Accumulation of environmental chitin in the lungs can lead to pulmonary fibrosis, characterized by inflammatory infiltration and fibrosis in acidic chitinase (Chia)-deficient mice. Transgenic expression of Chia in these mice ameliorated the symptoms, indicating the potential of enzyme supplementation as a promising therapeutic strategy for related lung diseases. This study focuses on utilizing hyperactivated human Chia, which exhibits low activity. We achieved significant activation of human Chia by incorporating nine amino acids derived from the crab-eating monkey (Macaca fascicularis) Chia, known for its robust chitin-degrading activity. The modified human Chia retained high activity across a broad pH spectrum and exhibited enhanced thermal stability. The amino acid substitutions associated with hyperactivation of human Chia activity occurred species specifically in monkey Chia. This discovery highlights the potential of hyperactivated Chia in treating pulmonary diseases resulting from chitin accumulation in human lungs.

• MeSH
• Enzyme Activation drug effects   MeSH
• Chitin metabolism   chemistry   MeSH
• Chitinases * metabolism   genetics   chemistry   MeSH
• Hydrogen-Ion Concentration MeSH
• Humans MeSH
• Macaca fascicularis MeSH
• Mice MeSH
• Lung metabolism   pathology   enzymology   MeSH
• Enzyme Stability MeSH
• Amino Acid Substitution MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

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
• Chlorocebus aethiops MeSH
• Cercopithecus microbiology   MeSH
• Yaws * microbiology   transmission   MeSH
• Phylogeny * MeSH
• Genome, Bacterial MeSH
• Humans MeSH
• Monkey Diseases microbiology   transmission   MeSH
• Papio anubis microbiology   MeSH
• Papio cynocephalus microbiology   genetics   MeSH
• Primates microbiology   MeSH
• Whole Genome Sequencing * MeSH
• Treponema pallidum genetics   isolation & purification   classification   MeSH
• Treponema MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Tanzania MeSH

Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8+ T cells, thereby promoting an innate and adaptive anti-tumor inflammatory microenvironment in mouse tumor models either in monotherapy or combined with an anti-programmed cell death protein 1 (PD-1) antibody. In cynomolgus monkeys, a clinical schedule was identified, which translated into the design of a phase 1/1b clinical trial, AURELIO-03 (NCT04234113). In 51 patients with advanced/metastatic solid tumors, nanril increased the proportions of CD8+ T cells and NK cells in peripheral blood and tumors. It had a favorable safety profile when administered subcutaneously on days 1, 2, 8, and 9 of each 21-day cycle as monotherapy (0.25-15 μg/kg) or combined (1.5-12 μg/kg) with the anti-PD-1 pembrolizumab (200 mg). The most frequent treatment-emergent adverse events were pyrexia, injection site reactions, and chills. Furthermore, early clinical efficacy was observed, including in immune checkpoint blockade-resistant/refractory patients.

• MeSH
• Programmed Cell Death 1 Receptor * antagonists & inhibitors   immunology   MeSH
• Killer Cells, Natural immunology   drug effects   MeSH
• CD8-Positive T-Lymphocytes immunology   drug effects   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   pharmacology   MeSH
• Immune Checkpoint Inhibitors pharmacology   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Macaca fascicularis MeSH
• Neoplasms * drug therapy   pathology   immunology   MeSH
• Aged MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH

In the last decade, geopolitical instability across the globe has increased the risk of a large-scale radiological event, when radiation biomarkers would be needed for an effective triage of an irradiated population. Ionizing radiation elicits a complex response in the proteome, genome, and metabolome and hence can be leveraged as rapid and sensitive indicators of irradiation-induced damage. We analyzed the plasma of total-body irradiated (TBI) leukemia patients (n = 24) and nonhuman primates (NHPs; n = 10) before and 24 h after irradiation, and we performed a global metabolomic study aiming to provide plasma metabolites as candidate radiation biomarkers for biological dosimetry. Peripheral blood samples were collected according to the appropriate ethical approvals, and metabolites were extracted and analyzed by liquid chromatography mass spectrometry. We identified an array of metabolites significantly altered by irradiation, including bilirubin, cholesterol, and 18-hydroxycorticosterone, which were detected in leukemia patients and NHPs. Pathway analysis showed overlapping perturbations in steroidogenesis, porphyrin metabolism, and steroid hormone biosynthesis and metabolism. Additionally, we observed dysregulation in bile acid biosynthesis and tyrosine metabolism in the TBI patient cohort. This investigation is, to our best knowledge, among the first to provide valuable insights into a comparison between human and NHP irradiation models. The findings from this study could be leveraged for translational biological dosimetry.

• MeSH
• Biomarkers blood   MeSH
• Whole-Body Irradiation * MeSH
• Adult MeSH
• Radiation, Ionizing MeSH
• Leukemia blood   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Macaca mulatta MeSH
• Metabolome * MeSH
• Metabolomics methods   MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

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

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.

• 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

Sensory processing is influenced by neuromodulators such as serotonin, thought to relay behavioural state. Recent work has shown that the modulatory effect of serotonin itself differs with the animal's behavioural state. In primates, including humans, the serotonin system is anatomically important in the primary visual cortex (V1). We previously reported that in awake fixating macaques, serotonin reduces the spiking activity by decreasing response gain in V1. But the effect of serotonin on the local network is unknown. Here, we simultaneously recorded single-unit activity and local field potentials (LFPs) while iontophoretically applying serotonin in V1 of alert monkeys fixating on a video screen for juice rewards. The reduction in spiking response we observed previously is the opposite of the known increase of spiking activity with spatial attention. Conversely, in the local network (LFP), the application of serotonin resulted in changes mirroring the local network effects of previous reports in macaques directing spatial attention to the receptive field. It reduced the LFP power and the spike-field coherence, and the LFP became less predictive of spiking activity, consistent with reduced functional connectivity. We speculate that together, these effects may reflect the sensory side of a serotonergic contribution to quiet vigilance: The lower gain reduces the salience of stimuli to suppress an orienting reflex to novel stimuli, whereas at the network level, visual processing is in a state comparable to that of spatial attention.

• MeSH
• Action Potentials physiology   MeSH
• Humans MeSH
• Macaca mulatta MeSH
• Serotonin MeSH
• Photic Stimulation MeSH
• Visual Perception physiology   MeSH
• Evoked Potentials, Visual * MeSH
• Visual Cortex * physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Intramural 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.

• 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

Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC50 values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. Reduced antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2); however, a synergistic improvement in antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy.

• MeSH
• Antiviral Agents chemical synthesis   chemistry   pharmacology   MeSH
• Biological Products chemical synthesis   chemistry   pharmacology   MeSH
• A549 Cells MeSH
• Chlorocebus aethiops MeSH
• COVID-19 metabolism   MeSH
• COVID-19 Drug Treatment MeSH
• Cysteine Proteinase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Cathepsin L antagonists & inhibitors   metabolism   MeSH
• Antimicrobial Cationic Peptides chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Conformation MeSH
• Proteomics MeSH
• SARS-CoV-2 drug effects   MeSH
• Vero Cells MeSH
• Dose-Response Relationship, Drug 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
• Research Support, N.I.H., Extramural MeSH

Carbapenem resistance observed in Klebsiella pneumoniae strains limits treatment options. Therefore, use of antibiotics combined with bioactive compounds may be an important strategy to control K. pneumoniae. The purpose of this study was to evaluate the activity of combination of carvacrol and meropenem on carbapenem-resistant K. pneumoniae (CRKP) strains. The presence of blaOXA-48 carbapenemase in all 25 CRKP strains was identified using the PCR technique. The combination of carvacrol and meropenem was tested for antimicrobial activity on CRKP strains. The minimum inhibitory concentrations of carvacrol and meropenem were detected within a range of 32-128 μg/mL using the broth microdilution method. Synergy between carvacrol and meropenem was observed on 8 of the 25 CRKP strains by checkerboard assay (FICI = 0.5) and confirmed by time-kill assay. According to the live-dead test results, the viability percentage of the cells exposed to synergistic combination was 35.47% at the end of 24 h. The membrane damage caused by the synergistic combination was spectrophotometrically measured (A = 0.21) and further confirmed by SEM analysis. According to the MTT assay, both carvacrol and meropenem did not show any statistically significant cytotoxic effect on Vero cells (p > 0.05). In conclusion, the results suggest that carvacrol and meropenem can act synergistically to inhibit the growth of CRKP.

• MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• beta-Lactamases * genetics   MeSH
• Chlorocebus aethiops MeSH
• Cymenes MeSH
• Carbapenems pharmacology   MeSH
• Klebsiella pneumoniae * MeSH
• Meropenem pharmacology   MeSH
• Microbial Sensitivity Tests MeSH
• Drug Synergism MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH