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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Aus dem Inhalt dieser Ausage: BEITRÄGE: Claudio Donati: Militärstrukturen der italienischen Staaten in der frühen Neuzeit: ein Forschungsbericht jüngster Studien; Sascha Möbius: Friedrich Engels und der Bauernkrieg in der Historiographie der DDR PROJEKTE: Andree Brumshagen: Das Bremer Stadtmilitär 1618-1810. Zur Bedeutung und Funktion des Soldaten in der reichsstädtischen Gesellschaft; Tomasz Przerwa und Grzegorz Podruczny: Festung Silberberg – Forschungsprojekt Universität zu Wroclaw; Gabriel Zeilinger: Der süddeutsche Städtekrieg 1449/50 – Fehdeorganisation und Kriegsalltag, soziale Verfasstheiten und die 'Ökonomie' des Krieges in einem Großkonflikt des 15. Jahrhunderts; Dirk Reitz: Der Wehrarchitekt der Reichsstadt – Wolf-Jacob Stromer Ratsbaumeister zu Nürnberg 1561-1614. Militärische Aspekte der Baumeisterbücher I-XII. BERICHTE: Ulla Schuh: Policey, öffentliche Ordnung und Militär. Aufgaben des Militärs zur Aufrechterhaltung "guter Policey" in der Frühneuzeit. Bericht über die 6. Tagung des Arbeitskreises "Policey/Polizei im vormodernen Europa" (APO); Daniela Morgenstern und Nele Thomsen: Tagung "Mars und die Musen" - Das Wechselspiel von Militär, Krieg und Kunst in der Frühen Neuzeit vom 22. - 24. September 2003 REZENSIONEN: Heinrich Lang: Herfried Münkler, Über den Krieg. Stationen der Kriegsge-schichte im Spiegel ihrer theoretischen Reflexion, Frankfurt am Main 2002; Martin Winter: Gerhard von Scharnhorst. Private und dienstliche Schriften, Bd. 1: Schüler, Lehrer, Kriegsteilnehmer. Kurhannover bis 1795, hrsg. von Johannes Kunisch, bearb. von Michael Sikora und Tilman Stive, Köln u. a.: Böhlau 2002; Uwe Tresp: Rainer Leng, Ars belli. Deutsche taktische und kriegstechni-sche Bilderhandschriften und Traktate im 15. und 16. Jahrhun-dert, Wiesbaden: Reichert 2002; Ewa Herfordt: Roland Vetter, "Kein Stein soll auf den anderen bleiben". Mannheims Untergang während des Pfälzischen Erbfolge-krieges im Spiegel französischer Kriegsberichte Heidelberg u.a.: Verlag Regionalkultur 2002; Daniela Feistauer: Thomas Michael Schneider, Heeresergänzung und Sozialordnung. Dienstpflichtige, Einsteher und Freiwillige in Württem-berg zur Zeit des Deutschen Bundes, Frankfurt am Main, Berlin, Bern, Brüssel, New York, Oxford, Wien: Peter Lang Europäischer Verlag der Wissenschaften 2002; Andrea Pühringer: Wolfgang Kruse, Die Erfindung des modernen Militarismus. Krieg, Militär und bürgerliche Gesellschaft im politischen Diskurs der Französischen Revolution 1789-1799, München: R. Oldenbourg Verlag 2003; Matthias Franz: Heinz-Dieter Heimann / Uwe Tresp (Hrsg.), Thüringische und böhmische Söldner in der Soester Fehde. Quellen zum landes-herrlichen Militärwesen im 15. Jahrhundert aus thüringischen und sächsischen Archiven, hrsg. von Heinz-Dieter Heimann und Uwe Tresp, Potsdam 2002; Holger Th. Gräf: Achim Riether, Rudolf Meyer (1605-1638). Schweizer Zeichen-kunst zwischen Spätmanierismus und Frühbarock. Katalog der Handzeichnungen, München: scaneg Verlag 2002
Dumortierite was synthesized in piston-cylinder experiments at 2.5-4.0 GPa, 650-700 degrees C in the Al2O3 -B2O3-SiO2-H2O (ABSH) system. Electron-microprobe (EMP) analyses reveal significant boron-excess (up to 0.26 B-[4] per formula unit, pfu) and silicon-deficiency relative to the ideal anhydrous dumortierite stoichiometry Al7BSi3O18 . The EMP data in conjunction with results from single-crystal Raman spectroscopy and powder X-ray diffraction provide evidence that silicon at the tetrahedral site is replaced by excess boron via the substitution Si-[4] <--> B-[4] + H. The Raman spectrum of synthetic dumortierite in the frequency region 2000 4000 cm(-1) comprises eight bands, of which six are located at frequencies below 3400 cm(-1). This points to strong hydrogen bonding, most likely O2-H center dot center dot center dot O7 and O7-H center dot center dot center dot O2, arising from a high number of octahedral vacancies at the All site and substitution of trivalent Al3+ and B3+ for Si4+ at Si1 and Si2 sites, causing decreasing acceptor-donor distances and lower incident valence at the acceptor oxygen. Contrary to the synthetic high-pressure ABSH-dumortierite, magnesiodumortierite from the Dora-Maira Massif, which is assumed to have formed at similar conditions (2.5-3.0 GPa, 700 degrees C), does not show any B-excess. Tourmaline shows an analogous behaviour in that magnesium-rich (e.g., dravitic) tourmaline formed at high pressure shows no or only minor amounts of tetrahedral boron, whereas natural aluminum-rich tourmaline and synthetic olenitic tourmaline formed at high pressures can incorporate significant amounts of tetrahedral boron. Two mechanisms might account for this discrepancy: (i) Structural avoidance of Mg-[6]-(OR3+)-R-[4] configurations in magnesiodumortierite due to charge deficieny at the oxygens O2 and O7 and strong local distortion of M1 due to decreased O2-O7 bond length, and/or (ii) decreasing fluid mobility of boron in Al-rich systems at high pressures.
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru-and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
Feedback inhibition of starch degradation in arabidopsis leaves mediated by trehalose 6-phosphate
(2013)
Many plants accumulate substantial starch reserves in their leaves during the day and remobilize them at night to provide carbon and energy for maintenance and growth. In this paper, we explore the role of a sugar-signaling metabolite, trehalose-6-phosphate (Tre6P), in regulating the accumulation and turnover of transitory starch in Arabidopsis (Arabidopsis thaliana) leaves. Ethanol-induced overexpression of trehalose-phosphate synthase during the day increased Tre6P levels up to 11-fold. There was a transient increase in the rate of starch accumulation in the middle of the day, but this was not linked to reductive activation of ADP-glucose pyrophosphorylase. A 2- to 3-fold increase in Tre6P during the night led to significant inhibition of starch degradation. Maltose and maltotriose did not accumulate, suggesting that Tre6P affects an early step in the pathway of starch degradation in the chloroplasts. Starch granules isolated from induced plants had a higher orthophosphate content than granules from noninduced control plants, consistent either with disruption of the phosphorylation-dephosphorylation cycle that is essential for efficient starch breakdown or with inhibition of starch hydrolysis by beta-amylase. Nonaqueous fractionation of leaves showed that Tre6P is predominantly located in the cytosol, with estimated in vivo Tre6P concentrations of 4 to 7 mu M in the cytosol, 0.2 to 0.5 mu M in the chloroplasts, and 0.05 mu M in the vacuole. It is proposed that Tre6P is a component in a signaling pathway that mediates the feedback regulation of starch breakdown by sucrose, potentially linking starch turnover to demand for sucrose by growing sink organs at night.
Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
Ultrahigh-pressure (UHP), coesite-bearing edogites in the Himalaya have been documented from the Kaghan Valley in Pakistan and the Tso Morani area in northwest India. These complexes are part of the northern edge of the Indian plate that has been subducted to, and metamorphosed at, mantle depths of more than 100 km before being exhumed. Both UHP complexes are located today directly adjacent to the Indus-Tsangpo suture zone and are not separated by non-metamorphosed sequences of Tethyan sediments from the Asian margin. Herein, we present new data for one fresh coesite-bearing eclogite from the Tso Moran massif. Therein, garnets are zoned reflecting their growth during prograde and peak metamorphism and showing a thin retrograde overgrowth. Inclusions can be directly correlated to the compositional zoning and are seen as either relicts of the protolith mineral paragenesis and as "snap shots" of the mineral paragenesis during subduction and under peak conditions. Rare earth element concentrations (REE) were obtained for garnet, mineral inclusions in garnet and matrix minerals. The REE pattern in garnet reflects a sequential change in matrix minerals and their proportions due to net transfer reactions during subduction and peak metamorphism. Using conventional geothermobarometry, a peak pressure of ca. 44-48 kbar at 560-760 degrees C followed by an S-shaped exhumation curve has been deduced. Gibbs free energy minimization modelling was used to supplement our analytical findings. (C) 2015 Elsevier B.V. All rights reserved.