D-xylofuranosyl nucleoside analogues bearing alkylthio and glucosylthio substituents at the C3'-position were prepared by photoinitiated radical-mediated hydrothiolation reactions from the corresponding 2',5'-di-O-silyl-3'-exomethylene uridine. Sequential desilylation and 5'-O-butyrylation of the 3'-thiosubstituted molecules produced a 24-membered nucleoside series with diverse substitution patterns, and the compounds were evaluated for their in vitro antiviral activity against three dangerous human RNA viruses, SARS-CoV-2, SINV and CHIKV. Eight compounds exhibited SARS-CoV-2 activity with low micromolar EC50 values in Vero E6 cells, and two of them also inhibited virus growth in human Calu cells. The best anti-SARS-CoV-2 activity was exhibited by 2',5'-di-O-silylated 3'-C-alkylthio nucleosides. Twelve compounds showed in vitro antiviral activity against CHIKV and fourteen against SINV with low micromolar EC50 values, with the 5'-butyryl-2'-silyl-3'-alkylthio substitution pattern being the most favorable against both viruses. In the case of the tested nucleosides, removal of the 2'-O-silyl group completely abolished the antiviral activity of the compounds against all three viruses. Overall, the most potent antiviral agent was the disilylated 3'-glucosylthio xylonucleoside, which showed excellent and specific antiviral activity against SINV with an EC50 value of 3 μM and no toxic effect at the highest tested concentration of 120 μM.

• Keywords
• Chikungunya virus (CHIKV), Nucleoside analogue antivirals, Photochemical thiol-ene reaction, Severe acute respiratory syndrome coronavirus (SARS-CoV-2), Sindbis virus (SINV),
• MeSH
• Antiviral Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Chlorocebus aethiops MeSH
• Humans MeSH
• Nucleosides * pharmacology   chemical synthesis   chemistry   MeSH
• RNA Viruses * drug effects   MeSH
• SARS-CoV-2 drug effects   MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents * MeSH
• Nucleosides * 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
• Anti-Bacterial Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Azepines pharmacology   chemistry   chemical synthesis   MeSH
• Chlorocebus aethiops MeSH
• Humans MeSH
• Methicillin-Resistant Staphylococcus aureus * drug effects   MeSH
• Microbial Sensitivity Tests * MeSH
• Molecular Structure MeSH
• Vero Cells MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents * MeSH
• Azepines 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
• Cell Membrane ultrastructure   virology   MeSH
• Chlorocebus aethiops MeSH
• COS Cells MeSH
• Cytoplasm virology   MeSH
• Cryoelectron Microscopy MeSH
• Endocytosis * MeSH
• Endosomes * pathology   virology   MeSH
• HeLa Cells MeSH
• Humans MeSH
• Macrolides pharmacology   MeSH
• Picornaviridae Infections * virology   MeSH
• Rhinovirus * genetics   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• bafilomycin A1 MeSH Browser
• Macrolides 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.

• Keywords
• binding activity, infectivity test, sterilization mechanisms, structural characteristics, topographical characteristics,
• MeSH
• Chlorocebus aethiops MeSH
• COVID-19 * MeSH
• Virus Inactivation * drug effects   radiation effects   MeSH
• Humans MeSH
• Microscopy, Atomic Force * MeSH
• Ozone * chemistry   pharmacology   MeSH
• Plasma Gases chemistry   pharmacology   MeSH
• SARS-CoV-2 * drug effects   MeSH
• Sterilization methods   MeSH
• Ultraviolet Rays * MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ozone * MeSH
• Plasma Gases 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.

• Keywords
• COVID‐19, EG.5.1, ORF9b, Omicron, SARS‐CoV‐2, pathogenicity,
• MeSH
• Antiviral Agents pharmacology   MeSH
• Chlorocebus aethiops MeSH
• COVID-19 * virology   MeSH
• Cryoelectron Microscopy MeSH
• Phylogeny * MeSH
• Spike Glycoprotein, Coronavirus * genetics   chemistry   MeSH
• Humans MeSH
• Mice MeSH
• SARS-CoV-2 * genetics   MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents MeSH
• Spike Glycoprotein, Coronavirus * MeSH
• spike protein, SARS-CoV-2 MeSH Browser

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
• Chlorocebus aethiops MeSH
• COS Cells MeSH
• Zebrafish genetics   MeSH
• Child MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Intellectual Disability * genetics   MeSH
• Microcephaly * genetics   pathology   MeSH
• Mice MeSH
• Neurons metabolism   pathology   MeSH
• Child, Preschool MeSH
• Microtubule-Associated Proteins genetics   metabolism   MeSH
• Nerve Tissue Proteins genetics   metabolism   MeSH
• Developmental Disabilities * genetics   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• NAV3 protein, human MeSH Browser
• Microtubule-Associated Proteins MeSH
• Nerve Tissue Proteins 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.

• Keywords
• Antimicrobial properties, Cytotoxicity, Electro-spraying, Silver nanoparticle, Wound healing,
• MeSH
• Anti-Bacterial Agents * pharmacology   chemistry   MeSH
• Biocompatible Materials * chemistry   pharmacology   MeSH
• Chlorocebus aethiops MeSH
• Escherichia coli * drug effects   growth & development   MeSH
• Metal Nanoparticles chemistry   MeSH
• Microbial Sensitivity Tests MeSH
• Polyesters * chemistry   MeSH
• Polyvinyl Alcohol * chemistry   pharmacology   MeSH
• Staphylococcus aureus * drug effects   MeSH
• Silver * chemistry   pharmacology   MeSH
• Tissue Scaffolds chemistry   MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article 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.

• Keywords
• Filopodia, SARS-CoV-2, Scanning electron microscopy (SEM), Surface morphology, Vero cells,
• MeSH
• Cell Line MeSH
• Chlorocebus aethiops MeSH
• COVID-19 * MeSH
• Microscopy, Electron, Scanning MeSH
• SARS-CoV-2 * MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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.

• Keywords
• Diani Kenya, STKDE+, before-after study design, horizontal-ladder design, road overpass mitigation,
• MeSH
• Spatio-Temporal Analysis MeSH
• Chlorocebus aethiops MeSH
• Colobus * MeSH
• Accidents, Traffic MeSH
• Haplorhini MeSH
• Primates * MeSH
• Spatial Analysis MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of Coronavirus Disease 2019 (COVID-19) pandemic, poses an immediate need for potent drugs. Enveloped viruses infect the host cell by cellular membrane fusion, a crucial mechanism required for virus replication. The SARS-CoV-2 spike glycoprotein, due to its primary interaction with the human angiotensin-converting enzyme 2 (ACE2) cell-surface receptor, is considered a potential target for drug development. In this study, around 5,800 molecules were virtually screened using molecular docking. Five molecules were selected for in vitro experiments from those that reported docking scores lower than -6 kcal/mol. Imatinib, a Bcr-Abl tyrosine kinase inhibitor, showed maximum antiviral activity in Vero cells. We further investigated the interaction of imatinib, a compound under clinical trials for the treatment of COVID-19, with SARS-CoV-2 RBD, using in silico methods. Molecular dynamics simulations verified that imatinib interacts with RBD residues that are critical for ACE2 binding. This study also provides significant molecular insights on potential repurposable small-molecule drugs and chemical scaffolds for the development of novel drugs targeting the SARS-CoV-2 spike RBD.Communicated by Ramaswamy H. Sarma.

• Keywords
• ACE2, Bcr-Abl tyrosine kinase inhibitor, COVID-19, SARS-CoV-2, Wuhan, acute respiratory disease, betacoronavirus, imatinib, molecular docking, surface structural spike glycoprotein,
• MeSH
• Angiotensin-Converting Enzyme 2 MeSH
• Chlorocebus aethiops MeSH
• COVID-19 * MeSH
• Imatinib Mesylate MeSH
• Humans MeSH
• SARS-CoV-2 * MeSH
• Molecular Docking Simulation MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Angiotensin-Converting Enzyme 2 MeSH
• Imatinib Mesylate MeSH