Biology subjects

Bernauer, T.

Publications and source records attributed to Bernauer, T..

3 recordsLinked to original sources

bioRxiv2025

Monitoring Urban Air Pollution in the Global South: Large Gaps Associated with Economic Conditions and Political Institutions

Ambient air pollution has highly adverse effects on public health and the environment, particularly in urban areas of the Global South. Systematic air quality monitoring (AQM) is a precondition for effective policies to mitigate this problem, and making AQM data publicly available also signals commitment to take action. Thus far, little is known about the global capacity for public AQM, and how it varies across geographic location, pollution exposure, and socio-economic characteristics. We thus constructed a novel, geocoded dataset on AQM behavior in more than ten thousand urban areas of low to middle-income countries. In almost 90% of these urban areas, we are unable to identify any monitoring activity, and the form and extent of AQM in the remaining 10% varies greatly. Income levels and characteristics of political institutions (democracy) turn out to be key drivers of variation in AQM activity, with urban areas in more democratic countries more likely to respond with more AQM to high air pollution levels. The evidence provided here can serve as a wake-up call for public authorities, international institutions, and civil society stakeholders to invest far more than hitherto the case into AQM, particularly in under-monitored, less affluent, and less democratic settings. HighlightsO_LIAmbient air pollution has highly adverse effects on public health and the environment, particularly in urban areas of lower income countries. C_LIO_LISystematic air quality monitoring (AQM) is a precondition for effective clean air policies. C_LIO_LILittle is known about the global capacity for public AQM, and how it varies across geographic location, pollution exposure, and socio-economic conditions. C_LIO_LIWe address this gap based on a novel, geocoded dataset on AQM behavior in more than 10000 urban areas of lower income countries. C_LIO_LIIn almost 90% of these urban areas, we are unable to identify any monitoring activity. C_LIO_LIIncome levels and characteristics of political institutions (democracy) turn out to be key drivers of variation in AQM activity. C_LIO_LIUrban areas in more democratic countries are more likely to respond with more AQM to high air pollution levels. C_LIO_LIMajor efforts are required to improve AQM, particularly in under-monitored, less affluent, and less democratic settings. C_LI

ecology↗

bioRxiv2024

Synthesis and Biological Evaluation of Novel MB327 Analogs as Resensitizers for Desensitized Nicotinic Acetylcholine Receptors after Intoxication with Nerve Agents

Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising 4-aminopyridinium ion-substituted MB327 analogs (PTM0056, PTM0062 and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new 4-aminopyridinium ion-substituted analogs of the aforementioned compounds (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90-0012 and PTMD90-0015) designed to substitute energetically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research.

pharmacology and toxicology↗

bioRxiv2023

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Desensitization of nicotinic acetylcholine receptors (nAChRs) can be induced by overstimulation with acetylcholine (ACh) caused by an insufficient degradation of ACh after poisoning with organophosphorus compounds (OPCs). Currently, there is no generally applicable treatment for OPC poisoning that directly targets the desensitized nAChR. The bispyridinium compound MB327, an allosteric modulator of nAChR, has been shown to act as a resensitizer of nAChRs, indicating that drugs binding directly to nAChRs can have beneficial effects after OPC poisoning. However, MB327 also acts as an inhibitor of nAChRs at higher concentrations and can thus not be used for OPC poisoning treatment. Consequently, novel, more potent resensitizers are required. To successfully design novel ligands, the knowledge of the binding site is of utmost importance. Recently, we performed in silico studies to identify a new potential binding site of MB327, MB327-PAM-1, for which a more affine ligand, UNC0646, has been described. In this work, we performed ligand-based screening approaches to identify novel analogs of UNC0646 to help further understand the structure-affinity relationship of this compound class. Furthermore, we used structure-based screenings and identified compounds representing four new chemotypes binding to MB327-PAM-1. One of these compounds, cycloguanil, is the active metabolite of the antimalaria drug proguanil and shows a higher affinity towards MB327-PAM-1 than MB327. Furthermore, cycloguanil can reestablish the muscle force in soman-inhibited rat muscles. These results can act as a starting point to develop more potent resensitizers of nAChR and to close the gap in the treatment after OPC poisoning.

pharmacology and toxicology↗