Introduction/objective: Suppression of the SOS response in combination with drugs damaging DNA has been proposed as a potential target to tackle antimicrobial resistance. The SOS response is the pathway used to repair bacterial DNA damage induced by antimicrobials such as quinolones. The extent of lexA-regulated protein expression and other associated systems under pressure of agents that damage bacterial DNA in clinical isolates remains unclear. The aim of this study was to assess the impact of this strategy consisting on suppression of the SOS response in combination with quinolones on the proteome profile of Escherichia coli clinical strains.
Materials and methods: Five clinical isolates of E. coli carrying different chromosomally- and/or plasmid-mediated quinolone resistance mechanisms with different phenotypes were selected, with E. coli ATCC 25922 as control strain. In addition, from each clinical isolate and control, a second strain was created, in which the SOS response was suppressed by deletion of the recA gene. Bacterial inocula from all 12 strains were then exposed to 1xMIC ciprofloxacin treatment (relative to the wild-type phenotype for each isogenic pair) for 1 h. Cell pellets were collected, and proteins were digested into peptides using trypsin. Protein identification and label-free quantification were done by liquid chromatography-mass spectrometry (LC–MS) in order to identify proteins that were differentially expressed upon deletion of recA in each strain. Data analysis and statistical analysis were performed using the MaxQuant and Perseus software.
Results: The proteins with the lowest expression levels were: RecA (as control), AphA, CysP, DinG, DinI, GarL, PriS, PsuG, PsuK, RpsQ, UgpB and YebG; those with the highest expression levels were: Hpf, IbpB, TufB and RpmH. Most of these expression alterations were strain-dependent and involved DNA repair processes and nucleotide, protein and carbohydrate metabolism, and transport. In isolates with suppressed SOS response, the number of underexpressed proteins was higher than overexpressed proteins.
Conclusion: High genomic and proteomic variability was observed among clinical isolates and was not associated with a specific resistant phenotype. This study provides an interesting approach to identify new potential targets to combat antimicrobial resistance.
View lessFuture dynamics of biological invasions are highly uncertain because they depend on multiple social–ecological drivers. We used a scenario-based approach to explore potential management options for invasive species in Europe. During two workshops involving a multidisciplinary team of experts, we developed a management strategy arranged into 19 goals relating to policy, research, public awareness, and biosecurity. We conceived solutions for achieving these goals under different plausible future scenarios, and identified four interrelated recommendations around which any long-term strategy for managing invasive species can be structured: (1) a European biosecurity regime, (2) a dedicated communication strategy, (3) data standardization and management tools, and (4) a monitoring and assessment system. Finally, we assessed the feasibility of the management strategy and found substantial differences among scenarios. Collectively, our results indicate that it is time for a new strategy for managing biological invasions in Europe, one that is based on a more integrative approach across socioeconomic sectors and countries.
View lessMemory effects emerge as a fundamental consequence of dimensionality reduction when low-dimensional observables are used to describe the dynamics of complex many-body systems. In the context of molecular dynamics (MD) data analysis, accounting for memory effects using the framework of the generalized Langevin equation (GLE) has proven efficient, accurate, and insightful, particularly when working with high-resolution time series data. However, in experimental systems, high-resolution data are often unavailable, raising questions about the impact of the data resolution on the estimated GLE parameters. This study demonstrates that direct memory extraction from time series data remains accurate when the discretization time is below the memory time. To obtain memory functions reliably, even when the discretization time exceeds the memory time, we introduce a Gaussian Process Optimization (GPO) scheme. This scheme minimizes the deviation of discretized two-point correlation functions between time series data and GLE simulations and is able to estimate accurate memory kernels as long as the discretization time stays below the longest time scale in the data, typically the barrier crossing time.
View lessBimetallic Al(III) catalysis mediates thioanhydride/epoxide copolymerisation at greatly improved rates and monomer tolerance than analogous Cr(III) catalysis. Moving to sulfurated monomers furthermore generally improves rates and selectivites.
Background
We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed.
Methods
In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses.
Results
Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration–time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined.
Conclusion
This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation.
Clinical Trial Registration
EudraCT number: 2021-006643-39.
View lessDeviations between macrorheological and particle-based microrheological measurements are often considered to be a nuisance and neglected. We study aqueous poly(ethylene oxide) (PEO) hydrogels for varying PEO concentrations and chain lengths that contain microscopic tracer particles and show that these deviations reveal the nanoscopic viscoelastic properties of the particle–hydrogel interface. Based on the transient Stokes equation, we first demonstrate that the deviations are not due to finite particle radius, compressibility, or surface-slip effects. Small-angle neutron scattering rules out hydrogel heterogeneities. Instead, we show that a generalized Stokes–Einstein relation, accounting for an interfacial shell around tracers with viscoelastic properties that deviate from bulk, consistently explains our macrorheological and microrheological measurements. The extracted shell diameter is comparable to the PEO end-to-end distance, indicating the importance of dangling chain ends. Our methodology reveals the nanoscopic interfacial rheology of hydrogels and is applicable to different kinds of viscoelastic fluids and particles.
View lessIn this paper I argue that the pervasive reality of unjust heterosex necessitates greater attention to the concept of “sexual fluency” (Cahill 2014). This paper elaborates on what it means to be a sexually fluent and disfluent subject, and its broader ethical and political significance. As part of this discussion, I explore the relationship between sexual (dis)fluency and embedded imaginaries, and critically reflect on the promise and limitations of particular interventions to disrupt patterns of sexual disfluency among sexual actors.
View lessThis study examined the effects of a 3-strain Bacillus-based probiotic (BP; Bacillus amyloliquefaciens and two Bacillus subtilis) in broiler diets with different rye levels on performance, mucus, viscosity, and nutrient digestibility. We distributed 720 one-d-old female broilers into 72 pens and designed nine diets using a 3 × 3 factorial approach, varying BP levels (0, 1.2 × 106, and 1.2 × 107 CFU/g) and rye concentrations (0, 200, 400 g/kg). On d 35, diets with 200 or 400 g/kg rye reduced broiler weight gain (BWG). Diets with 400 g/kg rye had the highest FCR, while rye-free diets had the lowest (p ≤0.05). Adding BP increased feed intake and BWG in weeks two and three (p ≤0.05). It should be noted that the overall performance fell below the goals of the breed. Including rye in diets reduced the coefficient of apparent ileal digestibility (CAID) for protein, ether extract (EE), calcium, phosphorus, and all amino acids (p ≤0.05). Rye-free diets exhibited the highest CAID for all nutrients, except for methionine, EE, and calcium, while diets with 400 g/kg of rye demonstrated the lowest CAID (p ≤0.05). BP in diets decreased phosphorus CAID (p ≤0.05). Diets containing 1.2 × 107 CFU/g (10X) of BP exhibited higher CAID of methionine than the other two diets (p ≤0.05). Diets containing 10X of BP showed higher CAID of cysteine than diets with no BP (p ≤0.05). Ileal viscosity increased as the inclusion level of rye in the diets increased (p ≤0.05). The ileal concentration of glucosamine in chickens fed diets with 400 g/kg of rye was higher than in those fed diets with no rye (p ≤0.05). Furthermore, ileal galactosamine concentrations were elevated in diets with 200 and 400 g/kg of rye when compared to rye-free diets (p ≤0.05). However, BP in diets had no impact on ileal viscosity, galactosamine, or glucosamine (p > 0.05). In conclusion, the applied Bacillus strains appeared to have a limited capacity to produce arabinoxylan-degrading enzymes and were only partially effective in mitigating the negative impacts of rye arabinoxylans on broilers.
View lessTriphenylpnictogens EPh3 (E = N, P, As, Sb, Bi) are able to displace the perfluorinated Cp* ligand in [Rh(COD)(C5(CF3)5)] (COD = 1,5-cyclooctadiene) in up to quantitative yield. The resulting ionic products contain [C5(CF3)5]− as uncoordinated counter anion. The cations feature [Rh(COD)]+ fragments, coordinated by one (N, Bi), two (P, As) or three (Sb) triphenylpnictogen moieties. Whereas coordination via the pnictogen is observed for P, As and Sb, π-coordination of the aryl rings is observed for N and Bi.
View lessFor a detailed understanding of chemical processes in nature and industry, we need accurate models of chemical reactions in complex environments. While Eyring transition state theory is commonly used for modeling chemical reactions, it is most accurate for small molecules in the gas phase. A wide range of alternative rate theories exist that can better capture reactions involving complex molecules and environmental effects. However, they require that the chemical reaction is sampled by molecular dynamics simulations. This is a formidable challenge since the accessible simulation timescales are many orders of magnitude smaller than typical timescales of chemical reactions. To overcome these limitations, rare event methods involving enhanced molecular dynamics sampling are employed. In this work, thermal isomerization of retinal is studied using tight-binding density functional theory. Results from transition state theory are compared to those obtained from enhanced sampling. Rates obtained from dynamical reweighting using infrequent metadynamics simulations were in close agreement with those from transition state theory. Meanwhile, rates obtained from application of Kramers' rate equation to a sampled free energy profile along a torsional dihedral reaction coordinate were found to be up to three orders of magnitude higher. This discrepancy raises concerns about applying rate methods to one-dimensional reaction coordinates in chemical reactions.
View lessReliable probabilistic primality tests are fundamental in public-key cryptography. In adversarial scenarios, a composite with a high probability of passing a specific primality test could be chosen. In such cases, we need worst-case error estimates of the test. However, in many scenarios, the numbers are randomly chosen and thus have a significantly smaller error probability. We are hence interested in average-case error estimates. In this paper we establish such bounds for the strong Lucas primality test, as there exist only worst-case, but no average-case error bounds. This allows us to use this test with more confidence. Let us examine an algorithm that draws odd k-bit integers uniformly and independently, runs t independent iterations of the strong Lucas test with randomly chosen parameters, and outputs the first number that passes all t consecutive rounds. We attain numerical upper bounds on the probability that a composite is returned. Moreover, we examine a slight modification of this algorithm that only considers integers that are not divisible by small primes, yielding improved bounds. In addition, we classify the numbers that contribute most to our estimate.
View lessA pressing societal and scientific question is how social media use affects our cognitions, emotions, and behaviors. To answer this question, fine-grained insight into the content of individuals’ social media use is needed. It is difficult to study content-based social media effects with traditional survey methods because such methods are incapable of capturing the extreme volume and variety of social media content that is shared and received. Therefore, this special issue aims to illustrate how content-based social media effects could be examined by integrating communication sciences and computational methods. We describe a three-step method to investigate content-based media effects, which involves (a) collecting digital trace data, (b) performing automated textual and visual content analysis, and (c) conducting linkage analysis. This Special Issue zooms in on these steps and describes the strengths and weaknesses of different computational methods. We conclude with some challenges that need to be addressed in future research.
View lessOptimizing agroecosystems and crops for micronutrient uptake while reducing issues with inorganic contaminants (metal(loid)s) is a challenging task. One promising approach is to use arbuscular mycorrhizal fungi (AMF) and investigate the physiological, molecular and epigenetic changes that occur in their presence and that lead to changes in plant metal(loid) concentration (biofortification of micronutrients or mitigation of contaminants). Moreover, it is important to understand these mechanisms in the context of the soil microbiome, particularly those interactions of AMF with other soil microbes that can further shape crop nutrition. To address these challenges, a two-pronged approach is recommended: exploring molecular mechanisms and investigating microbiome management and engineering. Combining both approaches can lead to benefits in human health by balancing nutrition and contamination caused by metal(loid)s in the agro-ecosystem.
View lessFirms struggle to respond to product recalls and achieve high recall effectiveness, i.e., the percentage of affected consumers who participate in corrective actions. We present the first comprehensive study of recall effectiveness that analyzes a broader set of product categories, identifies managerially relevant drivers, outlines boundary conditions, and demonstrates the underlying psychological processes. Specifically, three studies investigate the impact of remedy choice, incident likelihood, and their interaction with firm reputation on recall effectiveness. In Study 1 (unique secondary data set), we show that remedy choice and incident likelihood each interact with the firm’s reputation to influence recall effectiveness. In two subsequent experiments, we not only test the findings of the secondary data in a causal setting but also examine the underlying psychological process. We find that offering full remedy leads to higher recall effectiveness for high reputation firms and that recall effectiveness is higher for recalls with a high incident likelihood, but only for high reputation firms. In both cases, firms not only make consumers feel like they would benefit more from participating in the recall, but they also make them feel more comfortable in their ability to participate in the recall. These nuanced findings enable us to derive actionable guidelines for firms to increase recall effectiveness.
View lessIn social media effects research, the role of specific social media content is understudied, in part attributable to the fact that communication science previously lacked methods to access social media content directly. Digital trace data (DTD) can shed light on textual and audio-visual content of social media use and enable the analysis of content usage on a granular individual level that has been previously unavailable. However, because digital trace data are not specifically designed for research purposes, collection and analysis present several uncertainties. This article is a collaborative effort by scholars to provide an overview of how three methods of digital trace data collection - APIs, data donations, and tracking - can be used in studying the effects of social media content in three important topic areas of communication research: misinformation, algorithmic bias, and well-being. We address the question of how to collect raw social media content data and arrive at meaningful measures with multiple state-of-the-art data collection techniques that can be used to study the effects of social media use on different levels of detail. We conclude with a discussion of best practices for the implementation of each technique, and a comparison of their advantages and disadvantages.
View lessResearch suggests that people prefer human over algorithmic decision-makers at work. Most of these studies, however, use hypothetical scenarios and it is unclear whether such results replicate in more realistic contexts. We conducted two between-subjects studies (N=270; N=183) in which the decision-maker (human vs. algorithmic, Study 1 and 2), explanations regarding the decision- process (yes vs. no, Study 1 and 2), and the type of selection test (requiring human vs. mechanical skills for evaluation, Study 2) were manipulated. While Study 1 was based on a hypothetical scenario, participants in pre-registered Study 2 volunteered to participate in a qualifying session for an attractively remunerated product test, thus competing for real incentives. In both studies, participants in the human condition reported higher levels of trust and acceptance. Providing explanations also positively influenced trust, acceptance, and perceived transparency in Study 1, while it did not exert any effect in Study 2. Type of the selection test affected fairness ratings, with higher ratings for tests requiring human vs. mechanical skills for evaluation. Results show that algorithmic decision-making in personnel selection can negatively impact trust and acceptance both in studies with hypothetical scenarios as well as studies with real incentives.
View lessSchon Goethes Faust wusste, dass das, was »ihr den Geist der Zeiten heißt« vielmehr »der Herren eigene[n] Geist« darstellt. Nach linguistic turn und Diskursanalyse sind sich auch Historiker zeitgeistiger Einflüsse auf die Geschichtsschreibung bewusst geworden. Im Kontext der Wissenschaftsgeschichte altorientalistischer Forschung lässt sich eine Tendenz erkennen, zeitgeistige Einflüsse grundsätzlich einzugestehen, wobei dies aber nicht unbedingt zur (Neu-)Bewertung älterer Publikationen, sondern allenfalls zu deren ›Aussortierung‹ führt. Zeitgeist erscheint dabei als diffuser Begriff, mit dem vieles ›entschuldigt‹, aber wenig wirklich erklärt wird. Hinzu tritt das Phänomen der Instrumentalisierung von Vergangenheit zur Erklärung der eigenen gesellschaftspolitischen Gegenwart. Der Band will diesem historiographischen ›Framing‹ nachgehen und Darstellungen zur altägyptischen »Arbeiterbewegung«, dem »Königtum in Mesopotamien«, »Totaler Religion« in Amarna oder einer »sumerischen Renaissance« u.a. analysieren. Die Auseinandersetzung hiermit relativiert nicht den Wert altertumswissenschaftlicher Forschung, sondern leistet einen Beitrag zu dessen Aufrechterhaltung.
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