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Polycyclic aromatic hydrocarbons (PAHs) and their N- and O-containing derivatives (N-/O-PAHs) are environmental pollutants and synthetically attractive building blocks in pharmaceuticals. Functionalization of PAHs can be achieved via C-H activation by cytochrome P450 enzymes (e.g., P450 CYP3A4) in an environmentally friendly manner. Despite its broad substrate scope, the contribution of CYP3A4 to metabolize common PAHs in humans was found to be small. We recently showcased the potential of CYP3A4 in whole-cell biocatalysis with recombinant yeast Komagataella phaffii (Pichia pastoris) catalysts for the preparative-scale synthesis of naturally occurring metabolites in humans. In this study, we aimed at exploring the substrate scope of CYP3A4 towards (N-/O)-PAHs and conducted a bioconversion experiment at 10 L scale to validate the synthetic potential of CYP3A4 for the preparative-scale production of functionalized PAH metabolites. Hydroxylated products were purified and characterized using HPLC and NMR analysis. In total, 237 mg of fluorenol and 48 mg of fluorenone were produced from 498 mg of fluorene, with peak productivities of 27.7 μmol/L/h for fluorenol and 5.9 μmol/L/h for fluorenone; the latter confirmed that CYP3A4 is an excellent whole-cell biocatalyst for producing authentic human metabolites.

Functionalisation of polycyclic aromatic hydrocarbons (PAHs) and their N-heteroarene analogues (NPAHs) is a tedious synthetic endeavour that requires diverse bottom-up approaches. Cytochrome P450 enzymes of white-rot fungi were shown to participate in the fungal detoxification of xenobiotics and environmental hazards via hydroxylation of PAH compounds. In this paper, the recently discovered activity of the monooxygenase CYP5035S7 towards (N)PAHs was investigated in detail, and products formed from the substrates azulene, acenaphthene, fluorene, anthracene, and phenanthrene by whole-cell biocatalysis were isolated and characterised. The observed regioselectivity of CYP5035S7 could be explained by a combination of the substrate’s electron density and steric factors influencing the substrate orientation giving insight into the active-site geometry of the enzyme.

Sensory navigation results from coordinated transitions between distinct behavioral programs. During chemotaxis in the Drosophila melanogaster larva, the detection of positive odor gradients extends runs while negative gradients promote stops and turns. This algorithm represents a foundation for the control of sensory navigation across phyla. In the present work, we identified an olfactory descending neuron, PDM-DN, which plays a pivotal role in the organization of stops and turns in response to the detection of graded changes in odor concentrations. Artificial activation of this descending neuron induces deterministic stops followed by the initiation of turning maneuvers through head casts. Using electron microscopy, we reconstructed the main pathway that connects the PDM-DN neuron to the peripheral olfactory system and to the pre-motor circuit responsible for the actuation of forward peristalsis. Our results set the stage for a detailed mechanistic analysis of the sensorimotor conversion of graded olfactory inputs into action selection to perform goal-oriented navigation.

Many bacterial natural products contain C‐branched sugars, including components from the outer cell wall or antibiotically active metabolites. The enzymatic C‐branching of keto sugars leading to longer side chains (≥C2) is catalyzed by thiamine diphosphate (ThDP)‐dependent enzymes. Chiral tertiary α‐hydroxy ketones are formed in this process. The ThDP‐dependent enzymes that catalyze C‐branching reactions belong to one of three enzymatic superfamilies: decarboxylases, transketolases, and α‐ketoacid dehydrogenases 2, but branching of keto sugars has only been demonstrated for decarboxylases. In this study, we showed that an α‐ketoacid dehydrogenase is responsible for C‐branching of the deoxyketo sugar amycolose in the biosynthesis of kibdelomycin in Kibdelosporangium sp. MA7385. In addition, we characterized an amino transferase in the same biosynthetic gene cluster (BGC) that accepts a sterically demanding tertiary α‐hydroxy ketone in a downstream reaction. Subsequently, we identified approximately 400 similar BGCs in silico, suggesting that there is a large diversity of possible ThDP‐dependent enzymes catalyzing the C‐branching of keto sugars and subsequent modifications. [ABSTRACT FROM AUTHOR]

Sensory navigation results from coordinated transitions between distinct behavioral programs. During chemotaxis in the Drosophila melanogaster larva, the detection of positive odor gradients extends runs while negative gradients promote stops and turns. This algorithm represents a foundation for the control of sensory navigation across phyla. In the present work, we identified an olfactory descending neuron, PDM-DN, which plays a pivotal role in the organization of stops and turns in response to the detection of graded changes in odor concentrations. Artificial activation of this descending neuron induces deterministic stops followed by the initiation of turning maneuvers through head casts. Using electron microscopy, we reconstructed the main pathway that connects the PDM-DN neuron to the peripheral olfactory system and to the pre-motor circuit responsible for the actuation of forward peristalsis. Our results set the stage for a detailed mechanistic analysis of the sensorimotor conversion of graded olfactory inputs into action selection to perform goal-oriented navigation.

Since the late 2010s, the idea of phase-out planning for animal experimentation (PPAE) has come to the foreground of political debates, but central notions and arguments are understood differently by different participants and stand in need of clarification. This article draws on public communications on ten political projects related to PPAE to propose a philosophical explication of PPAE and to articulate the proponents' central moral argument. According to the argument, the phase-out of animal experimentation is morally desirable, and planned interventions are both necessary and sufficient to achieve it. The normative and descriptive premises of the argument are stated and discussed, flagging questions that need answering for a more thorough assessment of the argument. This results in a series of seven action points for researchers and stakeholders of PPAE. The overall goal is to enable an open and productive discussion about PPAE in public, political, and academic settings. [ABSTRACT FROM AUTHOR]

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The article aims to draw attention to the book Quale Europa cristiana? La continuità di una presenza (Which Christian Europe? The Continuity of a Presence) by Franco Buzzi, a Milanese theologian and renowned scholar of the Lutheran Reformation. It particularly focuses on Buzzi’s intention to explore the relationship between Western Europe and Christianity, not only regarding the developments stemming from the birth and spread of Luther’s Reformation but also concerning the critique of Luther’s thought and reformist work, which continues to characterise certain strands of Catholic historiography and theology. At the core of this critique lies a twofold conviction: that Luther is the instigator of the division of Christianity and Europe, and that he is the primary cause of the decline of European Christendom. The article explains why Buzzi considers these convictions to be entirely unfounded and unjust. Moreover, it demonstrates that his interpretative stance offers important insights, enabling further progress in exploring the theme of ‘Europe and Christianity’ and examining the interconnection between the unity of Europe and the unity of Christianity.

Abstract Background Constant organizational change is the norm in many companies today. At present, evidence on the impact of organizational change on psychosocial risks at work and employee mental health is limited. We investigate organizational change and its association with psychosocial risks and mental health in three consecutive surveys covering 12 years. Methods The study was based on data from three cross-sectional waves (2006, 2012, 2018) of the German BIBB/BAuA Employment Survey, comprising 53,295 employees. Four change indicators (i.e., introduction of new software, changes in goods and services produced/provided, downsizing and restructuring), five indicators of psychosocial risks (i.e., time pressure, interruptions, multitasking, working to the limits of capability, and working very quickly) and four mental health indicators (i.e., sleep disturbances, nervousness, tiredness and depressive symptoms) were investigated. We applied Poisson regression analysis to examine associations between organizational change, psychosocial risks, and mental health. Results According to the pooled analysis of all three waves, the majority of employees reported having experienced at least one organizational change, such as downsizing or restructuring, between 2006 and 2018. Organizational change was negatively associated with psychosocial risks (e.g., working to the limits of one’s capability, PR: 1.66; 95% CI: 1.48–1.86) and with employee mental health (PR: 1.82; 95% CI: 1.61–2.04). Conclusions Organizational change is omnipresent in the modern economy. Our research suggests that transformation processes in organizations can bear risks to employees’ health as psychosocial risks increase. Therefore, companies planning organizational change should accompany such processes with occupational health and safety measures.

Abstract Background Structural and behavioral interventions to manage work-related stress are effective in employees. Nonetheless, they have been implemented insufficiently, particularly in micro- and small-sized enterprises (MSE). Main barriers include a lack of knowledge and limited resources, which could potentially be overcome with simplified web-based alternatives for occupational stress prevention. However, there is a lack of implementation research about web-based prevention in realistic settings of MSE. Objective The aim of this study is to evaluate the implementation process and success of an integrated web-based platform for occupational stress prevention (“System P”) and to identify potential barriers for its uptake and use in MSE in Germany. Methods This study with a mixed-methods approach investigates eight process-related outcomes in a quantitative part I (adoption, reach, penetration, fidelity/dose, costs, acceptability) and a qualitative part II (acceptability, appropriateness and feasibility). Part I has a pre-post design with two measurements (6 months apart) with 98 individual participants and part II consists of 12 semi-structured interviews with managers and intercorporate stakeholders. Results Part I revealed shortcomings in the implementation process. Adoption/Reach: Despite extensive marketing efforts, less than 1% of the contacted MSE responded to the offer of System P. A total of 40 MSE registered, 24 of which, characterized by good psychosocial safety climate, adopted System P. Penetration: Within these 24 MSE, 15% of the employees used the system. Fidelity/Dose: 11 MSE started a psychosocial risk-assessment (PRA), and no MSE finished it. The stress-management training (SMT) was started by 25 users and completed by 8. Costs: The use of System P was free of charge, but the time required to engage with was an indirect cost. Part II added insights on the perception of the web-based intervention: Acceptance of System P by users and stakeholders was good and it was assessed as appropriate for MSE. Results for feasibility were mixed. Conclusions Although System P was generally perceived as useful and appropriate, only a small number of contacted MSE implemented it as intended. Prior experience and sensitivity for occupational (stress) prevention were mentioned as key facilitators, while (perceived) indirect costs were a key barrier. Enabling MSE to independently manage stress prevention online did not result in successful implementation. Increasing external support could be a solution. ⁺ Full project name “PragmatiKK – Pragmatische Lösungen für die Implementation von Maßnahmen zur Stressprävention in Kleinst- und Kleinbetrieben” (= Pragmatic solutions for the implementation of stress prevention interventions in micro and small-sized enterprises). Trial registration German Register of Clinical Studies (DRKS) DRKS00026154, date of registration 2021-09-16.

CRISPR–Cas technologies contribute to enhancing our understanding of plant gene functions, and to the precise breeding of crop traits. Here, we review the latest progress in plant genome editing, focusing on emerging CRISPR–Cas systems, DNA-free delivery methods, and advanced editing approaches. By illustrating CRISPR–Cas applications for improving crop performance and food quality, we highlight the potential of genome-edited crops to contribute to sustainable agriculture and food security.

Abstract Purpose The purpose of this study was to explore the role of self-directed ageism in the relationship between frailty and quality of life in community-dwelling older adults. Methods Secondary data-analysis on data from the Belgian Ageing Studies. A stratified sample of 1895 participants, based on census data by gender and age, was drawn between 2017 and 2019. Frailty, quality of life and self-directed ageism were assessed by the Comprehensive Frailty Assessment Instrument, a numeric rating scale and a newly developed self-directed ageism scale, respectively. The validity of this new scale was assessed by exploratory factor analysis, while mediation analysis was used to explore if self-directed ageism mediates the relationship between frailty and quality of life. Results The self-directed ageism scale proved highly reliable (Cronbach’s α = 0.898, Spearman-Brown = 0.906), explaining 58.86% of the variance in self-directed ageism. Respondents scored an average of 23.6 on 40 for self-directed ageism, 26.94 on 100 for frailty, and a median of 8 on 10 for quality of life. Mediation analysis showed that frailty negatively correlates with quality of life, and that this relationship is partially mediated by self-directed ageism. Conclusion Most respondents were identified as mild frail, experienced self-directed ageism, and those 80 or older rated their quality of life lower. The present study showed that frailty negatively correlates with quality of life and this relationship is partially mediated by self-directed ageism. We conclude that every effort should be made to prevent frailty, ageism and self-directed ageism as they impact community-dwelling older people’s quality of life.

Abstract Background Besides macrolevel characteristics of a health care system, mesolevel access characteristics can exert influence on socioeconomic inequalities in healthcare use. These reflect access to healthcare, which is shaped on a smaller scale than the national level, by the institutions and establishments of a health system that individuals interact with on a regular basis. This scoping review maps the existing evidence about the influence of mesolevel access characteristics and socioeconomic position on healthcare use. Furthermore, it summarizes the evidence on the interaction between mesolevel access characteristics and socioeconomic inequalities in healthcare use. Methods We used the databases MEDLINE (PubMed), Web of Science, Scopus, and PsycINFO and followed the ‘Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols extension for scoping reviews (PRISMA-ScR)’ recommendations. The included quantitative studies used a measure of socioeconomic position, a mesolevel access characteristic, and a measure of individual healthcare utilisation. Studies published between 2000 and 2020 in high income countries were considered. Results Of the 9501 potentially eligible manuscripts, 158 studies were included after a two-stage screening process. The included studies contained a wide spectrum of outcomes and were thus summarised to the overarching categories: use of preventive services, use of curative services, and potentially avoidable service use. Exemplary outcomes were screening uptake, physician visits and avoidable hospitalisations. Access variables included healthcare system characteristics such as physician density or distance to physician. The effects of socioeconomic position on healthcare use as well as of mesolevel access characteristics were investigated by most studies. The results show that socioeconomic and access factors play a crucial role in healthcare use. However, the interaction between socioeconomic position and mesolevel access characteristics is addressed in only few studies. Conclusions Socioeconomic position and mesolevel access characteristics are important when examining variation in healthcare use. Additionally, studies provide initial evidence that moderation effects exist between the two factors, although research on this topic is sparse. Further research is needed to investigate whether adapting access characteristics at the mesolevel can reduce socioeconomic inequity in health care use.

Abstract Background In Germany, various preventive services are offered to children and adolescents. These include regular standardized examinations (so called U/J examinations) and several vaccinations. Although strongly recommended, most of them are not mandatory. Our aim is to identify factors associated with the use of U/J examinations and vaccination against diphtheria, hepatitis B, Hib, pertussis, polio, and tetanus. While previous research has focused on sociodemographic factors, we also include socioeconomic, behavioral, and psychosocial factors. Methods We analyzed cross-sectional data from 15,023 participants (aged 0–17 years) of the nationwide representative KiGGS Wave 2 Survey. Participation in U/J examinations was assessed using a questionnaire, filled out by participants and/or their parents. Information on vaccination status was drawn from the participants’ vaccination booklets. To identify relevant determinants for the use of preventive examinations and vaccinations, unadjusted and adjusted logistic regression models were employed with up to 16 different independent variables. Results Various independent variables showed an association with the use of preventive services. Higher socioeconomic status, absence of migration background, and lower household size were associated with significantly higher utilization of U examinations. Parents’ marital status, area of residence, behavioral and psychosocial factors yielded insignificant results for most U/J examinations. Higher vaccination rates were found for children with no migration background, with residence in eastern Germany, lower household size, and with married parents. Conclusion This study attempted to depict the influence of sociodemographic, psychosocial, and behavioral factors on the use of several preventive services. Our results indicate that predominantly sociodemographic variables influence the use of preventive services. Further efforts should be made to investigate the interplay of different determinants of healthcare use in children and adolescents.

Equivalent circuit models represent one of the most efficient virtual representations of battery systems, with numerous applications supporting the design of electric vehicles, such as powertrain evaluation, power electronics development, and model-based state estimation. Due to their popularity, their parameter extraction and model parametrization procedures present high interest within the research community, with novel approaches at an elementary level still being identified. This article introduces and compares in detail two novel parameter extraction methods based on the distinct application of least squares linear regression in relation to the autoregressive exogenous as well as the state-space equations of the double polarization equivalent circuit model in an iterative optimization-type manner. Following their application using experimental data obtained from an NCA Sony VTC6 cell, the results are benchmarked against a method employing differential evolution. The results indicate the least squares linear regression applied to the state-space format of the model as the best overall solution, providing excellent accuracy similar to the results of differential evolution, but averaging only 1.32% of the computational cost. In contrast, the same linear solver applied to the autoregressive exogenous format proves complementary characteristics by being the fastest process but presenting a penalty over the accuracy of the results.