| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 3. |
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| 4. |
- Chapman, Henry N, et al.
(författare)
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Femtosecond X-ray protein nanocrystallography.
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 470:7332, s. 73-7
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Tidskriftsartikel (refereegranskat)abstract
- X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (∼200nm to 2μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.
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| 5. |
- 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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| 6. |
- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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| 7. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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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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| 8. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 9. |
- Kollmer, Marius, et al.
(författare)
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Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:20, s. 5604-5609
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Tidskriftsartikel (refereegranskat)abstract
- Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.
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| 10. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 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
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 11. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 12. |
- Vasan, Ramachandran S, et al.
(författare)
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Genetic variants associated with cardiac structure and function : a meta-analysis and replication of genome-wide association data
- 2009
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 302:2, s. 168-178
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
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| 13. |
- Wain, Louise V., et al.
(författare)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 14. |
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| 15. |
- Alriksson-Schmidt, Ann I., et al.
(författare)
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The natural history of spina bifida in children pilot project : Research protocol
- 2013
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Ingår i: JMIR Research Protocols. - : JMIR Publications Inc.. - 1929-0748. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Population-based empirical information to inform health care professionals working with children with spina bifida currently is lacking. Spina bifida is a highly complex condition that not only affects mobility but many additional aspects of life. We have developed a pilot project that focuses on a broad range of domains: Surgeries, development and learning, nutrition and physical growth, mobility and functioning, general health, and family demographics. Specifically, we will: (1) explore the feasibility of identifying and recruiting participants using different recruitment sources, (2) test a multidisciplinary module to collect the data, (3) determine the utility of different methods of retrieving the data, and (4) summarize descriptive information on living with spina bifida. Objective: The overall objective of the project was to provide information for a future multistate prospective study on the natural history of spina bifida. Methods: Families with a child 3 to 6 years of age with a diagnosis of spina bifida were eligible for enrollment. Eligible families were identified through a US population-based tracking system for birth defects and from a local spina bifida clinic. Results: This is an ongoing project with first results expected in 2013. Conclusions: This project, and the planned multistate follow-up project, will provide information both to health care professionals experienced in providing care to patients with spina bifida, and to those who have yet to work with this population. The long-term purpose of this project is to increase the knowledge about growing up with spina bifida and to guide health care practices by prospectively studying a cohort of children born with this condition.
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| 16. |
- Anderson, Christopher J., et al.
(författare)
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Response to Comment on "Estimating the reproducibility of psychological science"
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 351:6277
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Gilbert et al. conclude that evidence from the Open Science Collaboration's Reproducibility Project: Psychology indicates high reproducibility, given the study methodology. Their very optimistic assessment is limited by statistical misconceptions and by causal inferences from selectively interpreted, correlational data. Using the Reproducibility Project: Psychology data, both optimistic and pessimistic conclusions about reproducibility are possible, and neither are yet warranted.
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| 17. |
- Banerjee, Sambhasan, et al.
(författare)
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Amyloid fibril structure from the vascular variant of systemic AA amyloidosis
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Systemic AA amyloidosis is a debilitating protein misfolding disease in humans and animals. In humans, it occurs in two variants that are called 'vascular' and 'glomerular', depending on the main amyloid deposition site in the kidneys. Using cryo electron microscopy, we here show the amyloid fibril structure underlying the vascular disease variant. Fibrils purified from the tissue of such patients are mainly left-hand twisted and contain two non-equal stacks of fibril proteins. They contrast in these properties to the fibrils from the glomerular disease variant which are right-hand twisted and consist of two structurally equal stacks of fibril proteins. Our data demonstrate that the different disease variants in systemic AA amyloidosis are associated with different fibril morphologies.
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| 18. |
- Behr, A. C., et al.
(författare)
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Impairment of bile acid metabolism by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in human HepaRG hepatoma cells
- 2020
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 94, s. 1673-1686
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are man-made chemicals that are used for the fabrication of many products with water- and dirt-repellent properties. The toxicological potential of both substances is currently under debate. In a recent Scientific Opinion, the European Food Safety Authority (EFSA) has identified increased serum total cholesterol levels in humans as one major critical effect being associated with exposure to PFOA or PFOS. In animal studies, both substances induced a decrease of serum cholesterol levels, and the underlying molecular mechanism(s) for these opposed effects are unclear so far. In the present study, we examined the impact of PFOA and PFOS on cholesterol homoeostasis in the human HepaRG cell line as a model for human hepatocytes. Cholesterol levels in HepaRG cells were not affected by PFOA or PFOS, but both substances strongly decreased synthesis of a number of bile acids. The expression of numerous genes whose products are involved in synthesis, metabolism and transport of cholesterol and bile acids was strongly affected by PFOA and PFOS at concentrations above 10 mu M. Notably, both substances led to a strong decrease of CYP7A1, the key enzyme catalyzing the rate-limiting step in the synthesis of bile acids from cholesterol, both at the protein level and at the level of gene expression. Moreover, both substances led to a dilatation of bile canaliculi that are formed by differentiated HepaRG cells in vitro. Similar morphological changes are known to be induced by cholestatic agents in vivo. Thus, the strong impact of PFOA and PFOS on bile acid synthesis and bile canalicular morphology in our in vitro experiments may allow the notion that both substances have a cholestatic potential that is connected to the observed increased serum cholesterol levels in humans in epidemiological studies.
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| 19. |
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| 20. |
- Boll, Rebecca, et al.
(författare)
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Imaging molecular structure through femtosecond photoelectron diffraction on aligned and oriented gas-phase molecules
- 2014
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Ingår i: Faraday Discussions. - : Royal Society of Chemistry (RSC). - 1364-5498. ; 171, s. 57-80
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Tidskriftsartikel (refereegranskat)abstract
- This paper gives an account of our progress towards performing femtosecond time-resolved photoelectron diffraction on gas-phase molecules in a pump-probe setup combining optical lasers and an X-ray free-electron laser. We present results of two experiments aimed at measuring photoelectron angular distributions of laser-aligned 1-ethynyl-4-fluorobenzene (C8H5F) and dissociating, laser-aligned 1,4-dibromobenzene (C6H4Br2) molecules and discuss them in the larger context of photoelectron diffraction on gas-phase molecules. We also show how the strong nanosecond laser pulse used for adiabatically laser-aligning the molecules influences the measured electron and ion spectra and angular distributions, and discuss how this may affect the outcome of future time-resolved photoelectron diffraction experiments.
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| 21. |
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| 22. |
- Borenäs, Marcus, et al.
(författare)
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ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 1091-6490. ; 121:1
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Tidskriftsartikel (refereegranskat)abstract
- High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
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| 23. |
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| 24. |
- Broadbent, Jeffrey, et al.
(författare)
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Conflicting Climate Change Frames in a Global Field of Media Discourse
- 2016
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Ingår i: Socius: Sociological Research for a Dynamic World. - : SAGE Publications. - 2378-0231. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Reducing global emissions will require a global cosmopolitan culture built from detailed attention to conflicting national climate change frames (interpretations) in media discourse. The authors analyze the global field of media climate change discourse using 17 diverse cases and 131 frames. They find four main conflicting dimensions of difference: validity of climate science, scale of ecological risk, scale of climate politics, and support for mitigation policy. These dimensions yield four clusters of cases producing a fractured global field. Positive values on the dimensions show modest association with emissions reductions. Data-mining media research is needed to determine trends in this global field.
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| 25. |
- Brucalassi, Anna, et al.
(författare)
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Full System Test and early Preliminary Acceptance Europe results for CRIRES
- 2018
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Ingår i: Ground-Based And Airborne Instrumentation For Astronomy VII. - : SPIE. - 9781510619586
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Konferensbidrag (refereegranskat)abstract
- CRIRES+ is the new high-resolution NIR echelle spectrograph intended to be operated at the platform B of VLT Unit telescope UT3. It will cover from Y to M bands (0.95-5.3um) with a spectral resolution of R = 50000 or R = 100000. The main scientific goals are the search of super-Earths in the habitable zone of low-mass stars, the characterisation of transiting planets atmosphere and the study of the origin and evolution of stellar magnetic fields. Based on the heritage of the old adaptive optics (AO) assisted VLT instrument CRIRES, the new spectrograph will present improved optical layout, a new detector system and a new calibration unit providing optimal performances in terms of simultaneous wavelength coverage and radial velocity accuracy (a few m/s). The total observing efficiency will be enhanced by a factor of 10 with respect to CRIRES. An innovative spectro-polarimetry mode will be also offered and a new metrology system will ensure very high system stability and repeatability. Fiinally, the CRIRES+ project will also provide the community with a new data reduction software (DRS) package. CRIRES+ is currently at the initial phase of its Preliminary Acceptance in Europe (PAE) and it will be commissioned early in 2019 at VLT. This work outlines the main results obtained during the initial phase of the full system test at ESO HQ Garching.
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| 26. |
- Burmann, Björn Marcus, 1979, et al.
(författare)
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Regulation of alpha-synuclein by chaperones in mammalian cells
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7788, s. 127-32
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein alpha-synuclein(1). The aggregation propensity of alpha-synuclein in cells is modulated by specific factors that include post-translational modifications(2,3), Abelson-kinase-mediated phosphorylation(4,5) and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear(6-8). Here we systematically characterize the interaction of molecular chaperones with alpha-synuclein in vitro as well as in cells at the atomic level. We find that six highly divergent molecular chaperones commonly recognize a canonical motif in alpha-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of alpha-synuclein. NMR experiments(9) in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between alpha-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90 beta, results in transient membrane binding and triggers a remarkable re-localization of alpha-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of alpha-synuclein at Tyr39 directly impairs the interaction of alpha-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson's disease. Our results establish a master regulatory mechanism of alpha-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson's disease.
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| 27. |
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| 28. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 29. |
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| 30. |
- Gorkhover, Tais, et al.
(författare)
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Femtosecond and nanometre visualization of structural dynamics in superheated nanoparticles
- 2016
-
Ingår i: Nature Photonics. - : Springer Science and Business Media LLC. - 1749-4885 .- 1749-4893. ; 10:2, s. 93-97
-
Tidskriftsartikel (refereegranskat)abstract
- The ability to observe ultrafast structural changes in nanoscopic samples is essential for understanding non-equilibrium phenomena such as chemical reactions, matter under extreme conditions, ultrafast phase transitions and intense light-matter interactions. Established imaging techniques are limited either in time or spatial resolution and typically require samples to be deposited on a substrate, which interferes with the dynamics. Here, we show that coherent X-ray diffraction images from isolated single samples can be used to visualize femtosecond electron density dynamics. We recorded X-ray snapshot images from a nanoplasma expansion, a prototypical non-equilibrium phenomenon. Single Xe clusters are superheated using an intense optical laser pulse and the structural evolution of the sample is imaged with a single X-ray pulse. We resolved ultrafast surface softening on the nanometre scale at the plasma/vacuum interface within 100 fs of the heating pulse. Our study is the first time-resolved visualization of irreversible femtosecond processes in free, individual nanometre-sized samples.
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| 31. |
- Hall, Marcus, et al.
(författare)
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Reproductive homing and fine-scaled genetic structuring of anadromous Baltic Sea perch (Perca fluviatilis)
- 2022
-
Ingår i: Fisheries Management and Ecology. - : John Wiley & Sons. - 0969-997X .- 1365-2400. ; 29:5, s. 586-596
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate the population dynamics of anadromous Baltic Sea perch Perca fluviatilis (Linnaeus), we studied the migratory behaviour (arrival to spawning location) and population structure (genetic structure and differentiation) of three closely located (<50 km) populations. Spawning migration lasted for 32-80 days, and passive integrated transponder tag (PIT-tag) data indicated that anadromous perch displayed reproductive homing. Populations were differentiated, despite low levels of gene flow (3%-5%), and differentiation increased with increasing geographic distance. This fine-scaled spatial structuring was likely, at least partly, explained by homing behaviour. Analyses of temporal within-stream substructuring yielded inconclusive results, so further studies are required to evaluate this. Taken together, our findings highlight the potential for fine-scaled genetic structuring in anadromous perch and indicate that multiple mechanisms, such as isolation by distance, homing, and reproductive timing could contribute to this pattern. This illustrates the importance of considering cryptic barriers to accurately identify reproductive units, and points to the need for local management of anadromous perch.
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| 32. |
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| 33. |
- Heinken, Thilo, et al.
(författare)
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The European Forest Plant Species List (EuForPlant): Concept and applications
- 2022
-
Ingår i: Journal of Vegetation Science. - : Wiley. - 1654-1103 .- 1100-9233. ; 33:3, s. 1-16
-
Tidskriftsartikel (refereegranskat)abstract
- Question: When evaluating forests in terms of their biodiversity, distinctiveness and naturalness, the affinity of the constituent species to forests is a crucial parameter. Here we ask to what extent are vascular plant species associated with forests, and does species’ affinity to forests vary between European regions?Location: Temperate and boreal forest biome of Northwestern and Central Europe. Methods: We compiled EuForPlant, a new extensive list of forest vascular plant spe- cies in 24 regions spread across 13 European countries using vegetation databases and expert knowledge. Species were region-specifically classified into four categories reflecting the degree of their affinity to forest habitats: 1.1, species of forest interiors; 1.2, species of forest edges and forest openings; 2.1, species that can be found in forest as well as open vegetation; and 2.2, species that can be found partly in forest, but mainly in open vegetation. An additional “O” category was distinguished, covering species typical for non-forest vegetation.Results: EuForPlant comprises 1,726 species, including 1,437 herb-layer species, 159 shrubs, 107 trees, 19 lianas and 4 epiphytic parasites. Across regions, generalist forest species (with 450 and 777 species classified as 2.1 and 2.2, respectively) significantly outnumbered specialist forest species (with 250 and 137 species classified as 1.1 and 1.2, respectively). Even though the degree of shifting between the categories of for- est affinity among regions was relatively low (on average, 17.5%), about one-third of the forest species (especially 1.2 and 2.2) swapped categories in at least one of the study regions.Conclusions: The proposed list can be used widely in vegetation science and global change ecology related to forest biodiversity and community dynamics. Shifting of forest affinity among regions emphasizes the importance of a continental-scale forest plant species list with regional specificity.
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| 34. |
- Hellwig, Birte, et al.
(författare)
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Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy
- 2016
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: In breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery.Methods: Affymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early-and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer.Results: Ten late-and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer.Conclusions: Ribosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.
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| 35. |
- Holzapfel, Damian M., et al.
(författare)
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Influence of ion irradiation-induced defects on phase formation and thermal stability of Ti0.27Al0.21N0.52 coatings
- 2022
-
Ingår i: Acta Materialia. - : Elsevier. - 1359-6454 .- 1873-2453. ; 237
-
Tidskriftsartikel (refereegranskat)abstract
- The influence of changes induced by ion irradiation on structure and thermal stability of metastable cubic (Ti,Al)N coatings deposited by cathodic arc evaporation is systematically investigated by correlating experiments and theory. Decreasing the nitrogen deposition pressure from 5.0 to 0.5 Pa results in an ion flux-enhancement by a factor of three and an increase of the average ion energy from 15 to 30 eV, causing the stress-free lattice parameter to expand from 4.170 to 4.206 Å, while the chemical composition of Ti0.27Al0.21N0.52 remains unchanged. The 0.9% lattice parameter increase is a consequence of formation of Frenkel pairs induced by ion bombardment, as revealed by density functional theory (DFT) simulations. The influence of the presence of Frenkel pairs on the thermal stability of metastable Ti0.27Al0.21N0.52 is investigated by scanning transmission electron microscopy, differential scanning calorimetry, atom probe tomography and in-situ synchrotron X-ray powder diffraction. It is demonstrated that the ion flux and ion energy induced formation of Frenkel pairs increases the thermal stability as the Al diffusion enabled crystallization of the wurtzite solid solution is retarded. This can be rationalized by DFT predictions since the presence of Frenkel pairs increases the activation energy for Al diffusion by up to 142%. Hence, the thermal stability enhancement is caused by a hitherto unreported mechanism - the Frenkel pair impeded Al mobility and thereby retarded formation of wurtzite solid solution.
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| 36. |
- Horn, Lars-Christian, et al.
(författare)
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Immunostaining for p16(INK4a) used as a conjunctive tool improves interobserver agreement of the histologic diagnosis of cervical intraepithelial neoplasia
- 2008
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Ingår i: American Journal of Surgical Pathology. - 1532-0979. ; 32:4, s. 502-512
-
Tidskriftsartikel (refereegranskat)abstract
- The quality of cervical histopathology is critical to cervical cancer prevention, cancer treatment, and research programs. On the basis of the histology results further patient management is determined. However, the diagnostic interpretation of histologic hematoxylin-eosin (H&E)-stained slides is affected by substantial rates of discordance among pathologists. Overexpression of the cyclin-dependent kinase inhibitor p16(INK4a), a cell cycle regulating protein, has been shown to be strongly correlated with dysplastic lesions of the cervix uteri. In this study.. we assessed whether p16(INK4a) immunohistochemistry may increase the performance of pathologists in diagnosing squamous lesions in cervical punch and cone biopsies. When using a consecutive p 16(INK4a)-stained slide in conjunction to the H&E-stained slide, interobserver agreement between 6 pathologists improved significantly for both cervical punch and cone biopsies (P < 0.001). For punch biopsies (n = 247), K value increased from 0.49 (moderate agreement) to 0.64 indicating substantial agreement, and interobserver agreement for cone biopsies (n = 249) improved from 0.63 (conventional H&E slide reading) to 0.70 when H&E-stained slides were read conjunctively with p16(INK4a)-stained slides. In comparison to a common consensus diagnosis established by 3 independent experts, 4 pathologists reached an improvement with the conjunctive p16(INK4a) test, 2 of them showing significantly better agreement (P < 0.001 and P = 0.002, respectively). P-16INK4a immunohistochemistry as an adjunct to conventional H&E-stained specimens thus contributes to a more reproducible diagnosis of cervical intraepithelial neoplasia, and may be a valuable aid for the interpretation of cervical histology.
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| 37. |
- Höhn, Peter, et al.
(författare)
-
Li16Sr6Ge6N, Li16Sr6Ge6.5 and related lithium alkaline-earth metal tetrelides : Alternative filling of voids by nitride or tetrelide ions
- 2022
-
Ingår i: Zeitschrift für Anorganische und Allgemeines Chemie. - : Wiley. - 0044-2313 .- 1521-3749. ; 648:23
-
Tidskriftsartikel (refereegranskat)abstract
- Large black single crystals with a metallic luster of Li16Sr6Ge6N and several other representatives of the series Li16Ae6Tt6N and Li16Ae6Tt6.5 (Ae=Ca, Sr; Tt=Si, Ge, Sn, Pb) were grown from mixtures of the respective elements with addition of binary alkaline-earth metal nitrides or lithium nitride in the case of the nitrides. For the synthesis a modified high-temperature centrifugation-aided filtration (HTCAF) technique using reactive lithium melts was employed. These metallic phases crystallize in an ordered defect-variant of the Sc11Ir4 type with selective occupation of the smaller octahedral voids in the origin (000) with N and the larger rhombic dodecahedral voids in (00 1/2 ) with Tt. Charge balance assuming the presence of exclusively closed shell ions for all examples accounts for an electronic excess. Diamagnetism despite metallic properties is consistent with results from electronic structure calculations.
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| 38. |
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| 39. |
- Keller, Magdalena, et al.
(författare)
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Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth
- 2023
-
Ingår i: Journal of Experimental & Clinical Cancer Research. - : BioMed Central (BMC). - 1756-9966. ; 42
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Intrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored.Methods: EDI3 mRNA and protein expression in human breast cancer tissue were investigated using publicly-available Affymetrix gene expression microarray datasets (n = 540) and with immunohistochemistry on a tissue microarray (n = 265), respectively. A panel of breast cancer cell lines of different molecular subtypes were used to investigate expression and activity of EDI3 in vitro. To determine whether EDI3 expression is regulated by HER2 signalling, the effect of pharmacological inhibition and siRNA silencing of HER2, as well as the influence of inhibiting key components of signalling cascades downstream of HER2 were studied. Finally, the influence of silencing and pharmacologically inhibiting EDI3 on viability was investigated in vitro and on tumour growth in vivo.Results: In the present study, we show that EDI3 expression is highest in ER-HER2 + human breast tumours, and both expression and activity were also highest in ER-HER2 + breast cancer cell lines. Silencing HER2 using siRNA, as well as inhibiting HER2 signalling with lapatinib decreased EDI3 expression. Pathways downstream of PI3K/Akt/mTOR and GSK3 beta, and transcription factors, including HIF1 alpha, CREB and STAT3 were identified as relevant in regulating EDI3 expression. Silencing EDI3 preferentially decreased cell viability in the ER-HER2 + cells. Furthermore, silencing or pharmacologically inhibiting EDI3 using dipyridamole in ER-HER2 + cells resistant to HER2-targeted therapy decreased cell viability in vitro and tumour growth in vivo.Conclusions: Our results indicate that EDI3 may be a potential novel therapeutic target in patients with HER2-targeted therapy-resistant ER-HER2 + breast cancer that should be further explored.
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| 40. |
- Koh, Ara, et al.
(författare)
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Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1
- 2018
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Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 175:4
-
Tidskriftsartikel (refereegranskat)abstract
- Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38 gamma MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.
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| 41. |
- Kuepper, Jochen, et al.
(författare)
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X-Ray Diffraction from Isolated and Strongly Aligned Gas-Phase Molecules with a Free-Electron Laser
- 2014
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 112:8, s. 083002-
-
Tidskriftsartikel (refereegranskat)abstract
- We report experimental results on x-ray diffraction of quantum-state-selected and strongly aligned ensembles of the prototypical asymmetric rotor molecule 2,5-diiodobenzonitrile using the Linac Coherent Light Source. The experiments demonstrate first steps toward a new approach to diffractive imaging of distinct structures of individual, isolated gas-phase molecules. We confirm several key ingredients of single molecule diffraction experiments: the abilities to detect and count individual scattered x-ray photons in single shot diffraction data, to deliver state-selected, e.g., structural-isomer-selected, ensembles of molecules to the x-ray interaction volume, and to strongly align the scattering molecules. Our approach, using ultrashort x-ray pulses, is suitable to study ultrafast dynamics of isolated molecules.
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| 42. |
- Liberta, Falk, et al.
(författare)
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Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 angstrom and 2.7 angstrom for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-beta sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar beta-arch conformations within the N-terminal similar to 21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.
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| 43. |
- 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
-
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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| 44. |
- Lohr, Miriam, et al.
(författare)
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Identification of sample annotation errors in gene expression datasets
- 2015
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 89:12, s. 2265-2272
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Tidskriftsartikel (refereegranskat)abstract
- The comprehensive transcriptomic analysis of clinically annotated human tissue has found widespread use in oncology, cell biology, immunology, and toxicology. In cancer research, microarray-based gene expression profiling has successfully been applied to subclassify disease entities, predict therapy response, and identify cellular mechanisms. Public accessibility of raw data, together with corresponding information on clinicopathological parameters, offers the opportunity to reuse previously analyzed data and to gain statistical power by combining multiple datasets. However, results and conclusions obviously depend on the reliability of the available information. Here, we propose gene expression-based methods for identifying sample misannotations in public transcriptomic datasets. Sample mix-up can be detected by a classifier that differentiates between samples from male and female patients. Correlation analysis identifies multiple measurements of material from the same sample. The analysis of 45 datasets (including 4913 patients) revealed that erroneous sample annotation, affecting 40 % of the analyzed datasets, may be a more widespread phenomenon than previously thought. Removal of erroneously labelled samples may influence the results of the statistical evaluation in some datasets. Our methods may help to identify individual datasets that contain numerous discrepancies and could be routinely included into the statistical analysis of clinical gene expression data.
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| 45. |
- Mahmoodi, Bakhtawar K., et al.
(författare)
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Association of Factor V Leiden With Subsequent Atherothrombotic Events A GENIUS-CHD Study of Individual Participant Data
- 2020
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 142:6, s. 546-555
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16];I-2=28%;P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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| 46. |
- Misra, Deepankar, et al.
(författare)
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Two-Center Double-Capture Interference in Fast He2++H2 Collisions
- 2009
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 102:15, s. 153201-
-
Tidskriftsartikel (refereegranskat)abstract
- We report the first observation of Young-type interference effects in a two-electron transfer process. These effects change strongly as the projectile velocity changes in fast (1.2 and 2.0 MeV) He^{2+}-H_2 collisions as manifested in strong variations of the double-electron capture rates with the H_2 orientation. This is consistent with fully quantum mechanical calculations, which ignore sequential electron transfer, and a simple projectile de Broglie wave picture assuming that two-electron transfer probabilities are higher in collisions where the projectile passes close to either one of the H_2 nuclei.
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| 47. |
- Molinaro, Antonio, et al.
(författare)
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Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.
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| 48. |
- Morán, Diana, et al.
(författare)
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Bio-based starch nanoparticles with controlled size as antimicrobial agents nanocarriers
- 2024
-
Ingår i: Reactive and Functional Polymers. - 1381-5148. ; 198
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Tidskriftsartikel (refereegranskat)abstract
- Starch nanoparticles (SNPs) have been synthesized by nanoprecipitation method using starches from different botanical sources in native form and modified with octenyl succinic anhydride (OSA). SNPs were characterized in terms of size, morphology, charge, XRPD, FTIR and thermal properties. Spherical particles were obtained with sizes ranging from 54 to 108 nm and zeta potential values from −2 to −27 mV. Changes in size and stability related to the % OSA were observed for each starch. Starch granules showed A-type crystalline pattern while a loss of crystallinity was observed for SNPs. FTIR spectra demonstrated that OSA modification was barely affected by the nanoprecipitation and SNPs showed thermal properties similar to those of starch granules. SNPs with specific size can be synthesized by selecting the appropriate starch granules as raw material. This is especially relevant in certain bio-applications, where size must be precisely controlled, e.g., as nanocarriers for drug release or food fortification. To investigate the feasibility of SNPs as nanocarriers, vanillin-loaded SNPs were synthesized, achieving encapsulation efficiencies of 30% and loading capacities of 60%. The antimicrobial activity of vanillin-loaded SNPs was tested against Escherichia Coli (E. coli) with satisfactory results.
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| 49. |
- Mtchedlidze, Salome, et al.
(författare)
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Evolution of Primordial Magnetic Fields during Large-scale Structure Formation
- 2022
-
Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 929:2
-
Tidskriftsartikel (refereegranskat)abstract
- Primordial magnetic fields (PMFs) could explain the large-scale magnetic fields present in the universe. Inflation and phase transitions in the early universe could give rise to such fields with unique characteristics. We investigate the magnetohydrodynamic evolution of these magnetogenesis scenarios with cosmological simulations. We evolve inflation-generated magnetic fields either as (i) uniform (homogeneous) or as (ii) scale-invariant stochastic fields, and phase-transition-generated ones either as (iii) helical or as (iv) nonhelical fields from the radiation-dominated epoch. We find that the final distribution of magnetic fields in the simulated cosmic web shows a dependence on the initial strength and the topology of the seed field. Thus, the observed field configuration retains information on the initial conditions at the moment of the field generation. If detected, PMF observations would open a new window for indirect probes of the early universe. The differences between the competing models are revealed on the scale of galaxy clusters, bridges, as well as filaments and voids. The distinctive spectral evolution of different seed fields produces imprints on the correlation length today. We discuss how the differences between rotation measures from highly ionized regions can potentially be probed with forthcoming surveys.
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| 50. |
- Music, Denis, et al.
(författare)
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Electrical resistivity modulation of thermoelectric iron based nanocomposites
- 2018
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Ingår i: Vacuum. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0042-207X .- 1879-2715. ; 157, s. 384-390
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Tidskriftsartikel (refereegranskat)abstract
- Iron oxides are promising thermoelectrics, but their high electrical resistivity impedes broader applications. In this work, we have studied Fe oxides with metallic contributions. Pt and Ir additions are also considered to enhance the valence electron concentration and further modify the transport properties. Based on density functional theory explorations, Fe based clusters (Fe-3, Fe-4, and Fe3Pt) are suggested to act as nucleation sites for metallic crystallites, while O leads to formation of an amorphous matrix. This has been validated by transmission electron microscopy and x-ray photoelectron spectroscopy of sputter-grown Fe-Pt-Ir-O thin films. Densely packed bcc Fe grains, approx. 2-3 nm in diameter, are embedded in an amorphous Fe-O matrix in the as-grown state. The Seebeck coefficient reaches even -411 mu V K-1 and the electrical resistivity is up to 5 orders of magnitude lower than that of previously reported literature data on Fe oxides. We suggest that this peculiarity of our films is due to finite states localized at the Fermi level in these nanocomposites.
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