TY - JOUR A1 - Wurzbacher, Christian A1 - Fuchs, Andrea A1 - Attermeyer, Katrin A1 - Frindte, Katharina A1 - Grossart, Hans-Peter A1 - Hupfer, Michael A1 - Casper, Peter A1 - Monaghan, Michael T. T1 - Shifts among Eukaryota, Bacteria, and Archaea define the vertical organization of a lake sediment JF - Microbiome N2 - Background: Lake sediments harbor diverse microbial communities that cycle carbon and nutrients while being constantly colonized and potentially buried by organic matter sinking from the water column. The interaction of activity and burial remained largely unexplored in aquatic sediments. We aimed to relate taxonomic composition to sediment biogeochemical parameters, test whether community turnover with depth resulted from taxonomic replacement or from richness effects, and to provide a basic model for the vertical community structure in sediments. Methods: We analyzed four replicate sediment cores taken from 30-m depth in oligo-mesotrophic Lake Stechlin in northern Germany. Each 30-cm core spanned ca. 170 years of sediment accumulation according to Cs-137 dating and was sectioned into layers 1-4 cm thick. We examined a full suite of biogeochemical parameters and used DNA metabarcoding to examine community composition of microbial Archaea, Bacteria, and Eukaryota. Results: Community beta-diversity indicated nearly complete turnover within the uppermost 30 cm. We observed a pronounced shift from Eukaryota- and Bacteria-dominated upper layers (<5 cm) to Bacteria-dominated intermediate layers (5-14 cm) and to deep layers (>14 cm) dominated by enigmatic Archaea that typically occur in deep-sea sediments. Taxonomic replacement was the prevalent mechanism in structuring the community composition and was linked to parameters indicative of microbial activity (e.g., CO2 and CH4 concentration, bacterial protein production). Richness loss played a lesser role but was linked to conservative parameters (e.g., C, N, P) indicative of past conditions. Conclusions: By including all three domains, we were able to directly link the exponential decay of eukaryotes with the active sediment microbial community. The dominance of Archaea in deeper layers confirms earlier findings from marine systems and establishes freshwater sediments as a potential low-energy environment, similar to deep sea sediments. We propose a general model of sediment structure and function based on microbial characteristics and burial processes. An upper "replacement horizon" is dominated by rapid taxonomic turnover with depth, high microbial activity, and biotic interactions. A lower "depauperate horizon" is characterized by low taxonomic richness, more stable "low-energy" conditions, and a dominance of enigmatic Archaea. KW - Archaea KW - Eukaryota KW - Bacteria KW - Community KW - Freshwater KW - Lake KW - DNA metabarcoding KW - Beta-diversity KW - Sediment KW - Turnover Y1 - 2017 U6 - https://doi.org/10.1186/s40168-017-0255-9 SN - 2049-2618 VL - 5 PB - BioMed Central CY - London ER - TY - GEN A1 - Zimmermann, Heike Hildegard A1 - Raschke, Elena A1 - Epp, Laura Saskia A1 - Stoof-Leichsenring, Kathleen Rosemarie A1 - Schwamborn, Georg A1 - Schirrmeister, Lutz A1 - Overduin, Pier Paul A1 - Herzschuh, Ulrike T1 - Sedimentary ancient DNA and pollen reveal the composition of plant organic matter in Late Quaternary permafrost sediments of the Buor Khaya Peninsula (north-eastern Siberia) T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Organic matter deposited in ancient, ice-rich permafrost sediments is vulnerable to climate change and may contribute to the future release of greenhouse gases; it is thus important to get a better characterization of the plant organic matter within such sediments. From a Late Quaternary permafrost sediment core from the Buor Khaya Peninsula, we analysed plant-derived sedimentary ancient DNA (sedaDNA) to identify the taxonomic composition of plant organic matter, and undertook palynological analysis to assess the environmental conditions during deposition. Using sedaDNA, we identified 154 taxa and from pollen and non-pollen palynomorphs we identified 83 taxa. In the deposits dated between 54 and 51 kyr BP, sedaDNA records a diverse low-centred polygon plant community including recurring aquatic pond vegetation while from the pollen record we infer terrestrial open-land vegetation with relatively dry environmental conditions at a regional scale. A fluctuating dominance of either terrestrial or swamp and aquatic taxa in both proxies allowed the local hydrological development of the polygon to be traced. In deposits dated between 11.4 and 9.7 kyr BP (13.4-11.1 cal kyr BP), sedaDNA shows a taxonomic turnover to moist shrub tundra and a lower taxonomic richness compared to the older samples. Pollen also records a shrub tundra community, mostly seen as changes in relative proportions of the most dominant taxa, while a decrease in taxonomic richness was less pronounced compared to sedaDNA. Our results show the advantages of using sedaDNA in combination with palynological analyses when macrofossils are rarely preserved. The high resolution of the sedaDNA record provides a detailed picture of the taxonomic composition of plant-derived organic matter throughout the core, and palynological analyses prove valuable by allowing for inferences of regional environmental conditions. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 670 KW - NE Siberia KW - vegetation patterns KW - environmental DNA KW - Arctic vegetation KW - frozen sediments KW - lake-sediments KW - gas-production KW - carbon KW - polygon KW - climate Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-417130 SN - 1866-8372 IS - 670 ER - TY - THES A1 - Kruse, Stefan T1 - Larix treeline dynamics in northern Siberia inferred from population genetics and individual-based modelling Y1 - 2017 ER - TY - GEN A1 - Weisser, Karin A1 - Stübler, Sabine A1 - Matheis, Walter A1 - Huisinga, Wilhelm T1 - Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products T2 - Regulatory toxicology and pharmacology : official journal of the International Society for Regulatory Toxicology and Pharmacology N2 - As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously reevaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment. (C) 2017 Elsevier Inc. All rights reserved. KW - Aluminium KW - Aluminium adjuvants KW - Absorption kinetics KW - Toxicokinetic modelling KW - In vitro dissolution Y1 - 2017 U6 - https://doi.org/10.1016/j.yrtph.2017.02.018 SN - 0273-2300 SN - 1096-0295 VL - 88 SP - 310 EP - 321 PB - Elsevier CY - San Diego ER - TY - THES A1 - Hethey, Christoph Philipp T1 - Cell physiology based pharmacodynamic modeling of antimicrobial drug combinations T1 - Zellphysiologie-basierte pharmakodynamische Modellierung von antimikrobiellen Wirkstoffkombinationen N2 - Mathematical models of bacterial growth have been successfully applied to study the relationship between antibiotic drug exposure and the antibacterial effect. Since these models typically lack a representation of cellular processes and cell physiology, the mechanistic integration of drug action is not possible on the cellular level. The cellular mechanisms of drug action, however, are particularly relevant for the prediction, analysis and understanding of interactions between antibiotics. Interactions are also studied experimentally, however, a lacking consent on the experimental protocol hinders direct comparison of results. As a consequence, contradictory classifications as additive, synergistic or antagonistic are reported in literature. In the present thesis we developed a novel mathematical model for bacterial growth that integrates cell-level processes into the population growth level. The scope of the model is to predict bacterial growth under antimicrobial perturbation by multiple antibiotics in vitro. To this end, we combined cell-level data from literature with population growth data for Bacillus subtilis, Escherichia coli and Staphylococcus aureus. The cell-level data described growth-determining characteristics of a reference cell, including the ribosomal concentration and efficiency. The population growth data comprised extensive time-kill curves for clinically relevant antibiotics (tetracycline, chloramphenicol, vancomycin, meropenem, linezolid, including dual combinations). The new cell-level approach allowed for the first time to simultaneously describe single and combined effects of the aforementioned antibiotics for different experimental protocols, in particular different growth phases (lag and exponential phase). Consideration of ribosomal dynamics and persisting sub-populations explained the decreased potency of linezolid on cultures in the lag phase compared to exponential phase cultures. The model captured growth rate dependent killing and auto-inhibition of meropenem and - also for vancomycin exposure - regrowth of the bacterial cultures due to adaptive resistance development. Stochastic interaction surface analysis demonstrated the pronounced antagonism between meropenem and linezolid to be robust against variation in the growth phase and pharmacodynamic endpoint definition, but sensitive to a change in the experimental duration. Furthermore, the developed approach included a detailed representation of the bacterial cell-cycle. We used this representation to describe septation dynamics during the transition of a bacterial culture from the exponential to stationary growth phase. Resulting from a new mechanistic understanding of transition processes, we explained the lag time between the increase in cell number and bacterial biomass during the transition from the lag to exponential growth phase. Furthermore, our model reproduces the increased intracellular RNA mass fraction during long term exposure of bacteria to chloramphenicol. In summary, we contribute a new approach to disentangle the impact of drug effects, assay readout and experimental protocol on antibiotic interactions. In the absence of a consensus on the corresponding experimental protocols, this disentanglement is key to translate information between heterogeneous experiments and also ultimately to the clinical setting. N2 - Der Zusammenhang zwischen antibiotischer Exposition und antibakterieller Wirkung wird derzeitlich erfolgreich mithilfe von mathematischen Bakterienwachstumsmodellen studiert. Üblicherweise ignorieren diese Modelle jedoch die bakterielle Physiologie und Prozesse auf Zellebene. Es folgt, dass das mechanistische Einbinden von Wirkstoffeffekten auf Zellebene nicht möglich ist. Jedoch ist der zelluläre Wirkmechanismus besonders relevant für die Vorhersage, die Analyse und das Verständnis von Antibiotikainteraktionen. Leider gibt es keinen Konsens bezüglich des experimentellen Protokolls, um diese Interaktionen zu untersuchen. Das ist einer der Gründe, warum wir in der Literatur widersprüchliche Klassifizierungen von Antibiotikainteraktionen als additiv, synergistisch oder antagonistisch finden. In der vorliegenden Arbeit entwickelten wir ein neuartiges mathematisches Bakterienwachstumsmodel, welches Prozesse auf Zellebene in das Populationswachstum einbindet. Der Anwendungszweck dieses Models ist die Vorhersage bakteriellen Wachstums unter antimikrobieller Mehrfachexposition in vitro. Um das zu erreichen, kombinierten wir die Zellebene beschreibende Daten aus der Literatur mit Wachstumsdaten für Bacillus subtilis, Escherichia coli und Staphylococcus aureus. Die die Zellebene beschreibenden Daten bezogen sich auf Wachstums-bestimmende Charakteristika einer Referenzzelle, unter anderem auf die ribosomale Konzentration und Effizienz. Die Wachstumsdaten beinhalteten umfangreiche Zeit-Absterbe-Kurven für klinisch relevante Antibiotika (Tetracyclin, Chloramphenicol, Vancomycin, Meropenem, Linezolid) und Zweifachkombinationen aus diesen. Der neue Zellebenen-Ansatz erlaubt es erstmalig, einzelne und kombinierte Effekte der erwähnten Antibiotika für unterschiedliche experimentelle Protokolle gleichzeitig zu beschreiben. Insbesondere beziehen sich diese Unterschiede auf die Wachstumsphasen (Lag oder exponentiellen Phase). Die Berücksichtigung der ribosomalen Konzentration und persistenter Subpopulationen erklärte die verminderte Potenz von Linezolid gegen Kulturen in der Lag Phase im Vergleich zu Kulturen, die sich in der exponentiellen Phase befanden. Das Model erfasst Wachstumsraten-abhängiges Zelltöten und die Selbstinhibierung von Meropenem und - ebenso für Vancomycin - ein Wiederanwachsen der bakteriellen Kulturen aufgrund von adaptiver Resistenzentwicklung. Stochastische Analysen der Interaktionsoberflächen zeigen, dass der ausgeprägte Antagonismus zwischen Meropenem und Linezolid zwar robust gegenüber Variation der Wachstumsphase und der Definition des pharmakodynamischen Endpunktes reagiert, jedoch empfindlich von der Zeitspanne des Experiments beeinflusst wird. Desweiteren enthält der entwickelte Ansatz eine detaillierte Repräsentation des bakteriellen Zellzyklus. Wir nutzten diese Repräsentation, um Septierungsdynamiken während des Übergangs einer bakteriellen Kultur aus der exponentiellen Phase in die stationäre Phase zu beschreiben. Basierend auf einem neugewonnenen mechanistischen Verständnis für diese Übergänge, konnten wir außerdem die zeitliche Verzögerung erklären, die zwischen dem Anstieg der Zellanzahl und der Biomasse während des Übergangs von Lag zu exponentieller Phase auftritt. Außerdem reproduziert unser Modell den erhöhten intrazellulären RNA Massenanteil, der auftritt, wenn Bakterien Chloramphenikol ausgesetzt werden. Zusammenfassend steuern wir einen neuen Ansatz bei, der es erlaubt, die Einflüsse von Wirkstoffeffekten, Endpunktdefinitionen und des experimentellen Protokolls zu entflechten. Da kein Konsens hinsichtlich eines entsprechenden experimentellen Protokolls existiert, ist eine solche Entflechtung der Schlüssel, um Informationen zwischen unterschiedlichen Experimenten - und letztendlich auch in die Klinik - zu transferieren. KW - antibiotic combinations KW - bacterial population growth KW - pharmacodynamics KW - drug drug interactions KW - time-kill curves KW - ribosomal dynamics KW - Antibiotika KW - Wirkstoffinteraktionen KW - Pharmakodynamik KW - mathematische Modellierung KW - mathematical modelling Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-401056 ER - TY - JOUR A1 - Ehmann, Lisa A1 - Zoller, Michael A1 - Minichmayr, Iris K. A1 - Scharf, Christina A1 - Maier, Barbara A1 - Schmitt, Maximilian V. A1 - Hartung, Niklas A1 - Huisinga, Wilhelm A1 - Vogeser, Michael A1 - Frey, Lorenz A1 - Zander, Johannes A1 - Kloft, Charlotte T1 - Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients BT - a prospective observational study JF - Critical care N2 - Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100% T->MIC, 50% T->4xMIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Results: Large inter-and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100% T->MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50% T->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy-and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed. KW - beta-Lactam KW - Intensive care KW - Pharmacokinetics/Pharmacodynamics KW - Target attainment KW - Renal function KW - Risk assessment tool KW - Continuous renal replacement therapy Y1 - 2017 U6 - https://doi.org/10.1186/s13054-017-1829-4 SN - 1466-609X SN - 1364-8535 VL - 21 PB - BioMed Central CY - London ER - TY - GEN A1 - Zibulski, Romy A1 - Wesener, Felix A1 - Wilkes, Heinz A1 - Plessen, Birgit A1 - Pestryakova, Luidmila Agafyevna A1 - Herzschuh, Ulrike T1 - C / N ratio, stable isotope (δ 13 C, δ 15 N), and n-alkane patterns of brown mosses along hydrological gradients of low-centred polygons of the Siberian Arctic T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Mosses are a major component of the arctic vegetation, particularly in wetlands. We present C / N atomic ratio, delta C-13 and delta N-15 data of 400 brown-moss samples belonging to 10 species that were collected along hydrological gradients within polygonal mires located on the southern Taymyr Peninsula and the Lena River delta in northern Siberia. Additionally, n-alkane patterns of six of these species (16 samples) were investigated. The aim of the study is to see whether the inter-and intraspecific differences in C / N, isotopic compositions and n-alkanes are indicative of habitat, particularly with respect to water level. Overall, we find high variability in all investigated parameters for two different moisture-related groups of moss species. The C / N ratios range between 11 and 53 (median: 32) and show large variations at the intraspecific level. However, species preferring a dry habitat (xero-mesophilic mosses) show higher C / N ratios than those preferring a wet habitat (meso-hygrophilic mosses). The delta C-13 values range between 37.0 and 22.5% (median D 27.8 %). The delta N-15 values range between 6.6 and C 1.7%(median D 2.2 %). We find differences in delta C-13 and delta N-15 compositions between both habitat types. For some species of the meso-hygrophilic group, we suggest that a relationship between the individ-ual habitat water level and isotopic composition can be inferred as a function of microbial symbiosis. The n-alkane distribution also shows differences primarily between xeromesophilic and meso-hygrophilic mosses, i. e. having a dominance of n-alkanes with long (n-C29, n-C31 /and intermediate (n-C25 /chain lengths, respectively. Overall, our results reveal that C / N ratios, isotopic signals and n-alkanes of studied brown-moss taxa from polygonal wetlands are characteristic of their habitat. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 672 KW - atmospheric nitrogen deposition KW - Lena River delta KW - free amino-acids KW - ombrotrophic peat KW - carbon isotopes KW - aquatic macrophytes KW - methane oxidation KW - organic matter KW - soil-nitrogen KW - plants Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-417104 SN - 1866-8372 IS - 672 ER - TY - JOUR A1 - Shahnejat-Bushehri, Sara A1 - Allu, Annapurna Devi A1 - Mehterov, Nikolay A1 - Thirumalaikumar, Venkatesh P. A1 - Alseekh, Saleh A1 - Fernie, Alisdair R. A1 - Mueller-Roeber, Bernd A1 - Balazadeh, Salma T1 - Arabidopsis NAC Transcription Factor JUNGBRUNNEN1 Exerts Conserved Control Over Gibberellin and Brassinosteroid Metabolism and Signaling Genes in Tomato JF - Frontiers in plant science N2 - The Arabidopsis thaliana NAC transcription factor JUNGBRUNNEN1 (AtJUB1) regulates growth by directly repressing GA3ox1 and DWF4, two key genes involved in gibberellin (GA) and brassinosteroid (BR) biosynthesis, respectively, leading to GA and BR deficiency phenotypes. AtJUB1 also reduces the expression of PIF4, a bHLH transcription factor that positively controls cell elongation, while it stimulates the expression of DELLA genes, which are important repressors of growth. Here, we extend our previous findings by demonstrating that AtJUB1 induces similar GA and BR deficiency phenotypes and changes in gene expression when overexpressed in tomato (Solanum lycopersicum). Importantly, and in accordance with the growth phenotypes observed, AtJUB1 inhibits the expression of growth-supporting genes, namely the tomato orthologs of GA3ox1, DWF4 and PIF4, but activates the expression of DELLA orthologs, by directly binding to their promoters. Overexpression of AtJUB1 in tomato delays fruit ripening, which is accompanied by reduced expression of several ripeningrelated genes, and leads to an increase in the levels of various amino acids (mostly proline, beta-alanine, and phenylalanine), gamma-aminobutyric acid (GABA), and major organic acids including glutamic acid and aspartic acid. The fact that AtJUB1 exerts an inhibitory effect on the GA/BR biosynthesis and PIF4 genes but acts as a direct activator of DELLA genes in both, Arabidopsis and tomato, strongly supports the model that the molecular constituents of the JUNGBRUNNEN1 growth control module are considerably conserved across species. KW - Arabidopsis KW - tomato KW - fruit KW - growth KW - transcription factor KW - gibberellic acid KW - brassinosteroid KW - DELLA proteins Y1 - 2017 U6 - https://doi.org/10.3389/fpls.2017.00214 SN - 1664-462X VL - 8 PB - Frontiers Research Foundation CY - Lausanne ER - TY - THES A1 - de Souza, Leonardo Perez T1 - Functional characterization of biosynthesis and regulation of plant secondary metabolism Y1 - 2017 ER - TY - GEN A1 - Kramer, Elena M. A1 - Lenhard, Michael T1 - Shape and form in plant development T2 - Seminars in cell & developmental biology Y1 - 2017 U6 - https://doi.org/10.1016/j.semcdb.2017.11.004 SN - 1084-9521 VL - 79 SP - 1 EP - 2 PB - Elsevier CY - London ER -