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Sökning: WFRF:(Gustafsson Claes) > (2015-2019)

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1.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • The role of membrane ER alpha signaling in bone and other major estrogen responsive tissues
  • 2016
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen receptor a (ER alpha) signaling leads to cellular responses in several tissues and in addition to nuclear ER alpha-mediated effects, membrane ER alpha (mER alpha) signaling may be of importance. To elucidate the significance, in vivo, of mER alpha signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ER alpha to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mER alpha signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mER alpha (<35% reduction in estrogen response in NOER mice). In conclusion, mER alpha signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ER alpha actions may provide means to develop new selective estrogen receptor modulators with improved profiles.
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2.
  • Movérare-Skrtic, Sofia, et al. (författare)
  • The bone-sparing effects of estrogen and WNT16 are independent of each other
  • 2015
  • 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. ; 112:48, s. 14972-14977
  • Tidskriftsartikel (refereegranskat)abstract
    • Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16-/- mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females isWNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl- Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl- Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16-/- mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16-/- and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16- targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.
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3.
  • Abarenkov, Kessy, et al. (författare)
  • Annotating public fungal ITS sequences from the built environment according to the MIxS-Built Environment standard – a report from a May 23-24, 2016 workshop (Gothenburg, Sweden)
  • 2016
  • Ingår i: MycoKeys. - : Pensoft Publishers. - 1314-4057 .- 1314-4049. ; 16, s. 1-15
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent molecular studies have identified substantial fungal diversity in indoor environments. Fungi and fungal particles have been linked to a range of potentially unwanted effects in the built environment, including asthma, decay of building materials, and food spoilage. The study of the built mycobiome is hampered by a number of constraints, one of which is the poor state of the metadata annotation of fungal DNA sequences from the built environment in public databases. In order to enable precise interrogation of such data – for example, “retrieve all fungal sequences recovered from bathrooms” – a workshop was organized at the University of Gothenburg (May 23-24, 2016) to annotate public fungal barcode (ITS) sequences according to the MIxS-Built Environment annotation standard (http://gensc.org/mixs/). The 36 participants assembled a total of 45,488 data points from the published literature, including the addition of 8,430 instances of countries of collection from a total of 83 countries, 5,801 instances of building types, and 3,876 instances of surface-air contaminants. The results were implemented in the UNITE database for molecular identification of fungi (http://unite.ut.ee) and were shared with other online resources. Data obtained from human/animal pathogenic fungi will furthermore be verified on culture based metadata for subsequent inclusion in the ISHAM-ITS database (http://its.mycologylab.org).
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4.
  • Antonson, P., et al. (författare)
  • Identification of proteins highly expressed in uterine fluid from mice with hydrometra
  • 2015
  • Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 466:4, s. 650-655
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen receptor alpha (ER alpha) is an important regulator of the estrous cycle and mice with global ER alpha deletion, as well as some conditional knockout mouse lines, have an interruption in the estrous cycle. In this study we observed that conditional ERa knockout mice where the Cre gene is regulated by the rat insulin promoter (RIP), RIP-Cre/ER alpha(KO) mice, have a 3.7-fold increase in serum 17 beta-estradiol levels, blocked estrous cycle, and develop a fluid-filled uterus (hydrometra). Using a proteomics approach, we identified three proteins, lactoferrin, complement C3 and chitinase 3-like protein 1 (CHI3L1), as highly expressed proteins in hydrometra fluid. The mRNA levels of the corresponding genes were more than 50-fold higher in RIP-Cre/ER alpha(KO) uterus compared to controls. High expression of CHI3L1 in the uterine fluid was not reflected as elevated levels in the serum. The high expression of lactoferrin, complement C3 and CHI3L1 in the uterine fluid, in association with elevated estrogen levels, prompted us to address if the expression of these genes is related to reproduction. However, gonadotropin treatment of mice reduced the uterine expression of these genes in a model of in vitro fertilization. Our findings identify lactoferrin, complement C3 and CHI3L1 as highly expressed proteins in hydrometra fluid in association with chronically elevated serum estradiol levels. (C) 2015 Elsevier Inc. All rights reserved.
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5.
  • Banyai, Gabor, et al. (författare)
  • Cyclin C influences the timing of mitosis in fission yeast.
  • 2017
  • Ingår i: Molecular biology of the cell. - 1939-4586. ; 28:13, s. 1738-1744
  • Tidskriftsartikel (refereegranskat)abstract
    • The multiprotein Mediator complex is required for the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator contains the Cdk8 regulatory subcomplex, which directs periodic transcription and influences cell cycle progression in fission yeast. Here we investigate the role of CycC, the cognate cyclin partner of Cdk8, in cell cycle control. Previous reports suggested that CycC interacts with other cellular Cdks, but a fusion of CycC to Cdk8 reported here did not cause any obvious cell cycle phenotypes. We find that Cdk8 and CycC interactions are stabilized within the Mediator complex and the activity of Cdk8-CycC is regulated by other Mediator components. Analysis of a mutant yeast strain reveals that CycC, together with Cdk8, primarily affects M-phase progression but mutations that release Cdk8 from CycC control also affect timing of entry into S phase.
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6.
  • Bergbrede, T., et al. (författare)
  • An Adaptable High-Throughput Technology Enabling the Identification of Specific Transcription Modulators
  • 2017
  • Ingår i: Slas Discovery. - : Elsevier BV. - 2472-5552. ; 22:4, s. 378-386
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondria harbor the oxidative phosphorylation (OXPHOS) system, which under aerobic conditions produces the bulk of cellular adenosine triphosphate (ATP). The mitochondrial genome encodes key components of the OXPHOS system, and it is transcribed by the mitochondrial RNA polymerase, POLRMT. The levels of mitochondrial transcription correlate with the respiratory activity of the cell. Therefore, compounds that can increase or decrease mitochondrial gene transcription may be useful for fine-tuning metabolism and could be used to treat metabolic diseases or certain forms of cancer. We here report the establishment of a novel high-throughput assay technology that has allowed us to screen a library of 430,000 diverse compounds for effects on mitochondrial transcription in vitro. Following secondary screens facilitated by the same assay principle, we identified 55 compounds that efficiently and selectively inhibit mitochondrial transcription and that are active also in cell culture. Our method is easily adaptable to other RNA or DNA polymerases and varying spectroscopic detection technologies.
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7.
  • Berglund, Anna-Karin, 1979, et al. (författare)
  • Nucleotide pools dictate the identity and frequency of ribonucleotide incorporation in mitochondrial DNA. : Mapping ribonucleotides in mitochondrial DNA
  • 2017
  • Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous work has demonstrated the presence of ribonucleotides in human mitochondrial DNA (mtDNA) and in the present study we use a genome-wide approach to precisely map the location of these. We find that ribonucleotides are distributed evenly between the heavy- and light-strand of mtDNA. The relative levels of incorporated ribonucleotides reflect that DNA polymerase γ discriminates the four ribonucleotides differentially during DNA synthesis. The observed pattern is also dependent on the mitochondrial deoxyribonucleotide (dNTP) pools and disease-causing mutations that change these pools alter both the absolute and relative levels of incorporated ribonucleotides. Our analyses strongly suggest that DNA polymerase γ-dependent incorporation is the main source of ribonucleotides in mtDNA and argues against the existence of a mitochondrial ribonucleotide excision repair pathway in human cells. Furthermore, we clearly demonstrate that when dNTP pools are limiting, ribonucleotides serve as a source of building blocks to maintain DNA replication. Increased levels of embedded ribonucleotides in patient cells with disturbed nucleotide pools may contribute to a pathogenic mechanism that affects mtDNA stability and impair new rounds of mtDNA replication.
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8.
  • Bäcklin, Christofer, 1983-, et al. (författare)
  • Self-tuning density estimation based on Bayesian averaging of adaptive kernel density estimations yields state-of-the-art performance
  • 2018
  • Ingår i: Pattern Recognition. - : ELSEVIER SCI LTD. - 0031-3203 .- 1873-5142. ; 78, s. 133-143
  • Tidskriftsartikel (refereegranskat)abstract
    • Non-parametric probability density function (pdf) estimation is a general problem encountered in many fields. A promising alternative to the dominating solutions, kernel density estimation (KDE) and Gaussian mixture modeling, is adaptive KDE where kernels are given individual bandwidths adjusted to the local data density. Traditionally the bandwidths are selected by a non-linear transformation of a pilot pdf estimate, containing parameters controlling the scaling, but identifying parameters values yielding competitive performance has turned out to be non-trivial. We present a new self-tuning (parameter free) pdf estimation method called adaptive density estimation by Bayesian averaging (ADEBA) that approximates pdf estimates in the form of weighted model averages across all possible parameter values, weighted by their Bayesian posterior calculated from the data. ADEBA is shown to be simple, robust, competitive in comparison to the current practice, and easily generalize to multivariate distributions. An implementation of the method for R is publicly available.
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9.
  • Carlsten, Jonas O P, et al. (författare)
  • Loss of the Mediator subunit Med20 affects transcription of tRNA and other non-coding RNA genes in fission yeast
  • 2016
  • Ingår i: Biochimica Et Biophysica Acta-Gene Regulatory Mechanisms. - : Elsevier BV. - 1874-9399. ; 1859:2, s. 339-347
  • Tidskriftsartikel (refereegranskat)abstract
    • Mediator is a co-regulator of RNA polymerase II (Pol II), transducing signals from regulatory elements and transcription factors to the general transcription machinery at the promoter. We here demonstrate that Med20 influences ribosomal protein expression in fission yeast. In addition, loss of Med20 leads to an accumulation of aberrant, readthrough tRNA transcripts. These transcripts are polyadenylated and targeted for degradation by the exosome. Similarly, other non-coding RNA molecules, such as snRNA, snoRNA and rRNA, are also enriched in the polyadenylate preparations in the absence of Med20. We suggest that fission yeast Mediator takes part in a regulatory pathway that affects Pol III-dependent transcripts.
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10.
  • Connor, T. M., et al. (författare)
  • Mutations in mitochondrial DNA causing tubulointerstitial kidney disease
  • 2017
  • Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 13:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A> T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNA(Phe), tRNA(Leu1) and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNA Phe (m.616T> C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNA(Phe)
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11.
  • Daniel, Maria, et al. (författare)
  • Effect of Myocardial Infarction With Nonobstructive Coronary Arteries on Physical Capacity and Quality-of-Life
  • 2017
  • Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 120:3, s. 341-346
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with myocardial infarction with nonobstructive coronary arteries (MINOCA), including Takotsubo syndrome (TS), are considered to have a better survival compared with those with coronary heart disease (CHD). Studies of patients with MINOCA measuring physical and mental function including matched control groups are lacking. The aim of this study was to determine the physical capacity and quality of life in patients with MINOCA. One-hundred patients with MINOCA along with TS (25%) were investigated from 2007 to 2011. A bicycle exercise stress test was performed 6 weeks after hospitalization and QoL was investigated by the Short Form Survey 36 at 3 months' follow-up. Both a healthy and a CHD group that were age and gender matched were used as controls. The MINOCA group had a lower physical capacity (139 ± 42 W) compared with the healthy control group (167 ± 53 W, p <0.001) but better than the CHD control group (124 ± 39 W, p = 0.023). Patients with MINOCA had lower physical and mental component summary scores compared with the healthy controls (p <0.001) and lower mental component summary (p = 0.012), mental health (p = 0.016), and vitality (p = 0.008) scores compared with the CHD controls. In conclusion, the findings of this first study on exercise capacity and QoL in patients with MINOCA showed both physical and mental distress from 6 weeks to 3 months after the acute event similar to CHD controls and in some perspectives even lower scores especially in the mental component of QoL.
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12.
  • Farman, Helen H., 1983, et al. (författare)
  • Extra-nuclear effects of estrogen on cortical bone in males require ERαAF-1
  • 2017
  • Ingår i: Journal of Molecular Endocrinology. - 0952-5041. ; 58:2, s. 105-111
  • Tidskriftsartikel (refereegranskat)abstract
    • Estradiol (E2) signaling via estrogen receptor alpha (ERα) is important for the male skeleton as demonstrated by ERα inactivation in both mice and man. ERα mediates estrogenic effects not only by translocating to the nucleus and affecting gene transcription but also by extra-nuclear actions e.g., triggering cytoplasmic signaling cascades. ERα contains various domains, and the role of activation function 1 (ERαAF-1) is known to be tissue specific. The aim of this study was to determine the importance of extra-nuclear estrogen effects for the skeleton in males and to determine the role of ERαAF-1 for mediating these effects. Five-month-old male wild-type (WT) and ERαAF-1-inactivated (ERαAF-10) mice were orchidectomized and treated with equimolar doses of 17β-estradiol (E2) or an estrogen dendrimer conjugate (EDC), which is incapable of entering the nucleus and thereby only initiates extra-nuclear ER actions or their corresponding vehicles for 3.5 weeks. As expected, E2 treatment increased cortical thickness and trabecular bone volume per total volume (BV/TV) in WT males. EDC treatment increased cortical thickness in WT males, whereas no effect was detected in trabecular bone. In ERαAF-10 males, E2 treatment increased cortical thickness, but did not affect trabecular bone. Interestingly, the effect of EDC on cortical bone was abolished in ERαAF-10 mice. In conclusion, extra-nuclear estrogen signaling affects cortical bone mass in males, and this effect is dependent on a functional ERαAF-1. Increased knowledge regarding estrogen signaling mechanisms in the regulation of the male skeleton may aid the development of new treatment options for male osteoporosis.
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13.
  • Farman, Helen H., 1983, et al. (författare)
  • Membrane estrogen receptor alpha is essential for estrogen signaling in the male skeleton
  • 2018
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 239:3, s. 303-312
  • Tidskriftsartikel (refereegranskat)abstract
    • The importance of estrogen receptor alpha (ER alpha) for the regulation of bone mass in males is well established. ERa mediates estrogenic effects both via nuclear and membraneinitiated ER alpha (mER alpha) signaling. The role of mERa signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERa signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ER alpha to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (mu CT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mER alpha is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.
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14.
  • Govindarajan, Sridhar, et al. (författare)
  • Mapping of Amino Acid Substitutions Conferring Herbicide Resistance in Wheat Glutathione Transferase
  • 2015
  • Ingår i: ACS Synthetic Biology. - : American Chemical Society (ACS). - 2161-5063. ; 4:3, s. 221-227
  • Tidskriftsartikel (refereegranskat)abstract
    • We have used design of experiments (DOE) and systematic variance to efficiently explore glutathione transferase substrate specificities caused by amino acid substitutions. Amino acid substitutions selected using phylogenetic analysis were synthetically combined using a DOE design to create an information-rich set of gene variants, termed infologs. We used machine learning to identify and quantify protein sequence-function relationships against 14 different substrates The resulting models were quantitative and predictive, serving as a guide for engineering of glutathione transferase activity toward a diverse set of herbicides Predictive quantitative models like those presented here have broad applicability for bioengineering.
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15.
  • Grahnemo, Louise, et al. (författare)
  • Increased bone mass in a mouse model with low fat mass.
  • 2018
  • Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 315:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Mice with impaired acute inflammatory responses within adipose tissue display reduced diet-induced fat mass gain associated with glucose intolerance and systemic inflammation. Therefore, acute adipose tissue inflammation is needed for a healthy expansion of adipose tissue. Because inflammatory disorders are associated with bone loss, we hypothesized that impaired acute adipose tissue inflammation leading to increased systemic inflammation results in a lower bone mass. To test this hypothesis, we used mice overexpressing an adenoviral protein complex - the receptor internalization and degradation (RID) complex that inhibits pro-inflammatory signaling - under the control of the aP2-promotor (RID tg mice), resulting in suppressed inflammatory signaling in adipocytes. As expected, RID tg mice had a lower high-fat diet-induced weight and fat mass gain and higher systemic inflammation than their littermate wild type controls. Contrary to our hypothesis, the RID tg mice had increased bone mass in long bones and vertebrae, affecting trabecular and cortical parameters, as well as improved humeral biomechanical properties. We did not find any differences in bone formation or resorption parameters as determined by histology or enzyme immunoassay. However, bone marrow adiposity, often negatively associated with bone mass, was decreased in male RID tg mice as determined by histological analysis of tibia. In conclusion, mice with reduced fat mass, due to impaired adipose tissue inflammation, have increased bone mass.
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16.
  • Gustafsson, Anders, et al. (författare)
  • Developing service research - paving the way to transdisciplinary research
  • 2016
  • Ingår i: Journal of Service Management. - 1757-5818 .- 1757-5826. ; 27:1, s. 9-20
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose - The purpose of this paper is to discuss how service, as an interdisciplinary area of research, can increase its potential for transdisciplinary contributions from the perspective of what signifies intra-, multi-, inter-, and transdisciplinary research. Design/methodology/approach - The essay first discusses common perspectives on the service concept before presenting a review on what signifies intra-, multi-, inter-, and transdisciplinary research. The emerging theoretical framework is followed by a discussion on the challenges and opportunities for service research in making interdisciplinary and transdisciplinary theoretical contributions. Findings - The research provides a typological framework for understanding intra-, multi-, inter-, and transdisciplinary service research and, implications related to how service research contributions can become increasingly inter- and transdisciplinary. Originality/value - The paper contributes to widening the scope of service research by focussing on how the domain can overcome hurdles and increase its potential for making theoretical contributions that are applicable across and beyond established research disciplines.
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17.
  • Gustafsson, Claes, et al. (författare)
  • Improvisation – An emergence theory perspective
  • 2017
  • Ingår i: Culture and Organization. - : Informa UK Limited. - 1475-9551 .- 1477-2760. ; 23:3, s. 177-196
  • Tidskriftsartikel (refereegranskat)abstract
    • The paper addresses the occurrence of improvisation and intuition within dynamic business environments from an emergence theory perspective. As argued, the dynamics of the so-called red queen principle forces competition towards the verge of the manageable, making improvised and intuitive action and decision-making not a shortcoming but a necessity in a successful business context. Particularly, the paper discusses how we may interpret the highly rationalistic acts and outcomes of planning and plans in such chaotic and uncertain contexts. We draw upon a longitudinal study of large industrial project deliveries incorporating more than 25 such deliveries.
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18.
  • Gustafsson, Claes M, 1966, et al. (författare)
  • Maintenance and Expression of Mammalian Mitochondrial DNA
  • 2016
  • Ingår i: Annual Review of Biochemistry. - : Annual Reviews. - 0066-4154 .- 1545-4509. ; 85, s. 133-160
  • Tidskriftsartikel (refereegranskat)abstract
    • Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.
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19.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • ER alpha expression in T lymphocytes is dispensable for estrogenic effects in bone
  • 2018
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 238:2, s. 129-136
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERa) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERa expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERa expression specifically in T lymphocytes (Lck-ERa-/-) and ERaflox/flox littermate (control) mice. Deletion of ERa expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERa-/compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERa-/- mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERa-/- led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERa in T lymphocytes. In conclusion, ERa expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice.
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20.
  • Högström, Claes, 1979-, et al. (författare)
  • Strategic brand management : Archetypes for managing brands through paradoxes
  • 2015
  • Ingår i: Journal of Business Research. - : Elsevier. - 0148-2963 .- 1873-7978. ; 68:2, s. 391-404
  • Tidskriftsartikel (refereegranskat)abstract
    • Although brands are acknowledged as significant assets in a firm's value creation and differentiation process, branding literature often describes opposing perspectives and contradictory demands. This article develops a framework of three strategic brand management archetypes that provide new insights into the complexity and often paradoxical ambiguity of branding. By combining an empirical qualitative study with extant brand management and relational exchange theory, the authors suggests that firms create, reinforce, switch, or allow certain brand management archetypes to coexist to optimize specific effects and manage paradoxes. From a managerial perspective, the article suggests that understanding strategic brand management and related paradoxes is fundamental for organizations to achieve desired effects with their value creation. (C) 2014 Elsevier Inc All rights reserved.
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21.
  • Jansson, John-Olov, 1954, et al. (författare)
  • Body weight homeostat that regulates fat mass independently of leptin in rats and mice.
  • 2018
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:2, s. 427-432
  • Tidskriftsartikel (refereegranskat)abstract
    • Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass.
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22.
  • Jemt, Elisabeth, et al. (författare)
  • Regulation of DNA replication at the end of the mitochondrial D-loop involves the helicase TWINKLE and a conserved sequence element
  • 2015
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:19, s. 9262-9275
  • Tidskriftsartikel (refereegranskat)abstract
    • The majority of mitochondrial DNA replication events are terminated prematurely. The nascent DNA remains stably associated with the template, forming a triple-stranded displacement loop (D-loop) structure. However, the function of the D-loop region of the mitochondrial genome remains poorly understood. Using a comparative genomics approach we here identify two closely related 15 nt sequence motifs of the D-loop, strongly conserved among vertebrates. One motif is at the D-loop 5'-end and is part of the conserved sequence block 1 (CSB1). The other motif, here denoted coreTAS, is at the D-loop 3'-end. Both these sequences may prevent transcription across the D-loop region, since light and heavy strand transcription is terminated at CSB1 and coreTAS, respectively. Interestingly, the replication of the nascent D-loop strand, occurring in a direction opposite to that of heavy strand transcription, is also terminated at coreTAS, suggesting that coreTAS is involved in termination of both transcription and replication. Finally, we demonstrate that the loading of the helicase TWINKLE at coreTAS is reversible, implying that this site is a crucial component of a switch between D-loop formation and full-length mitochondrial DNA replication.
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23.
  • Kashif, Muhammad, et al. (författare)
  • Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism
  • 2017
  • Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 103952-103967
  • Tidskriftsartikel (refereegranskat)abstract
    • We analyzed survival effects for 15 different pairs of clinically relevant anticancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy (TM) II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.
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24.
  • Kashif, Muhammad, et al. (författare)
  • In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index
  • 2015
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • In vitro-based search for promising anti-cancer drug combinations may provide important leads to improved cancer therapies. Currently there are no integrated computational-experimental methods specifically designed to search for combinations, maximizing a predefined therapeutic index (TI) defined in terms of appropriate model systems. Here, such a pipeline is presented allowing the search for optimal combinations among an arbitrary number of drugs while also taking experimental variability into account. The TI optimized is the cytotoxicity difference (in vitro) between a target model and an adverse side effect model. Focusing on colorectal carcinoma (CRC), the pipeline provided several combinations that are effective in six different CRC models with limited cytotoxicity in normal cell models. Herein we describe the identification of the combination (Trichostatin A, Afungin, 17-AAG) and present results from subsequent characterisations, including efficacy in primary cultures of tumour cells from CRC patients. We hypothesize that its effect derives from potentiation of the proteotoxic action of 17-AAG by Trichostatin A and Afungin. The discovered drug combinations against CRC are significant findings themselves and also indicate that the proposed strategy has great potential for suggesting drug combination treatments suitable for other cancer types as well as for other complex diseases.
  •  
25.
  • Kashif, Muhammad (författare)
  • Integrated Computational and Experimental Approaches for Accelerated Drug Combination Discovery and Development : Applications in Cancer Pharmacology
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Today the norm in modern cancer treatment is to use different forms of drug combinations. Recently anti-cancer treatment using drug combinations has gained increased attention due to the outstanding pharmacotherapeutic opportunities provided by combination therapies. However, the potential of this field is largely unexplored, partly due to the complexities associated with the astronomical number of possible combinations and partly due to the lack of means for quantifying clinically relevant adverse side effects in the early stages of the combination discovery and development process. This has resulted in relatively limited progress in this area. Motivated by this unfortunate state-of-affairs, the research reported in this thesis was aimed at developing and implementing computational and experimental methods to facilitate and accelerate the discovery and development of anti-cancer therapies. In paper I, the largely overlooked concept of therapeutic synergy is re-introduced and demonstrated to be useful already at the level of combination discovery by taking both curative and adverse effects into account. In paper II, a semiautomatic combination discovery platform was developed based on a tailored programming of a pipetting robot system and application of a new in-house developed combination search algorithm, the therapeutic algorithmic combinatorial screen (TACS) algorithm. TACS seems to be the first algorithm of its kind that takes experimental variability into account during the iterative search process. The semiautomatic hardware platform along with TACS can perform de novo or knowledge based combination drug discovery and development without brute force comprehensive search efforts. One promising discovery made using this platform is a combination of the drugs 17-AAG, afungin and trichostatin a for treatment of colorectal cancer carcinoma (CRC). In paper III, an algorithm is developed and applied in order to use single drug induced systemic gene expression profiles for rational drug combination design by assuming additive combination effects. The resulting algorithm, combo-CMap, is applied and validated using a slightly extended version of the freely available Connectivity Map (CMap) database which is currently containing 6190 chemically induced mRNA gene expression signatures. In paper IV, a software (R package) was developed and applied to perform improved synergy/antagonism analysis, in particular joint Loewe and Bliss analyses while taking associated experimental variability into account using non-parametric statistics including bootstrap intervals. Applying this software to the synergy analysis of interaction effects among clinically used and/or relevant drugs in CRC cell lines revealed complex patterns of synergy and antagonism. In conclusion, the work presented here offers important contributions and findings that may accelerate and/or improve different parts of the field of drug combination discovery and development.
  •  
26.
  • Kilpeläinen, Tuomas O, et al. (författare)
  • Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
  •  
27.
  • Kuhl, I., et al. (författare)
  • POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA
  • 2016
  • Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 2:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA(+) Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression.
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28.
  • Lindberg, Karolin, et al. (författare)
  • Validation of the Inventory of Interpersonal Problems (IIP-64) : a comparison of Swedish female outpatients with anorexia nervosa or bulimia nervosa and controls
  • 2018
  • Ingår i: Nordic Journal of Psychiatry. - : Taylor & Francis. - 0803-9488 .- 1502-4725. ; 72:5, s. 347-353
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: The aim of the study was to explore the psychometric properties of the Inventory of Interpersonal Problems (IIP-64) and to compare levels of interpersonal distress in Swedish female outpatients with anorexia nervosa or bulimia nervosa with age- and gender-matched controls.METHODS: Totally, 401 participants were included; anorexia nervosa (n = 74), bulimia nervosa (n = 85) and controls (n = 242). All participants completed the IIP-64. The eating disorder (ED) patients also filled out the Eating Disorder Inventory-2/3 (EDI).RESULTS: Internal consistency of IIP-64 was acceptable to high. Principal component analyses with varimax rotation of the IIP-64 subscales confirmed the circumplex structure with two underlying orthogonal dimensions; affiliation and dominance. Significant correlations between EDI-3 composite scales ineffectiveness and interpersonal problems and IIP-64 were found. ED patients reported higher levels of interpersonal distress than controls on all but one subscale (intrusive/needy).CONCLUSIONS: IIP-64 can be considered to have acceptable to good reliability and validity in a Swedish ED sample. IIP-64 can be a useful complement in assessment of interpersonal problems in ED.
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29.
  • Lionikaite, Vikte, et al. (författare)
  • Clinically relevant doses of Vitamin A decrease cortical bone mass in mice
  • 2018
  • Ingår i: Journal of Endocrinology. - 0022-0795 .- 1479-6805. ; 239:3, s. 389-402
  • Tidskriftsartikel (refereegranskat)abstract
    • Excess vitamin A has been associated with decreased cortical bone thickness and increased fracture risk. While most studies in rodents have employed high dosages of vitamin A for short periods of time, we investigated the bone phenotype in mice after longer exposure to more clinically relevant doses. For 1, 4 and 10 weeks, mice were fed a control diet (4.5µg retinyl acetate/g chow), a diet modeled from the human upper tolerable limit (UTL; 20µg retinyl acetate/g chow) and a diet three times UTL (supplemented; 60µg retinyl acetate/g chow). Time-dependent decreases in periosteal circumference and bone mineral content were noted with the supplemented dose. These reductions in cortical bone resulted in a significant time-dependent decrease of predicted strength and a non-significant trend toward reduced bone strength as analyzed by three-point bending. Trabecular bone in tibiae and vertebrae remained unaffected when vitamin A was increased in the diet. Dynamic histomorphometry demonstrated that bone formation was substantially decreased after 1 week of treatment at the periosteal site with the supplemental dose. Increasing amount of vitamin A decreased endocortical circumference, resulting in decreased marrow area, a response associated with enhanced endocortical bone formation. In the presence of bisphosphonate, vitamin A had no effect on cortical bone, suggesting that osteoclasts are important, even if effects on bone resorption were not detected by osteoclast counting, genes in cortical bone or analysis of serum TRAP5b and CTX. In conclusion, our results indicate that even clinically relevant doses of vitamin A have a negative impact on the amount of cortical bone. © 2018 The authors Published by Bioscientifica Ltd.
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30.
  • Locke, Adam E, et al. (författare)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • 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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31.
  • Lu, Yingchang, et al. (författare)
  • New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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32.
  • Macao, Bertil, 1969, et al. (författare)
  • The exonuclease activity of DNA polymerase gamma is required for ligation during mitochondrial DNA replication
  • 2015
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondrial DNA (mtDNA) polymerase gamma (POL gamma) harbours a 3'-5' exonuclease proofreading activity. Here we demonstrate that this activity is required for the creation of ligatable ends during mtDNA replication. Exonuclease-deficient POL gamma fails to pause on reaching a downstream 5'-end. Instead, the enzyme continues to polymerize into double-stranded DNA, creating an unligatable 5'-flap. Disease-associated mutations can both increase and decrease exonuclease activity and consequently impair DNA ligation. In mice, inactivation of the exonuclease activity causes an increase in mtDNA mutations and premature ageing phenotypes. These mutator mice also contain high levels of truncated, linear fragments of mtDNA. We demonstrate that the formation of these fragments is due to impaired ligation, causing nicks near the origin of heavy-strand DNA replication. In the subsequent round of replication, the nicks lead to double-strand breaks and linear fragment formation.
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33.
  • Molin, M., et al. (författare)
  • Case management at an outpatient unit for severe and enduring eating disorder patients at Stockholm Centre for Eating Disorders : a study protocol
  • 2016
  • Ingår i: International Journal of Eating Disorders. - London, United Kingdom : BioMed Central. - 0276-3478 .- 1098-108X .- 2050-2974. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Patients with severe and enduring eating disorders (SEED) are seriously ill and have a low quality of life. Case management (CM), originally developed for adult patients with severe mental disabilities, has been shown to enhance social functioning and improve quality of life, while reducing the number and length of hospitalizations. In 2014, a special unit based on CM, for patients with SEED (the Eira unit) was started at Stockholm Centre for Eating Disorders, Sweden.Method/Design: This study aims to investigate if CM can improve SEED patients' quality of life, and reduce their eating disorder symptoms as well as their health care consumption. Methods for data collection are a semi-structured diagnostic interview, self-report questionnaires, and a qualitative interview. The diagnostic interview and the self-report assessments will be done at start of treatment and at follow-ups after 1, 2, and 3years. The qualitative interview will be conducted 1 year after start of treatment. The study is approved by the ethical review board in Stockholm in compliance with the Helsinki Declaration.Discussion: CM is a possible new contribution to the treatment methods for SEED. It does not aim at remission, but rather to accept life as it is, and to enhance quality of life in the presence of the ED. This study will investigate the potential benefits of this novel intervention in a special unit for SEED patients.Trail Registration: Clinicaltrials.gov Id: NCT02897622.
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34.
  • Mondal, Tanmoy, 1981, et al. (författare)
  • MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures
  • 2015
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3, we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA–DNA triplex formation. We have found that RNA–DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA–DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.
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35.
  • Nazir, Madiha, et al. (författare)
  • Targeting tumor cells based on Phosphodiesterase 3A expression
  • 2017
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 361:2, s. 308-315
  • Tidskriftsartikel (refereegranskat)abstract
    • We and others have previously reported a correlation between high phosphodiesterase 3 A (PDE3A) expression and selective sensitivity to phosphodiesterase (PDE) inhibitors. This indicates that PDE3A could serve both as a drug target and a biomarker of sensitivity to PDE3 inhibition. In this report, we explored publicly available mRNA gene expression data to identify cell lines with different PDE3A expression. Cell lines with high PDE3A expression showed marked in vitro sensitivity to PDE inhibitors zardaverine and quazinone, when compared with those having low PDE3A expression. Immunofluorescence and immunohistochemical stainings were in agreement with PDE3A mRNA expression, providing suitable alternatives for biomarker analysis of clinical tissue specimens. Moreover, we here demonstrate that tumor cells from patients with ovarian carcinoma show great variability in PDE3A protein expression and that level of PDE3A expression is correlated with sensitivity to PDE inhibition. Finally, we demonstrate that PDE3A is highly expressed in subsets of patient tumor cell samples from different solid cancer diagnoses and expressed at exceptional levels in gastrointestinal stromal tumor (GIST) specimens. Importantly, vulnerability to PDE3 inhibitors has recently been associated with co-expression of PDE3A and Schlafen family member 12 (SLFN12). We here demonstrate that high expression of PDE3A in clinical specimens, at least on the mRNA level, seems to be frequently associated with high SLFIV12 expression. In conclusion, PDE3A seems to be both a promising biomarker and drug target for individualized drug treatment of various cancers.
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36.
  • Nero, Daniella, et al. (författare)
  • Personality Traits in Patients with Myocardial Infarction with Nonobstructive Coronary Arteries.
  • 2019
  • Ingår i: The American journal of medicine. - : Elsevier BV. - 1555-7162 .- 0002-9343. ; 132:3, s. 374-381
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of this study was to describe type A behavior pattern and trait anger in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) and compare them with patients with coronary heart disease and healthy controls. Type A behavior pattern and anger have been linked to coronary heart disease in previous studies. This is the first study to assess type A behavior pattern and trait anger in MINOCA patients.One hundred MINOCA patients, consecutively recruited during 2007-2011 at 5 coronary care units in Stockholm, were matched for sex and age to 100 coronary heart disease patients and 100 healthy controls. All participants completed the Bortner Rating Scale to quantify type A behavior pattern and the Spielberger Trait Anger Scale to quantify anger 3 months after the acute event.MINOCA patients' Bortner Rating Scale score was 70.9 ± 10.8 (mean ± SD) and Spielberger Trait Anger Scale score was 14 (12-17) (median; interquartile range). Coronary heart disease patients' Bortner Rating Scale score was 70.5 ± 10.2 and Spielberger Trait Anger Scale score was 14 (12-17). Healthy controls' Bortner Rating Scale score was 71.9 ± 9.1 and Spielberger Trait Anger Scale score was 13 (11-16).We found no significant differences in Bortner Rating Scale score and Spielberger Trait Anger Scale score among MINOCA, coronary heart disease patients, and healthy controls, regardless of whether total scores, subscales, or cutoffs were used to classify type A behavior pattern and trait anger. However, we cannot exclude the existence of an occasional episode of anger or mental stress in relation to the coronary event. This is the first study to assess type A behavior pattern and trait anger in patients with MINOCA, and future studies need to confirm the current findings before any firm conclusions can be made.
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37.
  • Nicholls, Thomas J., et al. (författare)
  • Dinucleotide Degradation by REXO2 Maintains Promoter Specificity in Mammalian Mitochondria
  • 2019
  • Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 76:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Oligoribonucleases are conserved enzymes that degrade short RNA molecules of up to 5 nt in length and are assumed to constitute the final stage of RNA turnover. Here we demonstrate that REXO2 is a specialized dinucleotide-degrading enzyme that shows no preference between RNA and DNA dinucleotide substrates. A heart- and skeletal-muscle-specific knockout mouse displays elevated dinucleotide levels and alterations in gene expression patterns indicative of aberrant dinucleotide-primed transcription initiation. We find that dinucleotides act as potent stimulators of mitochondrial transcription initiation in vitro. Our data demonstrate that increased levels of dinucleotides can be used to initiate transcription, leading to an increase in transcription levels from both mitochondrial promoters and other, nonspecific sequence elements in mitochondrial DNA. Efficient RNA turnover by REXO2 is thus required to maintain promoter specificity and proper regulation of transcription in mammalian mitochondria.
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38.
  • Nicholls, Thomas J., et al. (författare)
  • Separating and Segregating the Human Mitochondrial Genome
  • 2018
  • Ingår i: Trends in Biochemical Sciences. - : Elsevier BV. - 0968-0004. ; 43:11, s. 869-881
  • Tidskriftsartikel (refereegranskat)abstract
    • Cells contain thousands of copies of the mitochondrial genome. These genomes are distributed within the tubular mitochondrial network, which is itself spread across the cytosol of the cell. Mitochondrial DNA (mtDNA) replication occurs throughout the cell cycle and ensures that cells maintain a sufficient number of mtDNA copies. At replication termination the genomes must be resolved and segregated within the mitochondrial network. Defects in mtDNA replication and segregation are a cause of human mitochondrial disease associated with failure of cellular energy production. This review focuses upon recent developments on how mitochondrial genomes are physically separated at the end of DNA replication, and how these genomes are subsequently segregated and distributed around the mitochondrial network.
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39.
  • Nicholls, Thomas J., et al. (författare)
  • Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA
  • 2018
  • Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 69:1
  • Tidskriftsartikel (refereegranskat)abstract
    • How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network. The importance of this process is highlighted in a patient with mitochondrial disease caused by biallelic pathogenic variants in TOP3A, characterized by muscle-restricted mtDNA deletions and chronic progressive external ophthalmoplegia (CPEO) plus syndrome. Our work establishes Top3α as an essential component of the mtDNA replication machinery and as the first component of the mtDNA separation machinery. Nicholls et al. identify a role for topoisomerase 3α in the separation of mtDNA following replication. Loss of Top3α activity impairs mtDNA segregation and, consequently, segregation of the mtDNA nucleoid within the mitochondrial network. Mutations in TOP3A cause human mitochondrial disease associated with mtDNA deletions and impaired mtDNA separation. © 2017 Elsevier Inc.
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40.
  • Nilsson, Kristofer F., 1981-, et al. (författare)
  • Organic mononitrites of 1,2-propanediol act as an effective NO-releasing vasodilator in pulmonary hypertension and exhibit no cross-tolerance with nitroglycerin in anesthetized pigs
  • 2018
  • Ingår i: Drug Design, Development and Therapy. - : DOVE Medical Press Ltd.. - 1177-8881. ; 12, s. 685-694
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Clinically available intravenous (IV) nitric oxide (NO) donor drugs such as nitroglycerin (GTN) cause systemic hypotension and/or tolerance development. In a porcine model, novel NO donor compounds - the organic mononitrites of 1,2-propanediol (PDNO) were compared to GTN with regard to pulmonary selectivity and tolerance development. The vasodilatory effects of inorganic nitrite were investigated.Materials and methods: In anesthetized piglets, central hemodynamics were monitored. At normal pulmonary vascular resistance (PVR), IV infusions of PDNO (15-60 nmol kg(-1) min(-1)), GTN (13-132 nmol kg(-1) min(-1)), and inorganic nitrite (dosed as PDNO) were administered. At increased PVR (by U46619 IV), IV infusions of PDNO (60-240 nmol kg(-1) min(-1)) and GTN (75-300 nmol kg(-1) min(-1)) before and after a 5 h infusion of GTN (45 nmol kg-1 min-1) were given.Results: At normal PVR, PDNO (n=12) and GTN (n=7) caused significant dose-dependent decreases in mean systemic and pulmonary arterial pressures, whereas inorganic nitrite (n=13) had no significant effect. At increased PVR, PDNO (n=6) and GTN (n=6) significantly decreased mean systemic and pulmonary pressures and resistances, but only PDNO reduced the ratio between pulmonary and systemic vascular resistances significantly. After the 5 h GTN infusion, the hemodynamic response to GTN infusions (n=6) was significantly suppressed, whereas PDNO (n=6) produced similar hemodynamic effects to those observed before the GTN infusion.Conclusion: PDNO is a vasodilator with selectivity for pulmonary circulation exhibiting no cross-tolerance to GTN, but GTN causes non selective vasodilatation with substantial tolerance development in the pulmonary and systemic circulations. Inorganic nitrite has no vasodilatory properties at relevant doses.
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41.
  • Ohlsson, Claes, 1965, et al. (författare)
  • Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice.
  • 2018
  • Ingår i: The Journal of endocrinology. - 1479-6805. ; 237:2, s. 113-122
  • Tidskriftsartikel (refereegranskat)abstract
    • Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of cortical bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult cortical bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in cortical bone were reduced and cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, cortical thickness and cortical bone strength with no effect on trabecular bone volume fraction. Mechanistic studies demonstrated that the reduced cortical bone thickness was caused by a combination of increased bone resorption and reduced periosteal bone formation. In conclusion, WNT16 is a crucial regulator of cortical bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at cortical bone sites.
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42.
  • Ohlsson, Claes, 1965, et al. (författare)
  • WNT16 overexpression partly protects against glucocorticoid-induced bone loss
  • 2018
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 314:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Therapeutic use of glucocorticoids (GCs) is a major cause of secondary osteoporosis, but the molecular mechanisms responsible for the deleterious effects of GCs in bone are only partially understood. WNT16 is a crucial physiological regulator of bone mass and fracture susceptibility, and we hypothesize that disturbed WNT16 activity might be involved in the deleterious effects of GC in bone. Twelve-week-old female Obl-Wnt16 mice (WNT16 expression driven by the rat procollagen type I alpha 1 promoter) and wild-type (WT) littermates were treated with prednisolone (7.6 mg.kg(-1).day(-1)) or vehicle for 4 wk. We first observed that GC treatment decreased the Wnt16 mRNA levels in bone of female mice (-56.4 +/- 6.1% compared with vehicle, P < 0.001). We next evaluated if WNT16 overexpression protects against GC-induced bone loss. Dual-energy X-ray absorptiometry analyses revealed that GC treatment decreased total body bone mineral density in WT mice (-3.9 +/- 1.2%, P = 0.028) but not in Obl-Wnt16 mice (+1.3 +/- 1.4%, nonsignificant). Microcomputed tomography analyses showed that GC treatment decreased trabecular bone volume fraction (BV/TV) of the femur in WT mice (P = 0.019) but not in Obl-Wnt16 mice. Serum levels of the bone formation marker procollagen type I N-terminal propeptide were substantially reduced by GC treatment in WT mice (-50.3 +/- 7.0%, P = 0.008) but not in Obl-Wnt16 mice (-3.8 +/- 21.2%, nonsignificant). However, the cortical bone thickness in femur was reduced by GC treatment in both WT mice and Obl-Wnt16 mice. In conclusion. GC treatment decreases Wnt16 mRNA levels in bone and WNT16 overexpression partly protects against GC-induced bone loss.
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43.
  • Persson, Örjan, 1974, et al. (författare)
  • Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions
  • 2019
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.
  •  
44.
  • Posse, Viktor, et al. (författare)
  • Human Mitochondrial Transcription Factor B2 Is Required for Promoter Melting during Initiation of Transcription
  • 2017
  • Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 292:7, s. 2637-2645
  • Tidskriftsartikel (refereegranskat)abstract
    • The mitochondrial transcription initiation machinery in humans consists of three proteins: the RNA polymerase (POLRMT) and two accessory factors, transcription factors A and B2 (TFAM and TFB2M, respectively). This machinery is required for the expression of mitochondrial DNA and the biogenesis of the oxidative phosphorylation system. Previous experiments suggested that TFB2M is required for promoter melting, but conclusive experimental proof for this effect has not been presented. Moreover, the role of TFB2M in promoter unwinding has not been discriminated from that of TFAM. Here we used potassium permanganate footprinting, DNase I footprinting, and in vitro transcription from the mitochondrial light-strand promoter to study the role of TFB2M in transcription initiation. We demonstrate that a complex composed of TFAM and POLRMT was readily formed at the promoter but alone was insufficient for promoter melting, which only occurred when TFB2M joined the complex. We also show that mismatch bubble templates could circumvent the requirement of TFB2M, but TFAM was still required for efficient initiation. Our findings support a model in which TFAM first recruits POLRMT to the promoter, followed by TFB2M binding and induction of promoter melting.
  •  
45.
  • Posse, Viktor, et al. (författare)
  • RNase H1 directs origin-specific initiation of DNA replication in human mitochondria
  • 2019
  • Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Human mitochondrial DNA (mtDNA) replication is first initiated at the origin of H-strand replication. The initiation depends on RNA primers generated by transcription from an upstream promoter (LSP). Here we reconstitute this process in vitro using purified transcription and replication factors. The majority of all transcription events from LSP are prematurely terminated after 120 nucleotides, forming stable R-loops. These nascent R-loops cannot directly prime mtDNA synthesis, but must first be processed by RNase H1 to generate 3-ends that can be used by DNA polymerase to initiate DNA synthesis. Our findings are consistent with recent studies of a knockout mouse model, which demonstrated that RNase H1 is required for R-loop processing and mtDNA maintenance in vivo. Both R-loop formation and DNA replication initiation are stimulated by the mitochondrial single-stranded DNA binding protein. In an RNase H1 deficient patient cell line, the precise initiation of mtDNA replication is lost and DNA synthesis is initiated from multiple sites throughout the mitochondrial control region. In combination with previously published in vivo data, the findings presented here suggest a model, in which R-loop processing by RNase H1 directs origin-specific initiation of DNA replication in human mitochondria. Author summary Human mitochondria contain a double-stranded DNA genome that codes for key components of the oxidative phosphorylation system. The mitochondrial DNA (mtDNA) is replicated by a replication machinery distinct from that operating in the nucleus and mutations affecting individual replication factors have been associated with an array of rare, human diseases. In the present work, we demonstrate that RNase H1 directs origin-specific initiation of DNA replication in human mitochondria and that disease-causing mutations may impair this process. A unique feature of mtDNA replication is that primers required for initiation of leading-strand DNA replication are produced by the mitochondrial transcription machinery. A substantial fraction of all transcription events is prematurely terminated about 120 nucleotides downstream of the promoter and the RNA remains firmly associated with the genome, forming R-loops. Interestingly, the free 3-end of these R-loops cannot directly prime initiation of DNA synthesis, but must first be processed by RNase H1. The process is stimulated by the mitochondrial single-stranded DNA binding protein and faithfully reconstitutes replication events mapped in vivo. In combination with mapping of replication events in fibroblasts derived from patients with mutations in RNASEH1, our findings point to a possible model for replication initiation in human mitochondria similar to that previously described in the E. coli plasmid, ColE1.
  •  
46.
  • Posse, Viktor, et al. (författare)
  • TEFM is a potent stimulator of mitochondrial transcription elongation in vitro
  • 2015
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:5, s. 2615-2624
  • Tidskriftsartikel (refereegranskat)abstract
    • A single-subunit RNA polymerase, POLRMT, transcribes the mitochondrial genome in human cells. Recently, a factor termed as the mitochondrial transcription elongation factor, TEFM, was shown to stimulate transcription elongation in vivo, but its effect in vitro was relatively modest. In the current work, we have isolated active TEFM in recombinant form and used a reconstituted in vitro transcription system to characterize its activities. We show that TEFM strongly promotes POLRMT processivity as it dramatically stimulates the formation of longer transcripts. TEFM also abolishes premature transcription termination at conserved sequence block II, an event that has been linked to primer formation during initiation of mtDNA synthesis. We show that POLRMT pauses at a wide range of sites in a given DNA sequence. In the absence of TEFM, this leads to termination; however, the presence of TEFM abolishes this effect and aids POLRMT in continuation of transcription. Further, we show that TEFM substantially increases the POLRMT affinity to an elongation-like DNA: RNA template. In combination with previously published in vivo observations, our data establish TEFM as an essential component of the mitochondrial transcription machinery.
  •  
47.
  • Shi, Yonghong, et al. (författare)
  • Mitochondrial transcription termination factor 1 directs polar replication fork pausing
  • 2016
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 44:12, s. 5732-5742
  • Tidskriftsartikel (refereegranskat)abstract
    • During replication of nuclear ribosomal DNA (rDNA), clashes with the transcription apparatus can cause replication fork collapse and genomic instability. To avoid this problem, a replication fork barrier protein is situated downstream of rDNA, there preventing replication in the direction opposite rDNA transcription. A potential candidate for a similar function in mitochondria is the mitochondrial transcription termination factor 1 (MTERF1, also denoted mTERF), which binds to a sequence just downstream of the ribosomal transcription unit. Previous studies have shown that MTERF1 prevents antisense transcription over the ribosomal RNA genes, a process which we here show to be independent of the transcription elongation factor TEFM. Importantly, we now demonstrate that MTERF1 arrests mitochondrial DNA (mtDNA) replication with distinct polarity. The effect is explained by the ability of MTERF1 to act as a directional contrahelicase, blocking mtDNA unwinding by the mitochondrial helicase TWINKLE. This conclusion is also supported by in vivo evidence that MTERF1 stimulates TWINKLE pausing. We conclude that MTERF1 can direct polar replication fork arrest in mammalian mitochondria.
  •  
48.
  • Shungin, Dmitry, et al. (författare)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • 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.
  •  
49.
  • Sofou, Kalliopi, et al. (författare)
  • Whole exome sequencing reveals mutations in NARS2 and PARS2, encoding the mitochondrial asparaginyl-tRNA synthetase and prolyl-tRNA synthetase, in patients with Alpers syndrome.
  • 2015
  • Ingår i: Molecular genetics & genomic medicine. - : Wiley. - 2324-9269. ; 3:1, s. 59-68
  • Tidskriftsartikel (refereegranskat)abstract
    • Alpers syndrome is a progressive neurodegenerative disorder that presents in infancy or early childhood and is characterized by diffuse degeneration of cerebral gray matter. While mutations in POLG1, the gene encoding the gamma subunit of the mitochondrial DNA polymerase, have been associated with Alpers syndrome with liver failure (Alpers-Huttenlocher syndrome), the genetic cause of Alpers syndrome in most patients remains unidentified. With whole exome sequencing we have identified mutations in NARS2 and PARS2, the genes encoding the mitochondrial asparaginyl-and prolyl-tRNA synthetases, in two patients with Alpers syndrome. One of the patients was homozygous for a missense mutation (c.641C>T, p.P214L) in NARS2. The affected residue is predicted to be located in the stem of a loop that participates in dimer interaction. The other patient was compound heterozygous for a one base insertion (c.1130dupC, p.K378 fs*1) that creates a premature stop codon and a missense mutation (c.836C>T, p.S279L) located in a conserved motif of unknown function in PARS2. This report links for the first time mutations in these genes to human disease in general and to Alpers syndrome in particular.
  •  
50.
  • Stewart, James B, et al. (författare)
  • Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations across Diverse Human Cancers.
  • 2015
  • Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 11:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Somatic mutations in the nuclear genome are required for tumor formation, but the functional consequences of somatic mitochondrial DNA (mtDNA) mutations are less understood. Here we identify somatic mtDNA mutations across 527 tumors and 14 cancer types, using an approach that takes advantage of evidence from both genomic and transcriptomic sequencing. We find that there is selective pressure against deleterious coding mutations, supporting that functional mitochondria are required in tumor cells, and also observe a strong mutational strand bias, compatible with endogenous replication-coupled errors as the major source of mutations. Interestingly, while allelic ratios in general were consistent in RNA compared to DNA, some mutations in tRNAs displayed strong allelic imbalances caused by accumulation of unprocessed tRNA precursors. The effect was explained by altered secondary structure, demonstrating that correct tRNA folding is a major determinant for processing of polycistronic mitochondrial transcripts. Additionally, the data suggest that tRNA clusters are preferably processed in the 3' to 5' direction. Our study gives insights into mtDNA function in cancer and answers questions regarding mitochondrial tRNA biogenesis that are difficult to address in controlled experimental systems.
  •  
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