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Rocaglates and pateamines target the DEAD-box RNA helicase eIF4A from Schistosoma mansoni and demonstrate anti-schistosomal activity in vitro
Abstract For decades, infections with the parasite Schistosoma mansoni have been treated with praziquantel, the only available drug, which highlights the urgent need of treatment alternatives. Natural compounds including rocaglates from plants of the genus Aglaia and pateamines isolated from the marine sponge Mycale hentscheli have exhibited promising anti-viral, anti-cancer, and anti-pathogenic properties. These compounds target the eukaryotic translation initiation factor 4A (eIF4A), which is a crucial factor for unwinding RNA structures in the 5’-UTR of selected mRNAs, and prevent the unwinding activity of eIF4A, which interferes with protein synthesis. Preliminary data indicated anthelminthic activity of the rocaglate silvestrol against S. mansoni in vitro. In this study, we confirmed the interaction of rocaglates and pateamines with recombinant S. mansoni eIF4A and analyzed the activity of these compounds against adult S. mansoni in vitro. Our findings showed reduced parasite vitality and stem-cell proliferation as well as impaired embryogenesis after rocaglate or pateamine treatment in the nanomolar range. Furthermore, we observed that rocaglate-treated S. mansoni recovered during washout experiments, while pateamine treatment displayed irreversible effects finally killing most of the worms. Although some properties of the used compounds impede their suitability as anti-schistosomal candidates, eIF4A remains a promising drug target in this parasite.
Tamoxifen induces region-specific osteocytic recombination and transiently alters bone structure in Dmp1-Cre-ERT2 mice
Numerical simulation on water migration in compacted loess subgrade under extreme rainfall conditions
Correction: Glyceraldehyde-3-phosphate dehydrogenase/1,3-bisphosphoglycerate-NADH as key determinants in controlling human retinal endothelial cellular functions: Insights from glycolytic screening
Physiology and reproductive responses of disease-free soybean plants to triazole, strobilurin, and carboxamide fungicides under greenhouse conditions
An isotype-specific phosphorylation of Hsp90 rewires co-chaperone regulations
Transient recovery voltage for load current switching test of MV load break switch
Circulating inflammatory biomarkers and antifungal susceptibility in Candida albicans vulvovaginal candidiasis: a retrospective observational cohort study
Environmental serious games foster pro-environmental intentions through spillover moderated by connectedness to nature and awe
Projected region-of-attraction analysis of coupled two-region low-altitude air traffic using microsimulation-calibrated MFDs
Quantifying land use trade-offs in Sub-Saharan Africa: spatiotemporal dynamics and drivers of production-living-ecological spaces in Tanzania (2000–2020)
Integrated computational and in vitro analysis reveals the toxic mechanisms of PFAS in female diminished ovarian reserve
Wavelet-derived periodic variability and regional differences of surface ozone in southeastern Nigeria from 2002 to 2023
A bilateral US-UK airplane wastewater monitoring pilot demonstrates the feasibility of an international wastewater surveillance network
Abstract We present findings from the first known pilot study of transatlantic airplane wastewater monitoring, conducted over six months at two connected international airports in the United States and the United Kingdom. This study demonstrates the feasibility of implementing bilateral wastewater-based pathogen surveillance at international travel hubs. We outline the operational and analytical methodologies employed, highlight key challenges encountered in transnational coordination, and provide recommendations for the design and implementation of future surveillance programs at points of entry.
Volumetric comparison of brain structures in early and advanced bilateral glaucoma patients using 7 tesla MRI
Abstract Glaucoma is a progressive neurodegenerative disorder characterized by retinal ganglion cell loss and corresponding visual field (VF) impairment. Although traditionally viewed as an ocular disease, accumulating evidence suggests involvement of central nervous system structures, particularly the lateral geniculate nucleus (LGN). In this cross-sectional study, we enrolled 67 participants: 25 with bilateral early-stage glaucoma, 27 with bilateral advanced-stage glaucoma, and 15 age-matched healthy controls. All participants underwent 7‑Tesla magnetic resonance imaging, including high-resolution 3D T1‑weighted and magnetization transfer‑weighted SILENT sequences. LGN volumes were manually segmented, and whole‑brain volumetry was assessed with FreeSurfer. Compared with both early glaucoma patients and healthy controls, advanced glaucoma patients presented significantly reduced LGN volumes. LGN volume was positively correlated with retinal nerve fiber layer thickness, particularly in the superior and inferior quadrants, and decreased with increasing visual field loss expressed as mean deviation (MD). The correlation between LGN volume and MD was stronger for the right side than for the left side. No significant volumetric differences were observed in other major visual or brain regions across groups. These findings support structural involvement of the central visual pathway in glaucoma and suggest that LGN volume may reflect disease severity, particularly in advanced stages. At present, 7 Tesla MRI should be considered primarily as a research tool that may complement understanding of glaucoma related visual pathway changes.
A novel CD69 binding ankyrin repeat protein (Ankyron®) enables detection of early activated and antigen-specific T cells in pigs
Abstract T cells are essential for a wide range of protective immune responses, but significant gaps remain in our understanding of their phenotypic and functional diversity, especially in large animal models, like the pig. This is partly due to the limited availability of porcine-specific reagents and validated markers to study T-cell activation and differentiation. One marker involved in both of these processes is CD69: In mice and humans, it serves as an early activation marker and is used to define tissue-resident memory T cells. However, its use for the identification and functional assessment of T-cell subsets in pigs has been previously restricted by the lack of monoclonal antibodies. To address this limitation, we evaluated an alternative approach to antibodies: A novel ankyrin repeat protein, Ankyron ® EG40360, was used as a tool to detect porcine CD69. Ankyrin repeat proteins offer advantages over conventional antibodies, including their small size and simplified integration into flow cytometry panels due to the absence of isotype restrictions. We confirmed specific binding of Ankyron EG40360 to porcine CD69 using both flow cytometry and microscopy in porcine CD69-transfected HEK293T cells. Thereafter, we studied CD69 expression in PBMCs stimulated with PMA/ionomycin. While CD69 was basically absent in non-stimulated control cells, CD69 was highly expressed upon PMA/ionomycin stimulation as early as 4 h post stimulation. Thereby, we could confirm CD69 as an early marker of lymphocyte activation in pigs. To further assess the expression of CD69 with the Ankyron EG40360 in a more natural setting, we studied CD69 expression in PBMCs from pigs that received a protein subunit vaccine. Following in vitro restimulation with the vaccine antigen, the frequency of CD4 and CD8 T cells expressing CD69 and CD25 increased indicating detection of antigen-specific T cells and making CD69 a potential target for activation-induced marker assays in pigs. Thus, Ankyron EG40360 expands the porcine immunology toolkit and will facilitate a more comprehensive characterization of activated T cells in vaccine development and infection studies.