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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.
Pancreatic secretory zymogen-granule membrane glycoprotein 2 (GP2) has been identified to be a major autoantigenic target in Crohn’s disease patients. It was discussed recently that a long and a short isoform of GP2 exists whereas the short isoform is often detected by GP2-specific autoantibodies. In the outcome of inflammatory bowel diseases, these GP2-specific autoantibodies are discussed as new serological markers for diagnosis and therapeutic monitoring. To investigate this further, camelid nanobodies were generated by phage display and selected against the short isoform of GP2 in order to isolate specific tools for the discrimination of both isoforms. Nanobodies are single domain antibodies derived from camelid heavy chain only antibodies and characterized by a high stability and solubility. The selected candidates were expressed, purified and validated regarding their binding properties in different enzyme-linked immunosorbent assays formats, immunofluorescence, immunohistochemistry and surface plasmon resonance spectroscopy. Four different nanobodies could be selected whereof three recognize the short isoform of GP2 very specifically and one nanobody showed a high binding capacity for both isoforms. The KD values measured for all nanobodies were between 1.3 nM and 2.3 pM indicating highly specific binders suitable for the application as diagnostic tool in inflammatory bowel disease.
During the Ring Grazing orbits near the end of Cassini mission, the spacecraft crossed the equatorial plane near the orbit of Janus/Epimetheus (similar to 2.5 Rs). This region is populated with dust particles that can be detected by the Radio and Plasma Wave Science (RPWS) instrument via an electric field antenna signal. Analysis of the voltage waveforms recorded on the RPWS antennas provides estimations of the density and size distribution of the dust particles. Measured RPWS profiles, fitted with Lorentzian functions, are shown to be mostly consistent with the Cosmic Dust Analyzer, the dedicated dust instrument on board Cassini. The thickness of the dusty ring varies between 600 and 1,000 km. The peak location shifts north and south within 100 km of the ring plane, likely a function of the precession phase of Janus orbit.
Empirical data providing evidence for a colimitation of an herbivore by two or more essential nutrients are scarce, particularly in regard to biochemical resources. Here, a graphical model is presented, which describes the growth of an herbivore in a system with two potentially limiting resources. To verify this model, life-history experiments were conducted with the herbivore Daphnia magna feeding on the picocyanobacterium Synechococcus elongatus, which was supplemented with increasing amounts of cholesterol either in the presence or the absence of saturating amounts of eicosapentaenoic acid (EPA). For comparison, D. magna was raised on diets containing different proportions of S. elongatus and the cholesterol- and EPA-rich eukaryotic alga Nannochloropsis limnetica. Somatic and population growth of D. magna on a sterol- and EPA-deficient diet was initially constrained by the absence of sterols. With increased sterol availability, a colimitation by EPA became apparent and when the sterol requirements were met, the growth- limiting factor was shifted from a limitation by sterols to a limitation by EPA. These data imply that herbivores are frequently limited by two or more essential nutrients simultaneously. Hence, the concept of colimitation has to be incorporated into models assessing nutrient-limited growth kinetics of herbivores to accurately predict demographic changes and population dynamics.
Plain Language Summary Cassini flew through the gap between Saturn and its rings for 22 times before plunging into the atmosphere of Saturn, ending its 20-year mission. The radio and plasma waves instrument on board Cassini helped quantify the dust hazard in this previously unexplored region. The measured density of large dust particles was much lower than expected, allowing high-value science observations during the subsequent Grand Finale orbits.
Energie
(2001)
Starch is an important plant product widely used as a nutrient, as a source of renewable energy, and for many technological applications. In plants, starch is the almost ubiquitous storage carbohydrate whereas most heterotrophic prokaryotes and eukaryotes rely on glycogen. Despite close similarities in basic chemical features, starch and glycogen differ in both structural and physicochemical properties. Glycogen is a hydrosoluble macromolecule with evenly distributed branching points. Starch exists as a water-insoluble particle having a defined (and evolutionary conserved) internal structure. The biochemistry of starch requires the co-operation of up to 40 distinct (iso)enzymes whilst approximately 10 (iso)enzymes permit glycogen metabolism. The biosynthesis and degradation of native starch include the transition of carbohydrates from the soluble to the solid phase and vice versa. In this review, two novel aspects of the eukaryotic plastidial starch degradation are discussed: Firstly, biochemical reactions that take place at the surface of particulate glucans and mediate the phase transition of carbohydrates. Secondly, processes that occur downstream of the export of starch-derived sugars into the cytosol. Degradation of transitory starch mainly results in the formation of neutral sugars, such as glucose and maltose, that are transported into the cytosol via the respective translocators. The cytosolic metabolism of the neutral sugars includes the action of a hexokinase, a phosphoglucomutase, and a transglucosidase that utilizes high molecular weight glycans as a transient glucosyl acceptor or donor. Data are included on the transglucosidase (disproportionating isozyme 2) in Cyanophora paradoxa that accumulates storage carbohydrates in the cytosol rather than in the plastid.