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Aims: The MARLINA-T2D study (ClinicalTrials. gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/ mol), estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m(2) and urinary albumin-tocreatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% +/- 0.9% (62.2 +/- 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P <.0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P =.1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.
One of the most significant Late Holocene climate shifts occurred around 2800 years ago, when cooler and wetter climate conditions established in western Europe. This shift coincided with an abrupt change in regional atmospheric circulation between 2760 and 2560 cal years BP, which has been linked to a grand solar minimum with the same duration (the Homeric Minimum). We investigated the temporal sequence of hydroclimatic and vegetation changes across this interval of climatic change (Homeric climate oscillation) by using lipid biomarker stable hydrogen isotope ratios (ED values) and pollen assemblages from the annually-laminated sediment record from lake Meerfelder Maar (Germany). Over the investigated interval (3200-2000 varve years BP), terrestrial lipid biomarker ED showed a gradual trend to more negative values, consistent with the western Europe long-term climate trend of the Late Holocene. At ca. 2640 varve years BP we identified a strong increase in aquatic plants and algal remains, indicating a rapid change in the aquatic ecosystem superimposed on this long-term trend. Interestingly, this aquatic ecosystem change was accompanied by large changes in ED values of aquatic lipid biomarkers, such as nC(21) and nC(23) (by between 22 and 30%(0)). As these variations cannot solely be explained by hydroclimate changes, we suggest that these changes in the Wag value were influenced by changes in n-alkane source organisms. Our results illustrate that if ubiquitous aquatic lipid biomarkers are derived from a limited pool of organisms, changes in lake ecology can be a driving factor for variations on sedimentary lipid MN values, which then could be easily misinterpreted in terms of hydro climatic changes. (C) 2017 Elsevier Ltd. All rights reserved.
Reaching the Sustainable Development Goals requires a fundamental socio-economic transformation accompanied by substantial investment in low-carbon infrastructure. Such a sustainability transition represents a non-marginal change, driven by behavioral factors and systemic interactions. However, typical economic models used to assess a sustainability transition focus on marginal changes around a local optimum, whichby constructionlead to negative effects. Thus, these models do not allow evaluating a sustainability transition that might have substantial positive effects. This paper examines which mechanisms need to be included in a standard computable general equilibrium model to overcome these limitations and to give a more comprehensive view of the effects of climate change mitigation. Simulation results show that, given an ambitious greenhouse gas emission constraint and a price of carbon, positive economic effects are possible if (1) technical progress results (partly) endogenously from the model and (2) a policy intervention triggering an increase of investment is introduced. Additionally, if (3) the investment behavior of firms is influenced by their sales expectations, the effects are amplified. The results provide suggestions for policy-makers, because the outcome indicates that investment-oriented climate policies can lead to more desirable outcomes in economic, social and environmental terms.
The phylogenetic structure of communities (PSC) reveals how evolutionary history affects community assembly processes. However, there are important knowledge gaps on PSC patterns for annual communities and there is a need for studies along environmental gradients in dry ecosystems where several processes shape PSC. Here, we investigated the PSC of annual plants along an aridity gradient in Israel, including eight years, two spatial scales, the effects of shrubs on understory, and the phylogenetic signal of important traits. Increasing drought stress led to overdispersed PSC at the drier end of the gradient, indicating that species were less related than expected by chance. This was supported at a smaller spatial scale, where within the drier sites, communities in open- more arid- habitats were more overdispersed than those under nurse shrubs. Interestingly, some key traits related to drought resistance were not conserved in the phylogeny. Together, our findings suggested that while habitat filtering selected for drought resistance strategies, these strategies evolved independently along multiple contrasting evolutionary lineages. Our comprehensive PSC study provides strong evidence for the interacting effects of habitat filtering and plant- plant interactions, particularly highlighting that the conservative evolution of traits should not be assumed in future interpretations of PSC patterns.
Reaching the Sustainable Development Goals requires a fundamental socio-economic transformation accompanied by substantial investment in low-carbon infrastructure. Such a sustainability transition represents a non-marginal change, driven by behavioral factors and systemic interactions. However, typical economic models used to assess a sustainability transition focus on marginal changes around a local optimum, whichby constructionlead to negative effects. Thus, these models do not allow evaluating a sustainability transition that might have substantial positive effects. This paper examines which mechanisms need to be included in a standard computable general equilibrium model to overcome these limitations and to give a more comprehensive view of the effects of climate change mitigation. Simulation results show that, given an ambitious greenhouse gas emission constraint and a price of carbon, positive economic effects are possible if (1) technical progress results (partly) endogenously from the model and (2) a policy intervention triggering an increase of investment is introduced. Additionally, if (3) the investment behavior of firms is influenced by their sales expectations, the effects are amplified. The results provide suggestions for policy-makers, because the outcome indicates that investment-oriented climate policies can lead to more desirable outcomes in economic, social and environmental terms.
The Influence of Land Use Intensity on the Plant-Associated Microbiome of Dactylis glomerata L.
(2017)
In this study, we investigated the impact of different land use intensities (LUI) on the root-associated microbiome of Dactylis glomerata (orchardgrass). For this purpose, eight sampling sites with different land use intensity levels but comparable soil properties were selected in the southwest of Germany. Experimental plots covered land use levels from natural grassland up to intensively managed meadows. We used 16S rRNA gene based barcoding to assess the plant-associated community structure in the endosphere, rhizosphere and bulk soil of D. glomerata. Samples were taken at the reproductive stage of the plant in early summer. Our data indicated that roots harbor a distinct bacterial community, which clearly differed from the microbiome of the rhizosphere and bulk soil. Our results revealed Pseudomonadaceae, Enterobacteriaceae and Comamonadaceae as the most abundant endophytes independently of land use intensity. Rhizosphere and bulk soil were dominated also by Proteobacteria, but the most abundant families differed from those obtained from root samples. In the soil, the effect of land use intensity was more pronounced compared to root endophytes leading to a clearly distinct pattern of bacterial communities under different LUI from rhizosphere and bulk soil vs. endophytes. Overall, a change of community structure on the plant-soil interface was observed, as the number of shared OTUs between all three compartments investigated increased with decreasing land use intensity. Thus, our findings suggest a stronger interaction of the plant with its surrounding soil under low land use intensity. Furthermore, the amount and quality of available nitrogen was identified as a major driver for shifts in the microbiome structure in all compartments.
Aims. We present an extensive study of the BL Lac object Mrk 501 based on a data set collected during the multi-instrument campaign spanning from 2009 March 15 to 2009 August 1, which includes, among other instruments, MAGIC, VERITAS, Whipple 10 m, and Fermi-LAT to cover the gamma-ray range from 0.1 GeV to 20 TeV; RXTE and Swift to cover wavelengths from UV to hard X-rays; and GASP-WEBT, which provides coverage of radio and optical wavelengths. Optical polarization measurements were provided for a fraction of the campaign by the Steward and St. Petersburg observatories. We evaluate the variability of the source and interband correlations, the gamma-ray flaring activity occurring in May 2009, and interpret the results within two synchrotron self-Compton (SSC) scenarios. Methods. The multiband variability observed during the full campaign is addressed in terms of the fractional variability, and the possible correlations are studied by calculating the discrete correlation function for each pair of energy bands where the significance was evaluated with dedicated Monte Carlo simulations. The space of SSC model parameters is probed following a dedicated grid-scan strategy, allowing for a wide range of models to be tested and offering a study of the degeneracy of model-to-data agreement in the individual model parameters, hence providing a less biased interpretation than the "single-curve SSC model adjustment" typically reported in the literature. Results. We find an increase in the fractional variability with energy, while no significant interband correlations of flux changes are found on the basis of the acquired data set. The SSC model grid-scan shows that the flaring activity around May 22 cannot be modeled adequately with a one-zone SSC scenario (using an electron energy distribution with two breaks), while it can be suitably described within a two (independent) zone SSC scenario. Here, one zone is responsible for the quiescent emission from the averaged 4.5-month observing period, while the other one, which is spatially separated from the first, dominates the flaring emission occurring at X-rays and very-high-energy (> 100 GeV, VHE) gamma-rays. The flaring activity from May 1, which coincides with a rotation of the electric vector polarization angle (EVPA), cannot be satisfactorily reproduced by either a one-zone or a two-independent-zone SSC model, yet this is partially affected by the lack of strictly simultaneous observations and the presence of large flux changes on sub-hour timescales (detected at VHE gamma rays). Conclusions. The higher variability in the VHE emission and lack of correlation with the X-ray emission indicate that, at least during the 4.5-month observing campaign in 2009, the highest energy (and most variable) electrons that are responsible for the VHE gamma rays do not make a dominant contribution to the similar to 1 keV emission. Alternatively, there could be a very variable component contributing to the VHE gamma-ray emission in addition to that coming from the SSC scenario. The studies with our dedicated SSC grid-scan show that there is some degeneracy in both the one-zone and the two-zone SSC scenarios probed, with several combinations of model parameters yielding a similar model-to-data agreement, and some parameters better constrained than others. The observed gamma-ray flaring activity, with the EVPA rotation coincident with the first gamma-ray flare, resembles those reported previously for low frequency peaked blazars, hence suggesting that there are many similarities in the flaring mechanisms of blazars with different jet properties.
Dark matter constraints from a joint analysis of dwarf Spheroidal galaxy observations with VERITAS
(2017)
We present constraints on the annihilation cross section of weakly interacting massive particles dark matter based on the joint statistical analysis of four dwarf galaxies with VERITAS. These results are derived from an optimized photon weighting statistical technique that improves on standard imaging atmospheric Cherenkov telescope (IACT) analyses by utilizing the spectral and spatial properties of individual photon events. We report on the results of similar to 230 hours of observations of five dwarf galaxies and the joint statistical analysis of four of the dwarf galaxies. We find no evidence of gamma-ray emission from any individual dwarf nor in the joint analysis. The derived upper limit on the dark matter annihilation cross section from the joint analysis is 1.35 x 10(-23) cm(3) s(-1) at 1 TeV for the bottom quark (b (b) over bar) final state, 2.85 x 10(-24) cm(3) s(-1) at 1 TeV for the tau lepton (tau+tau(-)) final state and 1.32 x 10-25 cm(3) s(-1) at 1 TeV for the gauge boson (gamma gamma) final state.
The crystallization kinetics of silicate liquids were studied experimentally in the system haplogranite-B-Li-H2O, at variable degrees of undercooling and variable water concentration. We investigated the kinetics of nucleation and crystallization of unseeded synthetic hydrous haplogranite with 1 wt % Li2O + 2 center dot 3 wt % B2O3 added (composition C1) and 2 wt % Li2O + 4 center dot 6 wt % B2O3 added (composition C2). Compositions C1 and C2 are simplified representative bulk compositions of Li-rich pegmatites and their highly differentiated cores, respectively. Starting water contents varied between 3 and 9 wt %. With few exceptions, the system remained water-undersaturated. About 86 isothermal runs of 1-60 days duration, grouped in 25 time series of constant temperature and initial H2O content, were carried out at temperatures from 400 to 700A degrees C at 300 MPa, corresponding to variable degrees of undercooling between the liquidus and glass transition. Viscosity measurements indicate that the glass transition for both compositions is below 400A degrees C for 3 wt % water and below 300A degrees C for 6 center dot 5 wt % water. The melts remained virtually crystal free at 400A degrees C, about 100A degrees C and 120A degrees C above the glass transition for compositions C1 and C2, respectively, in experiments up to 30 days long. This result is consistent with the existence of low-temperature, undercooled melts in the crust. At lower values of undercooling the runs crystallized partially, up to about 70% volume fraction. Undercooling and the amount of water are the main factors controlling nucleation and growth rates, and therefore textures. Minerals nucleate and grow sequentially according to mineral-specific nucleation delays. The mineral assemblage started with Li-Al stuffed quartz (in C1) and virgilite (in C2), solid-solutions between quartz and gamma-spodumene. The quartz-like phases were typically followed by spherulitic alkali feldspar-quartz intergrowths, euhedral petalite, and fine-grained muscovite. Nearly pure quartz formed as rims and replacement of metastable virgilite and stuffed quartz, in particular at the boron- and water-rich crystallization front of large feldspar or petalite. With the exception of muscovite, all minerals nucleated heterogeneously, on the capsule wall or on pre-existing minerals, and grew inwards, towards the capsule center. Experimental textures resembled the textures of zoned pegmatites, including skeletal, graphic, unidirectional, radiating, spherulitic, massive, and replacement textures. In some cases, when fluid saturation was reached, miarolitic cavities developed containing euhedral crystals. Although unidirectional growth rates appeared to slow down in time, volumetric rates for stable graphic alkali-feldspar quartz intergrowths and petalite remained constant for up to 60 days and similar to 70% crystallization. Metastable stuffed quartz and virgilite diminished in their growth rates in runs of 30 days or longer, were resorbed in the melt, and were partially replaced by second-generation quartz. Unobstructed, self-sustained crystal growth in conditions of very low nucleation density appears to be the dominant mechanism to form giant pegmatitic crystals, although experimental growth rates are much slower than predicted in nature based on conductive-cooling models.
The standard model for GRB afterglow emission treats the accelerated electron population as a simple power law, N(E) proportional to E-p for p greater than or similar to 2. However, in standard Fermi shock acceleration, a substantial fraction of the swept-up particles do not enter the acceleration process at all. Additionally, if acceleration is efficient, then the nonlinear back-reaction of accelerated particles on the shock structure modifies the shape of the nonthermal tail of the particle spectra. Both of these modifications to the standard synchrotron afterglow impact the luminosity, spectra, and temporal variation of the afterglow. To examine the effects of including thermal particles and nonlinear particle acceleration on afterglow emission, we follow a hydrodynamical model for an afterglow jet and simulate acceleration at numerous points during the evolution. When thermal particles are included, we find that the electron population is at no time well fitted by a single power law, though the highest-energy electrons are; if the acceleration is efficient, then the power-law region is even smaller. Our model predicts hard-soft-hard spectral evolution at X-ray energies, as well as an uncoupled X-ray and optical light curve. Additionally, we show that including emission from thermal particles has drastic effects (increases by factors of 100 and 30, respectively) on the observed flux at optical and GeV energies. This enhancement of GeV emission makes afterglow detections by future gamma-ray observatories, such as CTA, very likely.
We present a search for magnetically broadened gamma-ray emission around active galactic nuclei (AGNs), using VERITAS observations of seven hard-spectrum blazars. A cascade process occurs when multi-TeV gamma-rays from an AGN interact with extragalactic background light (EBL) photons to produce electron-positron pairs, which then interact with cosmic microwave background photons via inverse-Compton scattering to produce gamma-rays. Due to the deflection of the electron- positron pairs, a non-zero intergalactic magnetic field (IGMF) would potentially produce detectable effects on the angular distribution of the cascade emission. In particular, an angular broadening compared to the unscattered emission could occur. Through non-detection of angularly broadened emission from 1ES 1218 vertical bar 304, the source with the largest predicted cascade fraction, we exclude a range of IGMF strengths around 10(-14) G at the 95% confidence level. The extent of the exclusion range varies with the assumptions made about the intrinsic spectrum of 1ES. 1218+304 and the EBL model used in the simulation of the cascade process. All of the sources are used to set limits on the flux due to extended emission.
Context:
Massive binaries play a crucial role in the Universe. Knowing the distributions of their orbital parameters is important for a wide range of topics from stellar feedback to binary evolution channels and from the distribution of supernova types to gravitational wave progenitors, yet no direct measurements exist outside the Milky Way.
Aims:
The Tarantula Massive Binary Monitoring project was designed to help fill this gap by obtaining multi-epoch radial velocity (RV) monitoring of 102 massive binaries in the 30 Doradus region.
Methods:
In this paper we analyze 32 FLAMES/GIRAFFE observations of 93 O- and 7 B-type binaries. We performed a Fourier analysis and obtained orbital solutions for 82 systems: 51 single-lined (SB1) and 31 double-lined (SB2) spectroscopic binaries.
Results:
Overall, the binary fraction and orbital properties across the 30 Doradus region are found to be similar to existing Galactic samples. This indicates that within these domains environmental effects are of second order in shaping the properties of massive binary systems. A small difference is found in the distribution of orbital periods, which is slightly flatter (in log space) in 30 Doradus than in the Galaxy, although this may be compatible within error estimates and differences in the fitting methodology. Also, orbital periods in 30 Doradus can be as short as 1.1 d, somewhat shorter than seen in Galactic samples. Equal mass binaries (q> 0.95) in 30 Doradus are all found outside NGC 2070, the central association that surrounds R136a, the very young and massive cluster at 30 Doradus’s core. Most of the differences, albeit small, are compatible with expectations from binary evolution. One outstanding exception, however, is the fact that earlier spectral types (O2–O7) tend to have shorter orbital periods than later spectral types (O9.2–O9.7).
Conclusions:
Our results point to a relative universality of the incidence rate of massive binaries and their orbital properties in the metallicity range from solar (Z⊙) to about half solar. This provides the first direct constraints on massive binary properties in massive star-forming galaxies at the Universe’s peak of star formation at redshifts z ~ 1 to 2 which are estimated to have Z ~ 0.5 Z⊙.
Intensive land use is a major cause of biodiversity loss, but most studies comparing the response of multiple taxa rely on simple diversity measures while analyses of other community attributes are only recently gaining attention. Species-abundance distributions (SADs) are a community attribute that can be used to study changes in the overall abundance structure of species groups, and whether these changes are driven by abundant or rare species. We evaluated the effect of grassland management intensity for three land-use modes (fertilization, mowing, grazing) and their combination on species richness and SADs for three belowground (arbuscular mycorrhizal fungi, prokaryotes and insect larvae) and seven aboveground groups (vascular plants, bryophytes and lichens; arthropod herbivores; arthropod pollinators; bats and birds). Three descriptors of SADs were evaluated: general shape (abundance decay rate), proportion of rare species (rarity) and proportional abundance of the commonest species (dominance). Across groups, taxonomic richness was largely unaffected by land-use intensity and only decreased with increasing mowing intensity. Of the three SAD descriptors, abundance decay rate became steeper with increasing combined land-use intensity across groups. This reflected a decrease in rarity among plants, herbivores and vertebrates. Effects of fertilization on the three descriptors were similar to the combined land-use intensity effects. Mowing intensity only affected the SAD descriptors of insect larvae and vertebrates, while grazing intensity produced a range of effects on different descriptors in distinct groups. Overall, belowground groups had more even abundance distribtitions than aboveground groups. Strong differences among aboveground groups and between above- and belowground groups indicate that no single taxonomic group can serve as an indicator for effects in other groups. In the past, the use of SADs has been hampered by concerns over theoretical models underlying specific forms of SADs. Our study shows that SAD descriptors that are not connected to a particular model are suitable to assess the effect of land use on community structure.
Das prolongierte Weaning von Patienten mit neurologischen oder neurochirurgischen Erkrankungen weist Besonderheiten auf, denen die Deutsche Gesellschaft für Neurorehabilitation e. V. in einer eigenen Leitlinie Rechnung trägt.
Im Hinblick auf Definitionen (z. B. Weaningerfolg und -versagen), Weaningkategorien, Pathophysiologie des Weaningversagens und allgemeine Weaningstrategien wird ausdrücklich auf die aktuelle S2k-Leitlinie der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V. verwiesen.
In der neurologisch-neurochirurgischen Frührehabilitation werden Patienten mit zentralen Störungen der Atmungsregulation (z. B. Hirnstammläsionen), des Schluckaktes (neurogene Dysphagien), mit neuromuskulären Problemen (z. B. Critical-illness-Polyneuropathie, Guillain-Barre-Syndrom, Querschnittlähmungen, Myasthenia gravis) und/oder kognitiven Störungen (z. B. Bewusstseins- und Vigilanzstörungen, schwere Kommunikationsstörungen) versorgt, deren Betreuung bei der Entwöhnung von der Beatmung neben intensivmedizinischer Kompetenz auch neurologische bzw. neurochirurgische und neurorehabilitative Expertise erfordert. In Deutschland wird diese Kompetenz in Zentren der neurologisch-neurochirurgischen Frührehabilitation vorgehalten, und zwar als Krankenhausbehandlung.
Der Leitlinie liegt eine systematische Recherche von Leitliniendatenbanken und Medline zugrunde. Unter Moderation durch die Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) erfolgte die Konsensfindung mittels nominalen Gruppenprozesses und Delphi-Verfahren.
In der vorliegenden Leitlinie der DGNR wird auf die strukturellen und inhaltlichen Besonderheiten der neurologisch-neurochirurgischen Frührehabilitation sowie vorhandene Studien zum Weaning in Frührehabilitationseinrichtungen eingegangen.
Adressaten der Leitlinie sind Neurologen, Neurochirurgen, Anästhesisten, Palliativmediziner, Logopäden, Intensivpflegekräfte, Ergotherapeuten, Physiotherapeuten und Neuropsychologen. Ferner richtet sich diese Leitlinie zur Information an Fachärzte für Physikalische Medizin und Rehabilitation (PMR), Pneumologen, Internisten, Atmungstherapeuten, den Medizinischen Dienst der Krankenkassen (MDK) und des Spitzenverbands Bund der Krankenkassen e. V. (MDS). Das wesentliche Ziel dieser Leitlinie ist es, den aktuellen Wissensstand zum Thema „Prolongiertes Weaning in der neurologisch-neurochirurgischen Frührehabilitation“ zu vermitteln.
Der Leserbrief fokussiert in weiten Teilen auf das Gutachterwesen, weshalb wir ausschließlich auf die inhaltlichen Punkte im Zusammenhang mit unserer Arbeit eingehen. Untersucht wurden schmerzpsychologische Interventionen, wie beschrieben definiert als psychologische Interventionen, deren primäres Ziel die Schmerzreduktion war.
Die extrahierten Zielgrößen, wie Lebensqualität oder Depressivität, ergaben sich aus den in den Primärstudien untersuchten Hauptoutcomes und nicht aus der Suchstrategie.
Zur Einschätzung der methodischen Qualität der Primärstudien konnte ein Kriterium des von Johannsen und Kollegen [2] gebildeten Scores nicht berücksichtigt werden, da die eingeschlossenen Primärstudien keine metaanalytische Zusammenfassung erlaubten. Stellt man dies in Rechnung, bleibt die Vergleichbarkeit beider Werte erhalten.
Die Evidenzsynthese erfolgte narrativ in Text- und Tabellenform, d. h. in Form einer strukturierten Zusammenfassung und Diskussion von Studien [1].
Um unsere Arbeit zu fokussieren, hätten wir eine weitergehende Gegenüberstellung wie auch eine Überprüfung von Zitaten und Übersetzungen selbstverständlich vorgenommen, wenn wir den Hinweis dazu vor Publikation erhalten hätten.
ecoAO
(2017)
Although aldehyde oxidase (AO) is an important hepatic drug-metabolizing enzyme, it remains understudied and is consequently often overlooked in preclinical studies, an oversight that has resulted in the failure of multiple clinical trials. AO’s preclusion to investigation stems from the following: (1) difficulties synthesizing metabolic standards due to the chemospecificity and regiospecificity of the enzyme and (2) significant inherent variability across existing in vitro systems including liver cytosol, S9 fractions, and primary hepatocytes, which lack specificity and generate discordant expression and activity profiles. Here, we describe a practical bacterial biotransformation system, ecoAO, addressing both issues simultaneously. ecoAO is a cell paste of MoCo-producing Escherichia coli strain TP1017 expressing human AO. It exhibits specific activity toward known substrates, zoniporide, 4-trans-(N,N-dimethylamino)cinnamaldehyde, O6-benzylguanine, and zaleplon; it also has utility as a biocatalyst, yielding milligram quantities of synthetically challenging metabolite standards such as 2-oxo-zoniporide. Moreover, ecoAO enables routine determination of kcat and V/K, which are essential parameters for accurate in vivo clearance predictions. Furthermore, ecoAO has potential as a preclinical in vitro screening tool for AO activity, as demonstrated by its metabolism of 3-aminoquinoline, a previously uncharacterized substrate. ecoAO promises to provide easy access to metabolites with the potential to improve pharmacokinetic clearance predictions and guide drug development.
100 Jahre Roter Oktober
(2017)
1. For managed temperate forests, conservationists and policymakers favour fine-grained uneven-aged (UEA) management over more traditional coarse-grained even-aged (EA) management, based on the assumption that within-stand habitat heterogeneity enhances biodiversity. There is, however, little empirical evidence to support this assumption. We investigated for the first time how differently grained forest management systems affect the biodiversity of multiple above- and below-ground taxa across spatial scales. 2. We sampled 15 taxa of animals, plants, fungi and bacteria within the largest contiguous beech forest landscape of Germany and classified them into functional groups. Selected forest stands have been managed for more than a century at different spatial grains. The EA (coarse-grained management) and UEA (fine-grained) forests are comparable in spatial arrangement, climate and soil conditions. These were compared to forests of a nearby national park that have been unmanaged for at least 20years. We used diversity accumulation curves to compare -diversity for Hill numbers D-0 (species richness), D-1 (Shannon diversity) and D-2 (Simpson diversity) between the management systems. Beta diversity was quantified as multiple-site dissimilarity. 3. Gamma diversity was higher in EA than in UEA forests for at least one of the three Hill numbers for six taxa (up to 77%), while eight showed no difference. Only bacteria showed the opposite pattern. Higher -diversity in EA forests was also found for forest specialists and saproxylic beetles. 4. Between-stand -diversity was higher in EA than in UEA forests for one-third (all species) and half (forest specialists) of all taxa, driven by environmental heterogeneity between age-classes, while -diversity showed no directional response across taxa or for forest specialists. 5. Synthesis and applications. Comparing EA and uneven-aged forest management in Central European beech forests, our results show that a mosaic of different age-classes is more important for regional biodiversity than high within-stand heterogeneity. We suggest reconsidering the current trend of replacing even-aged management in temperate forests. Instead, the variability of stages and stand structures should be increased to promote landscape-scale biodiversity.