Search Results (462)

Background/Objectives/Methods: A bioassay-informed investigation of the Australian pasture soil-derived Streptomyces sp. S4S-00193A39 yielded the anthelmintic principals as three new spiroketal polyketide alkaloids, goondoxazoles A–C (1–3), with structures assigned by detailed spectroscopic analysis. Results: A structure–activity relationship based on the ability to inhibit the motility of Dirofilaria immitis microfilariae (mf) revealed a positive correlation for the benzoxazole moiety present in 2 and 3 (EC₅₀ 55–85 nM) versus the ring-opened aminobenzoic acid moiety evident in 1 (EC₅₀ 1.38 µM). This hypothesis was strengthened by extension of the SAR assessment to the known benzoxazole natural products A-33583 (12), UK-1 (13) and nataxazole (14), and the new analogue 5-hydroxynataxazole (15), which were isolated in our lab from three additional Australian pasture soil-derived Streptomyces spp. Of note, while the benzoxazole methyl esters 13–15 exhibited approximately 9- to 65-fold lower potency against D. immitis mf compared with 2 and 3, the carboxylic acid substituted benzoxazole 12 displayed comparable activity (EC₅₀ 72 nM) against D. immitis mf, and >5-fold improved potency against D. immitis L4 larvae (EC₅₀ 0.43 µM). Conclusions: These observations reveal the promising anthelmintic potential (against D. immitis) for the new structurally complex and chiral goondoxazoles (e.g., 2 and 3), and demonstrate that this effect can be replicated, even improved, by simpler, achiral benzoxazole microbial natural products (e.g., 12). Full article

Background/Objectives: Bacterial biofilms are structured communities of sessile cells embedded in a self-produced extracellular matrix. Within biofilms, bacteria become highly tolerant toenvironmental stressors such as host immune responses and antimicrobial treatments. In response to specific cues, however, biofilm cells can revert to a planktonic free-swimming lifestyle through a process termed biofilm dispersal. When dispersed cells escape the biofilm matrix, they lose biofilm-associated antibiotic tolerance, a major barrier to treating medical biofilms. As such, dispersal-inducing compounds like nitric oxide (NO) are actively investigated as adjuvants to potentiate the biofilm-eradicating activity of existing antibiotics. We recently characterised the transcriptomic responses elicited during spontaneous biofilm dispersal in closed culture-grown Pseudomonas aeruginosa biofilms. Here, we evaluated the transcriptional profiles of P. aeruginosa biofilms treated with the NO donor Spermine-NONOate (SP-NONO) and the nitroxide C-TEMPO, an NO analogue, to determine potential pathways involved in NO-mediated dispersal. Methods: Dispersal activity on P. aeruginosa PAO1 biofilms by SP-NONOate and C-TEMPO was quantified by crystal violet staining. Cellular responses to each compound were profiled by RNA-seq on treated and untreated cells. Results: While both compounds disrupted the transcription of ANR-regulated energy metabolism pathways, only SP-NONO activated canonical NO-regulated responses. Considering that only SP-NONO showed biofilm dispersal activity in this culture system, we investigated shared transcriptional shifts in SP-NONO-treated and spontaneously dispersed biofilms to identify pathways likely involved in central dispersal responses. These mostly included genes involved in the catabolism of branched-chain amino acids (leucine, valine, isoleucine) and lysine, as well as 9 of 14 genes previously defined as transcriptional biomarkers of spontaneous biofilm dispersal. Conclusions: This study suggests that NO disrupts biofilm maturation by prematurely stimulating central pathways of spontaneous biofilm dispersal and highlights this set of biomarkers as robust indicators of dispersal responses. Full article

Müllerian anomalies are anatomical variations of the female reproductive tract resulting from the incomplete development of the embryonic Müllerian ducts. The molecular mechanisms driving Müllerian duct development are complex and poorly understood, resulting in the largely unexplained aetiology of these conditions. WNT5A is a critical regulator of key developmental processes, including patterning, cell proliferation, and migration. Mutations of WNT5A have been associated with Robinow syndrome, a congenital condition characterized by skeletal and genital anomalies. In the mouse, WNT5A is necessary for the posterior development of the Müllerian duct, and ablation of Wnt5a results in vaginal agenesis. However, Wnt5a-/- uterine horns are hypoplastic and over 60% shorter than the wild type, suggesting specific functions in anterior Müllerian duct development. To better understand the role of Wnt5a, we performed single-cell RNA sequencing of developing Müllerian ducts. We found that the non-canonical Wnt PCP pathway was dysregulated in Wnt5a-/- mice. In addition, Wnt5a-/- Müllerian ducts were enriched in oviductal mesenchymal cells due to the transformation of the anterior uterine horns into oviducts. Our results indicate additional roles for Wnt5a during Müllerian duct development, prompting further investigations into uterine functions and anatomy in complex clinical cases of Müllerian anomalies including Robinow syndrome. Full article

After numerous false starts, the global microalgae industry is re-emerging, driven by its potential to address critical challenges in food and nutrition, sustainable energy, nutraceuticals, cosmetics and pharmaceuticals, and climate change mitigation. Although technical advances in microalgae production show value adding potential, progressing from innovation to product launch and competitiveness is complex. It requires an integrated understanding of technology readiness, regulatory compliance, financial necessities, and market competition. This study presents a novel analytical framework underpinning a data-enabled, evidence-based approach to navigating the innovation pathways to market and beyond. The framework integrates value-add opportunities, identifying key stages faced in pre-competitive (including Technology Readiness Level (TRL), R&D spend, and patent trends), and competitive market stages (including product launches, product claims, market size, market share, growth/maturity, international markets, distribution channels, sectoral profile, and competitive landscape), aligned with regulatory requirements. Although not without limitations, such as incomplete data for emerging products, as well as reliance on secondary sources for product stage determination and market size estimates which can influence the accuracy of TRL classification and market potential estimates. This integration of multiple analyses can help in identifying market opportunities and business competitiveness via product, business, and industry level analyses in the pre-competitive (pre-market launch) and competitive (on market) landscapes. Building on the team’s interdisciplinary experience of developing interactive dashboards for food and beverage industries, and microalga processes, this paper provides an overview of the framework, which was designed to guide businesses and researchers in an emerging microalgae industry through the complex landscape of product development along regulatory and commercial pathways. Full article

Delivering net-zero CO₂ emissions by 2050 requires rapid, large-scale carbon sequestration. Global photosynthesis, driven by cyanobacteria, microalgae, and higher plants, captures CO₂ and constitutes the dominant natural carbon sink (biomass). The built environment represents a second major sink. Large-scale microalgal cultivation and the integration of its bioproducts into building materials offers a pathway to capture and store CO₂ in built infrastructure. Colourful sustainably produced biopolymers offer one such route for carbon sequestration. Although pigments have a minor direct contribution, their coloration potential can accelerate the adoption of C-containing materials to increase architectural carbon sequestration. Here, we blended (individually and in combination) a range of structurally different pigments; the carotenoids—lutein (yellow) and astaxanthin (red), a water-soluble chlorophyll derivative—sodium copper chlorophyllin (green), and a water-soluble protein (phycocyanin, blue) into two biopolymers, polyhydroxybutyrate-hydroxyhexanoate and polycaprolactone with melting points of 135 °C and 60 °C, respectively. Six blending processes were evaluated for homogeneous coloured biopolymer production. UV resistance of coloured biopolymers was evaluated and enhanced by the application of a UV-protective coating. The best of the coloured biopolymer samples were integrated into a small-scale curved architectural structure to gain insight into the use and performance of the translucent materials produced for exhibition. Full article

Equinin B (GQCQRKCLGHCSKKCPKHPQCRKRCIRRCFGYCL), a marine peptide from Actinia equina exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria. To identify a smaller active region and explore tunable properties, three peptide fragments were synthesized: GQCQRKCLGHCS (EB1), KKCPKHPQCRK (EB2), and RCIRRCFGYCL (EB3), yielding peptides with key AMP-like properties, including the most positively charged and most hydrophobic regions. Only the 11-residue C-terminal fragment showed selective activity against Gram-positive bacteria, including Staphylococcus epidermidis, Bacillus subtilis, and Enterococcus hirae, while remaining inactive against Escherichia coli. Peptide modifications, achieved by replacing cysteine residues with arginine, generally did not enhance activity, but in the C-terminal fragment EB3 they reduced hemolytic activity and increased bacterial specificity. Membrane depolarization assays confirmed that the unmodified fragment EB3 strongly compromises bacterial membranes, whereas the modified variant showed minimal depolarization, highlighting its markedly reduced membrane-perturbing potential. In silico modelling revealed that the EB3 can adopt multiple membrane-disruption modes, from transient shallow pores to carpet-like mechanisms, while the cysteine-to-arginine variant interacts mainly via partial insertion anchored by arginine residues. Phenylalanine appears to interact with the membrane, and reducing hydrophobicity by its removal abolished antibacterial activity. These findings highlight the 11-residue C-terminal fragment as a tunable, membrane-targeting motif with mechanistic novelty, offering a blueprint for developing safer, selective antimicrobial peptides with reduced cytotoxicity. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with uncertain etiology. Chronic viral infection, including Epstein–Barr virus (EBV), has been implicated as a potential driver of repetitive epithelial injury and dysregulated repair. We sought to evaluate and define the breadth versus specificity of EBV-directed humoral immunity in IPF. We performed proteome-scale serological profiling using an EBV protein microarray (202 proteins) representing all proteins expressed by the EBV proteome (type I and II) on plasma samples from 32 patients with confirmed IPF (87.5% male; mean age 60.9 years) and 15 healthy disease-free controls (40% male; mean age 57.9 years). Per-sample global EBV IgG means were higher in IPF than controls (Welch p = 0.005), and the difference persisted after sex adjustment (p = 0.012). Although no single antigen met a stringent FDR significance threshold, 10 EBV antigen-specific antibody responses showed nominal elevation in IPF, with 2 remaining nominally significant after sex adjustment and 5 additional antibody responses reaching significance only in linear regression models. Overall, these results support the concept that IPF is associated with a diffuse elevation of EBV-directed humoral responses rather than antigen-specific dominance, consistent with ongoing, low-level viral reactivation. The presence of an EBV-negative subgroup within the IPF cohort underscores etiological heterogeneity within IPF. Full article

To clarify microbial assembly during saline–alkali wetland degradation, we analyzed bacterial (16S rRNA) and fungal (ITS) communities across four habitats: pristine wetland (PW), transitional meadow wetland (TMW), halophytic herbaceous community (HHC), and converted farmland (CF). Soil water content collapsed from PW (42.22%) to ≤18.40% elsewhere, and soils were alkaline with pH highest in HHC (10.08). Nutrient pools and enzyme activities were highest in PW (SOC 35.03 g kg⁻¹; URE 142.58 mg g⁻¹; SUC 527.83 mg g⁻¹) but declined sharply under natural degradation, reaching minima in HHC (SOC 8.02 g kg⁻¹). ACP and CAT were also lowest in HHC. Bacterial communities were dominated by Actinomycetota and Pseudomonadota, with Acidobacteriota and Bacillota enriched in CF. Bacterial diversity peaked in CF, whereas fungal richness was highest in CF and Shannon diversity peaked in TMW. Ordination and redundancy analyses indicated stronger edaphic control on bacteria than fungi, with pH, SOC, and moisture as key drivers. Null-model analyses showed bacterial assembly shifted toward deterministic selection under saline–alkali stress and agricultural conversion, whereas fungal assembly remained predominantly stochastic. Co-occurrence networks further suggested higher bacterial vulnerability under extreme degradation but comparatively higher fungal robustness. Overall, bacteria and fungi follow divergent assembly rules during saline–alkali wetland degradation. Full article

The red fluorescent protein mCherry is one of the most widely used fluorescent proteins in biology. Here, we have changed the chromophore chemistry by converting the thioether group of M66 to a thiol group through mutation to cysteine. The new variant, termed mCoral (due to its orange fluorescence hue), has similar brightness to mCherry but improved resistance to hydrogen peroxide. The variant is also responsive to pH with low and high pKa forms that have distinct spectral properties, which DFT analysis suggests is due to protonation state changes in the newly introduced thiol group, as well as the phenol group. The structure of mCoral reveals that the M66C mutation creates a space within the β-barrel structure that is filled by a water molecule, which makes new polar interactions, including the backbone carbonyl group of F65. Molecular dynamics simulations suggest that this additional water molecule, together with local solvation around the chromophore, could play a role in promoting planarity of the full conjugated system comprising the chromophore. The mCoral chromophore makes slightly more H-bonds with water than mCherry. The main water exit point for mCherry is also narrower in mCoral, providing a potential explanation for increased resistance to hydrogen peroxide. Overall, a small structural change to mCherry has resulted in a new fluorescent protein with potentially useful characteristics and an insight into the role of dynamics and water in defining the structure–function relationship in red fluorescent proteins. Full article

Natural products are and continue to be a remarkable resource, rich in structural diversity, and endowed with valuable chemical and biological properties that have advanced both science and society. Some natural products, especially those from marine organisms, are chemically reactive, and during extraction and handling can partially or totally transform into artifacts. All too often overlooked or mischaracterised as natural products, artifacts can be invaluable indicators of a uniquely evolved and primed chemical space, with enhanced chemical and biological properties highly prized for drug discovery. To demonstrate this potential, we review a wide selection of marine and microbial case studies, revealing the factors that initiate artifact formation (e.g., solvents, heat, pH, light and air oxidation) and commenting on the mechanisms behind artifact formation. We conclude with reflections on how to recognise and control artifact formation, and how to exploit knowledge of artifacts as a window into unique regions of natural product chemical space—to better inform the development of future marine bioproducts. Full article

LD-Transpeptidases (LDTs) are a widely conserved class of peptidoglycan (PG) crosslinking enzymes in bacteria. They are sometimes overlooked as they often act secondary to penicillin binding proteins (PBPs) under standard conditions. However, LDTs are essential in key pathogens such as Clostridioides difficile and are responsible for β-lactam resistance in Mycobacterium tuberculosis and Enterococcus faecium due their low affinity for penicillins and cephalosporins, allowing them to form LD-crosslinks when DD-crosslinking PBPs are inactivated. This role makes LDTs a promising target when developing new treatments for these pathogens. LDTs can perform different enzymatic reactions. Most commonly they reinforce the PG with 3,3-LD-crosslinks or, in a few cases, 1,3-LD-crosslinks, during stationary phase or stress responses. Some LDTs also incorporate endogenous and exogenous non-canonical D-amino acids into the PG. In many Gram-negative bacteria, specialised LDTs tether lipoproteins or outer membrane proteins (OMPs) to the PG to maintain cell envelope integrity; in some cases this regulates virulence factors. Specialised LDTs have also been implied to have roles in polar growth, toxin secretion, and symbiotic colonisation. Recent discoveries include novel subgroups of the major YkuD family and the identification of the VanW family; this has opened new research directions surrounding LDTs. We aim to understand LDTs and their roles to expand our knowledge of PG synthesis and modification and how these enzymes can be targeted for antibiotic treatment. Full article

Chronic and hard-to-heal wounds remain burdensome because microbial contamination, dysregulated inflammation, and fragile tissue regeneration slow closure, while passive dressings often injure new tissue during removal. This review synthesizes polymer- and lipid-based nanostructures through a barrier-resolved lens that links composition, architecture, and processing to performance in protease- and salt-rich exudate across topical and transdermal routes. Quantitative trends include effective diameters of approximately 50–300 nm, practical constraints of sterile filtration at 0.2 μm, and therapeutic windows that prioritize contamination control on the first day, support proliferation around day three, and sustain remodeling beyond one week. Mechanistic evidence indicates that interfacial charge and the protein corona govern residence and uptake, lipid bilayers enable dual loading, degradable polymer matrices provide depot-like behavior, and hybrid constructs temper the early burst while improving storage stability. Full article

Spider-derived venoms are a rich source of cystine knot peptides with immense therapeutic potential. Many of these peptides exert unique biological activities through the modulation of ion channels, including of human voltage-gated sodium (Na_V1.1–Na_V1.9) channels. Na_V channel subtypes have diverse functions determined by their tissue and cellular distribution and biophysical properties, and are pathophysiology mediators in various diseases. Therefore, Na_Vs are central in studies of human biology. This work investigated the pharmacological properties of venom of the Thai theraphosid Ornithoctonus aureotibialis on Na_V channels. We discovered a predominant venom peptide named Oa1a and assessed its pharmacological properties across human Na_V channel subtypes. Synthetic forms of the peptide Oa1a showed preferential inhibition of Na_V1.1 and Na_V1.7, while recombinant Oa1a displayed a preference for inhibiting Na_V1.2, Na_V1.6, and Na_V1.7. Interestingly, all versions of Oa1a peptides exerted dual pharmacological effect by reducing the peak current and slowing fast inactivation of Na_V1.3, consistent with Oa1a having more than one binding site on Na_V channels. Such complex pharmacology was previously observed for a venom peptide in a Central American and Costa Rican tarantula, suggesting a conserved mechanism of action amongst these geographically distinct species. However, Oa1a lacked activity in the T-type channels observed in the tarantula peptide from Central America. Structure–function relationships investigated using molecular modelling showed that the dual pharmacology is driven by a conserved mechanism utilizing a mix of aromatic and charged residues, while the T-type activity appears to require additional charged residues in loop 2 and fewer positive charges in loop 4. Future structure–activity relationship studies of Oa1a will guide the development of pharmacological tools as well as next-generation drugs to treat Na_V channel dysfunction associated with neurological disorders. Full article

We adapt previous conceptual and numerical models of ciguateric food chains for the bioaccumulation of Pacific-ciguatoxin-1 (P-CTX-1) to a general model for bioaccumulation of P-CTX3C by parrotfish (Scarus frenatus, S. niger, and S. psittacus) that feed by scraping turf algae, and surgeonfish (Naso unicornis) that mostly feed on macroalgae. We also include the Indian Ocean parrotfish Chlorurus sordidus as a model for an excavator feeding parrotfish and include comparisons with the detritivorous surgeonfish Ctenochaetus striatus that brush-feeds on turf algae. Our food chain model suggests that, of the Gambierdiscus and Fukuyoa species so far analysed for ciguatoxin (CTX) production from the Pacific, only G. polynesiensis produces sufficient P-CTX3C to consistently produce parrotfish or N. unicornis with poisonous flesh. Our model suggests that insufficient CTX would accumulate into the flesh of parrotfish or N. unicornis to become poisonous from ingesting benthic dinoflagellates producing ≤0.03 pg P-CTX3C eq./cell, except from extended feeding times on high-density blooms and in the absence of significant depuration of CTX. Apart from G. polynesiensis, only G. belizeanus and possibly G. silvae and G. australes are thought to produce >0.03 pg P-CTX3C eq./cell in the Pacific. However, with relatively low maximum concentrations of ≤0.1 pg P-CTX3C eq./cell it is likely that their contribution is minimal. Our model also suggests that the differences between the area of turf algae grazed by parrotfish and similar sized C. striatus results in greater accumulation of CTX by this surgeonfish. This makes C. striatus a higher ciguatera risk than similar sized parrotfish, either directly for human consumption or as prey for higher trophic level fishes, consistent with poisoning data from Polynesia. It also suggests the possibility that C. striatus could bioaccumulate sufficient CTX to become mildly poisonous from feeding on lower toxicity Gambierdiscus or Fukuyoa species known to produce ≥0.02 P-CTX3C eq./cell. This indicates the potential for at least two food chain pathways to produce ciguateric herbivorous fishes, depending on the CTX concentrations produced by resident Gambierdiscus or Fukuyoa on a reef and the grazing capacity of herbivorous fish. However, only G. polynesiensis appears to produce sufficient P-CTX3C to consistently accumulate in food chains to produce higher trophic level fishes that cause ciguatera in the Pacific. We incorporate CTX depuration into our model to explore scenarios where mildly poisonous parrotfish or N. unicornis ingest CTX at a rate that is balanced by depuration to estimate the Gambierdiscus/Fukuyoa densities and CTX concentrations required for these fish to remain poisonous on a reef. Full article

Background: Human bioaccumulation of micro- and nanoplastics (MNPs) is increasingly being recognised in the aetiology and pathophysiology of human disease. This systematic scoping review aims to provide a comprehensive investigation of studies examining the presence and effects of MNPs on the human pulmonary system. Methods: A scoping review was conducted in line with JBI guidelines. Five databases (PubMed, SCOPUS, CINAHL, Web of Science and EMBASE) were systematically searched. Results: Sixty-eight articles were identified, with fifteen reporting the presence of MNPs in human respiratory tissues and fluids. The data reported in the remaining toxicology-focused studies suggest that MNPs induce widespread cellular dysfunction in pulmonary-related human cell lines. Exposure to MNPs was associated with significant cytotoxicity, genotoxicity and altered metabolic activity, including mitochondrial damage, increased reactive oxygen species and reduced membrane potential. Functionalised and smaller particles had more pronounced effects. Conclusions: The reported presence of MNPs, coupled with their biological toxicity, represents a growing global health concern. Evidence suggests MNPs may contribute to the rising burden of pulmonary disease worldwide, including cancer, COPD, interstitial lung disease and ARDS. Urgent international research is needed to characterise exposure pathways, develop standardised detection methods and understand the long-term health implications of MNP inhalation across the lifespan. Full article