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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.
Electrospray ionization-ion mobility spectrometry was employed for the determination of collision cross sections (CCS) of 25 synthetically produced peptides in the mass range between 540-3310 Da. The experimental measurement of the CCS is complemented by their calculation applying two different methods. One prediction method is the intrinsic size parameter (ISP) method developed by the Clemmer group. The second new method is based on the evaluation of molecular dynamics (MD) simulation trajectories as a whole, resulting in a single, averaged collision cross-section value for a given peptide in the gas phase. A high temperature MD simulation is run in order to scan through the whole conformational space. The lower temperature conformational distribution is obtained through thermodynamic reweighting. In the first part, various correlations, e.g. CCS vs. mass and inverse mobility vs. m/z correlations, are presented. Differences in CCS between peptides are also discussed in terms of their respective mass and m/z differences, as well as their respective structures. In the second part, measured and calculated CCS are compared. The agreement between the prediction results and the experimental values is in the same range for both calculation methods. While the calculation effort of the ISP method is much lower, the MD method comprises several tools providing deeper insights into the conformations of peptides. Advantages and limitations of both methods are discussed. Based on the separation of two pairs of linear and cyclic peptides of virtually the same mass, the influence of the structure on the cross sections is discussed. The shift in cross section differences and peak shape after transition from the linear to the cyclic peptide can be well understood by applying different MD tools, e.g. the root-mean-square deviation (RMSD) and the root mean square fluctuation (RMSF). (C) 2018 Elsevier B.V. All rights reserved.
River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth’s biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented “next-generation biomonitoring” by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.
initMIP-Antarctica
(2019)
Ice sheet numerical modeling is an important tool to estimate the dynamic contribution of the Antarctic ice sheet to sea level rise over the coming centuries. The influence of initial conditions on ice sheet model simulations, however, is still unclear. To better understand this influence, an initial state intercomparison exercise (initMIP) has been developed to compare, evaluate, and improve initialization procedures and estimate their impact on century-scale simulations. initMlP is the first set of experiments of the Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6), which is the primary Coupled Model Intercomparison Project Phase 6 (CMIP6) activity focusing on the Greenland and Antarctic ice sheets. Following initMlP-Greenland, initMlP-Antarctica has been designed to explore uncertainties associated with model initialization and spin-up and to evaluate the impact of changes in external forcings. Starting from the state of the Antarctic ice sheet at the end of the initialization procedure, three forward experiments are each run for 100 years: a control run, a run with a surface mass balance anomaly, and a run with a basal melting anomaly beneath floating ice. This study presents the results of initMlP-Antarctica from 25 simulations performed by 16 international modeling groups. The submitted results use different initial conditions and initialization methods, as well as ice flow model parameters and reference external forcings. We find a good agreement among model responses to the surface mass balance anomaly but large variations in responses to the basal melting anomaly. These variations can be attributed to differences in the extent of ice shelves and their upstream tributaries, the numerical treatment of grounding line, and the initial ocean conditions applied, suggesting that ongoing efforts to better represent ice shelves in continental-scale models should continue.
Objectives
The aims of this study were to investigate the effects of a six-week in-season period of soccer training and games (congested period) on plasma volume variations (PV), hematological parameters, and physical fitness in elite players. In addition, we analyzed relationships between training load, hematological parameters and players’ physical fitness.
Methods
Eighteen elite players were evaluated before (T1) and after (T2) a six-week in-season period interspersed with 10 soccer matches. At T1 and T2, players performed the Yo-Yo intermittent recovery test level 1 (YYIR1), the repeated shuttle sprint ability test (RSSA), the countermovement jump test (CMJ), and the squat jump test (SJ). In addition, PV and hematological parameters (erythrocytes [M/mm3], hematocrit [%], hemoglobin [g/dl], mean corpuscular volume [fl], mean corpuscular hemoglobin content [pg], and mean hemoglobin concentration [%]) were assessed. Daily ratings of perceived exertion (RPE) were monitored in order to quantify the internal training load.
Results
From T1 to T2, significant performance declines were found for the YYIR1 (p<0.001, effect size [ES] = 0.5), RSSA (p<0.01, ES = 0.6) and SJ tests (p< 0.046, ES = 0.7). However, no significant changes were found for the CMJ (p = 0.86, ES = 0.1). Post-exercise, RSSA blood lactate (p<0.012, ES = 0.2) and PV (p<0.01, ES = 0.7) increased significantly from T1 to T2. A significant decrease was found from T1 to T2 for the erythrocyte value (p<0.002, ES = 0.5) and the hemoglobin concentration (p<0.018, ES = 0.8). The hematocrit percentage rate was also significantly lower (p<0.001, ES = 0.6) at T2. The mean corpuscular volume, mean corpuscular hemoglobin content and the mean hemoglobin content values were not statistically different from T1 to T2. No significant relationships were detected between training load parameters and percentage changes of hematological parameters. However, a significant relationship was observed between training load and changes in RSSA performance (r = -0.60; p<0.003).
Conclusions
An intensive period of “congested match play” over 6 weeks significantly compromised players’ physical fitness. These changes were not related to hematological parameters, even though significant alterations were detected for selected measures.
Objectives
The aims of this study were to investigate the effects of a six-week in-season period of soccer training and games (congested period) on plasma volume variations (PV), hematological parameters, and physical fitness in elite players. In addition, we analyzed relationships between training load, hematological parameters and players’ physical fitness.
Methods
Eighteen elite players were evaluated before (T1) and after (T2) a six-week in-season period interspersed with 10 soccer matches. At T1 and T2, players performed the Yo-Yo intermittent recovery test level 1 (YYIR1), the repeated shuttle sprint ability test (RSSA), the countermovement jump test (CMJ), and the squat jump test (SJ). In addition, PV and hematological parameters (erythrocytes [M/mm3], hematocrit [%], hemoglobin [g/dl], mean corpuscular volume [fl], mean corpuscular hemoglobin content [pg], and mean hemoglobin concentration [%]) were assessed. Daily ratings of perceived exertion (RPE) were monitored in order to quantify the internal training load.
Results
From T1 to T2, significant performance declines were found for the YYIR1 (p<0.001, effect size [ES] = 0.5), RSSA (p<0.01, ES = 0.6) and SJ tests (p< 0.046, ES = 0.7). However, no significant changes were found for the CMJ (p = 0.86, ES = 0.1). Post-exercise, RSSA blood lactate (p<0.012, ES = 0.2) and PV (p<0.01, ES = 0.7) increased significantly from T1 to T2. A significant decrease was found from T1 to T2 for the erythrocyte value (p<0.002, ES = 0.5) and the hemoglobin concentration (p<0.018, ES = 0.8). The hematocrit percentage rate was also significantly lower (p<0.001, ES = 0.6) at T2. The mean corpuscular volume, mean corpuscular hemoglobin content and the mean hemoglobin content values were not statistically different from T1 to T2. No significant relationships were detected between training load parameters and percentage changes of hematological parameters. However, a significant relationship was observed between training load and changes in RSSA performance (r = -0.60; p<0.003).
Conclusions
An intensive period of “congested match play” over 6 weeks significantly compromised players’ physical fitness. These changes were not related to hematological parameters, even though significant alterations were detected for selected measures.
In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all-cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis-epoxy-PUFA (mixture of R,S- and S,R-enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis- and trans-epoxy-PUFA (mixture of R,R- and S,S-enantiomers). Here, we investigated for the first time trans-epoxy-PUFA and the trans/cis-epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert-butyl hydroperoxide (t-BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis-epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis-epoxy-PUFA ratio in response to the applied t-BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cisepoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis-epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation.
Day length is a key indicator of seasonal information that determines major patterns of behavior in plants and animals. Photoperiodism has been described in plants for about 100 years, but the underlying molecular mechanisms of day length perception and signal transduction in many systems are not well understood. In trees, photoperiod perception plays a major role in growth cessation during the autumn as well as activating the resumption of shoot growth in the spring, both processes controlled by FLOWERING LOCUS T2 (FT2) expression levels and critical for the survival of perennial plants over winter [1-4]. It has been shown that the conserved role of poplar orthologs to Arabidopsis CONSTANS (CO) directly activates FT2 expression [1, 5]. Overexpression of poplar CO is, however, not sufficient to sustain FT2 expression under short days [5] , pointing to the presence of an additional short-day-dependent FT2 repression pathway in poplar. We find that night length information is transmitted via the expression level of a poplar clock gene, LATE ELONGATED HYPOCOTYL 2 (LHY2), which controls FT2 expression. Repression of FT2 is a function of the night extension and LHY2 expression level. We show that LHY2 is necessary and sufficient to activate night length repressive signaling. We propose that the photoperiodic control of shoot growth in poplar involves a balance between FT2 activating and repressing pathways. Our results show that poplar relies on night length measurement to determine photoperiodism through interaction between light signaling pathways and the circadian clock.
The size structure of autotroph communities – the relative abundance of small vs. large individuals – shapes the functioning of ecosystems. Whether common mechanisms underpin the size structure of unicellular and multicellular autotrophs is, however, unknown. Using a global data compilation, we show that individual body masses in tree and phytoplankton communities follow power-law distributions and that the average exponents of these individual size distributions (ISD) differ. Phytoplankton communities are characterized by an average ISD exponent consistent with three-quarter-power scaling of metabolism with body
mass and equivalence in energy use among mass classes. Tree communities deviate from this pattern in a manner consistent with equivalence in energy use among diameter size classes. Our findings suggest that whilst universal metabolic constraints ultimately underlie the emergent size structure of autotroph communities, divergent aspects of body size (volumetric vs. linear dimensions) shape the ecological outcome of metabolic scaling in forest vs. pelagic ecosystems.
The size structure of autotroph communities - the relative abundance of small vs. large individuals - shapes the functioning of ecosystems. Whether common mechanisms underpin the size structure of unicellular and multicellular autotrophs is, however, unknown. Using a global data compilation, we show that individual body masses in tree and phytoplankton communities follow power-law distributions and that the average exponents of these individual size distributions (ISD) differ. Phytoplankton communities are characterized by an average ISD exponent consistent with three-quarter-power scaling of metabolism with body mass and equivalence in energy use among mass classes. Tree communities deviate from this pattern in a manner consistent with equivalence in energy use among diameter size classes. Our findings suggest that whilst universal metabolic constraints ultimately underlie the emergent size structure of autotroph communities, divergent aspects of body size (volumetric vs. linear dimensions) shape the ecological outcome of metabolic scaling in forest vs. pelagic ecosystems.