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.

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.

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.

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.

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.

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+ ).

Donor-acceptor bonding in novel low-coordinated compounds of boron and group-14 atoms C-Sn.

A summary of theoretical and experimental work in the area of low-coordinated compounds of boron and group-14 atoms C-Sn in the last decade is presented. The focus of the account lies on molecules EL2, E2L2 and E3L3, which possess dative bonds between one, two or three atoms E and σ-donor ligands L that stabilize the atoms E through L→E donor-acceptor interactions. The interplay between theory and experiment provides detailed insight into the bonding situation of the molecules, which serves as guideline for the synthesis of molecules that possess unusual bonding motifs.

The Chemical Bond in C2.

Quantum chemical calculations using the complete active space of the valence orbitals have been carried out for Hn CCHn (n=0-3) and N2. The quadratic force constants and the stretching potentials of Hn CCHn have been calculated at the CASSCF/cc-pVTZ level. The bond dissociation energies of the C-C bonds of C2 and HC≡CH were computed using explicitly correlated CASPT2-F12/cc-pVTZ-F12 wave functions. The bond dissociation energies and the force constants suggest that C2 has a weaker C-C bond than acetylene. The analysis of the CASSCF wavefunctions in conjunction with the effective bond orders of the multiple bonds shows that there are four bonding components in C2, while there are only three in acetylene and in N2. The bonding components in C2 consist of two weakly bonding σ bonds and two electron-sharing π bonds. The bonding situation in C2 can be described with the σ bonds in Be2 that are enforced by two π bonds. There is no single Lewis structure that adequately depicts the bonding situation in C2. The assignment of quadruple bonding in C2 is misleading, because the bond is weaker than the triple bond in HC≡CH.

Reaction Mechanism of the Hydrogermylation/Hydrostannylation of Unactivated Alkenes with Two-Coordinate E(II) Hydrides (E=Ge, Sn): A Theoretical Study.

Quantum chemical calculations using density functional theory with the TPSS+D3(BJ) and M06-2X+D3(ABC) functionals have been carried out to understand the mechanisms of catalyst-free hydrogermylation/hydrostannylation reactions between the two-coordinate hydrido-tetrylenes :E(H)(L(+) ) (E=Ge or Sn, L(+) =N(Ar(+) )(SiiPr3 ); Ar(+) =C6 H2 {C(H)Ph2 }2 iPr-2,6,4) and a range of unactivated terminal (C2 H3 R, R=H, Ph, or tBu) and cyclic [(CH)2 (CH2 )2 (CH2 )n , n=1, 2, or 4] alkenes. The calculations suggest that the addition reactions of the germylenes and stannylenes to the cyclic and acyclic alkenes occur as one-step processes through formal [2+2] addition of the E-H fragment across the C-C π bond. The reactions have moderate barriers and are weakly exergonic. The steric bulk of the tetrylene amido groups has little influence on the activation barriers and on the reaction energies of the anti-Markovnikov pathway, but the Markovnikov addition is clearly disfavored by the size of the substituents. The addition of the tetrylenes to the cyclic alkenes is less exergonic than the addition to the terminal alkenes, which agrees with the experimentally observed reversibility of the former reactions. The hydrogermylation reactions have lower activation energies and are more exergonic than the stannylene addition. An energy decomposition analysis of the transition state for the hydrogermylation of cyclohexene shows that the reaction takes place with simultaneous formation of the Ge-C and (Ge)H-C' bonds. The dominant orbitals of the germylene are the σ-type lone pair MO of Ge, which serves as a donor orbital, and the vacant p(π) MO of Ge, which acts as acceptor orbital for the π* and π MOs of the olefin. Inspection of the transition states of some selected reactions suggests that the differences between the activation energies come from a delicate balance between the deformation energies of the interacting species and their interaction energies.

Observation of Main-Group Tricarbonyls [B(CO)3 ] and [C(CO)3 ](+) Featuring a Tilted One-Electron Donor Carbonyl Ligand.

A combined experimental and theoretical study on the main-group tricarbonyls [B(CO)3 ] in solid noble-gas matrices and [C(CO)3 ](+) in the gas phase is presented. The molecules are identified by comparing the experimental and theoretical IR spectra and the vibrational shifts of nuclear isotopes. Quantum chemical ab initio studies suggest that the two isoelectronic species possess a tilted η(1) (µ1 -CO)-bonded carbonyl ligand, which serves as an unprecedented one-electron donor ligand. Thus, the central atoms in both complexes still retain an 8-electron configuration. A thorough analysis of the bonding situation gives quantitative information about the donor and acceptor properties of the different carbonyl ligands. The linearly bonded CO ligands are classical two-electron donors that display classical σ-donation and π-back-donation following the Dewar-Chatt-Duncanson model. The tilted CO ligand is a formal one-electron donor that is bonded by σ-donation and π-back-donation that involves the singly occupied orbital of the radical fragments [B(CO)2 ] and [C(CO)2 ](+) .

The [B3(NN)3](+) and [B3(CO)3](+) Complexes Featuring the Smallest π-Aromatic Species B3(+).

We report the spectroscopic identification of the [B3 (NN)3](+) and [B3 (CO)3](+) complexes, which feature the smallest π-aromatic system B3 (+). A quantum chemical bonding analysis shows that the adducts are mainly stabilized by L→[B3 L2 ](+) σ-donation.

Low coordinate germanium(II) and tin(II) hydride complexes: efficient catalysts for the hydroboration of carbonyl compounds.

This study details the first use of well-defined low-valent p-block metal hydrides as catalysts in organic synthesis. That is, the bulky, two-coordinate germanium(II) and tin(II) hydride complexes, L(†)(H)M: (M = Ge or Sn, L(†) = -N(Ar(†))(SiPr(i)3), Ar(†) = C6H2{C(H)Ph2}2Pr(i)-2,6,4), are shown to act as efficient catalysts for the hydroboration (with HBpin, pin = pinacolato) of a variety of unactivated, and sometimes very bulky, carbonyl compounds. Catalyst loadings as low as 0.05 mol % are required to achieve quantitative conversions, with turnover frequencies in excess of 13 300 h(-1) in some cases. This activity rivals that of currently available catalysts used for such reactions.

One-electron-mediated rearrangements of 2,3-disiladicarbene.

A disiladicarbene, (Cy-cAAC)2Si2 (2), was synthesized by reduction of Cy-cAAC:SiCl4 adduct with KC8. The dark-colored compound 2 is stable at room temperature for a year under an inert atmosphere. Moreover, it is stable up to 190 °C and also can be characterized by electron ionization mass spectrometry. Theoretical and Raman studies reveal the existence of a Si═Si double bond with a partial double bond between each carbene carbon atom and silicon atom. Cyclic voltammetry suggests that 2 can quasi-reversibly accept an electron to produce a very reactive radical anion, 2(•-), as an intermediate species. Thus, reduction of 2 with potassium metal at room temperature led to the isolation of an isomeric neutral rearranged product and an anionic dimer of a potassium salt via the formation of 2(•-).

Stabilization of a cobalt-cobalt bond by two cyclic alkyl amino carbenes.

(Me2-cAAC:)2Co2 (2, where Me2-cAAC: = cyclic alkyl amino carbene, :C(CH2)(CMe2)2N-2,6-iPr2C6H3)) was synthesized via the reduction of precursor (Me2-cAAC:Co(II)(µ-Cl)Cl)2 (1) with KC8. 2 contains two cobalt atoms in the formal oxidation state zero. Magnetic measurement revealed that 2 has a singlet spin ground state S = 0. The cyclic voltammogram of 2 exhibits both one-electron oxidation and reduction, indicating the possible synthesis of stable species containing 2(•-) and 2(•+) ions. The latter was synthesized via reduction of 1 with required equivalents of KC8 and characterized as [(Me2-cAAC:)2Co2](•+)OTf(-) (2(•+)OTf(-)). Electron paramagnetic resonance spectroscopy of 2(•+) reveals the coupling of the electron spin with 2 equiv (59)Co isotopes, leading to a (Co(0.5))2 state. The experimental Co1-Co2 bond distances are 2.6550(6) and 2.4610(6) Å for 2 and 2(•+)OTf(-), respectively. Theoretical investigation revealed that both 2 and 2(•+)OTf(-) possess a Co-Co bond with an average value of 2.585 Å. A slight increase of the Co-Co bond length in 2 is more likely to be caused by the strong π-accepting property of cAAC. 2(•+) is only 0.8 kcal/mol higher in energy than the energy minimum. The shortening of the Co-Co bond of 2(•+) is caused by intermolecular interactions.

Reaction mechanisms of small-molecule activation by amidoditetrylynes R(2)N-EE-NR(2) (E = Si, Ge, Sn).

The calculated reaction profiles using density functional theory at the BP86/TZVPP level for the reaction of small molecules with amidoditetrylynes R2N-EE-NR2 (E = Si, Ge, Sn) are discussed. Four projects are presented that feature the virtue of cooperation between theory and experiment. First, the calculated reaction paths for hydrogenation of the model systems (Me2N)EEL(NMe2) (E = Si, Ge, Sn), which possess E-E single bonds, are examined. The results for the germanium model systems are compared with hydrogenation of the real system L(†)GeGeL(†) where L(†) = NAr*(SiMe3) (Ar* = C6H2{C(H)Ph2}2Me-2,6,4). The second project introduced the multiply bonded amidodigermyne L(††)GeGeL(††), which carries the extremely bulky substituents L(††) = N(Ar(††))(SiPr(i)3), where Ar(††) = C6H2{C(H)Ph2}2Pr(i)-2,6,4. The theoretical reaction profile for dihydrogen addition to L(††)GeGeL(††) is discussed. Hydrogenation gives L(††)(H)GeGe(H)L(††) as the product, which is in equilibrium with the hydrido species Ge(H)L(††). The latter germanium hydride and tin homologue Sn(H)L(††) were found to be effective catalysts for hydroboration reactions, which is the topic of the third project. Finally, the calculated reaction course for the reduction of CO2 to CO with the amidodigermyne L(†)GeGeL(†) is discussed.

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.

Formation of a 1,4-diamino-2,3-disila-1,3-butadiene derivative.

A 1,4-diamino-2,3-disila-1,3-butadiene derivative of composition (Me2-cAAC)2(Si2Cl2) (Me2-cAAC = :C(CMe2)2(CH2)N-2,6-iPr2C6H3) was synthesized by reduction of the Me2-cAAC:SiCl4 adduct with KC8. This compound is stable at 0 °C for 3 months in an inert atmosphere. Theoretical studies reveal that the silicon atoms exhibit pyramidal coordination, where the Cl-Si-Si-Cl dihedral angle is twisted by 43.3° (calcd 45.9°). The two silicon-carbon bonds are intermediates between single and double Si-C bonds due to twisting of the C-Si-Si-C dihedral angle (163.6°).

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.

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.