Synthesis, Stereochemical Determination, and Antimicrobial Evaluation of Myxocoumarin A.

The myxobacterial natural product myxocoumarin A from Stigmatella aurantiaca MYX-030 has remarkable antifungal activity against agriculturally relevant pathogens. To broaden the initial evaluation of its biological potential, we herein completed the first total synthesis of myxocoumarin A. This synthetic access facilitated stereochemical investigations on the natural product structure, revealing its (R)-configuration. Biological activity profiling showed a lack of activity against Candida spp. and Gram-negative bacteria but revealed strong antibiotic activities against Bacillus subtilis and Staphylococcus aureus, including MRSA.

Two-color four-wave mixing contribution to an electrostrictive laser-induced grating signal in CO2-N2 mixtures and gas diagnostics: publisher's note.

This publisher's note corrects content in Appl. Opt.62, 8115 (2023)APOPAI0003-693510.1364/AO.497467.

Two-color four-wave mixing contribution to an electrostrictive laser-induced grating signal in CO2-N2 mixtures and gas diagnostics.

Multiparameter determination in the gas phase using the versatile laser-induced grating (LIG) technique is a challenging task due to interdependence of observables on multiple thermodynamic parameters. In C O 2-N 2 mixtures, simultaneous determination of species concentration and gas temperature can be achieved by using an additional C O 2 concentration-dependent contribution to the LIG signal, which appears if 1064 nm pump pulses are employed. This contribution can be attributed to a direct, quasi-resonant two-color four-wave mixing (TCFWM) of the pump and probe radiations in C O 2. A detailed study of the laser power and beam polarization, as well as mixture composition, pressure, and temperature dependencies of the TCFWM intensity relative to that of the LIG signal, allowed for the formulation of analytical relations enabling simultaneous mixture composition and temperature determination.

Strong Antibiotic Activity of the Myxocoumarin Scaffold in vitro and in vivo.

The increasing emergence of resistances against established antibiotics is a substantial threat to human health. The discovery of new compounds with potent antibiotic activity is thus of utmost importance. Within this work, we identify strong antibiotic activity of the natural product myxocoumarin B from Stigmatella aurantiaca MYX-030 against a range of clinically relevant bacterial pathogens, including clinical isolates of MRSA. A focused library of structural analogs was synthesized to explore initial structure-activity relationships and to identify equipotent myxocoumarin derivatives devoid of the natural nitro substituent to significantly streamline synthetic access. The cytotoxicity of the myxocoumarins as well as their potential to cure bacterial infections in vivo was established using a zebrafish model system. Our results reveal the exceptional antibiotic activity of the myxocoumarin scaffold and hence its potential for the development of novel antibiotics.

Improvement of the coherent model function for S-branch Raman linewidth determination in oxygen.

Determination of S-branch Raman linewidths of oxygen from picosecond time-domain pure rotational coherent anti-Stokes Raman spectroscopy (RCARS) measurements requires consideration of coherence beating. We present an optimization of the established model for fitting the coherence decay in oxygen, which leads to an improvement in Raman linewidth data quality, especially for the challenging small signal intensity and decay constant regime, enabling the application for low oxygen concentrations. Two modifications to the fitting procedure are discussed, which aim at reliably fitting the second coherence beat properly. These are evaluated statistically against simulated decay traces, and weighing the data by the inverse of the data magnitude gives the best agreement. The presented temperature dependent ${{\rm O}_2} {-} {{\rm O}_2}$ S-branch Raman linewidth from the modified model shows an improved data quality over the original model function for all studied temperatures. ${{\rm O}_2} {-} {{\rm N}_2}$ linewidths of oxygen in air for the temperature range from 295 K to 1900 K demonstrate applicability to small concentrations. Use of the determined RCARS ${{\rm O}_2} {-} {{\rm O}_2}$ S-branch linewidth instead of regularly used Q-branch derived linewidths leads to a lowering in evaluated RCARS temperature by about 21 K, thereby, a much better agreement with thermocouple measurements.

Temperature dependent determination of the S-branch Raman linewidths of oxygen and carbon dioxide in an oxyfuel relevant mixture.

The temperature dependence of the ${\rm O}_2$ and ${\rm CO}_2$ S-branch linewidths in a 30/70% ${\rm O}_2 - {\rm CO}_2$ mixture between 295 K and 1900 K has been studied by a picosecond time-resolved pure rotational coherent anti-Stokes Raman scattering (RCARS) approach. The S-branch Raman linewidths are required for diagnostics of thermodynamic properties in oxyfuel combustion processes by RCARS, where this mixture is of special interest, because it is regularly used to replace air when transiting from air-fed to oxyfuel combustion. The obtained linewidths for oxygen and carbon dioxide show a strong deviation from pure self-broadened linewidths and previously used Q-branch linewidths, respectively. A discussion on the expected impact on RCARS thermometry and concentration evaluations as well as a description of specific properties of oxygen and carbon dioxide and their effect on the dephasing behavior of the Raman coherences and, thereby the Raman linewidths, is included, along tabulated linewidths data of both molecules.

A natural catastrophic turnover event: individual sociality matters despite community resilience in wild house mice.

Natural disasters can cause rapid demographic changes that disturb the social structure of a population as individuals may lose connections. These changes also have indirect effects as survivors alter their within-group connections or move between groups. As group membership and network position may influence individual fitness, indirect effects may affect how individuals and populations recover from catastrophic events. Here we study changes in the social structure after a large predation event in a population of wild house mice (Mus musculus domesticus), when a third of adults were lost. Using social network analysis, we examine how heterogeneity in sociality results in varied responses to losing connections. We then investigate how these differences influence the overall network structure. An individual's reaction to losing associates depended on its sociality prior to the event. Those that were less social before formed more weak connections afterwards, while more social individuals reduced the number of survivors they associated with. Otherwise, the number and size of social groups were highly robust. This indicates that social preferences can drive how individuals adjust their social behaviour after catastrophic turnover events, despite the population's resilience in social structure.

Chemoenzymatic Total Synthesis of Sorbicatechol Structural Analogues and Evaluation of Their Antiviral Potential.

Sorbicillinoids are fungal polyketides characterized by highly complex and diverse molecular structures, with considerable stereochemical intricacy combined with a high degree of oxygenation. Many sorbicillinoids possess promising biological activities. An interesting member of this natural product family is sorbicatechol A, which is reported to have antiviral activity, particularly against influenza A virus (H1N1). Through a straightforward, one-pot chemoenzymatic approach with recently developed oxidoreductase SorbC, the characteristic bicyclo[2.2.2]octane core of sorbicatechol is structurally diversified by variation of its natural 2-methoxyphenol substituent. This facilitates the preparation of a focused library of structural analogues bearing substituted aromatic systems, alkanes, heterocycles, and ethers. Fast access to this structural diversity provides an opportunity to explore the antiviral potential of the sorbicatechol family.

Exploring the Binding Mechanism of GABAB Receptor Agonists and Antagonists through in Silico Simulations.

GABAB is a G protein-coupled receptor that functions as a constitutive heterodimer composed of the GABAB1a/b and GABAB2 subunits. It mediates slow and prolonged inhibitory neurotransmission in the nervous system, representing an attractive target for the treatment of various disorders. However, the molecular mechanism of the GABAB receptor is not thoroughly understood. Therefore, a better description of the binding of existing agonists and antagonists to this receptor is crucial to improve our knowledge about G protein-coupled receptor structure as well as for helping the development of new potent and more selective therapeutic agents. In this work, we used the recent X-ray cocrystallization data of agonists (GABA and baclofen) and antagonists (2-hydroxysaclofen, SCH50911, and CGP54626) bound to the GABAB orthosteric site together with quantum biochemistry and the molecular fractionation with conjugate caps (MFCC) scheme to describe the individual contribution of each amino acid residue involved in the GABAB-ligand interaction, pointing out differences and similarities among the compounds. Our quantum biochemical computational results show that the total binding energy of the ligands to the GABAB ligand pocket, with radius varying from 2.0 to 9.0 Å, is well-correlated with the experimental binding affinity. In addition, we found that the binding site is very similar for agonists or antagonists, showing small differences in the importance of the most significant amino acids. Finally, we predict the energetic relevance of the regions of the five ligands as well as the influence of each protein lobe on GABAB-ligand binding. These results provide important new information on the binding mechanism of the GABAB receptor and should facilitate the development of new chemicals targeting this receptor.

Intermolecular interactions of cn-716 and acyl-KR-aldehyde dipeptide inhibitors against Zika virus.

The emergent Zika virus (ZIKV) infection has become a threat to global health due to its association with severe neurological abnormalities, namely Guillain-Barré Syndrome (GBS) in adults and Congenital Zika virus Syndrome (CZS) in neonates. Many studies are nowadays being conducted to find an effective antiviral drug against ZIKV. In particular, NS2B-NS3 protease is an attractive drug target due to its essential function in viral replication, although a drug is not yet commercially available. In this context, we present here a comparative structural study, based on quantum chemistry calculations, to analyze the intermolecular binding energies between the crystallographic structure of NS2B-NS3 protease and dipeptide boronic acid (cn-716) and aldehyde (acyl-KR-aldehyde) peptidomimetic inhibitors, by using the molecular fractionation with conjugate caps (MFCC) scheme within the density functional theory (DFT) formalism. Most intermolecular interactions in cn-716/NS2B-NS3 (acyl-KR-aldehyde/NS2B-NS3) are due to the amino acid residues Asp83*, His51, Asp129, Ser81*, Gly133, Ala132, Tyr161, Asn152 and Asp75 (Asp83*, Asp129, His51, Asn152, Tyr161, Tyr130, Gly153, Gly151, Asp75, Pro131, and Gly82). Additionally, we have considered missense mutation analysis of these residues to evaluate the destabilization and the increase of the flexibility of the protease, showing that mutation of the residues Tyr161 and Tyr130 causes more impact. Our simulations are a valuable tool for a better understanding of the binding mechanism of recognized inhibitors of NS2B-NS3 protease, and can lead to the rational design and development of novel anti-Zika drugs with improved efficiency.

Metformin counteracts glucose-dependent lipogenesis and impairs transdeamination in the liver of gilthead sea bream ( Sparus aurata).

Metformin is an antidiabetic drug with a major impact on regulating blood glucose levels by decreasing hepatic gluconeogenesis, but also by affecting other pathways, including glucose transport and energy/lipid metabolism. Carnivorous fish are considered glucose intolerant, as they exhibit poor ability in using dietary carbohydrates. To increase the current knowledge about the molecular mechanisms by which metformin can improve glucose homeostasis in carnivorous fish, we addressed the effect of intraperitoneal administration of metformin, in the presence or absence of a glucose load, on metabolic rate-limiting enzymes and lipogenic factors in the liver of gilthead sea bream ( Sparus aurata). Hyperglycemia markedly upregulated the expression of glycolytic enzymes (glucokinase and 6-phosphofructo-1-kinase, PFK1) 5 h following glucose administration, while at 24 h posttreatment, it increased isocitrate dehydrogenase (IDH) activity, a key enzyme of the tricarboxylic acid cycle, and the expression of lipogenic factors (PGC1ß, Lpin1, and SREBP1). Metformin counteracted glucose-dependent effects, and downregulated glutamate dehydrogenase, alanine aminotransferase, and mammalian target of rapamycin 5 h posttreatment in the absence of a glucose load, leading to decreased long-term activity of PFK1 and IDH. The results of the present study suggest that hyperglycemia enhances lipogenesis in the liver of S. aurata and that metformin may exert specific metabolic effects in fish by decreasing hepatic transdeamination and suppressing the use of amino acids as gluconeogenic substrates. Our findings highlight the role of amino acid metabolism in the glucose-intolerant carnivorous fish model.

Long-Range Mass Transport during Structural Transitions in Metallic Glass-Forming Melts.

We investigate the structure and dynamics of the bulk metallic glass-forming alloys Zr_{41.2}Ti_{13.8}Cu_{12.5}Ni_{10}Be_{22.5} and Zr_{58.5}Cu_{15.6}Ni_{12.8}Al_{10.3}Nb_{2.8}. Combining in situ synchrotron x-ray diffraction and quasielastic neutron scattering with electrostatic levitation, we directly observe an abrupt change in the temperature dependence of the first structure factor maximum of these melts. We find that the kinetics of this liquid-liquid transition during cooling are on the order of tens of seconds, whereas its onset temperature depends only weakly on the applied cooling rate. Such slow transition kinetics require long-range mass transport, which is incompatible with a transition mechanism involving only local structural changes as in oxides or molecular liquids.

Synthesis and initial biological evaluation of myxocoumarin B.

The myxocoumarins A and B from Stigmatella aurantiaca MYX-030 are natural products featuring unusual nitro- and long-chain alkyl substitution. While myxocoumarin A was shown to exhibit strong antifungal properties, the antifungal potential of myxocoumarin B was not yet assessed due to low production titers during initial isolation. We therefore developed a total synthesis of myxocoumarin B that involves a late-stage Pd-catalyzed nitration of the coumarin core. The availability of synthetic material facilitated the initial evaluation of the bioactivity of myxocoumarin B, which revealed a lack of activity against medically relevant Candida sp. and low cytotoxicity in vitro against human fibroblasts (MRC-5) and in vivo (zebrafish).

Determination of N2-N2 and N2-O2 S-branch Raman linewidths using time-resolved picosecond pure rotational coherent anti-Stokes Raman scattering.

N2-N2 and N2-O2 S-branch Raman linewidths have been determined using picosecond dual-broadband pure rotational coherent anti-Stokes Raman scattering (CARS). Time-resolved rotational CARS measurements were performed in gas-phase N2 and air for temperatures up to 1900 K in order to determine the time constants of the coherence decay to subsequently calculate the S-branch Raman linewidths. Coherence decay time traces and the resulting S-branch Raman linewidths are presented for N2-N2 and N2-O2 collisions. Therewith, we reduce the gap of widely missing S-branch linewidth data in the temperature regime of many combustion processes. Further, we demonstrate that the standard monoexponential fitting of the coherence decay, as it is commonly done for nitrogen, is not applicable to oxygen.

Host population structure impedes reversion to drug sensitivity after discontinuation of treatment.

Intense use of antibiotics for the treatment of diseases such as tuberculosis, malaria, Staphylococcus aureus or gonorrhea has led to rapidly increasing population levels of drug resistance. This has generally necessitated a switch to new drugs and the discontinuation of older ones, after which resistance often only declines slowly or even persists indefinitely. These long-term effects are usually ascribed to low fitness costs of resistance in absence of the drug. Here we show that structure in the host population, in particular heterogeneity in number of contacts, also plays an important role in the reversion dynamics. Host contact structure acts both during the phase of intense treatment, leading to non-random distributions of the resistant strain among the infected population, and after the discontinuation of the drug, by affecting the competition dynamics resulting in a mitigation of fitness advantages. As a consequence, we observe both a lower rate of reversion and a lower probability that reversion to sensitivity on the population level occurs after treatment is stopped. Our simulations show that the impact of heterogeneity in the host structure is maximal in the biologically most plausible parameter range, namely when fitness costs of resistance are small.

Short-term activity cycles impede information transmission in ant colonies.

Rhythmical activity patterns are ubiquitous in nature. We study an oscillatory biological system: collective activity cycles in ant colonies. Ant colonies have become model systems for research on biological networks because the interactions between the component parts are visible to the naked eye, and because the time-ordered contact network formed by these interactions serves as the substrate for the distribution of information and other resources throughout the colony. To understand how the collective activity cycles influence the contact network transport properties, we used an automated tracking system to record the movement of all the individuals within nine different ant colonies. From these trajectories we extracted over two million ant-to-ant interactions. Time-series analysis of the temporal fluctuations of the overall colony interaction and movement rates revealed that both the period and amplitude of the activity cycles exhibit a diurnal cycle, in which daytime cycles are faster and of greater amplitude than night cycles. Using epidemiology-derived models of transmission over networks, we compared the transmission properties of the observed periodic contact networks with those of synthetic aperiodic networks. These simulations revealed that contrary to some predictions, regularly-oscillating contact networks should impede information transmission. Further, we provide a mechanistic explanation for this effect, and present evidence in support of it.

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives.

BACKGROUND: Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones. RESULTS: The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 µM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 µM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 µM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol. CONCLUSIONS: These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

A transcriptomic approach to study the effect of long-term starvation and diet composition on the expression of mitochondrial oxidative phosphorylation genes in gilthead sea bream (Sparus aurata).

BACKGROUND: The impact of nutritional status and diet composition on mitochondrial oxidative phosphorylation (OXPHOS) in fish remains largely unknown. To identify biomarkers of interest in nutritional studies, herein we obtained a deep-coverage transcriptome by 454 pyrosequencing of liver and skeletal muscle cDNA normalised libraries from long-term starved gilthead sea bream (Sparus aurata) and fish fed different diets. RESULTS: After clean-up of high-throughput deep sequencing reads, 699,991 and 555,031 high-quality reads allowed de novo assembly of liver and skeletal muscle sequences, respectively (average length: 374 and 441 bp; total megabases: 262 and 245 Mbp). An additional incremental assembly was completed by integrating data from both tissues (hybrid assembly). Assembly of hybrid, liver and skeletal muscle transcriptomes yielded, respectively, 19,530, 11,545 and 10,599 isotigs (average length: 1330, 1208 and 1390 bp, respectively) that were grouped into 15,954, 10,033 and 9189 isogroups. Following annotation, hybrid transcriptomic data were used to construct an oligonucleotide microarray to analyse nutritional regulation of the expression of 129 genes involved in OXPHOS in S. aurata. Starvation upregulated cytochrome c oxidase components and other key OXPHOS genes in the liver, which exhibited higher sensitive to food deprivation than the skeletal muscle. However, diet composition affected OXPHOS in the skeletal muscle to a greater extent than in the liver: most of genes upregulated under starvation presented higher expression among fish fed a high carbohydrate/low protein diet. CONCLUSIONS: Our findings indicate that the expression of coenzyme Q-binding protein (COQ10), cytochrome c oxidase subunit 6A2 (COX6A2) and ADP/ATP translocase 3 (SLC25A6) in the liver, and cytochrome c oxidase subunit 5B isoform 1 (COX5B1) in the liver and the skeletal muscle, are sensitive markers of the nutritional condition that may be relevant to assess the effect of changes in the feeding regime and diet composition on fish farming.

Iridium(III) Bis-Pyridine-2-Sulfonamide Complexes as Efficient and Durable Catalysts for Homogeneous Water Oxidation.

A family of tetradentate bis(pyridine-2-sulfonamide) (bpsa) compounds was synthesized as a ligand platform for designing resilient and electronically tunable catalysts capable of performing water oxidation catalysis and other processes in highly oxidizing environments. These wrap-around ligands were coordinated to Ir(III) octahedrally, forming an anionic complex with chloride ions bound to the two remaining coordination sites. NMR spectroscopy documented that the more rigid ligand frameworks-[Ir(bpsa-Cy)Cl2](-) and [Ir(bpsa-Ph)Cl2](-)-produced C1-symmetric complexes, while the complex with the more flexible ethylene linker in [Ir(bpsa-en)Cl2](-) displays C2 symmetry. Their electronic structure was explored with DFT calculations and cyclic voltammetry in nonaqueous environments, which unveiled highly reversible Ir(III)/Ir(IV) redox processes and more complex, irreversible reduction chemistry. Addition of water to the electrolyte revealed the ability of these complexes to catalyze the water oxidation reaction efficiently. Electrochemical quartz crystal microbalance studies confirmed that a molecular species is responsible for the observed electrocatalytic behavior and ruled out the formation of active IrOx. The electrochemical studies were complemented by work on chemically driven water oxidation, where the catalytic activity of the iridium complexes was studied upon exposure to ceric ammonium nitrate, a strong, one-electron oxidant. Variation of the catalyst concentrations helped to illuminate the kinetics of these water oxidation processes and highlighted the robustness of these systems. Stable performance for over 10 days with thousands of catalyst turnovers was observed with the C1-symmetric catalysts. Dynamic light scattering experiments ascertained that a molecular species is responsible for the catalytic activity and excluded the formation of IrOx particles.