Biological impact of Chernobyl radiation: a review of recent progress.

The incident of Chernobyl Nuclear Power Plant (CNPP) explosion has pioneered a plethora of studies unfolding various biological effects of radiation stress on several living systems. Determining radiation dose rates at which both acute and chronic biological effects occur in different biological systems will aid in the ex-situ generation of radiation-tolerant organisms. So far, the accumulation of data on different radiation doses from Chernobyl area demonstrating various biological impacts has not been documented altogether vastly. Therefore, this review aims to document the recorded doses in CNPP over the years at which different biological changes have been observed in plants, soil, aquatic organisms, birds, and animals. A total of 72 peer-reviewed papers obtained from PubMed, Google Scholar, Scopus, and Research4life were included in this review. A few factors have come under attention in this review. Firstly, plant and soil systems combinedly showed the most published studies after the catastrophe where plants showed a higher frequency of DNA methylation in their genome to resist radiation stress. Secondly, reduced species abundance, chromosomal aberrations, increased sterility, and mortality were mostly observed in the aftermath of Chernobyl catastrophe among plants, soil, aquatic organisms, birds, and small mammals. Furthermore, major scares of data after 2018 were prominently observed. Very few studies on radiation dose levels after 2018 are available. Hence, a major research area has emerged for radiation biologists to study present radiation levels and any genetic changes in the recent generation of the original victim species. This will help provide a standard dataset that can act as a reference resource for radiation biologists and future research on the impact of both acute and chronic radiation on the different biological systems.

Upregulation of Neuroinflammation-Associated Genes in the Brain of SARS-CoV-2-Infected Mice.

Neurological manifestations are a significant complication of coronavirus disease 2019 (COVID-19), but the underlying mechanisms are yet to be understood. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced neuroinvasion and encephalitis were observed in K18-hACE2 mice, leading to mortality. Our goal in this study was to gain insights into the molecular pathogenesis of neurological manifestations in this mouse model. To analyze differentially expressed genes (DEGs) in the brains of mice following SARS-CoV-2 infection, we performed NanoString gene expression analysis using three individual animal samples at 1, 3, and 6 days post-infection. We identified the DEGs by comparing them to animals that were not infected with the virus. We found that genes upregulated at day 6 post-infection were mainly associated with Toll-like receptor (TLR) signaling, RIG-I-like receptor (RLR) signaling, and cell death pathways. However, downregulated genes were associated with neurodegeneration and synaptic signaling pathways. In correlation with gene expression profiles, a multiplexed immunoassay showed the upregulation of multiple cytokines and chemokines involved in inflammation and cell death in SARS-CoV-2-infected brains. Furthermore, the pathway analysis of DEGs indicated a possible link between TLR2-mediated signaling pathways and neuroinflammation, as well as pyroptosis and necroptosis in the brain. In conclusion, our work demonstrates neuroinflammation-associated gene expression profiles, which can provide key insight into the severe disease observed in COVID-19 patients.

Spectrum of white matter abnormalities associated with FOXC1-related disorders in two unrelated cases.

The purpose of this study is to document the wide spectrum of white matter abnormalities associated with FOXC1 pathogenic variants. We report two adult individuals-a 60-year-old individual and a 24-year-old one, presenting with hearing loss, anterior eye segment dysgenesis, and very different severity of cerebral small vessel disease. Molecular testing documented the presence of FOXC1 pathogenic variants in both individuals. Our paper documents the broad spectrum of radiological white matter involvement in adult individuals with FOXC1-related disorders. Mild forms of FOXC1-related small vessel disease, as we observed in individual 2, should be included in the list of genetic mimickers of MS.

Precise timing of ERK phosphorylation/dephosphorylation determines the outcome of trial repetition during long-term memory formation.

Two-trial learning in Aplysia reveals nonlinear interactions between training trials: A single trial has no effect, but two precisely spaced trials induce long-term memory. Extracellularly regulated kinase (ERK) activity is essential for intertrial interactions, but the mechanism remains unresolved. A combination of immunochemical and optogenetic tools reveals unexpected complexity of ERK signaling during the induction of long-term synaptic facilitation by two spaced pulses of serotonin (5-hydroxytryptamine, 5HT). Specifically, dual ERK phosphorylation at its activating TxY motif is accompanied by dephosphorylation at the pT position, leading to a buildup of inactive, singly phosphorylated pY-ERK. Phosphorylation and dephosphorylation occur concurrently but scale differently with varying 5HT concentrations, predicting that mixed two-trial protocols involving both "strong" and "weak" 5HT pulses should be sensitive to the precise order and timing of trials. Indeed, long-term synaptic facilitation is induced only when weak pulses precede strong, not vice versa. This may represent a physiological mechanism to prioritize memory of escalating threats.

Differential Pathogenesis of SARS-CoV-2 Variants of Concern in Human ACE2-Expressing Mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current pandemic, resulting in millions of deaths worldwide. Increasingly contagious variants of concern (VoC) have fueled recurring global infection waves. A major question is the relative severity of the disease caused by previous and currently circulating variants of SARS-CoV-2. In this study, we evaluated the pathogenesis of SARS-CoV-2 variants in human ACE-2-expressing (K18-hACE2) mice. Eight-week-old K18-hACE2 mice were inoculated intranasally with a representative virus from the original B.1 lineage or from the emerging B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta), or B.1.1.529 (omicron) lineages. We also infected a group of mice with the mouse-adapted SARS-CoV-2 (MA10). Our results demonstrate that B.1.1.7, B.1.351 and B.1.617.2 viruses are significantly more lethal than the B.1 strain in K18-hACE2 mice. Infection with the B.1.1.7, B.1.351, and B.1.617.2 variants resulted in significantly higher virus titers in the lungs and brain of mice compared with the B.1 virus. Interestingly, mice infected with the B.1.1.529 variant exhibited less severe clinical signs and a high survival rate. We found that B.1.1.529 replication was significantly lower in the lungs and brain of infected mice in comparison with other VoC. The transcription levels of cytokines and chemokines in the lungs of B.1- and B.1.1.529-infected mice were significantly less when compared with those challenged with other VoC. Together, our data provide insights into the pathogenesis of previous and circulating SARS-CoV-2 VoC in mice.

SARS-CoV-2 Variants of Concern Infect the Respiratory Tract and Induce Inflammatory Response in Wild-Type Laboratory Mice.

The emergence of new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern pose a major threat to public health, due to possible enhanced virulence, transmissibility and immune escape. These variants may also adapt to new hosts, in part through mutations in the spike protein. In this study, we evaluated the infectivity and pathogenicity of SARS-CoV-2 variants of concern in wild-type C57BL/6 mice. Six-week-old mice were inoculated intranasally with a representative virus from the original B.1 lineage, or the emerging B.1.1.7 and B.1.351 lineages. We also infected a group of mice with a mouse-adapted SARS-CoV-2 (MA10). Viral load and mRNA levels of multiple cytokines and chemokines were analyzed in the lung tissues on day 3 after infection. Our data show that unlike the B.1 virus, the B.1.1.7 and B.1.351 viruses are capable of infecting C57BL/6 mice and replicating at high concentrations in the lungs. The B.1.351 virus replicated to higher titers in the lungs compared with the B.1.1.7 and MA10 viruses. The levels of cytokines (IL-6, TNF-α, IL-1ß) and chemokine (CCL2) were upregulated in response to the B.1.1.7 and B.1.351 infection in the lungs. In addition, robust expression of viral nucleocapsid protein and histopathological changes were detected in the lungs of B.1.351-infected mice. Overall, these data indicate a greater potential for infectivity and adaptation to new hosts by emerging SARS-CoV-2 variants.

Application of Structure-based Methods to Analyze Resistance Mutations for Chemically Diverse Non-Nucleoside Reverse Transcriptase Inhibitors.

BACKGROUND: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used in combination with antiretroviral therapy to suppress viral loads in HIV patients. The chemical design of NNRTIs has changed in recent years in response to resistance-associated mutations (RAMs) and resistance. NNRTIs are chemically diverse compounds that bind an allosteric site of HIV RT. Resistance- associated mutations (RAMs) identified in HIV patients are associated with NNRTI resistance. RAMs confer amino acid changes that alter both structural and physiochemical properties of the allosteric site. Ultimately, these changes reduce NNRTI affinity. Previously, we used a combination of computational and experimental methods to analyze and validate RAMs for 3 diarylpyrimidine (DAPY) NNRTIs. OBJECTIVE: The objective of this study is to apply these methods to other chemically diverse, non- DAPY NNRTIs. MATERIALS AND METHODS: We selected MIV-150 (experimental microbicide) and doravirine for this study. A computational and molecular modeling strategy was used to evaluate the effects of RAMs. Calculated changes in drug affinity and stability (ΔS + ΔA) were used to determine overall resistance levels: susceptible, low, intermediate, and high. The ΔS + ΔA values for K101P suggest that this mutation confers intermediate/high-level resistance to MIV-150, but remains susceptible to doravirine. Based on the determined resistance levels, we analyzed the models and used Molecular Dynamics (MD) to compare the interactions of MIV-150/doravirine with RT wild-type (WT) and RT (K101P). From MD, we found that key interactions were lost with RT (K101P), but were retained with doravirine. To experimentally validate our findings, we conducted a fluorescence-based reverse transcription assay for MIV-150 with RT (WT) and RT (K101P). IC50 values determined in assays showed a 101-fold change in potency for MIV-150, but essentially no change for doravirine. RESULTS: Our computational and experimental results are also consistent with antiviral data reported in the literature. CONCLUSION: We believe that this approach is effective for analyzing mutations to determine resistance profiles for chemically diverse NNRTIs in development.