SARS-CoV-2: Some Aspects of Molecular Evolution, Cellular Pathogenesis, and Immune System Mechanism Elusion

The purpose of this review is to address some of the latest aspects regarding molecular features, pathogenic mechanisms, and immune system response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), based on recent publications in this field from March 2020 to May 2021. Interpretation keys for periodic re-emergence of coronavirus infections and other lethal viral pandemics are suggested. Antibody-dependent enhancement (ADE) and other potential mechanisms of immune system deception are put forward. Therefore, vaccine development must take into account ADE and other unwanted side effects of immune-based medical intervention. Features reported in our review will allow both clinicians and basic science researchers to take home ideas to improve their knowledge about SARS-CoV-2.

Altered molecular pathways and prognostic markers in active systemic juvenile idiopathic arthritis: integrated bioinformatic analysis

Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and extra-articular symptoms. While recent advances have unraveled a range of risk factors, the pathomechanisms involved in SJIA and potential prognostic markers for treatment success remain partly unknown. In this study, we included 70 active SJIA and 55 healthy control patients from the National Center for Biotechnology Information to analyze for differentially expressed genes (DEGs) using R. Functional enrichment analysis, protein-protein interaction (PPI), and gene module construction were performed for DEGs and hub gene set. We additionally examined immune system cell composition with CIBERSORT and predicted prognostic markers and potential treatment drugs for SJIA. In total, 94 upregulated and 24 downregulated DEGs were identified. Two specific modules of interest and eight hub genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, PGLYRP1) were screened out. Functional enrichment analysis suggested that complex neutrophil-related functions play a decisive role in the disease pathogenesis. CIBERSORT indicated neutrophils, M0 macrophages, CD8+ T cells, and naïve B cells to be relevant drivers of disease progression. Additionally, we identified TPM2 and GZMB as potential prognostic markers for treatment response to canakinumab. Moreover, sulindac sulfide, (-)-catechin, and phenanthridinone were identified as promising treatment agents. This study provides a new insight into molecular and cellular pathogenesis of active SJIA and highlights potential targets for further research.

Nitric Oxide: The Common Link in Different Forms of Dementia

Dementia broadly refers to a global decline in cognitive and higher functions of the brain. With the gradually increasing number of aging population, the incidence of dementia has been steadily rising and expected to increase further in the coming years. The causes and forms of dementia are wide-ranging and diverse, with Alzheimer’s disease being its best studied form. With increasing knowledge about various effects and mechanisms of nitric oxide, this chemical neurotransmitter appears to be the connecting link in the cellular pathogenesis of dementia. An exhaustive search of research articles, commentaries and books published from 1990s onwards was performed with various words and combinations linked to dementia and nitric oxide. The existing medical literature shows both neuroprotective and neurotoxic effects of nitric oxide. The present article intends to delve into this topic and provide a lucid understanding of the role of nitric oxide in dementia. Keywords: Dementia, Nitric Oxide, Alzheimer’s disease, excitotoxicity, nitrosative stress.

Extended in vivo transcriptomes of two ascoviruses with different tissue tropisms reveal alternative mechanisms for enhancing virus reproduction in hemolymph

Ascoviruses are large dsDNA viruses characterized by the extraordinary changes they induce in cellular pathogenesis and architecture whereby after nuclear lysis and extensive hypertrophy, each cell is cleaved into numerous vesicles for virion reproduction. However, the level of viral replication and transcription in vesicles compared to other host tissues remains uncertain. Therefore, we applied RNA-Sequencing to compare the temporal transcriptome of Spodoptera frugiperda ascovirus (SfAV) and Trichoplusia ni ascovirus (TnAV) at 7, 14, and 21 days post-infection (dpi). We found most transcription occurred in viral vesicles, not in initial tissues infected, a remarkably novel reproduction mechanism compared to all other viruses and most other intracellular pathogens. Specifically, the highest level of viral gene expression occurred in hemolymph, for TnAV at 7 dpi, and SfAV at 14 dpi. Moreover, we found that host immune genes were partially down-regulated in hemolymph, where most viral replication occurred in highly dense accumulations of vesicles.

Extremely potent human monoclonal antibodies for the prophylaxis and therapy of Tetanus

Human monoclonal antibodies were used here to study the mechanism of neuron intoxication by tetanus neurotoxin protein toxins and as a safe preventive and therapeutic substitute of hyperimmune sera. By screening memory B cells of immune donors, we selected two monoclonal antibodies specific for tetanus neurotoxin with exceptionally high neutralizing activities, which have been extensively characterized both structurally and functionally. We found that these antibodies interfere with the binding and translocation of the neurotoxin into neurons by interacting with two epitopes, whose definition pinpoints crucial events in the cellular pathogenesis of tetanus. Some mechanistic aspects of tetanus neurotoxin intoxication were revealed, explaining at the same time, the unprecedented neutralization ability of these antibodies. Importantly, these antibodies are exceptionally efficient in preventing experimental tetanus when injected in mice long before the neurotoxin. Moreover, their Fab derivatives neutralize tetanus neurotoxin in post-exposure experiments, suggesting their potential therapeutic use upon intrathecal injection. As such, these human monoclonal antibodies, as well as their Fab derivatives, meet all requirements for being considered for prophylaxis and therapy of human tetanus and are ready for clinical trials.