Combined stress of an insecticide and heatwaves or elevated temperature induce community and food web effects in a Mediterranean freshwater ecosystem.

Ongoing global climate change will shift nature towards Anthropocene's unprecedented conditions by increasing average temperatures and the frequency and severity of extreme events, such as heatwaves. While such climatic changes pose an increased threat for freshwater ecosystems, other stressors like pesticides may interact with warming and lead to unpredictable effects. Studies that examine the underpinned mechanisms of multiple stressor effects are scarce and often lack environmental realism. Here, we conducted a multiple stressors experiment using outdoor freshwater mesocosms with natural assemblages of macroinvertebrates, zooplankton, phytoplankton, macrophytes, and microbes. The effects of the neonicotinoid insecticide imidacloprid (1 µg/L) were investigated in combination with three temperature scenarios representing ambient, elevated temperatures (+4 °C), and heatwaves (+0 to 8 °C), the latter two having similar energy input. We found similar imidacloprid dissipation patterns for all temperature treatments with lowest average dissipation half-lives under both warming scenarios (DT50: 3 days) and highest under ambient temperatures (DT50: 4 days) throughout the experiment. Amongst all communities, only the zooplankton community was significantly affected by the combined treatments. This community demonstrated low chemical sensitivity with lagged and significant negative imidacloprid effects only for cyclopoids. Heatwaves caused early and long-lasting significant effects on the zooplankton community as compared to elevated temperatures, with Polyarthra, Daphnia longispina, Lecanidae, and cyclopoids being the most negatively affected taxa, whereas Ceriodaphnia and nauplii showed positive responses to temperature. Community recovery from imidacloprid stress was slower under heatwaves, suggesting temperature-enhanced toxicity. Finally, microbial and macrofauna litter degradation were significantly enhanced by temperature, whereas the latter was also negatively affected by imidacloprid. A structural equation model depicted cascading food web effects of both stressors with stronger relationships and significant negative stressor effects at higher than at lower trophic levels. Our study highlights the threat of a series of heatwaves compared to elevated temperatures for imidacloprid-stressed freshwaters.

Alterations in trimethylamine-N-oxide in response to Empagliflozin therapy: a secondary analysis of the EMMY trial.

INTRODUCTION: The relationship between sodium glucose co-transporter 2 inhibitors (SGLT2i) and trimethylamine N-oxide (TMAO) following acute myocardial infarction (AMI) is not yet explored. METHODS: In this secondary analysis of the EMMY trial (ClinicalTrials.gov registration: NCT03087773), changes in serum TMAO levels were investigated in response to 26-week Empagliflozin treatment following an AMI compared to the standard post-MI treatment. Additionally, the association of TMAO changes with clinical risk factors and cardiorenal biomarkers was assessed. RESULTS: The mean age of patients (N = 367) was 57 ± 9 years, 82% were males, and 14% had type 2 diabetes. In the Empagliflozin group, the median TMAO value was 2.62 µmol/L (IQR: 1.81) at baseline, 3.74 µmol/L (2.81) at 6 weeks, and 4.20 µmol/L (3.14) at 26 weeks. In the placebo group, the median TMAO value was 2.90 µmol/L (2.17) at baseline, 3.23 µmol/L (1.90) at 6 weeks, and 3.35 µmol/L (2.50) at 26 weeks. The serum TMAO levels increased significantly from baseline to week 6 (coefficient: 0.233; 95% confidence interval 0.149-0.317, p < 0.001) and week 26 (0.320, 0.236-0.405, p < 0.001). The average increase in TMAO levels over time (pinteraction = 0.007) was significantly higher in the Empagliflozin compared to the Placebo group. Age was positively associated with TMAO, whereas eGFR and LVEF were negatively associated with TMAO. CONCLUSIONS: Our results are contrary to existing experimental studies that showed the positive impact of SGLT2i on TMAO precursors and cardiovascular events. Therefore, we recommend further research investigating the impact of SGLT2i therapy on acute and long-term changes in TMAO in cardiovascular cohorts.

Heatwaves, elevated temperatures, and a pesticide cause interactive effects on multi-trophic levels of a freshwater ecosystem.

Climate impacts of elevated temperatures and more severe and frequent weather extremes like heatwaves are globally becoming discernible on nature. While a mechanistic understanding is pivotal for ecosystem management, stressors like pesticides may interact with warming, leading to unpredictable effects on freshwater ecosystems. These multiple stressor studies are scarce and experimental designs often lack environmental realism. To investigate the multiple stressor effects, we conducted a microcosm experiment for 48 days comprising benthic macroinvertebrates, zooplankton, phytoplankton, macrophytes, and microbes. The fungicide carbendazim (100 µg/L) was investigated combined with temperature scenarios representing elevated temperatures (+4 °C) or heatwaves (+0 to +8 °C), both applied with similar energy input on a daily fluctuating ambient temperature (18 °C ± 1.5 °C), which served as control. Measurements showed the highest carbendazim dissipation in water under heatwaves followed by elevated and ambient temperatures. Average carbendazim concentrations were about 50% in water and 16% in sediment of the nominal concentration. In both heated cosms, zooplankton community dynamics revealed an unexpected shift from Rotifera to Cladocera and Copepoda nauplii, indicating variations in their thermal sensitivity, tolerance and resilience. Notably, warming and heatwaves shaped community responses similarly, suggesting heat intensity rather than distribution patterns determined the community structure. Heatwaves led to significant early and longer-lasting adverse effects that were exacerbated over time with Cladocera and Copepoda being most sensitive likely due to significant carbendazim interactions. Finally, a structural equation model demonstrated significant relationships between zooplankton and macrophytes and significantly negative carbendazim effects on zooplankton, whereas positive on macroinvertebrate abundances. The relationship between macroinvertebrate feeding and abundance was masked by significantly temperature-affected microbial leaf litter decomposition. Despite the thermal tolerance of zooplankton communities, our study highlights an increased pesticide threat under temperature extremes. More intense heatwaves are thus likely to cause significant alterations in community assemblages which will adversely affect ecosystem's processes and functions.

BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides.

We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity of the warhead. This study shows how three different in silico methods can predict the in vitro properties of propynamides, a covalent warhead class integrated into approved drugs on the market. Whereas the electrophilicity index is only applicable to individual subclasses of substitutions, adduct formation and transition state energies have a good predictability for the in vitro reactivity with glutathione (GSH). In summary, the reported methods are well suited to estimate the reactivity of propynamides. With this knowledge, the fine tuning of the reactivity is possible which leads to a speed up of the design process of covalent drugs.

Impacts of extreme climatic events on trophic network complexity and multidimensional stability.

Untangling the relationship between network complexity and ecological stability under climate change is an arduous challenge for theoretical and empirical ecology. Even more so, when considering extreme climatic events. Here, we studied the effects of extreme climatic events (heatwaves) on the complexity of realistic freshwater ecosystems using topological and quantitative trophic network metrics. Next, we linked changes in network complexity with the investigation of four stability components (temporal stability, resistance, resilience, and recovery) of community's functional, compositional, and energy flux stability. We found reduction in topological network complexity to be correlated with reduction of functional and compositional resistance. However, temperature-driven increase in link-weighted network complexity increased functional and energy flux recovery and resilience, but at the cost of increased compositional instability. Overall, we propose an overarching approach to elucidate the effects of climate change on multidimensional stability through the lens of network complexity, providing helpful insights for preserving ecosystems stability under climate change.

A transportable temperature and heatwave control device (TENTACLE) for laboratory and field simulations of different climate change scenarios in aquatic micro- and mesocosms.

Future global climate change with higher mean temperatures and increased intensity and frequency of heatwaves as extreme weather events will affect aquatic ecosystems with, yet, unpredictable severity and consequences. Although models suggest increased risk of species extinction up to the year 2050 for series of different climate change scenarios, environmental complexity may result in unconsidered effects of future temperature alterations on ecosystems. Apart from these environmental changes, additional anthropogenic stressors, e.g. chemical release, may cause unprecedented interaction effects on ecosystems. Ongoing efforts to better understand such temperature-chemical interaction effects comprise almost exclusively experimental designs using constant temperature regimes instead of environmentally realistic daily temperature variations. In this paper we describe an Arduino-based temperature and heatwave control device (TENTACLE) that is transportable, inexpensive, multifunctional, and easily reproducible. TENTACLE offers water temperature monitoring and manipulation of up to 3 different climate change-related scenarios: i) natural (ambient) sinusoidal fluctuations (laboratory applications), ii) elevated fluctuations, and iii) heatwaves as extreme events. The use of replaceable heating elements and low-cost materials suitable for field studies creates a high flexibility for researchers who may conduct in- or out-door, small- or large-scale, fresh- or salt-water experiments at different geographical locations.

Combined effects of heatwaves and micropollutants on freshwater ecosystems: Towards an integrated assessment of extreme events in multiple stressors research.

Freshwater ecosystems are strongly influenced by weather extremes such as heatwaves (HWs), which are predicted to increase in frequency and magnitude in the future. In addition to these climate extremes, the freshwater realm is impacted by the exposure to various classes of chemicals emitted by anthropogenic activities. Currently, there is limited knowledge on how the combined exposure to HWs and chemicals affects the structure and functioning of freshwater ecosystems. Here, we review the available literature describing the single and combined effects of HWs and chemicals on different levels of biological organization, to obtain a holistic view of their potential interactive effects. We only found a few studies (13 out of the 61 studies included in this review) that investigated the biological effects of HWs in combination with chemical pollution. The reported interactive effects of HWs and chemicals varied largely not only within the different trophic levels but also depending on the studied endpoints for populations or individuals. Hence, owing also to the little number of studies available, no consistent interactive effects could be highlighted at any level of biological organization. Moreover, we found an imbalance towards single species and population experiments, with only five studies using a multitrophic approach. This results in a knowledge gap for relevant community and ecosystem level endpoints, which prevents the exploration of important indirect effects that can compromise food web stability. Moreover, this knowledge gap impairs the validity of chemical risk assessments and our ability to protect ecosystems. Finally, we highlight the urgency of integrating extreme events into multiple stressors studies and provide specific recommendations to guide further experimental research in this regard.

ECORISK2050: An Innovative Training Network for predicting the effects of global change on the emission, fate, effects, and risks of chemicals in aquatic ecosystems.

By 2050, the global population is predicted to reach nine billion, with almost three quarters living in cities. The road to 2050 will be marked by changes in land use, climate, and the management of water and food across the world. These global changes (GCs) will likely affect the emissions, transport, and fate of chemicals, and thus the exposure of the natural environment to chemicals. ECORISK2050 is a Marie Sklodowska-Curie Innovative Training Network that brings together an interdisciplinary consortium of academic, industry and governmental partners to deliver a new generation of scientists, with the skills required to study and manage the effects of GCs on chemical risks to the aquatic environment. The research and training goals are to: (1) assess how inputs and behaviour of chemicals from agriculture and urban environments are affected by different environmental conditions, and how different GC scenarios will drive changes in chemical risks to human and ecosystem health; (2) identify short-to-medium term adaptation and mitigation strategies, to abate unacceptable increases to risks, and (3) develop tools for use by industry and policymakers for the assessment and management of the impacts of GC-related drivers on chemical risks. This project will deliver the next generation of scientists, consultants, and industry and governmental decision-makers who have the knowledge and skillsets required to address the changing pressures associated with chemicals emitted by agricultural and urban activities, on aquatic systems on the path to 2050 and beyond.

Covalent inhibitor reactivity prediction by the electrophilicity index-in and out of scope.

Drug discovery is an expensive and time-consuming process. To make this process more efficient quantum chemistry methods can be employed. The electrophilicity index is one property that can be calculated by quantum chemistry methods, and if calculated correctly gives insight into the reactivity of covalent inhibitors. Herein we present the usage of the electrophilicity index on three common warheads, i.e., acrylamides, 2-chloroacetamides, and propargylamides. We thoroughly examine the properties of the electrophilicity index, show which pitfalls should be avoided, and what the requirements to successfully apply the electrophilicity index are.

Observing the Structural Evolution in the Photodissociation of Diiodomethane with Femtosecond Solution X-Ray Scattering.

Resolving the structural dynamics of the initial steps of chemical reactions is challenging. We report the femtosecond time-resolved wide-angle x-ray scattering of the photodissociation of diiodomethane in cyclohexane. The data reveal with structural detail how the molecule dissociates into radicals, how the radicals collide with the solvent, and how they form the photoisomer. We extract how translational and rotational kinetic energy is dispersed into the solvent. We also find that 85% of the primary radical pairs are confined to their original solvent cage and discuss how this influences the downstream recombination reactions.

BIreactive: A Machine-Learning Model to Estimate Covalent Warhead Reactivity.

In the past decade, the pharmaceutical industry has paid closer attention to covalent drugs. Differently from standard noncovalent drugs, these compounds can exhibit peculiar properties, such as higher potency or longer duration of target inhibition with a potentially lower dosage. These properties are mainly driven by the reactive functional group present in the compound, the so-called warhead that forms a covalent bond with a specific nucleophilic amino-acid on the target. In this work, we report the possibility to combine ab initio activation energies with machine-learning to estimate covalent compound intrinsic reactivity. The idea behind this approach is to have a precise estimation of the transition state barriers, and thus of the compound reactivity, but with the speed of a machine-learning algorithm. We call this method "BIreactive". Here, we demonstrate this approach on acrylamides and 2-chloroacetamides, two warhead classes that possess different reaction mechanisms. In combination with our recently implemented truncation algorithm, we also demonstrate the possibility to use BIreactive not only for fragments but also for lead-like molecules. The generic nature of this approach allows also the extension to several other warheads. The combination of these factors makes BIreactive a valuable tool for the covalent drug discovery process in a pharmaceutical context.

Small-Angle X-ray Scattering Curves of Detergent Micelles: Effects of Asymmetry, Shape Fluctuations, Disorder, and Atomic Details.

Small-angle X-ray scattering (SAXS) is a widely used experimental technique, providing structural and dynamic insight into soft-matter complexes and biomolecules under near-native conditions. However, interpreting the one-dimensional scattering profiles in terms of three-dimensional structures and ensembles remains challenging, partly because it is poorly understood how structural information is encoded along the measured scattering angle. We combined all-atom SAXS-restrained ensemble simulations, simplified continuum models, and SAXS experiments of a n-dodecyl-ß-d-maltoside (DDM) micelle to decipher the effects of model asymmetry, shape fluctuations, atomic disorder, and atomic details on SAXS curves. Upon interpreting the small-angle regime, we find remarkable agreement between (i) a two-component triaxial ellipsoid model fitted against the data and (ii) a SAXS-refined all-atom ensemble. However, continuum models fail at wider angles, even if they account for shape fluctuations, disorder, and asymmetry of the micelle. We conclude that modeling atomic details is mandatory for explaining SAXS curves at wider angles.

Interpreting SAXS/WAXS Data with Explicit-Solvent Simulations: A Practical Guide.

Small- and wide-angle X-ray scattering (SAXS/WAXS/SWAXS) have evolved to be accurate tools used to gain structural information of biomolecules in solution. However, the interpretation of SWAXS data remains challenging owing to the low information content of the data and scattering contributions from the solvent. In recent years, methods for the interpretation of SWAXS data based on explicit-solvent molecular dynamics (MD) simulations have become increasingly popular. The physicochemical information in the MD force fields complements the low-information SWAXS data, thereby greatly reducing the risk of overfitting, and the explicit-solvent models may accurately account for scattering contributions from the solvent. In this chapter, we provide a practical introduction to MD-based methods for the interpretation of SWAXS data. First, we present the back-calculation of a SWAXS curve from an MD trajectory as required to validate an MD simulation against experimental SWAXS data. Second, we present the structure refinement of an atomic model against SWAXS data using SAXS-driven MD simulations. Common technical problems together with appropriate solutions are discussed.

Intercomparison of in-situ aircraft and satellite aerosol measurements in the stratosphere.

Aerosol composition and optical scattering from particles in the lowermost stratosphere (LMS) have been studied by comparing in-situ aerosol samples from the IAGOS-CARIBIC passenger aircraft with vertical profiles of aerosol backscattering obtained from the CALIOP lidar aboard the CALIPSO satellite. Concentrations of the dominating fractions of the stratospheric aerosol, being sulphur and carbon, have been obtained from post-flight analysis of IAGOS-CARIBIC aerosol samples. This information together with literature data on black carbon concentrations were used to calculate the aerosol backscattering which subsequently is compared with measurements by CALIOP. Vertical optical profiles were taken in an altitude range of several kilometres from and above the northern hemispheric extratropical tropopause for the years 2006-2014. We find that the two vastly different measurement platforms yield different aerosol backscattering, especially close to the tropopause where the influence from tropospheric aerosol is strong. The best agreement is found when the LMS is affected by volcanism, i.e., at elevated aerosol loadings. At background conditions, best agreement is obtained some distance (>2 km) above the tropopause in winter and spring, i.e., at likewise elevated aerosol loadings from subsiding aerosol-rich stratospheric air. This is to our knowledge the first time the CALIPSO lidar measurements have been compared to in-situ long-term aerosol measurements.

SAXS-Restrained Ensemble Simulations of Intrinsically Disordered Proteins with Commitment to the Principle of Maximum Entropy.

Intrinsically disordered proteins (IDPs) play key roles in biology and disease, rationalizing the wide interest in deriving accurate solution ensembles of IDPs. Molecular dynamics (MD) simulations of IDPs often suffer from force-field inaccuracies, suggesting that simulations must be complemented by experimental data to obtain physically correct ensembles. We present a method for integrating small-angle X-ray scattering (SAXS) data on-the-fly into MD simulations of disordered systems, with the aim to bias the conformational sampling toward agreement with ensemble-averaged SAXS data. By coupling a set of parallel replicas to the data and following the principle of maximum entropy, this method applies only a minimal bias. Using the RS peptide as a test case, we analyze the influence of (i) the number of parallel replicas, (ii) the scaling of the force constant for the SAXS-derived biasing energy with the number of parallel replicas, and (iii) the force field. The refined ensembles are cross-validated against experimental 3JHN-Hα couplings and further compared in terms of Cα distance maps and secondary structure content. Remarkably, we find that the applied force field only has a small influence on the SAXS-refined ensemble, suggesting that incorporating SAXS data into MD simulations may greatly reduce the force-field bias.

A novel method for assessing microplastic effect in suspension through mixing test and reference materials.

The occurrence of microplastic in the environment is of global concern. However, the microplastic hazard assessment is hampered by a lack of adequate ecotoxicological methods because of conceptual and practical problems with particle exposure. In the environment, suspended solids (e.g., clay and cellulose) in the same size range as microplastic, are ubiquitous. Therefore, it must be established whether the addition of microplastic to these background levels of particulate material represents a hazard. We present a novel approach employing a serial dilution of microplastic and reference particles, in mixtures, which allows disentangling the effect of the microplastic from that of the other particulates. We demonstrate the applicability of the method using an immobilization test with Daphnia magna exposed to polyethylene terephthalate (test microplastic; median particle diameter ~5 µm) and kaolin clay (reference material; ~3 µm). In the range of the suspended solids test concentrations (0-10 000 mg L-1), with microplastic contributing 0-100% of total mass, the LC50 values for the plastic mixtures were significantly lower compared to the kaolin exposure. Hence, the exposure to polyethylene terephthalate was more harmful to the daphnids than to the reference material alone. The estimated threshold for the relative contribution of the test microplastic to suspended matter above which significantly higher mortality was observed was 2.4% at 32 mg of the solids L-1. This approach has a potential for standardization of ecotoxicological testing of particulates, including microplastic.

Strong impact of wildfires on the abundance and aging of black carbon in the lowermost stratosphere.

Wildfires inject large amounts of black carbon (BC) particles into the atmosphere, which can reach the lowermost stratosphere (LMS) and cause strong radiative forcing. During a 14-month period of observations on board a passenger aircraft flying between Europe and North America, we found frequent and widespread biomass burning (BB) plumes, influencing 16 of 160 flight hours in the LMS. The average BC mass concentrations in these plumes (∼140 ng·m-3, standard temperature and pressure) were over 20 times higher than the background concentration (∼6 ng·m-3) with more than 100-fold enhanced peak values (up to ∼720 ng·m-3). In the LMS, nearly all BC particles were covered with a thick coating. The average mass equivalent diameter of the BC particle cores was ∼120 nm with a mean coating thickness of ∼150 nm in the BB plume and ∼90 nm with a coating of ∼125 nm in the background. In a BB plume that was encountered twice, we also found a high diameter growth rate of ∼1 nm·h-1 due to the BC particle coatings. The observed high concentrations and thick coatings of BC particles demonstrate that wildfires can induce strong local heating in the LMS and may have a significant influence on the regional radiative forcing of climate.

In vivo dosimetry with alanine/electron spin resonance dosimetry to evaluate the urethra dose during high-dose-rate brachytherapy.

PURPOSE: To determine the dose of the urethra during Ir-192 high-dose-rate brachytherapy in 15 patients, a new detector form developed for in vivo measurements was used as described by Anton et al. 2009. METHODS AND MATERIALS: The detector consists of alanine powder with paraffin as binder which was filled in a shrinkable tube for measurements. The alanine strand so produced was inserted in the foley catheter during high-dose-rate brachytherapy of the prostate. The measured dose was compared with the dose calculated by the treatment planning system SWIFT for 15 patients. After 8 patients, a marker was introduced for better positioning of the alanine strand using transrectal ultrasound images. RESULTS: The measurements of the dose of the urethra agreed very well with the dose calculated by SWIFT within the estimated standard uncertainty of the method for 8 patients with a mean absolute deviation of 0.08 Gy. However, for the other 7 patients, a mean absolute deviation between delivered and measured dose of -5.13 Gy was seen. For these patients, the active volume of the alanine dosimeter could not properly be reconstructed on the ultrasound images. CONCLUSION: The method presented in this study is useful for quality control of irradiations in vivo. To reconstruct the active volume on the corresponding ultrasound images, the correct application of the alanine strand in the urethra is very important. This procedure needs a well-trained physician.

Carbones as Ligands in Novel Main-Group Compounds E[C(NHC)2 ]2 (E=Be, B+ , C2+ , N3+ , Mg, Al+ , Si2+ , P3+ ): A Theoretical Study.

Quantum chemical calculations of the main-group compounds E[C(NHCMe )2 ]2 (E=Be, B+ , C2+ , N3+ , Mg, Al+ , Si2+ , P3+ ) have been carried out using density functional theory at the BP86/def2-TZVPP and BP86-D3(BJ)/def2-TZVPP levels of theory. The geometry optimization at BP86/def2-TZVPP gives equilibrium structures with two-coordinated species E and bending angles C-E-C between 152.5° (E=Be) and 110.5° (E=Al). Inclusion of dispersion forces at BP86-D3(BJ)/def2-TZVPP yields a three-coordinated beryllium compound Be[C(NHCMe )2 ]2 as the only energy minimum form. Three-coordinated isomers are found besides the two-coordinated energy minima for the boron and carbon cations B[C(NHCMe )2 ]2+ and C[C(NHCMe )2 ]22+ . The three-coordinated form of the boron compound is energetically lower lying than the two-coordinated form, while the opposite trend is calculated for the carbon species. The theoretically predicted bond dissociation energies suggest that all compounds are viable species for experimental studies. The X-ray structure of the benzoannelated homologue of P[C(NHCMe )2 ]23+ that was recently reported by Dordevic et al. agrees quite well with the calculated geometry of the molecule. A detailed bonding analysis using charge and energy decomposition methods shows that the two-coordinated neutral compounds Be[C(NHCMe )2 ]2 and Mg[C(NHCMe )2 ]2 possess strongly positively charged atoms Be and Mg. The carbodicarbene groups C(NHCMe )2 serve as acceptor ligands in the compounds and may be sketched with dative bonds (NHCMe )2 C←E→C(NHCMe )2 (E=Be, Mg). Dative bonds in which the carbones C(NHCMe )2 are donor ligands are suggested for the cations (NHCMe )2 C→E←C(NHCMe )2 (E=B+ , Al+ ). The dications and trications possess electron-sharing bonds in which the bonding situation is best described with the formula [(NHCMe )2 C]+ -E-[C(NHCMe )2 ]+ (E=C, Si, N+ , P+ ).