Candidate Sources Research Articles

λ ∼ 4.7 μm Quantum Cascade Distributed-Feedback Lasers for Free-Space Communications

Quantum cascade lasers (QCLs) have emerged as promising candidate sources for free-space communications. High optical power densities, short photon lifetimes, and low internal capacitance are important factors influencing the transmission bandwidth. We report the design and fabrication of 4.7 μm emitting, 1.5 mm cavity length, single-mode distributed-feedback QCLs, with a CW front-facet output power of 165 mW and a calculated photon lifetime of 11.6 ps, resulting in an electrically limited CW modulation with a 3 dB cutoff at 850 MHz.

Human microbiome derived synthetic antimicrobial peptides with activity against Gram-negative, Gram-positive, and antibiotic resistant bacteria.

The prevalence of antibacterial resistance has become one of the major health threats of modern times, requiring the development of novel antibacterials. Antimicrobial peptides are a promising source of antibiotic candidates, mostly requiring further optimization to enhance druggability. In this study, a series of new antimicrobial peptides derived from lactomodulin, a human microbiome natural peptide, was designed, synthesized, and biologically evaluated. Within the most active region of the parent peptide, linear peptide LM6 with the sequence LSKISGGIGPLVIPV-NH2 and its cyclic derivatives LM13a and LM13b showed strong antibacterial activity against Gram-positive bacteria, including resistant strains, and Gram-negative bacteria. The peptides were found to have a rapid onset of bactericidal activity and transmission electron microscopy clearly shows the disintegration of the cell membrane, suggesting a membrane-targeting mode of action.

Unveiling the Antimycobacterial Potential of Novel 4-Alkoxyquinolines: Insights into Selectivity, Mechanism of Action, and In Vivo Exposure.

This work presents a comprehensive investigation into the design, synthesis, and evaluation of a novel series of 4-alkoxyquinolines as potential antimycobacterial agents. The design approach, which combined molecular simplification and chain extension, resulted in compounds with potent and selective activity against both drug-susceptible and multidrug-resistant Mycobacterium tuberculosis strains. The lead molecule, targeting the cytochrome bc1 complex, exhibited favorable kinetic solubility and remarkable chemical stability under acidic conditions. Despite in vitro ADME evaluations showing low permeability and high metabolism in rat microsomes, the lead compound exhibited bacteriostatic activity in a murine macrophage model of TB infection and demonstrated promising in vivo exposure following gavage in mice, with an AUC0-t of 127.5 ± 5.7 μM h. To the best of our knowledge, for the first time, a simplified structure from 2-(quinolin-4-yloxy)acetamides has shown such potential. These findings suggest a new avenue for exploring this chemical class as a source of antituberculosis drug candidates.

Polarization entanglement enabled by orthogonally stacked van der Waals NbOCl2 crystals

Polarization entanglement holds significant importance for photonic quantum technologies. Recently emerging subwavelength nonlinear quantum light sources, e.g., GaP and LiNbO3 thin films, benefiting from the relaxed phase-matching constraints and volume confinement, have shown intriguing properties, such as high-dimensional hyperentanglement and robust entanglement anti-degradation. Van der Waals (vdW) NbOCl2 crystal, with strong optical nonlinearities, has emerged as a potential candidate for ultrathin quantum light sources. However, polarization entanglement is inaccessible in the NbOCl2 crystal due to its unfavorable nonlinear susceptibility tensor. Here, by leveraging the twist-stacking degree of freedom inherently in vdW systems, we showcase the preparation of polarization entanglement and quantum Bell states.

Simulating Genetic Mixing in Strongly Structured Populations of the Threatened Southern Brown Bandicoot (Isoodon obesulus).

Genetic mixing aims to increase the genetic diversity of small or isolated populations, by mitigating genetic drift and inbreeding depression, either by maximally increasing genetic diversity, or minimising the prevalence of recessive, deleterious alleles. However, few studies investigate this beyond a single generation of mixing. Here, we model genetic mixing using captive, low-diversity recipient population of the threatened Southern brown bandicoot (Isoodon obesulus) over 50 generations and compare wild populations across south-eastern Australia as candidate source populations. We first assess genetic differentiation between 12 populations, including the first genomic assessment of three mainland Australian and three Tasmanian populations. We assess genetic diversity in the 12 populations using an individualised autosomal heterozygosity pipeline, using these results to identify a candidate recipient population for genetic mixing simulations. We found that populations fell into four major groups of genetic similarity: Adelaide Hills, western Victoria, eastern Victoria, and Tasmania, but populations within these groups were also distinct, and additional substructure was observed in some populations. Our autosomal heterozygosity pipeline indicated significant variability in mean heterozygosity between populations, identifying one extremely genetically degraded population on Inner Sister Island, Tasmania. Genetic mixing simulations of a low heterozygosity captive population in Victoria suggested the greatest increase in heterozygosity would be reached by using highly differentiated populations as mixing sources. However, when removing populations that may represent taxonomically discrete lineages, neither metrics of differentiation nor heterozygosity was strongly correlated with modelled heterozygosity increase, indicating the value of simulation-based approaches when selecting source populations for population mixing.

Demography of Stellar Radio Population within 500 pc: A VLASS-Gaia DR3 Study

In this work, we have carried out a systematic analysis of the Very Large Array Sky Survey (VLASS) quick look catalogs together with Gaia DR3 to identify the optical counterparts of 3 GHz radio emitters within 500 pc to obtain a homogeneous statistical sample of stellar radio sources. We have identified distinct populations of 3 GHz emitters across the Gaia DR3 color–magnitude diagram. We also present candidate sources (transient, highly variable, or background artifacts) that can be confirmed by follow-up observations. A majority of the detected sources constitute main-sequence G-, K-, and M-type stars, including ultracool dwarfs. Pinning down the origin of radio emission from these populations can help us gain further insights into the origin of stellar and planetary magnetic fields. By analyzing the variation of brightness temperature of the sources with their spectral type, we have tentatively associated possible emission mechanisms with different object types. We inspected the correlation between quiescent radio and X-ray emission for our sample, which can provide crucial insights into the current understanding of the Gudel–Benz relationship, which is essential for modeling steady radio emission and coronal heating. This VLASS-Gaia DR3 analysis acts as a pilot study for follow-up observations at multiple wavelengths to better understand stellar structure, model flaring activities, and detect radio emission caused by star–planet interactions.

Pharmacophore-based virtual screening, molecular docking, and molecular dynamics investigation for the identification of novel, marine aromatase inhibitors.

Breast cancer remains a leading cause of mortality among women worldwide. Our current research focuses on identifying effective therapeutic agents by targeting the human aromatase enzyme. Aromatase inhibitors (AIs) have been effective in treating postmenopausal breast cancer but face challenges such as drug resistance and long-term side effects like cognitive decline and osteoporosis. Natural products, especially from marine organisms, are emerging as potential sources for new drug candidates due to their structural diversity and pharmacological properties. This study aims to discover marine natural products capable of inhibiting human aromatase by combining ligand-based and structure-based pharmacophore models for virtual screening against the Comprehensive Marine Natural Products Database. From the initial virtual screening of more than 31,000 compounds, 1,385 marine natural products were identified as possible candidates. Following initial molecular docking analysis, only four compounds managed to pass the criteria this research has introduced to confirm strong binding affinity to aromatase. All four compounds yielded acceptable binding affinities, with CMPND 27987 having the highest -10.1kcal/mol. All four hits were subjected to molecular dynamics, and CMPND 27987 was further confirmed to be the most stable at the protein's active site, with an MM-GBSA free binding energy of -27.75kcal/mol. Our in silico studies indicate that CMPND 27987 interacts effectively within the binding site of the human aromatase, maintaining high affinity and stability. Based on these findings, we propose that CMPND 27987 could hold significant potential for further lead optimization and drug development.

Effect of Gold Nanoparticles in Microbial Fuel Cells Based on Polypyrrole-Modified Saccharomyces cerevisiae.

Microbial fuel cells (MFCs) are a candidate for green energy sources due to microbes' ability to generate charge in their metabolic processes. The main problem in MFCs is slow charge transfer between microorganisms and electrodes. Several methods to improve charge transfer have been used until now: modification of microorganisms by conductive polymers, use of lipophilic mediators, and conductive nanomaterials. We created an MFC with a graphite anode, covering it with 9,10-phenatrenequinone and polypyrrole-modified Saccharomyces cerevisiae with and without 10 nm sphere gold nanoparticles. The MFC was evaluated using cyclic voltammetry and power density measurements. The peak current from cyclic voltammetry measurements increased from 3.76 mA/cm2 to 5.01 mA/cm2 with bare and polypyrrole-modified yeast, respectively. The MFC with polypyrrole- and nanoparticle-modified yeast reached a maximum power density of 150 mW/m2 in PBS with 20 mM Fe(III) and 20 mM glucose, using a load of 10 kΩ. The same MFC with the same load in wastewater reached 179.2 mW/m2. These results suggest that this MFC configuration can be used to improve charge transfer.

Where on the Moon was the eruption that produced the recently reported ∼ 120 million year old volcanic glass beads?

Three anomalously young, ∼120 Ma old lunar mare pyroclastic beads have recently been reported (Wang et al., 2024) from Chang'e-5 (CE-5 soils, particularly distinguished from impact melt beads by sulfur isotope (34S/32S) composition and correlations with sulfur concentration. We examine lunar pyroclastic eruption theory and candidate eruption conditions in order to locate the vent and assess its geological context, finding that the estimated maximum pyroclast dispersal range from a candidate source vent is likely to be ∼200 km, placing it within the area of the CE-5–2.0 Ga sampled Em4 unit. The greatest predicted dispersal distances are associated with an explosive eruption from a stalled dike several kilometers below the surface, creating an elongated, multi-km-scale pit crater potentially surrounded by a dark pyroclastic ring. We assessed the Chang'e-5 region for such candidates and found none. This raises the possibility that the ∼120 Ma pyroclastic beads might have been delivered to the site from an impact crater outside Em4, but the most likely candidates are sufficiently large and at such great distances that they are likely to have reset the ages of any young pyroclastic beads thus delivered. Lacking a clear source for extraordinarily young pyroclastic beads, we reassess the possibility that the ∼120 Ma beads may be of local impact melt origin. Evidence favoring this hypothesis includes the abundant CE-5 impact glass bead ages in the 100–200 Ma year range previously reported (Long et al., 2022), and the similarities in composition and characteristics of the three beads and those of local impact origin. To address these conundra, further regional searches for a source vent and continued geochemical characterization and dating of CE-5 regolith glass beads should be undertaken.

Durability of Highly Active PGM Catalyst MEA Tested Via Nitrogen and Air AST Cycling Under HDV Condition

Polymer electrolyte membrane fuel cells (PEMFCs) have emerged as leading power source candidates for electric vehicles due to their ultimate cleanness, high efficiency and rapid refueling capabilities. Their ability to facilitate fast refueling with minimal dead mass penalty, unlike Li-ion batteries, positions fuel cells as ideal power plants for heavy-duty vehicles (HDVs) such as electric long-haul trucks, coaches, ships and airplanes, each with unique drive cycles and operational requirements. These applications demand catalyst, ionomer and membrane with enhanced durability compared to light duty vehicles (LDVs). In addition, PEMFCs operating with pure oxygen exhibit superior performance and efficiency but may face heightened challenges regarding durability of membrane electrode assembly (MEA). Presently, catalyst and MEA stability are evaluated for durability using the protocol of accelerated stress test (AST) under hydrogen/nitrogen (anode/cathode) atmosphere. Comparing with nitrogen atmosphere, the air will exert more significant degradation on both catalysts and ionomer/membranes. However, the impact of hydrogen/air condition, particularly under HDV operating conditions, on catalyst, ionomer, membrane degradation and their differences from the hydrogen/nitrogen condition remains unclearly understood. In this work, two MEAs fabricated by our highly active catalysts, specifically 30wt% Pt/KB, as the cathode and a commercial Pt/C catalyst as the anode. These MEAs underwent testing under HDV conditions (250 kPa back pressure) at various relative humilities, following the standard protocol of accelerated stress test (AST) in hydrogen/nitrogen and hydrogen/air (M2FCT) for 180k cycles. The results indicate substantial performance degradation in both MEAs during AST cycling. MEAs subjected to AST in hydrogen/nitrogen maintained the current density of 1.4 A/cm2, 1.2 A/cm2, 1.0 A/cm2 and 0.9 A/cm2 at the cell voltage of 0.7 V after the AST of 30k, 60k, 90k and 120k cycles, respectively. Moreover, the hydrogen/nitrogen MEA performance significantly declined to 0.5 A/cm2 and 0.3 A/cm2 at the same voltage after 150k and 180k cycles, respectively. In comparison, the MEA tested with AST in hydrogen/air exhibit similar beginning-of-life performance but experienced faster performance loss, especially within the mass transfer region, accompanied with the significant increase in crossover current, which indicates the degradation of membrane. In summary, this study elucidates the distinct degradation and mechanisms observed in highly efficient and durable PGM-catalyst MEAs running AST in nitrogen and air under HDV conditions.

Van der Waals NbOCl2 Nanodisks for Enhanced Second-Harmonic Generation.

Niobium oxide dichloride (NbOCl2), a van der Waals crystal, exhibits exceptional second-harmonic generation (SHG) with high conversion efficiency, making it a promising candidate for on-chip quantum light sources, photon modulators, and sensors. To increase its suitability for integrated photonic systems, it is crucial to explore strategies for further improving optical nonlinear conversion efficiency. In this article, dielectric metasurfaces are employed to enhance SHG from patterned NbOCl2 nanodisks. By precisely tuning their geometric parameters to achieve optical resonance near the excitation wavelength, a remarkable 25-fold enhancement in second-harmonic emission at 400 nm is achieved in nanodisks compared to the unpatterned thin film. The strong field enhancement within the NbOCl2 nanodisks at nanophotonic resonances contributes to the observed increase in SHG. This work offers an effective strategy for boosting SHG in van der Waals NbOCl2 thin films, paving the way for the development of efficient nonlinear optical components in integrated nanophotonics.

New physics as a possible explanation for the Amaterasu particle

The Telescope Array experiment has recently reported the most energetic event detected in the hybrid technique era, with a reconstructed energy of 240 EeV, which has been named “Amaterasu” after the Shinto deity. Its origin is intriguing since no powerful enough candidate sources are located within the region consistent with its propagation horizon and arrival direction. In this work, we investigate the possibility of describing its origin in a scenario of new physics, specifically under a Lorentz Invariance Violation (LIV) assumption. The kinematics of UHECR propagation under a phenomenological LIV approach is investigated. The total mean free path for a particle with Amaterasu's energy increases from a few Mpc to hundreds of Mpc for -δ had,0 > 10-22, expanding significantly the region from which it could have originated. A combined fit of the spectrum and composition data of Telescope Array under different LIV assumptions was also performed. The data is best fitted with some level of LIV both with and without Amaterasu. Robustness with data from the Pierre Auger Observatory is investigated by exploring an intermediate composition scenario. Similar improvements in the description of the data with LIV are found for that. New physics in the form of LIV could, thus, provide a plausible and robust explanation for the Amaterasu particle.

In silico Evaluation of the Feasibility of Magnolia officinalis Electron-shuttling Compounds as Parkinson’s Disease Remedy

Background: Parkinson’s Disease is one of the leading neurodegenerative disorders in the world. Currently, there is still no treatment that could completely cure the disease. Traditional Chinese Medicine has been a source for drug candidates, and many studies have elucidated its pharmacokinetic capabilities. Previous studies showed that Magnolia officinalis has anti-inflammatory, antioxidant, and bioenergy generation activities. Furthermore, the electron-shuttling and bioenergy-stimulating capabilities of herbal and brain disorder medicines have been linked to their effectiveness as a remedy. Objective: This preliminary study aims to evaluate the electron-shuttling compounds of Magnolia officinalis (i.e., acteoside, isoquercitrin, magnatriol B, obovatol, quercitrin, randaiol, and rutin) as potential drug candidates for Parkinson’s Disease. Methods: The seven electron-shuttling compounds were individually docked to the five Parkinson’s Disease-related proteins, namely aromatic L-amino acid decarboxylase, α-synuclein, monoamine oxidase B, catechol-o-methyltransferase, and A2A adenosine receptor, using LibDock. ADMET predictions were also made to screen the compounds further. Results: Molecular docking results showed that all compounds have relatively high LibDock scores against the proteins, with acteoside, isoquercitrin, and rutin having the highest scores. However, considering the ADMET results, only magnatriol B, obovatol, and randaiol had optimal properties as candidates for neurodegenerative drugs. Conclusion: The electron-shuttling compounds of M. officinalis, magnatriol B, obovatol, and randaiol, have the potential to be a remedy for Parkinson’s Disease due to their high probability of binding to the proteins.

Evolution of lithium in the disc of the Galaxy and the role of novae

Context. Lithium plays a crucial role in probing stellar physics, stellar and primordial nucleosynthesis, and the chemical evolution of the Galaxy. Stars are considered to be the main source of Li, yet the identity of its primary stellar producer has long been a matter of debate. Aims. In light of recent theoretical and observational results, we investigate in this study the role of two candidate sources of Li enrichment in the Milky Way, namely asymptotic giant branch (AGB) stars and, in particular, novae. Methods. We utilised a one-zone Galactic chemical evolution (GCE) model to assess the viability of AGB stars and novae as stellar sources of Li. We used recent theoretical Li yields for AGB stars, while for novae we adopted observationally inferred Li yields and recently derived delay time distributions (DTDs). Subsequently, we extended our analysis by using a multi-zone model with radial migration to investigate spatial variations in the evolution of Li across the Milky Way disc and compared the results with observational data for field stars and open clusters. Results. Our analysis shows that AGB stars clearly fail to reproduce the meteoritic Li abundance. In contrast, novae appear as promising candidates within the adopted framework, allowing us to quantify the contribution of each Li source at the Sun’s formation and today. Our multi-zone model reveals the role of the differences in the DTDs of Type Ia supernovae and novae in shaping the evolution of Li in the various galactic zones. Its results are in fair agreement with the observational data for most open clusters, but small discrepancies appear in the outer disc.

The Large-scale Anisotropy and Flux (de)magnification of Ultrahigh-energy Cosmic Rays in the Galactic Magnetic Field

We calculate the arrival direction distribution of ultrahigh-energy cosmic rays (UHECRs) with a new suite of models of the Galactic magnetic field (GMF), assuming sources follow the large-scale structure of the Universe. Compared to previous GMF models, the amplitude of the dipole component of the UHECR arrival flux is significantly reduced. We find that the reduction is due to the accidentally coinciding position of the peak of the extragalactic UHECR flux and the boundary of strong flux demagnification due to the GMF toward the central region of the Galaxy. This serendipitous sensitivity of UHECR anisotropies to the GMF model will be a powerful probe of the source distribution as well as Galactic and extragalactic magnetic fields. Demagnification by the GMF also impacts the visibility of some popular source candidates.

Bidimensional Exploration of the warm-Temperature Ionised gaS (BETIS)

The extraplanar diffuse ionised gas (eDIG) is a key component for understanding the feedback processes that connect galactic discs and their halos. In this paper, we present the second study of the Bidimensional Exploration of the warm-Temperature Ionised Gas (BETIS) project, the aim of which is to explore the possible ionisation mechanisms and characteristics of the eDIG. We use a sample of eight edge-on galaxies observed with the Multi-Unit Spectroscopic Explorer (MUSE) integral field spectrograph (IFS) and apply the methodology developed in the first paper of the BETIS project for obtaining binned emission line maps. We find that the vertical and radial profiles of the [N II]/Hα, [S II]/Hα, [O III]/Hβ, and [O I]/Hα ratios depict a complex ionisation structure within galactic halos – which is influenced by the spatial distribution of H II regions across the galactic plane as observed from our line of sight–, with Lyman continuum photon leakage from OB associations constituting the main ionisation source. Moreover, the electron temperature and S+/S ionisation ratio also exhibit a dependency on the distribution of H II regions within the galactic discs. Our analysis excludes low-mass, hot, and evolved stars (HOLMES) as viable candidates for secondary ionisation sources to elucidate the unusual behaviour of the line ratios at greater distances from the galactic midplane. In contrast, we ascertain that shocks induced in the interstellar medium by star formation(SF)-related feedback mechanisms represent a promising secondary ionisation source of the eDIG. We present a suite of models integrating ionisation mechanisms arising from fast shocks and photoionisation associated with star formation. When applied to the classical Baldwin–Phillips–Terlevich (BPT) diagrams, these models reveal that the ionisation budget of the eDIG ranges from 20% to 50% across our sample, with local variations of up to 20% within individual galaxy halos. This contribution correlates with the presence of filaments and other structural components observed within galaxy halos. The presence of shocks is additionally supported by the observation of a high density of high [O I]/Hα ratios, which is characteristic of shock-compressed ionised gas, and is likely induced by feedback from regions of intense SF within the galactic disc. These results demonstrate consistency across all galaxies analysed in this sample.

Antimicrobial Potential of Scorpion-Venom-Derived Peptides.

The frequent and irrational use of antibiotics by humans has led to the escalating rise of antimicrobial resistance (AMR) with a high rate of morbidity-mortality worldwide, which poses a challenge to the development of effective treatments. A large number of host defense peptides from different organisms have gained interest due to their broad antibacterial spectrum, rapid action, and low target resistance, implying that these natural sources might be a new alternative to antimicrobial drugs. As important effectors of prey capture, defense against other animal attacks, and competitor deterrence, scorpion venoms have been developed as important candidate sources for modern drug development. With the rapid progress of bioanalytical and high throughput sequencing techniques, more and more scorpion-venom-derived peptides, including disulfide-bridged peptides (DBPs) and non-disulfide-bridged peptides (NDBPs), have been recently identified as having massive pharmacological activities in channelopathies, pathogen infections, and cancer treatments. In this review, we summarize the molecular diversity and corresponding structural classification of scorpion venom peptides with antibacterial, antifungal, and/or antiparasitic activity. We also aim to improve the understanding of the underlying mechanisms by which scorpion-venom-derived peptides exert these antimicrobial functions, and finally highlight their key aspects and prospects for antimicrobial therapeutic or pharmaceutical application.

Exploring marine natural products for identifying putative candidates as EBNA1 inhibitors: An insight from molecular docking, molecular dynamics, and DFT computations

Epstein-Barr virus (EBV), namely a DNA neoplasm virus, is liable for over 1 % of malignant neoplasms involving Hodgkin's and Burkitt's lymphoma as well as ventral cancer. Despite the crucial role of EBV in carcinoma evolution, no treatment has been discovered yet against EBV. Epstein-Barr nuclear antigen 1 (EBNA1), the EBV-encoded latent protein, is produced in all EBV-linked neoplasms and is the only latent protein in these cancer types. EBNA1 protein has multiple roles in the upkeep, reproduction, and EBV genome separation and can thus act as an attractive therapeutic target for treating EBV-related malignancies. In the past few decades, attempts have been made to develop specialized EBNA1 inhibitors to reduce EBNA1 expression or obstruct EBNA1-relied processes, but none has been approved yet. Marine natural products (MNPs) have garnered significant interest as potential sources of antiviral drug candidates. In seeking potent drug candidates to inhibit EBV reproduction, an MNP database containing >14,000 compounds was mined to hunt putative EBNA1 inhibitors using docking computations and molecular dynamics simulations (MDS). On the basis of binding energy (ΔGbinding) estimations over 200 ns MDS, UMHMNP351444649 and UMHMNP134128179 revealed a greater binding affinity towards EBNA1 compared to KWG, with ΔGbinding values of −35.6, −33.3, and −32.4 kcal/mol, respectively. Structural and energetical investigations of UMHMNP351444649 and UMHMNP134128179 complexed with EBNA1 were inspected, unveiling the great constancy of these inhibitors within the EBNA1 binding site. Moreover, the identified MNPs demonstrated favorable physicochemical and medicinal chemistry characteristics. Finally, density functional theory calculations were executed, and the results assured the outcomes obtained from docking computations and MDS. These findings proposed UMHMNP351444649 and UMHMNP134128179 as potential anti-EBV drug candidates that warrant further in-vitro and in-vivo assays.

4-Hydroxydictyolactone alleviates cerebral ischemia injury by regulating neuroinflammation and autophagy via AMPK signaling pathway

BackgroundCerebral ischemia (CI), a cerebrovascular disorder, is a major contributor to disability and mortality. Marine-derived compounds are an important source of new neuroprotective drug candidates. Xenicane-type diterpenes from brown algae of the genus Dictyota have exhibited potential neuroprotective effects against CI injury, attributed to their antioxidant properties. However, whether there are other underlying neuroprotective mechanisms of xenicane diterpenes against CI is still ambiguous. PurposeThis study aims to elucidate the neuroprotective efficacy and mechanism of 4-hydroxydictyolactone (HDTL) in the treatment of CI. MethodsThe LPS-induced BV2 cell model was used for anti-neuroinflammatory activity assay. Tandem Mass Tag (TMT)-based quantitative proteomics was employed to identify underlying mechanisms. The OGD/R-induced SH-SY5Y cell model and a MCAO mice model were used to assess the neuroprotective effect of HDTL against CI in vitro and in vivo. ResultsHDTL reduced inflammation in LPS-stimulated BV2 cells by inhibiting the IKK/IκB/NF-κB pathway and by enhancing AMPK phosphorylation. Additionally, in SH-SY5Y cells treated with OGD/R, HDTL facilitated autophagy and reduced apoptosis. The neuroprotective properties of HDTL were abrogated in AMPK- silenced SH-SY5Y cells. In MCAO mice, HDTL ameliorated CI injury as evidenced by decreases in neurological deficit scores and cerebral infarction. HDTL also promoted autophagy and reduced apoptosis in vivo through both the AMPK/mTOR and IKK/IκB/NF-κB pathways. ConclusionHDTL exhibits neuroprotective effects through regulating the AMPK/mTOR and IKK/IκB/NF-κB pathways. These findings suggest that HDTL is a promising therapeutic candidate for CI treatment.

Understanding the biosynthesis, metabolic regulation, and anti-phytopathogen activity of 3,7-dihydroxytropolone in Pseudomonas spp.

The genus Pseudomonas is a prolific source of specialized metabolites with significant biological activities, including siderophores, antibiotics, and plant hormones. These molecules play pivotal roles in environmental interactions, influencing pathogenicity, inhibiting microorganisms, responding to nutrient limitation and abiotic challenges, and regulating plant growth. These properties mean that pseudomonads are suitable candidates as biological control agents against plant pathogens. Multiple transposon-based screens have identified a Pseudomonas biosynthetic gene cluster (BGC) associated with potent antibacterial and antifungal activities, which produces 7-hydroxytropolone (7-HT). In this study, we show that this BGC also makes 3,7-dihydroxytropolone (3,7-dHT), which has strong antimicrobial activity toward Streptomyces scabies, a potato pathogen. Through metabolomics and reporter assays, we unveil the involvement of cluster-situated genes in generating phenylacetyl-coenzyme A, a key precursor for tropolone biosynthesis via the phenylacetic acid catabolon. The clustering of these phenylacetic acid genes within tropolone BGCs is unusual in other Gram-negative bacteria. Our findings support the interception of phenylacetic acid catabolism via an enoyl-CoA dehydratase encoded in the BGC, as well as highlighting an essential role for a conserved thioesterase in biosynthesis. Biochemical assays were used to show that this thioesterase functions after a dehydrogenation-epoxidation step catalyzed by a flavoprotein. We use this information to identify diverse uncharacterized BGCs that encode proteins with homology to flavoproteins and thioesterases involved in tropolone biosynthesis. This study provides insights into tropolone biosynthesis in Pseudomonas, laying the foundation for further investigations into the ecological role of tropolone production.IMPORTANCEPseudomonas bacteria produce various potent chemicals that influence interactions in nature, such as metal-binding molecules, antibiotics, or plant hormones. This ability to synthesize bioactive molecules means that Pseudomonas bacteria may be useful as biological control agents to protect plants from agricultural pathogens, as well as a source of antibiotic candidates. We have identified a plant-associated Pseudomonas strain that can produce 3,7-dihydroxytropolone, which has broad biological activity and can inhibit the growth of Streptomyces scabies, a bacterium that causes potato scab. Following the identification of this molecule, we used a combination of genetic, chemical, and biochemical experiments to identify key steps in the production of tropolones in Pseudomonas species. Understanding this biosynthetic process led to the discovery of an array of diverse pathways that we predict will produce new tropolone-like molecules. This work should also help us shed light on the natural function of antibiotics in nature.