TY - JOUR A1 - Van Hout, Cristopher V. A1 - Tachmazidou, Ioanna A1 - Backman, Joshua D. A1 - Hoffman, Joshua D. A1 - Liu, Daren A1 - Pandey, Ashutosh K. A1 - Gonzaga-Jauregui, Claudia A1 - Khalid, Shareef A1 - Ye, Bin A1 - Banerjee, Nilanjana A1 - Li, Alexander H. A1 - O'Dushlaine, Colm A1 - Marcketta, Anthony A1 - Staples, Jeffrey A1 - Schurmann, Claudia A1 - Hawes, Alicia A1 - Maxwell, Evan A1 - Barnard, Leland A1 - Lopez, Alexander A1 - Penn, John A1 - Habegger, Lukas A1 - Blumenfeld, Andrew L. A1 - Bai, Xiaodong A1 - O'Keeffe, Sean A1 - Yadav, Ashish A1 - Praveen, Kavita A1 - Jones, Marcus A1 - Salerno, William J. A1 - Chung, Wendy K. A1 - Surakka, Ida A1 - Willer, Cristen J. A1 - Hveem, Kristian A1 - Leader, Joseph B. A1 - Carey, David J. A1 - Ledbetter, David H. A1 - Cardon, Lon A1 - Yancopoulos, George D. A1 - Economides, Aris A1 - Coppola, Giovanni A1 - Shuldiner, Alan R. A1 - Balasubramanian, Suganthi A1 - Cantor, Michael A1 - Nelson, Matthew R. A1 - Whittaker, John A1 - Reid, Jeffrey G. A1 - Marchini, Jonathan A1 - Overton, John D. A1 - Scott, Robert A. A1 - Abecasis, Goncalo R. A1 - Yerges-Armstrong, Laura M. A1 - Baras, Aris T1 - Exome sequencing and characterization of 49,960 individuals in the UK Biobank JF - Nature : the international weekly journal of science N2 - The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world(1). Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, includingPIEZO1on varicose veins,COL6A1on corneal resistance,MEPEon bone density, andIQGAP2andGMPRon blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenicBRCA1andBRCA2variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community. KW - clinical exome KW - breast-cancer KW - mutations KW - recommendations KW - gene KW - metaanalysis KW - variants, KW - BRCA1 KW - risk KW - susceptibility Y1 - 2020 U6 - https://doi.org/10.1038/s41586-020-2853-0 SN - 0028-0836 SN - 1476-4687 VL - 586 IS - 7831 SP - 749 EP - 756 PB - Macmillan Publishers Limited CY - London ER - TY - JOUR A1 - Gancheva, Sofiya A1 - Ouni, Meriem A1 - Jelenik, Tomas A1 - Koliaki, Chrysi A1 - Szendroedi, Julia A1 - Toledo, Frederico G. S. A1 - Markgraf, Daniel Frank A1 - Pesta, Dominik H. A1 - Mastrototaro, Lucia A1 - De Filippo, Elisabetta A1 - Herder, Christian A1 - Jähnert, Markus A1 - Weiss, Jürgen A1 - Strassburger, Klaus A1 - Schlensak, Matthias A1 - Schürmann, Annette A1 - Roden, Michael T1 - Dynamic changes of muscle insulin sensitivity after metabolic surgery JF - Nature Communications N2 - The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity. Y1 - 2019 U6 - https://doi.org/10.1038/s41467-019-12081-0 SN - 2041-1723 VL - 10 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Graja, Antonia A1 - Garcia-Carrizo, Francisco A1 - Jank, Anne-Marie A1 - Gohlke, Sabrina A1 - Ambrosi, Thomas H. A1 - Jonas, Wenke A1 - Ussar, Siegfried A1 - Kern, Matthias A1 - Schürmann, Annette A1 - Aleksandrova, Krasimira A1 - Bluher, Matthias A1 - Schulz, Tim Julius T1 - Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism JF - Aging Cell N2 - Remodeling of the extracellular matrix is a key component of the metabolic adaptations of adipose tissue in response to dietary and physiological challenges. Disruption of its integrity is a well-known aspect of adipose tissue dysfunction, for instance, during aging and obesity. Adipocyte regeneration from a tissue-resident pool of mesenchymal stem cells is part of normal tissue homeostasis. Among the pathophysiological consequences of adipogenic stem cell aging, characteristic changes in the secretory phenotype, which includes matrix-modifying proteins, have been described. Here, we show that the expression of the matricellular protein periostin, a component of the extracellular matrix produced and secreted by adipose tissue-resident interstitial cells, is markedly decreased in aged brown and white adipose tissue depots. Using a mouse model, we demonstrate that the adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding is impaired in animals with systemic ablation of the gene encoding for periostin. Our data suggest that loss of periostin attenuates lipid metabolism in adipose tissue, thus recapitulating one aspect of age-related metabolic dysfunction. In human white adipose tissue, periostin expression showed an unexpected positive correlation with age of study participants. This correlation, however, was no longer evident after adjusting for BMI or plasma lipid and liver function biomarkers. These findings taken together suggest that age-related alterations of the adipose tissue extracellular matrix may contribute to the development of metabolic disease by negatively affecting nutrient homeostasis. KW - adipogenic progenitor cells KW - adipose tissue KW - aging KW - extracellular matrix KW - fatty acid metabolism KW - periostin Y1 - 2018 U6 - https://doi.org/10.1111/acel.12810 SN - 1474-9718 SN - 1474-9726 VL - 17 IS - 5 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Schrader, Sigurd A1 - Schürmann, H. A1 - Druska, P. A1 - Teppner, Randolf A1 - Prescher, Dietrich T1 - Ultraviolet photoelectron spectroscopy of conjugated organic model compounds Y1 - 1997 ER - TY - JOUR A1 - Schürmann, H. A1 - Koch, Norbert A1 - Vollmer, A. A1 - Schrader, Sigurd A1 - Neumann, M. T1 - Angle resolved ultraviolet photoelectron spectroscopy of oriented sexiphenyl layers Y1 - 2000 ER - TY - JOUR A1 - Schrader, Sigurd A1 - Schürmann, H. A1 - Koch, Norbert A1 - Prescher, Dietrich T1 - Electronic structure of new donor acceptor substituted chromophores Y1 - 1999 ER - TY - JOUR A1 - Schürmann, H. A1 - Koch, Norbert A1 - Vollmer, A. A1 - Schrader, Sigurd A1 - Neumann, M. T1 - Angle resolved ultraviolet photoelectron spectroscopy (ARUPS) of oriented sexiphenyl layers Y1 - 1999 ER - TY - JOUR A1 - Schürmann, H. A1 - Koch, Norbert A1 - Imperia, Paolo A1 - Schrader, Sigurd A1 - Jandke, M. A1 - Strohriegl, P. A1 - Schulz, Burkhard A1 - Leising, G. A1 - Brehmer, Ludwig T1 - Ultraviolet photoelectron spectroscopic study of heterocyclic model compounds for electroluminescent devices Y1 - 1999 ER - TY - JOUR A1 - McNulty, Margaret A. A1 - Goupil, Brad A. A1 - Albarado, Diana C. A1 - Castaño-Martinez, Teresa A1 - Ambrosi, Thomas H. A1 - Puh, Spela A1 - Schulz, Tim Julius A1 - Schürmann, Annette A1 - Morrison, Christopher D. A1 - Laeger, Thomas T1 - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions JF - Bone Reports N2 - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone. Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass. Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture. Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21. KW - dietary restriction KW - protein restriction KW - FGF21 KW - GCN2 KW - microcomputed tomography Y1 - 2020 U6 - https://doi.org/10.1016/j.bonr.2019.100241 SN - 2352-1872 VL - 12 SP - 1 EP - 10 PB - Elsevier CY - Amsterdam ER - TY - GEN A1 - McNulty, Margaret A. A1 - Goupil, Brad A. A1 - Albarado, Diana C. A1 - Castaño-Martinez, Teresa A1 - Ambrosi, Thomas H. A1 - Puh, Spela A1 - Schulz, Tim Julius A1 - Schürmann, Annette A1 - Morrison, Christopher D. A1 - Laeger, Thomas T1 - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone. Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass. Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture. Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1406 KW - dietary restriction KW - protein restriction KW - FGF21 KW - GCN2 KW - microcomputed tomography Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516297 SN - 1866-8372 ER -