| 1. |
- Humphreys, Keith, et al.
(författare)
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The Genetic Structure of the Swedish Population
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8, s. e22547-
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Tidskriftsartikel (refereegranskat)abstract
- Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise F(st)) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.
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| 2. |
- Leu, Monica, et al.
(författare)
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NordicDB : a Nordic pool and portal for genome-wide control data
- 2010
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 18:12, s. 1322-1326
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Tidskriftsartikel (refereegranskat)abstract
- A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from similar to 5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW-SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries. European Journal of Human Genetics (2010) 18, 1322-1326; doi: 10.1038/ejhg.2010.112; published online 28 July 2010
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| 3. |
- Lindberg, Johan, 1985-
(författare)
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Localic Categories of Models and Categorical Aspects of Intuitionistic Ramified Type Theory
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis contains three papers, all in the general area of categorical logic, together with an introductory part with some minor results and proofs of known results which does not appear to be (easily) available in the literature.In Papers I and II we investigate the formal system Intuitionistic Ramified Type Theory (IRTT), introduced by Erik Palmgren, as an approach to predicative topos theory. In Paper I we construct and study the category of "local sets" in IRTT, including an extension with inductive definitions. We there also give a model of IRTT in univalent type theory using h-sets. In Paper II we adapt triposes and hyperdoctrines to the ramified setting. These give a categorical semantics for certain formal languages ramified in the same way as IRTT.Paper III, which is part of a joint project with Henrik Forssell, concerns logical aspects of the localic groupoid/category representations of Grothendieck toposes that originate from the work of Joyal and Tierney. Working constructively, we give explicit logical descriptions of locales and localic categories used for representing classifying toposes of geometric theories. Aspects of these descriptions are related to work by Coquand, Sambin et al in formal topology, and we show how parts of their work can be captured and extended in our framework.
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| 4. |
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Norse romance. Vol. 3, Hærra Ivan
- 1999
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Hærra Ivan is the first major work of fiction in Swedish. It was translated from French into Old Swedish in 1303 at the request of the German-born queen Eufemia of Norway. This Arthurian romance introduced courtly literature in medieval Sweden and launched a new genre, the Knittel poetry. Its 6446 lines (in the present edition) are an important source to the knowledge of the language at the time. Hærra Ivan has previously been edited twice, by J. W. Liffman and George Stephens 1849 and by Erik Noreen in 1931. The present volume is based on the latter edition, with some minor alterations, but the text is transposed into normalized Old Swedish, the first full-scale attempt to do so with an Old Swedish text. Divergencies between the edition and the text of the main manuscript, Codex Homiensis D 4, are presented in an appendix. The poem is also translated into English and presented in an introductory chapter.
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| 5. |
- Palmgren, Henrik
(författare)
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Cell Membrane Homeostasis in Mammals - The roles of ADIPOR2 and TLCD1 & 2
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ten nanometers. That is the approximate thickness of the plasma membrane that separates the extracellular space from the entire cellular machinery. An asymmetrical bilayer consisting of predominantly phospholipids in which proteins and carbohydrates are anchored and exert their function. Together, these components determine the viscosity, thickness, fluidity, permeability and packing of the plasma membrane, which is constantly maintained within a near-optimal chemical composition for proper function, a phenomenon also known as membrane homeostasis. Dietary fatty acids become the building block for the major component of the membrane bilayer, namely the phospholipids, and its composition can reflect the composition in the food, giving some validity to the term “you are what you eat”. To mitigate the huge variation in dietary fatty acids ending up in the membrane, it is reasonable to believe that regulatory mechanisms exist that adjust the fatty acid composition when required. Surprisingly, not much is known regarding how such adaptive responses regulate membrane fatty acid composition on a molecular level. Within this thesis, novel insights into such regulatory mechanisms are presented. Founded on genetic modifications using CRISPR/Cas9, lipidomic analyses, and membrane fluidity measurements, we build upon previous work and provide further evidence implicating the mammalian adiponectin receptor 2 (ADIPOR2) as a master regulator of membrane homeostasis. Human cells that lack ADIPOR2 show a dramatic vulnerability to saturated fat (SFA) exposure, leading to a defective translational response, increased ER stress, impaired mitochondrial respiration, and importantly, a massive increase in SFA-containing phospholipids. By exploiting this phenotype, genetic ablation of ADIPOR2 in human and mouse pre-adipocytes led to cells with drastic elevation in SFA-containing phospholipids. These were deployed to study the effect of phospholipid saturation on insulin signaling in vitro and in vivo. Surprisingly, both human and mouse adipocytes showed normal insulin signaling despite excess SFA content in their phospholipids, thus highlighting the robustness of adipocytes in lipid handling. Separately, genetic suppressors of SFA vulnerability in PAQR-2 (homolog to mammalian ADIPOR2) deficient C. elegans worms, revealed a novel protein dubbed FLD-1 that influences the amount of fluidizing, long-chain polyunsaturated fatty acids (PUFAs) in membrane phospholipids. Further studies in transgenic mice, lacking the mammalian homologs TLCD1 and TLCD2, led to elucidating the mechanism of action of these proteins, namely that they regulate the incorporation of monounsaturated fatty acids (MUFAs) at the sn-1 position of phosphatidylethanolamines. In parallel, another genetic suppressor to the SFA vulnerability of PAQR-2 knockouts was discovered, namely ACS-13, that was shown to regulate mitochondrial activation of long-chain PUFAs, a function conserved in the human homolog ACSL1. Taken together, this thesis provides new insight into the mechanisms that regulate the fatty acid composition of cellular membranes and that are crucial for the ability of cells to maintain fluid membranes in the face of fluctuating levels of dietary fatty acids.
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| 6. |
- Palmgren, Henrik, et al.
(författare)
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Elevated Adipocyte Membrane Phospholipid Saturation Does Not Compromise Insulin Signaling
- 2023
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Ingår i: DIABETES. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:10, s. 1350-1363
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Tidskriftsartikel (refereegranskat)abstract
- Increased saturated fatty acid (SFA) levels in membrane phospholipids have been implicated in the development of metabolic disease. Here, we tested the hypothesis that increased SFA content in cell membranes negatively impacts adipocyte insulin signaling. Preadipocyte cell models with elevated SFA levels in phospholipids were generated by disrupting the ADIPOR2 locus, which resulted in a striking twofold increase in SFA-containing phosphatidylcholines and phosphatidylethanolamines, which persisted in differentiated adipocytes. Similar changes in phospholipid composition were observed in white adipose tissues isolated from the ADIPOR2-knockout mice. The SFA levels in phospholipids could be further increased by treating ADIPOR2-deficient cells with palmitic acid and resulted in reduced membrane fluidity and endoplasmic reticulum stress in mouse and human preadipocytes. Strikingly, increased SFA levels in differentiated adipocyte phospholipids had no effect on adipocyte gene expression or insulin signaling in vitro. Similarly, increased adipocyte phospholipid saturation did not impair white adipose tissue function in vivo, even in mice fed a high-saturated fat diet at thermoneutrality. We conclude that increasing SFA levels in adipocyte phospholipids is well tolerated and does not affect adipocyte insulin signaling in vitro and in vivo.
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| 7. |
- Petkevicius, K., et al.
(författare)
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TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis. The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.
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| 8. |
- Ruiz, Mario, 1984, et al.
(författare)
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Membrane fluidity is regulated by the C-elegans transmembrane protein FLD-1 and its human homologs TLCD1/2
- 2018
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Ingår i: eLife. - 2050-084X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Dietary fatty acids are the main building blocks for cell membranes in animals, and mechanisms must therefore exist that compensate for dietary variations. We isolated C. elegans mutants that improved tolerance to dietary saturated fat in a sensitized genetic background, including eight alleles of the novel gene fld-1 that encodes a homolog of the human TLCD1 and TLCD2 transmembrane proteins. FLD-1 is localized on plasma membranes and acts by limiting the levels of highly membrane-fluidizing long-chain polyunsaturated fatty acid-containing phospholipids. Human TLCD1/2 also regulate membrane fluidity by limiting the levels of polyunsaturated fatty acid-containing membrane phospholipids. FLD-1 and TLCD1/2 do not regulate the synthesis of long-chain polyunsaturated fatty acids but rather limit their incorporation into phospholipids. We conclude that inhibition of FLD-1 or TLCD1/2 prevents lipotoxicity by allowing increased levels of membrane phospholipids that contain fluidizing long-chain polyunsaturated fatty acids.
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| 9. |
- Smedby, Karin Ekström, et al.
(författare)
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Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma
- 2006
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 15:2, s. 258-265
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Tidskriftsartikel (refereegranskat)abstract
- The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.
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| 10. |
- Spjuth, Ola, 1977-, et al.
(författare)
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E-Science technologies in a workflow for personalized medicine using cancer screening as a case study
- 2017
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Ingår i: JAMIA Journal of the American Medical Informatics Association. - : Oxford University Press. - 1067-5027 .- 1527-974X. ; 24:5, s. 950-957
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We provide an e-Science perspective on the workflow from risk factor discovery and classification of disease to evaluation of personalized intervention programs. As case studies, we use personalized prostate and breast cancer screenings.Materials and Methods: We describe an e-Science initiative in Sweden, e-Science for Cancer Prevention and Control (eCPC), which supports biomarker discovery and offers decision support for personalized intervention strategies. The generic eCPC contribution is a workflow with 4 nodes applied iteratively, and the concept of e-Science signifies systematic use of tools from the mathematical, statistical, data, and computer sciences.Results: The eCPC workflow is illustrated through 2 case studies. For prostate cancer, an in-house personalized screening tool, the Stockholm-3 model (S3M), is presented as an alternative to prostate-specific antigen testing alone. S3M is evaluated in a trial setting and plans for rollout in the population are discussed. For breast cancer, new biomarkers based on breast density and molecular profiles are developed and the US multicenter Women Informed to Screen Depending on Measures (WISDOM) trial is referred to for evaluation. While current eCPC data management uses a traditional data warehouse model, we discuss eCPC-developed features of a coherent data integration platform.Discussion and Conclusion: E-Science tools are a key part of an evidence-based process for personalized medicine. This paper provides a structured workflow from data and models to evaluation of new personalized intervention strategies. The importance of multidisciplinary collaboration is emphasized. Importantly, the generic concepts of the suggested eCPC workflow are transferrable to other disease domains, although each disease will require tailored solutions.
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| 11. |
- Sukonina, Valentina, et al.
(författare)
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FOXK1 and FOXK2 regulate aerobic glycolysis.
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 566, s. 279-283
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Tidskriftsartikel (refereegranskat)abstract
- Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
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| 12. |
- Szulkin, Robert, et al.
(författare)
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Prostate cancer risk variants are not associated with disease progression
- 2012
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 72:1, s. 30-39
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Currently used prognostic markers are limited in their ability to accurately predict disease progression among patients with localized prostate cancer. We examined 23 reported prostate cancer susceptibility variants for association with disease progression. METHODS: Disease progression was explored among 4,673 Swedish patients treated for clinically localized prostate cancer between 1997 and 2002. Prostate cancer progression was defined according to primary treatment as a composed event reflecting termination of deferred treatment, biochemical recurrence, local progression, or presence of distant metastasis. Association between single variants, and all variants combined, were performed in Cox regression analysis assuming both log-additive and co-dominant genetic models. RESULTS: Three of the 23 genetic variants explored were nominally associated with prostate cancer progression; rs9364554 (P = 0.041) on chromosome 6q25 and rs10896449 (P = 0.029) on chromosome 11q13 among patients treated with curative intent; and rs4054823 (P = 0.008) on chromosome 17p12 among patients on surveillance. However, none of these associations remained statistically significant after correction for multiple testing. The combined effect of all susceptibility variants was not associated with prostate cancer progression neither among patients receiving treatment with curative intent (P = 0.14) nor among patients on surveillance (P = 0.92). CONCLUSIONS: We observed no evidence for an association between any of 23 established prostate cancer genetic risk variants and disease progression. Accumulating evidence suggests separate genetic components for initiation and progression of prostate cancer. Future studies systematically searching for genetic risk variants associated with prostate cancer progression and prognosis are warranted. Prostate © 2011 Wiley-Liss, Inc.
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| 13. |
- Sørensen, Danny Mollerup, et al.
(författare)
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The P5A ATPase Spf1p is stimulated by phosphatidylinositol 4-phosphate and influences cellular sterol homeostasis
- 2019
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Ingår i: Molecular Biology of the Cell. - : American Society for Cell Biology. - 1059-1524 .- 1939-4586. ; 30:9, s. 1069-1084
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Tidskriftsartikel (refereegranskat)abstract
- P5A ATPases are expressed in the endoplasmic reticulum (ER) of all eukaryotic cells, and their disruption results in severe ER stress. However, the function of these ubiquitous membrane proteins, which belong to the P-type ATPase superfamily, is unknown. We purified a functional tagged version of the Saccharomyces cerevisiae P5A ATPase Spf1p and observed that the ATP hydrolytic activity of the protein is stimulated by phosphatidylinositol 4-phosphate (PI4P). Furthermore, SPF1 exhibited negative genetic interactions with SAC1, encoding a PI4P phosphatase, and with OSH1 to OSH6, encoding Osh proteins, which, when energized by a PI4P gradient, drive export of sterols and lipids from the ER. Deletion of SPF1 resulted in increased sensitivity to inhibitors of sterol production, a marked change in the ergosterol/lanosterol ratio, accumulation of sterols in the plasma membrane, and cytosolic accumulation of lipid bodies. We propose that Spf1p maintains cellular sterol homeostasis by influencing the PI4P-induced and Osh-mediated export of sterols from the ER.
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