SARS-CoV-2 strains have made an appearance across the globe, causing over 757 million cases and over 6.85 million deaths at the time of writing. The emergence of these variants shows the amplitude of genetic variation to which the wild-type strains have been subjected. The rise of the different SARS-CoV-2 variants resulting from such genetic modification has significantly affected COVD-19's major impact on proliferation, virulence, and clinics. With the emergence of the variants of concern, the spike protein has been identified as a possible therapeutic target due to its critical role in binding to human cells and pathogenesis. These mutations could be linked to functional heterogeneity and use a different infection strategy. For example, the Omicron variant's multiple mutations should be carefully examined, as they represent one of the most widely spread strains and hint to us that there may be more genetic changes in the virus. As a result, we applied a common protocol where we reconstructed SARS-CoV-2 variants of concern and performed molecular dynamics simulations to study the stability of the ACE2-RBD complex in each variant. We also carried out free energy calculations to compare the binding and biophysical properties of the different SARS-CoV-2 variants when they interact with ACE2. Therefore, we were able to obtain consistent results and uncover new crucial residues that were essential for preserving a balance between maintaining a high affinity for ACE2 and the capacity to evade RBD-targeted antibodies. Our detailed structural analysis showed that SARS-CoV-2 variants of concern show a higher affinity for ACE2 compared to the Wuhan strain. Additionally, residues K417N and E484K/A might play a crucial role in antibody evasion, whereas Q498R and N501Y are specifically mutated to strengthen RBD affinity to ACE2 and, thereby, increase the viral effect of the COVID-19 virus.

The shelterin protein complex is required for telomere protection in various eukaryotic organisms. In mammals, the shelterin subunit TRF2 is specialized in preventing ATM activation at telomeres and chromosome end fusion in somatic cells. Here, we demonstrate that the zebrafish ortholog of TRF2 (encoded by the terfa gene) is protecting against unwanted ATM activation genome-wide. The terfa-compromised fish develop a prominent and specific embryonic neurodevelopmental failure. The heterozygous fish survive to adulthood but exhibit a premature aging phenotype. The recovery from embryonic neurodevelopmental failure requires both ATM inhibition and transcriptional complementation of neural genes. Furthermore, restoring the expression of TRF2 in glial cells rescues the embryonic neurodevelopment phenotype. These results indicate that the shelterin subunit TRF2 evolved in zebrafish as a general factor of genome maintenance and transcriptional regulation that is required for proper neurodevelopment and normal aging. These findings uncover how TRF2 links development to aging by separate functions in gene expression regulation and genome stability control.

Zebrafish is broadly used as a model organism in gene loss-of-function studies in vivo, but its employment in vitro is greatly limited by the lack of efficient gene knockdown approaches in zebrafish cell lines such as ZF4. In this article, we attempted to induce silencing of telomere associated genes in ZF4 by applying the frequently-used siRNA transfection technology and a novel moiety-linked morpholino (vivo-MO). By proceeding with integrated optimization of siRNAs transfection and vivo-MOs treatment, we compared five transfection reagents and vivo-MOs simultaneously to evaluate the efficiency of terfa silencing in ZF4. 48 h after siRNAs transfection, LipofectamineTM 3000 and X-tremeGENETM HP leaded to knockdown in 35% and 43% of terfa transcription, respectively, while vivo-MO-terfa modulated 58% down-expression of zfTRF2 in contrast to vivo-MO -ctrl 72 h after treatment. Further siRNAs transfection targeting telomere associated genes by X-tremeGENETM HP showed silencing in 40-68% of these genes without significant cytotoxicity and off-target effect. Our results confirmed the feasibility of gene loss-of function studies in a zebrafish cell line, offered a systematic optimizing strategy to employ gene silencing experiments, and presented LipofectamineTM 3000, X-tremeGENETM HP and vivo-morpholinos as candidate gene silencing approaches for zebrafish in vitro gene loss-of-function studies. Successfully knockdown of shelterin genes further opened a new field for telomeric study in zebrafish. (c) 2021 Published by Elsevier B.V.

Aging is a multifactorial process that results in progressive loss of regenerative capacity and tissue function while simultaneously favoring the development of a large array of age-related diseases. Evidence suggests that the accumulation of senescent cells in tissue promotes both normal and pathological aging. Oxic stress is a key driver of cellular senescence. Because symbiotic long-lived reef corals experience daily hyperoxic and hypoxic transitions, we hypothesized that these long-lived animals have developed specific longevity strategies in response to light. We analyzed transcriptome variation in the reef coral Stylophora pistillata during the day–night cycle and revealed a signature of the FoxO longevity pathway. We confirmed this pathway by immunofluorescence using antibodies against coral FoxO to demonstrate its nuclear translocation. Through qPCR analysis of nycthemeral variations of candidate genes under different light regimens, we found that, among genes that were specifically up- or downregulated upon exposure to light, human orthologs of two “light-up” genes (HEY1 and LONF3) exhibited anti-senescence properties in primary human fibroblasts. Therefore, these genes are interesting candidates for counteracting skin aging. We propose a large screen for other light-up genes and an investigation of the biological response of reef corals to light (e.g., metabolic switching) to elucidate these processes and identify effective interventions for promoting healthy aging in humans.