Cytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas. Based on consumption data, the kinetics after daily intake of retrorsine were simulated with concomitant rifampicin treatment. Strongest impact on retrorsine kinetics (plasma AUC24 and Cmax reduced to 67% and 74% compared to the rifampicin-free reference) was predicted directly after withdrawal of rifampicin. At this time point, the competitive inhibitory effect of rifampicin stopped, while CYP3A4 induction was still near its maximum. Due to the impacted metabolism kinetics, the cumulative formation of intestinal retrorsine CYP3A4 metabolites increased to 254% (from 10 to 25 nmol), while the cumulative formation of hepatic CYP3A4 metabolites was not affected (57 nmol). Return to baseline PA toxicokinetics was predicted 14 days after stop of a 14-day rifampicin treatment. In conclusion, the PBTK model showed to be a promising tool to assess the dynamic interplay of enzyme induction and toxification pathways.
Weniger anzeigenThe chemical synthesis of complex oligosaccharides relies on efficient and highly reproducible glycosylation reactions. The outcome of a glycosylation is contingent upon several environmental factors, such as temperature, acidity, the presence of residual moisture, as well as the steric, electronic, and conformational aspects of the reactants. Each glycosylation proceeds rapidly and with a high yield within a rather narrow temperature range. For better control over glycosylations and to ensure fast and reliable reactions, a systematic analysis of 18 glycosyl donors revealed the effect of reagent concentration, water content, protecting groups, and structure of the glycosyl donors on the activation temperature. With these insights, we parametrize the first step of the glycosylation reaction to be executed reliably and efficiently.
Weniger anzeigenAccording to international law, the sovereignty of nation-states and the rights of individuals constitute two equally important principles. However, in instances when a state massively violates human rights, then priority is given to the protection of individuals over the self-determination of the state, thereby justifying humanitarian military intervention. This paper presents findings from a survey across 26 countries, analyzing citizen support for such intervention. We find that the majority of respondents supports military intervention to protect human rights. To explain the differences in support, we draw on world society theory and modernization theory. At first sight, world society theory offers a better framework for understanding citizens' attitudes towards military intervention. However, charcateristics derived from modernization theory are affected by a “suppression effect:” individuals living in more modernized countries and holding postmaterialist values endorse enforcing human rights but concurrently reject the use of military force.
Weniger anzeigenPartial methanol oxidation proceeds with high selectivity to methyl formate (MeFo) on nanoporous gold (npAu) catalysts. As low-coordinated sites on npAu were suggested to affect the selectivity, we experimentally investigated their role in the isothermal selectivity for flat Au(111) and stepped Au(332) model surfaces using a molecular beam approach under well-defined conditions. Direct comparison shows that steps enhance desired MeFo formation and lower undesired overoxidation. DFT calculations reveal differences in oxygen distribution that enhance the barriers to overoxidation at steps. Thus, these results provide an atomic-level understanding of factors controlling the complex reaction network on gold catalysts, such as npAu.
Weniger anzeigenZu meinem Essay „Aufopferung als Gabe ohne Maß?“ habe ich vier sehr wertschätzende und bedenkenswerte Kommentare mit wichtigen Ergänzungen und Kritik erhalten, für die ich mich bedanken möchte. Ich kann nicht auf alle Punkte eingehen, auf manche nur implizit.
Objectives
Repetitive negative thinking (RNT) is a problematic thinking style that is related to multiple mental disorders. Detached mindfulness is a technique of metacognitive therapy that aims to reduce RNT. Our study set out to investigate the immediate effects of detached mindfulness in daily life.
Methods
Participants with elevated trait RNT (n = 50) were prompted to engage in detached mindfulness exercises three times a day for 5 consecutive days. Immediate effects on RNT and affect were assessed 15 and 30 min after each exercise using experience sampling methodology. We compared the effects of this exercise phase to (1) a 5-day non-exercise baseline phase and (2) a different group of participants that engaged in an active control exercise (n = 50).
Results
Results of Bayesian multilevel models showed that, across groups, improvements in RNT, negative affect, and positive affect were stronger during the exercise phase than during the non-exercise baseline phase (RNT after 15 min: b = -0.26, 95% CI = [-0.38, -0.14]). However, the two exercise groups did not differ in these improvements (RNT after 15 min: b = 0.02, 95% CI = [-0.22, 0.27]). Thus, the detached mindfulness and the active control exercises resulted in similar effects on RNT and affect in daily life.
Conclusions
Results of this study imply that there was no additional benefit of having participants observe their thoughts detached and non-judgmentally, compared to excluding these assumed mechanisms of action as done for the active control group. We discuss possible reasons for the non-difference between the groups.
Preregistration
This study was preregistered at https://osf.io/rze64.
Weniger anzeigenDer Text untersucht die Frage, ob Aufopferung moralisch gut ist und lotet das Verhältnis von Aufopferung und Supererogation aus. Ausgehend vom Kontext historisch dominierender Formen von Aufopferung wird die Pflege von Angehörigen paradigmatisch für die Aufopferung für jemanden (nicht für Sachen oder Ideen) in den Blick genommen. Die für Pflegebeziehungen typische Gefühlsdynamik macht deutlich, inwiefern diese Form der Aufopferung als eine Gabe ohne Maß betrachtet werden kann. Mit Rekurs auf die Theorie der Gabe werden Kriterien dafür entwickelt, unter welchen Bedingungen Aufopferung bewunderungswürdig oder womöglich moralisch falsch ist. Bewunderungswürdig ist die spezifische Gabe der Pflege von Angehörigen nur dann, so die entwickelte These, wenn sie seitens der sich aufopfernden Person mit einem ausgewogenen Gefühlshaushalt verbunden ist. Handelt es sich bei der Aufopferung dagegen um eine emotionale Dauerüberforderung, so ist diese Gabe zwar nicht mehr bewunderungswürdig, aber auch nicht moralisch falsch.
Weniger anzeigenZrO2 is a versatile material with diverse applications, including structural ceramics, sensors, and catalysts. The properties of ZrO2 are largely determined by its crystal structure, which is temperature- and atmosphere dependent. Thus, this work focuses on a quantitative analysis of the temperature- and gas atmosphere-dependent phase transformation of tetragonal t-ZrO2 into monoclinic m-ZrO2 during heating–cooling cycles from room temperature to 1273 K. Synchrotron-based in situ X-ray diffraction (XRD) studies in gas atmospheres of different reduction strengths, namely, 5 vol% H2/Ar, He, CO2, and air, revealed a stabilizing effect of inert and reductive environments, directly yielding different temperature onsets in the phase transformation during cooling (i.e., 435, 510, 710, and 793 K for 5 vol% H2/Ar, He, CO2, and air, respectively). Rietveld refinement shows a direct influence of the atmosphere on grain size, unit cell, and weight fraction of both polymorphs in the product composite matrix. The tetragonal-to-monoclinic (t–m) phase transformation is suppressed in the sample heated only up to ∼850 K, independent of the gas atmosphere. The results of ex situ XRD, transmission electron microscopic, electron paramagnetic resonance, and oxygen titration experiments confirmed that the phase transformation is accompanied by a change in the crystallite/particle size and the amount of lattice defects (i.e., oxygen vacancy). Due to the different onset temperatures, a complex interplay between kinetic limitations of phase transformation and grain sintering yields different pathways of the phase transformation and, eventually, very different final crystallite sizes of both t-ZrO2 and m-ZrO2.
Weniger anzeigenThis article contributes from a sociology of knowledge perspective to the ongoing sociological debate about statistics produced by international organisations taking the Global Estimates of Forced Labour published by the International Labour Organization (ILO) as a case of international quantification. We ask: what stages of negotiation were involved in the transformation of a legal category into a statistical category of forced labour oriented towards political action? The analysis combines the historical reconstruction of the political and organisational processes behind the production of the estimates with the study of the measurement framework of forced labour. The qualitative case study is based on semi-structured expert interviews and ILO documents. Our results highlight the processes by which a legal category was made practicable for statistical work and thereby point to the specific arrangements and connections between law, statistics, and policy within international organisations. As we argue, the estimates have provided consistency to a fragile social construct that originated in the imperial context of the interwar period, and that was turned into a ‘visible’ social and global phenomenon of the twenty-first century.
Weniger anzeigenIn the 16th century at the latest there were strong political, cultural and literary ties between the Iberian Peninsula and the Dutch speaking regions in north western Europe. Literature in general and especially romances from the ‘south’ were printed, translated and adapted in Dutch. After an introduction in which the contribution presents a short overview of the translation and adaptation of Iberian romances in Dutch the focus will be on the ‘Amadijs’ tradition especially. For the first time the Spanish source and the ‘Amadijs’ are compared, including an analysis of the paratextual elements of the first Dutch edition of ‘Amadijs’ (1546), which clearly shows that Nuyts did not follow his source as an inspiration for the design of his edition, but copied the design of earlier Dutch editions of narratives as a marketing strategy. Part four shows that the Dutch ‘Amadijs’ was obviously read by everyone in the early modern period.
Weniger anzeigenThis study analyzes the samarium diiodide-promoted cyclizations of 5-arylpentan-2-ones to dearomatized bicyclic products utilizing density functional theory. The reaction involves a single electron transfer to the carbonyl group, which occurs synchronously with the rate determining cyclization event, and a second subsequent proton-coupled electron transfer. These redox reactions are accurately computed employing small core pseudo potentials explicitly involving all f-electrons of samarium. Comparison of the energies of the possible final products rules out thermodynamic control of the observed regio- and diastereoselectivities. Kinetic control via appropriate transition states is correctly predicted, but to obtain reasonable energy levels the influence of the co-solvent hexamethylphosphortriamide has to be estimated by using a correction term. The steric effect of the bulky samarium ligands is decisive for the observed stereoselectivity. Carbonyl groups in para-position of the aryl group change the regioselectivity of the cyclization and lead to spiro compounds. The computations suggest again kinetic control of this deviating outcome. However, the standard mechanism has to be modified and the involvement of a complex activated by two SmI2 moieties is proposed in which two electrons are transferred simultaneously to form the new C–C bond. Computation of model intermediates show the feasibility of this alternative mechanism.
Weniger anzeigenWe report electrochemical metallization (ECM) resistive switching in polycrystalline YMnO3 memristive devices using Al as an active electrode. Al/YMnO3/Pt devices exhibit bipolar resistive switching with a high ROFF/RON ratio of 104, low operational voltages of VSet ≈ 1.7 V and VReset ≈ −0.36 V and good retention properties. The resistive switching is intimately linked to the coexistence of the orthorhombic and hexagonal YMnO3 phases. The characterization of these two nanocrystalline phases is realized not only by X-ray diffraction – which is shown to be unable to reveal the presence of the orthorhombic phase – but also by a set of correlative microscopy and spectroscopy methods (scanning electron microscopy, optical microscopy, Raman spectroscopy and conductive atomic force microscopy). The origin of resistive switching is ascribed to an Al filament-based electrochemical metallization mechanism that likely occurs along an oxygen-deficient grain boundary between the hexagonal and orthorhombic nanocrystalline YMnO3 phases. The unique microstructure provided by the mixed polycrystalline phase films allows to use Al as an active electrode in YMnO3-based ECM cells, and gives perspective for further miniaturization of the devices.
Weniger anzeigenFor the transition to renewable energy sources, novel energy storage materials are more important than ever. This review addresses so-called molecular solar thermal (MOST) systems, which appear very promising since they combine light harvesting and energy storing in one-photon one-molecule processes. The focus is on norbornadiene (NBD), a particularly interesting candidate, which is converted to the strained valence isomer quadricyclane (QC) upon irradiation. The stored energy can be released on demand. The energy-releasing cycloreversion from QC to NBD can be initiated by a thermal, catalytic, or electrochemical trigger. The reversibility of the energy storage and release cycles determines the general practicality of a MOST system. In the search for derivatives, which enable large-scale applications, fundamental surface science studies help to assess the feasibility of potential substituted NBD/QC couples. We focus on investigations under well-defined ultra-high vacuum (UHV) conditions as well as experiments in liquid phase. Next to mechanistic insights into the isomerization between the two valence isomers, information on adsorption geometries, thermal stability limits, and reaction pathways of the respective molecules are discussed. Moreover, laboratory-scaled test devices demonstrated the proof of concept in various areas of application.
Weniger anzeigenChromatographic modeling software packages are valuable tools during method optimization steps. These are well established for reversed-phase applications utilizing retention time (RT) prediction to optimize separations and receive robust methods, which is of high interest for the analysis of pharmaceuticals. In contrast to liquid chromatography, the knowledge of RT prediction in supercritical fluid chromatography is limited to a manageable number of studies.
This study uses the software DryLab to predict the RTs of the peptides bacitracin (Bac), colistin, tyrothricin (Tyro), and insulin analogs. Gradient time, column temperature, and the ternary composition (terC) of carbon dioxide, methanol (MeOH), and acetonitrile (ACN) in the gradient elution are varied in a feasibility approach using a neutral (Viridis BEH) and an amino-derivatized aromatic (Torus 2-PIC) stationary phase. In the second part, chromatographic optimization is performed in silico through gradient adjustments to optimize the separation of the fingerprint of Bac. The final gradient method utilizes a Viridis BEH column (100 × 3.0 mm, 1.7 μm), carbon dioxide, and a modifier consisting of ACN/MeOH/water/methanesulfonic acid (60:40:2:0.1, v:v:v:v). In addition, changes in the retention order of Tyro compounds with the proportion of the terC in combination with a Torus Diol column are investigated.
Weniger anzeigenBackground
Overriding spinous processes, also known as ‘kissing spines’, are one of the most common causes of back pain in horses. The aim of this study was to investigate which options for diagnosis and treatment are preferred by equine orthopaedic specialists and assess which techniques are used for local injection.
Methods
An online survey was distributed among members of the European/American College of Veterinary Surgeons, the European/American College of Veterinary Sports Medicine and Rehabilitation, the International Society of Equine Locomotor Pathology and nationally recognised advanced equine orthopaedic practitioners.
Results
The survey was completed by 353 respondents. The injection techniques most commonly used involve placing two needles abaxial to the interspinous space (42%) under ultrasonographic guidance (32%) or one needle in the midline (35%) between two spinous processes. The most popular combination for overriding dorsal spinous process therapy was local injection (26.7%) combined with controlled exercise (25.5%). Manual therapy was considered by 42% of European and 25% of American specialists (p = 0.01). Surgical intervention as a first-line treatment was recommended mainly by specialists working in the United States, the UK or Ireland (p = 0.001). Overall, most equine orthopaedic veterinarians (71%; n = 201) preferred conservative management and recommended surgery only for horses that did not respond to conservative therapy.
Limitations
Respondents’ personal bias may have skewed the findings.
Conclusions
Despite a growing body of evidence, the therapeutic approach to ‘kissing spines’ in horses is influenced by professional specialisation and regional preferences. Variations in injection techniques and differing criteria for surgical intervention warrant further investigation.
Weniger anzeigenThe random greedy algorithm for finding a maximal independent set in a graph constructs a maximal independent set by inspecting the graph's vertices in a random order, adding the current vertex to the independent set if it is not adjacent to any previously added vertex. In this paper, we present a general framework for computing the asymptotic density of the random greedy independent set for sequences of (possibly random) graphs by employing a notion of local convergence. We use this framework to give straightforward proofs for results on previously studied families of graphs, like paths and binomial random graphs, and to study new ones, like random trees and sparse random planar graphs. We conclude by analysing the random greedy algorithm more closely when the base graph is a tree.
Weniger anzeigenBackground
Internet-based interventions produce comparable effectiveness rates as face-to-face therapy in treating depression. Still, more than half of patients do not respond to treatment. Machine learning (ML) methods could help to overcome these low response rates by predicting therapy outcomes on an individual level and tailoring treatment accordingly. Few studies implemented ML algorithms in internet-based depression treatment using baseline self-report data, but differing results hinder inferences on clinical practicability. This work compares algorithms using features gathered at baseline or early in treatment in their capability to predict non-response to a 6-week online program targeting depression.
Methods
Our training and test sample encompassed 1270 and 318 individuals, respectively. We trained random forest algorithms on self-report and process features gathered at baseline and after 2 weeks of treatment. Non-responders were defined as participants not fulfilling the criteria for reliable and clinically significant change on PHQ-9 post-treatment. Our benchmark models were logistic regressions trained on baseline PHQ-9 sum or PHQ-9 early change, using 100 iterations of randomly sampled 80/20 train-test-splits.
Results
Best performances were reached by our models involving early treatment characteristics (recall: 0.75–0.76; AUC: 0.71–0.77). Therapeutic alliance and early symptom change constituted the most important predictors. Models trained on baseline data were not significantly better than our benchmark.
Conclusions
Fair accuracies were only attainable by involving information from early treatment stages. In-treatment adaptation, instead of a priori selection, might constitute a more feasible approach for improving response when relying on easily accessible self-report features. Implementation trials are needed to determine clinical usefulness.
Weniger anzeigenWhile laboratory and field experiments are the major items in the toolbox of behavioral economists, household panel studies can complement them and expand their research potential. We introduce the German Socio-Economic Panel’s Innovation Sample (SOEP-IS), which offers researchers detailed panel data and the possibility to collect personalized experimental and survey data for free. We discuss what SOEP-IS can offer to behavioral economists and illustrate a set of design ideas with examples. Although we build our discussion on SOEP-IS, our purpose is to provide a guide that can be generalized to other household panel studies as well.
Weniger anzeigen