48674 research outputs found
Sort by
A facile route to ‘naked’ Ag+ ions enabling the coordination of the weak Lewis base Ni(CO)4
No full textThe reaction of AgCN with two equivalents of tris(pentafluorophenyl)borane (BCF) in CH2Cl2 or ortho-difluorobenzene (oDFB) provides a straightforward access to (solvated) Ag+ salts of the weakly coordinating cyanide-bridged anion [µ-(CN)(BCF)2]− (suggested abbreviation [BCNB]). Reacting Ag[BCNB] with Ni(CO)4 yields the first structurally characterized complex in which Ni(CO)4 acts as a ligand towards a transition metal ion proving the extremely low basicity of the anion
Pesticide, Veterinary Medicines, and Microplastics: Bipartite and Tripartite Interactions Drive the Transformation of Albendazole and Pyraclostrobin in Agricultural Soils
No full textSoil constitutes a major sink for microplastics (MPs). In agricultural soils, microplastics co-occur with pesticides and veterinary medicines like anthelminthics (AHs). Little is known regarding the influence of microplastics on the dissipation of these organic pollutants. We hypothesized (a) that microplastics due to their hydrophobic surfaces would affect the dissipation of the anthelminthic albendazole (ABZ) and the fungicide pyraclostrobin (PYR), and (b) the outcome of this interaction will vary depending on the type (PBAT-based, Starch-based, and LDPE-based) and the concentration (0.1 and 0.01%) of plastics. (c) Besides microplastics, the co-occurrence of ABZ and PYR will influence each other’s dissipation. We tested the dissipation of ABZ and PYR in the presence and absence of microplastics in three soils. The dissipation of ABZ was accelerated in the presence of microplastics in Greek soil (DT50 2.8–8.2 days vs 13.9 days in the control) but not in the other two soils, while microplastics had no effect on the dissipation of PYR in all three soils. No systematic type- or concentration-driven effect of microplastics on ABZ and PYR soil dissipation was observed in the three soils. Regardless of microplastics’ presence, ABZ delayed PYR dissipation in Greek soil (DT50 47.5 to 99.4 days), an effect further exacerbated in the presence of microplastics (DT50 47.0–59.9 to 72.1–117.5 days). We suggest that complex tripartite interactions between pesticides–anthelminthics–microplastics are operative in agricultural soils affecting the dissipation of pesticides and anthelminthics. These interactions are not considered in the current framework of chemical risk assessment, and they are expected to have serious implications, undermining environmental quality and soil health
Characterizing mixed strongyle infections in foals and broodmares using cytochrome c oxidase subunit I deep amplicon sequencing
No full textBackground
Mixed strongyle infections represent the most prevalent equine parasitosis and can result in life-threatening disease, especially in young horses. Species involvement and pathogenesis of this parasitosis are poorly understood, and data on foals and broodmares are notably lacking.
Methods
In a longitudinal study undertaken in 2022 in Germany, individual faecal samples (n = 497) and metadata were collected for naturally infected foals and broodmares (n = 48) kept under conventional husbandry conditions. Nematode infections were detected coproscopically via the Mini-FLOTAC method. In a subset of strongyle egg-positive samples (n = 46), species were identified using cytochrome c oxidase subunit I deep amplicon sequencing. Species prevalence, richness, and alpha and beta diversity were compared between foals and mares.
Results
Overall, 22.2% of the foal samples and 10.2% of the mare samples were strongyle egg positive (eggs per gram > 5). Parascaris spp. were only detected in foals (15.1%). Strongyloides westeri was detected in one foal sample. Strongyle egg detection increased in likelihood with each additional sample timepoint (OR = 1.42, P < 0.001) and with ascarid egg detection (OR = 6.49, P < 0.001), while last anthelmintic treatment with pyrantel decreased the odds of detecting eggs (OR = 0.12, P = 0.002). Deep amplicon sequencing detected 16 species of small strongyles but no large strongyle species. Cylicostephanus goldi, Cylicostephanus minutus operational taxonomic unit II and Cylicocyclus ashworthi were significantly more prevalent in mares (P < 0.05), while Cylicostephanus calicatus operational taxonomic unit II was more prevalent in foals (P < 0.01). Mares showed a significantly higher amplicon sequence-variant-based richness (Chao 1 index, P < 0.001) and diversity (inverse Simpson index, P < 0.01) than foals. Group (foals vs. mares) explained some of the variance in beta diversity, according to permutational multivariate ANOVA. Co-infection with Parascaris spp. did not affect strongyle community composition in the foals. Bray–Curtis and Jaccard distance (dissimilarity) plots showed separate clusters for mares and foals, with some overlap and a moderate model fit.
Conclusions
Cytochrome oxidase-based characterization of mixed strongyle infections revealed strongyle community differences between broodmares and foals. Possible age associations were identified for four species of small strongyles, including two cryptic species. Low overall strongyle prevalence and egg-shedding intensity, non-random sampling and differences in anthelmintic treatment schemes limited the statistical power of this study
Development of a 3D printed multiple unit particle system (MUPS) containing metoprolol succinate
No full textThis study presents the development and characterisation of dual extrusion 3D printed multiple unit particle system (MUPS) tablets incorporating metoprolol succinate. Pharmaceutical-grade filaments were prepared via hot-melt extrusion, comprising a drug loaded sustained release formulation of Eudragit® RL PO, and a rapidly disintegrating tablet shell formulation based on Kollicoat® IR. The use of fused filament fabrication enabled the integration of drug-loaded cylindrical particles within the tablet shell. Comprehensive morphological and structural analyses, including scanning electron microscopy, X-ray micro-computed tomography, and digital microscopy, confirmed uniform particle geometry and distribution. The manufactured tablets met European Pharmacopoeia (Ph. Eur.) specifications for mass uniformity. Disintegration testing demonstrated complete disintegration of the tablet shell within 15 min. X-ray powder diffraction indicated the active pharmaceutical ingredient (API) was present in an amorphous state post-processing. High-performance liquid chromatography analysis revealed thermal degradation during 3D printing, with a reduction in API content from 97.8 % in the extruded filament to 65.9 % in the printed MUPS tablets. A linear correlation between the number of printed particle layers and the final drug content was shown, supporting the concept of dose individualisation. In vitro dissolution testing showed that 80 % of the incorporated API was released within 105 to 150 min. The findings confirm the feasibility of producing API-3D-MUPS tablets using pharmaceutical-grade materials, while also identifying critical product defects, formulation and process parameters such as thermal instability of the API or particle agglomeration - that require further optimisation of formulation and process parameters to enable broader application in personalised drug delivery
LncRNA CISTR-ACT regulates cell size in human and mouse by guiding FOSL2
No full textOrganisms regulate cell size and shape to function efficiently. Aberrant cell morphogenesis is commonly associated with disease, yet gene-regulatory mechanisms remain unknown. CISTR-ACT was the first lncRNA involved in inter- chromosomal proximities and Mendelian disease, and it is associated with mean corpuscular volume (red blood cell size). Here, functional dissection of CISTR-ACT ’s DNA- and RNA-encoded mechanisms by in vitro and in vivo perturbations reveals that CISTR-ACT regulates cell size across cell types and species. CISTR-ACT ’s locus is embedded in a stable inter- chromosomal environment which contains cell size genes that are regulated by CISTR-ACT in trans. CISTR-ACT ’s RNA also has function and directly interacts with transcription factor FOSL2 to guide its regulation of cell morphogenesis and cell-cell adhesion genes. In the absence of CISTR-ACT , the FOSL2-chromatin binding is perturbed. Our study exemplifies how a functionally conserved lncRNA regulates cell size with multiple modes of action and ultimately contributes to clinically relevant phenotypes
Predictive Processing Over the Course of Aging: Multiple Timescales of Effective Connectivity
No full textPredictive processing theories describe perception as a dynamic interplay between top-down predictions and bottom-up prediction errors across hierarchical stages of sensory processing. However, it remains unclear how neural connectivity flexibly adapts to changing sensory environments over time, and how these dynamics are influenced by aging. This study investigated how temporal factors on three distinct timescales, as well as age, shape neural responses and connectivity to dynamically changing auditory stimuli. Electroencephalography (EEG) data were recorded from 63 participants aged 18–75 as they listened to sequences of tones, where rare and unexpected “original deviants” became standards over time, and previously standard tones became “reverse deviants.” Event-related potentials (ERPs) were more pronounced for original deviants than reverse deviants. Amplitudes increased on short timescales (seconds) but declined over longer timescales (minutes) and with advancing age. To infer the neural mechanisms underlying these effects, dynamic causal modelling (DCM) was used to analyze effective connectivity. DCM revealed increased descending (top-down) connectivity for original deviants, consistent with a stronger reliance on predictions. Additionally, intrinsic (within-region) connectivity increased over seconds but decreased over minutes, reflecting timescale-dependent neural adaptation. Aging was associated with stronger modulation of descending connectivity by deviant type but weaker modulation by slow dynamics. These results underscore the brain's ability to dynamically adapt to changing sensory environments at multiple timescales and for the first time reveal age-related changes in the dynamics of this adaptation
Structural basis of quinone sensing by the MarR-type repressor MhqR in Staphylococcus aureus
No full textThe MarR-family regulator MhqR of Staphylococcus aureus (SaMhqR) was previously characterized as a quinone-sensing repressor of the mhqRED operon. Here, we solved the crystal structures of apo-SaMhqR and the 2-methylbenzoquinone (MBQ)-bound SaMhqR complex. AlphaFold3 modeling was used to predict the structure of SaMhqR in complex with its operator DNA. In the DNA-bound SaMhqR state, S65 and S66 of an allosteric α3–α4 loop adopted a helically wound conformation to elongate helix α4 for optimal DNA binding. Key residues for MBQ interaction were identified as F11, F39, E43, and H111, forming the MBQ-binding pocket. MBQ binding prevented the formation of the extended helix α4 in the allosteric loop, leading to steric clashes with the DNA. Molecular dynamics (MD) simulations revealed an increased intrinsic dynamics within the allosteric loop and the β1/β2-wing regions after MBQ binding to prevent DNA binding. Using mutational analyses, we validated that F11, F39, and H111 are required for quinone sensing in vivo, whereas S65 and S66 of the allosteric loop and D88, K89, V91, and Y92 of the β1/β2-wing are essential for DNA binding in vitro and in vivo. In conclusion, our structure-guided modeling and mutational analyses identified a quinone-binding pocket in SaMhqR and the mechanism of SaMhqR inactivation, which involves local structural rearrangements of an allosteric loop and high intrinsic dynamics to prevent DNA interactions. Our results provide novel insights into the redox mechanism of the conserved SaMhqR repressor, which functions as an important determinant of quinone and antimicrobial resistance in S. aureus
Feature-aware manifold meshing and remeshing of point clouds and polyhedral surfaces with guaranteed smallest edge length
No full textPoint clouds and polygonal meshes are widely used when modeling real-world scenarios. Here, point clouds arise, for instance, from acquisition processes applied in various surroundings, such as reverse engineering, rapid prototyping, or cultural preservation. Based on these raw data, polygonal meshes are created to, for example, run various simulations. For such applications, the utilized meshes must be of high quality. This paper presents an algorithm to derive triangle meshes from unstructured point clouds. The occurring edges have a close to uniform length and their lengths are bounded from below. Theoretical results guarantee the output to be manifold, provided suitable input and parameter choices. Further, the paper presents several experiments establishing that the algorithms can compete with widely used competitors in terms of quality of the output and timing and the output is stable under moderate levels of noise. Additionally, we expand the algorithm to detect and respect features on point clouds as well as to remesh polyhedral surfaces, possibly with features.
Supplementary material, an extended preprint, a link to a previously published version of the article, utilized models, and implementation details are made available online
Oligonucleotide therapeutics in sports? An antidoping perspective
Get PDFWithin the last two decades, the European Medicines Agency and the US Food and Drug Administration have approved several gene therapies. One category is oligonucleotide therapeutics, which allow for the regulation of the expression of target genes. Besides already approved therapeutics, there are several preclinical and clinical trials ongoing. The World Anti-Doping Agency prohibits the use of “nucleic acids or nucleic acid analogs that may alter genome sequences and/or alter gene expression by any mechanism” as a nonspecified method at all times. Hence, the administration of nucleic acids or analogs by athletes would cause an Anti-Doping Rule Violation. Herein, we discuss types of oligonucleotide therapeutics, their potential to be misused in sports, and considerations to sample preparation and mass spectrometric approaches with regard to antidoping analysis