BACKGROUND: Treponema pallidum subspecies pertenue (TPE) is the causative agent of human and nonhuman primate (NHP) yaws infection. The discovery of yaws bacterium in wild populations of NHPs opened the question of transmission mechanisms within NHPs, and this work aims to take a closer look at the transmission of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Our study determined eleven whole TPE genomes from NHP isolates collected from three national parks in Tanzania: Lake Manyara National Park (NP), Serengeti NP, and Ruaha NP. The bacteria were isolated from four species of NHPs: Chlorocebus pygerythrus (vervet monkey), Cercopithecus mitis (blue monkey), Papio anubis (olive baboon), and Papio cynocephalus (yellow baboon). Combined with previously generated genomes of TPE originating from NHPs in Tanzania (n = 11), 22 whole-genome TPE sequences have now been analyzed. Out of 231 possible combinations of genome-to-genome comparisons, five revealed an unexpectedly high degree of genetic similarity in samples collected from different NHP species, consistent with inter-species transmission of TPE among NHPs. We estimated a substitution rate of TPE of NHP origin, ranging between 1.77 × 10-7 and 3.43 × 10-7 per genomic site per year. CONCLUSIONS/SIGNIFICANCE: The model estimations predicted that the inter-species transmission happened recently, within decades, roughly in an order of magnitude shorter time compared to time needed for the natural diversification of all tested TPE of Tanzanian NHP origin. Moreover, the geographical separation of the sampling sites (NPs) does not preclude TPE transmission between and within NHP species.
- MeSH
- Cercopithecus aethiops MeSH
- Cercopithecus mikrobiologie MeSH
- frambézie * mikrobiologie přenos MeSH
- fylogeneze * MeSH
- genom bakteriální MeSH
- lidé MeSH
- nemoci opic mikrobiologie přenos MeSH
- Papio anubis mikrobiologie MeSH
- Papio cynocephalus mikrobiologie genetika MeSH
- primáti mikrobiologie MeSH
- sekvenování celého genomu * MeSH
- Treponema pallidum genetika izolace a purifikace klasifikace MeSH
- Treponema MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Tanzanie MeSH
Enveloped viruses, such as flaviviruses and coronaviruses, are pathogens of significant medical concern that cause severe infections in humans. Some photosensitizers are known to possess virucidal activity against enveloped viruses, targeting their lipid bilayer. Here we report a series of halogenated difluoroboron-dipyrromethene (BODIPYs) photosensitizers with strong virus-inactivating activity. Our structure-activity relationship analysis revealed that BODIPY scaffolds with a heavy halogen atom demonstrate significant efficacy against both tick-borne encephalitis virus (TBEV; Flaviviridae family) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Coronaviridae family) along with high singlet oxygen quantum yields. Moreover, select compounds also inactivated other enveloped viruses, such as herpes simplex virus type 1 and monkeypox virus. The nature and length of the alkyl side chain notably influenced the virus-inactivating activity of BODIPY molecules. Furthermore, molecular dynamics studies highlighted the critical importance of the positioning of the chromophore moiety within the lipid bilayer. As membrane-targeting photosensitizers, BODIPYs interact directly with virus particles, causing damage to the viral envelope membranes. Thus, TBEV pretreated with BODIPY was completely noninfective for lab mice. Consequently, BODIPY-based photosensitizers hold potential either as broad-spectrum virus-inactivating antivirals against a variety of phylogenetically unrelated enveloped viruses or as potent inactivators of viruses for the development of vaccines for preventing life-threatening emerging viral diseases.
- Klíčová slova
- BODIPY, enveloped viruses, membrane-targeting photosensitizer, singlet oxygen photogeneration, virus-inactivating activity,
- MeSH
- antivirové látky * farmakologie chemie MeSH
- Cercopithecus aethiops MeSH
- fotosenzibilizující látky * chemie farmakologie účinky záření MeSH
- halogenace MeSH
- lidé MeSH
- myši MeSH
- porfobilinogen analogy a deriváty chemie farmakologie MeSH
- SARS-CoV-2 účinky léků MeSH
- singletový kyslík * metabolismus chemie MeSH
- sloučeniny boru * chemie farmakologie MeSH
- Vero buňky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene MeSH Prohlížeč
- antivirové látky * MeSH
- dipyrromethene MeSH Prohlížeč
- fotosenzibilizující látky * MeSH
- porfobilinogen MeSH
- singletový kyslík * MeSH
- sloučeniny boru * MeSH
Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein, we describe the development of a novel class of 3-substituted benzoazepinedione derivatives with promising antibacterial activity. The pivotal compound, benzoazepinedione carboxylate 9, represents a highly electrophilic Michael acceptor, enabling divergent access to a wide range of thia-, aza-, oxa-, and phospha-Michael adducts. Notably, most prepared compounds exhibited potent antibacterial activity against both drug-susceptible and drug-resistant strains of Staphylococcus aureus (MIC90 of up to 2 μg mL-1). The cytotoxicity assessment in the VERO6 cell line revealed that thia-adduct 10d (IC50 of 36.5 μg mL-1) exhibits lower toxicity compared to its parent electrophile 9 (IC50 of 14.3 μg mL-1), which is in agreement with the hypothesis of covalently modified prodrugs. Additionally, stability studies of the prepared compounds in CD3OD and a DMSO-PBS mixture confirmed that thia-Michael adducts 10 are stable under neutral conditions while dynamic under mildly basic conditions. Moreover, 3D reconstructed tissue models (human lung epithelial EpiAirway™ and a human small intestine model) did not exhibit a viability decrease below 80% of the untreated control at all concentrations tested, indicating tolerance to higher concentrations of potential drugs and prodrugs.
- MeSH
- antibakteriální látky * farmakologie chemie chemická syntéza MeSH
- azepiny farmakologie chemie chemická syntéza MeSH
- Cercopithecus aethiops MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus * účinky léků MeSH
- mikrobiální testy citlivosti * MeSH
- molekulární struktura MeSH
- Vero buňky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antibakteriální látky * MeSH
- azepiny MeSH
Membrane penetration by non-enveloped viruses is diverse and generally not well understood. Enteroviruses, one of the largest groups of non-enveloped viruses, cause diseases ranging from the common cold to life-threatening encephalitis. Enteroviruses enter cells by receptor-mediated endocytosis. However, how enterovirus particles or RNA genomes cross the endosome membrane into the cytoplasm remains unknown. Here we used cryo-electron tomography of infected cells to show that endosomes containing enteroviruses deform, rupture, and release the virus particles into the cytoplasm. Blocking endosome acidification with bafilomycin A1 reduced the number of particles that released their genomes, but did not prevent them from reaching the cytoplasm. Inhibiting post-endocytic membrane remodeling with wiskostatin promoted abortive enterovirus genome release in endosomes. The rupture of endosomes also occurs in control cells and after the endocytosis of very low-density lipoprotein. In summary, our results show that cellular membrane remodeling disrupts enterovirus-containing endosomes and thus releases the virus particles into the cytoplasm to initiate infection. Since the studied enteroviruses employ different receptors for cell entry but are delivered into the cytoplasm by cell-mediated endosome disruption, it is likely that most if not all enteroviruses, and probably numerous other viruses from the family Picornaviridae, can utilize endosome rupture to infect cells.
- MeSH
- buněčná membrána ultrastruktura virologie MeSH
- Cercopithecus aethiops MeSH
- COS buňky MeSH
- cytoplazma virologie MeSH
- elektronová kryomikroskopie MeSH
- endocytóza * MeSH
- endozomy * patologie virologie MeSH
- HeLa buňky MeSH
- lidé MeSH
- makrolidy farmakologie MeSH
- pikornavirové infekce * virologie MeSH
- Rhinovirus * genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- bafilomycin A1 MeSH Prohlížeč
- makrolidy MeSH
Ultraviolet-C (UV-C) radiation and ozone gas are potential mechanisms employed to inactivate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), each exhibiting distinct molecular-level modalities of action. To elucidate these disparities and deepen our understanding, we delve into the intricacies of SARS-CoV-2 inactivation via UV-C and ozone gas treatments, exploring their distinct molecular-level impacts utilizing a suite of advanced techniques, including biological atomic force microscopy (Bio-AFM) and single virus force spectroscopy (SVFS). Whereas UV-C exhibited no perceivable alterations in virus size or surface topography, ozone gas treatment elucidated pronounced changes in both parameters, intensifying with prolonged exposure. Furthermore, a nuanced difference was observed in virus-host cell binding post-treatment: ozone gas distinctly reduced SARS-CoV-2 binding to host cells, while UV-C maintained the status quo. The results derived from these methodical explorations underscore the pivotal role of advanced Bio-AFM techniques and SVFS in enhancing our understanding of virus inactivation mechanisms, offering invaluable insights for future research and applications in viral contamination mitigation.
- Klíčová slova
- binding activity, infectivity test, sterilization mechanisms, structural characteristics, topographical characteristics,
- MeSH
- Cercopithecus aethiops MeSH
- COVID-19 * MeSH
- inaktivace viru * účinky léků účinky záření MeSH
- lidé MeSH
- mikroskopie atomárních sil * MeSH
- ozon * chemie farmakologie MeSH
- plazmové plyny chemie farmakologie MeSH
- SARS-CoV-2 * účinky léků MeSH
- sterilizace metody MeSH
- ultrafialové záření * MeSH
- Vero buňky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ozon * MeSH
- plazmové plyny MeSH
In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population.
- Klíčová slova
- COVID‐19, EG.5.1, ORF9b, Omicron, SARS‐CoV‐2, pathogenicity,
- MeSH
- antivirové látky farmakologie MeSH
- Cercopithecus aethiops MeSH
- COVID-19 * virologie MeSH
- elektronová kryomikroskopie MeSH
- fylogeneze * MeSH
- glykoprotein S, koronavirus * genetika chemie MeSH
- lidé MeSH
- myši MeSH
- SARS-CoV-2 * genetika MeSH
- Vero buňky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky MeSH
- glykoprotein S, koronavirus * MeSH
- spike protein, SARS-CoV-2 MeSH Prohlížeč
Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
- MeSH
- Cercopithecus aethiops MeSH
- COS buňky MeSH
- dánio pruhované genetika MeSH
- dítě MeSH
- HEK293 buňky MeSH
- lidé MeSH
- mentální retardace * genetika MeSH
- mikrocefalie * genetika patologie MeSH
- myši MeSH
- neurony metabolismus patologie MeSH
- předškolní dítě MeSH
- proteiny asociované s mikrotubuly genetika metabolismus MeSH
- proteiny nervové tkáně genetika metabolismus MeSH
- vývojové poruchy u dětí * genetika MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- NAV3 protein, human MeSH Prohlížeč
- proteiny asociované s mikrotubuly MeSH
- proteiny nervové tkáně MeSH
A chronic nonhealing wound poses a significant risk for infection and subsequent health complications, potentially endangering the patient's well-being. Therefore, effective wound dressings must meet several crucial criteria, including: (1) eliminating bacterial pathogen growth within the wound, (2) forming a barrier against airborne microbes, (3) promoting cell proliferation, (4) facilitating tissue repair. In this study, we synthesized 8 ± 3 nm Ag NP with maleic acid and incorporated them into an electrospun polycaprolactone (PCL) matrix with 1.6 and 3.4 µm fiber sizes. The Ag NPs were anchored to the matrix via electrospraying water-soluble poly(vinyl) alcohol (PVA), reducing the average sphere size from 750 to 610 nm in the presence of Ag NPs. Increasing the electrospraying time of Ag NP-treated PVA spheres demonstrated a more pronounced antibacterial effect. The resultant silver-based material exhibited 100% inhibition of gram-negative Escherichia coli and gram-positive Staphylococcus aureus growth within 6 h while showing non-cytotoxic effects on the Vero cell line. We mainly discuss the preparation method aspects of the membrane, its antibacterial properties, and cytotoxicity, suggesting that combining these processes holds promise for various medical applications.
- Klíčová slova
- Antimicrobial properties, Cytotoxicity, Electro-spraying, Silver nanoparticle, Wound healing,
- MeSH
- antibakteriální látky * farmakologie chemie MeSH
- biokompatibilní materiály * chemie farmakologie MeSH
- Cercopithecus aethiops MeSH
- Escherichia coli * účinky léků růst a vývoj MeSH
- kovové nanočástice chemie MeSH
- mikrobiální testy citlivosti MeSH
- polyestery * chemie MeSH
- polyvinylalkohol * chemie farmakologie MeSH
- Staphylococcus aureus * účinky léků MeSH
- stříbro * chemie farmakologie MeSH
- tkáňové podpůrné struktury chemie MeSH
- Vero buňky MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In this study, scanning electron microscopy (SEM) was used to study the cell structure of SARS-CoV-2 infected cells. Our measurements revealed infection remodeling caused by infection, including the emergence of new specialized areas where viral morphogenesis occurs at the cell membrane. Intercellular extensions for viral cell surfing have also been observed. Our results expand knowledge of SARS-CoV-2 interactions with cells, its spread from cell to cell, and their size distribution. Our findings suggest that SEM is a useful microscopic method for intracellular ultrastructure analysis of cells exhibiting specific surface modifications that could also be applied to studying other important biological processes.
- Klíčová slova
- Filopodia, SARS-CoV-2, Scanning electron microscopy (SEM), Surface morphology, Vero cells,
- MeSH
- buněčné linie MeSH
- Cercopithecus aethiops MeSH
- COVID-19 * MeSH
- mikroskopie elektronová rastrovací MeSH
- SARS-CoV-2 * MeSH
- Vero buňky MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Almost one-quarter of primate species are reported to be involved in vehicle collisions. To mitigate these collisions, canopy bridges are used though their effectiveness is not broadly substantiated. We studied bridge impact on 23 years of vehicle collisions (2000-2022: N = 765) with colobus (Colobus angolensis palliatus), Sykes' (Cercopithecus mitis albogularis), and vervet (Chlorocebus pygerythrus hilgerti) monkeys in Diani, Kenya. Along a 9 km road, collisions did not decrease over the study duration, although bridges increased from 8 to 30. Using the kernel density estimation plus (KDE+) method, collisions appeared highly concentrated at some locations. These concentrations, called hotspots, represent hazardous road segments, though the hotspots for all three species overlapped for only 3% of the road length. We then inspected the collision hotspots over time, using the spatiotemporal extension of the KDE+ method. We compared hotspot presence in the 3 years before and after bridge installation to determine if bridges mitigated these hotspots. Hotspots disappeared for ~60% of bridges postinstallation, suggesting that bridges effectively reduce some collisions. However, of the bridges installed in locations that were not hotspots, 13% had hotspots emerge. Surprisingly, regardless of preinstallation hotspot occurrence, almost one-fifth of bridges had postinstallation hotspots. To understand the extent to which bridges mitigate collisions, other factors need consideration, including species attributes and crossing behavior, and road features and vehicle volume. We used the novel analytical method because it best suited our data set, given the challenges of determining the bridge impact zone and the low collision frequency.
- Klíčová slova
- Diani Kenya, STKDE+, before-after study design, horizontal-ladder design, road overpass mitigation,
- MeSH
- časoprostorová analýza MeSH
- Cercopithecus aethiops MeSH
- Colobus * MeSH
- dopravní nehody MeSH
- Haplorrhini MeSH
- primáti * MeSH
- prostorová analýza MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
