. ; 3:6
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Tidskriftsartikel (refereegranskat)abstract
- Sensing mechanical tissue deformation in vivo can provide detailed information on organ functionality and tissue states. To bridge the huge mechanical mismatch between conventional electronics and biological tissues, stretchable electronic systems have recently been developed for interfacing tissues in healthcare applications. A major challenge for wireless electronic implants is that they typically require microchips, which adds complexity and may compromise long-term stability. Here, a chipless wireless strain sensor technology based on a novel soft conductor with high cyclic stability is reported. The composite material consists of gold-coated titanium dioxide nanowires embedded in a soft silicone elastomer. The implantable strain sensor is based on an resonant circuit which consists of a stretchable plate capacitor and a coil for inductive readout of its resonance frequency. Successful continuous wireless readout during 50% strain cycles is demonstrated. The sensor element has a Youngs modulus of 260 kPa, similar to that of the bladder in order to not impair physiological bladder expansion. A proof-of-principle measurement on an ex vivo porcine bladder is presented, which shows the feasibility of the presented materials and devices for continuous, wireless strain monitoring of various tissues and organs in vivo.
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