Tibetan sheep, a Chinese indigenous breed, are mainly distributed in plateau and mountain-valley areas at a terrestrial elevation between 2260 and 4100 m. The herd is genetically distinct from the other domestic sheep and undergoes acclimatization to adapt to the hypoxic environment. To date, whether the mitochondrial DNA modification of Tibetan sheep shares the same feature as the other domestic breed remains unknown. In this study, we compared the whole mitogenome sequences from 32 Tibetan sheep, 22 domestic sheep and 24 commercial sheep to identify the selection signatures of hypoxic-tolerant in Tibetan sheep. Nucleotide diversity analysis using the sliding window method showed that the highest level of nucleotide diversity was observed in the control region with a peak value of π = 0.05215, while the lowest π value was detected in the tRNAs region. qPCR results showed that the relative mtDNA copy number in Tibetan sheep was significantly lower than that in Suffolk sheep. None of the mutations in 12S rRNA were fixed in Tibetan sheep, which indicated that there has been less artificial selection in this herd than the other domestic and commercial breeds. Although one site (1277G) might undergo the purifying selection, it was not identified as the breed-specific allele in Tibetan sheep. We proposed that nature selection was the main drive during the domestication of Tibetan sheep and single mutation (or locus) could not reveal the signature of selection as for the high diversity in the mitogenome of Tibetan sheep.

Continued emergence of SARS-CoV-2 variants highlights the critical need for adaptable and translational animal models for acute COVID-19. Limitations to current animal models for SARS CoV-2 (e.g., transgenic mice, non-human primates, ferrets) include subclinical to mild lower respiratory disease, divergence from clinical COVID-19 disease course, and/or the need for host genetic modifications to permit infection. We therefore established a feline model to study COVID-19 disease progression and utilized this model to evaluate infection kinetics and immunopathology of the rapidly circulating Delta variant (B.1.617.2) of SARS-CoV-2. In this study, specific-pathogen-free domestic cats (n = 24) were inoculated intranasally and/or intratracheally with SARS CoV-2 (B.1.617.2). Infected cats developed severe clinical respiratory disease and pulmonary lesions at 4- and 12-days post-infection (dpi), even at 1/10 the dose of previously studied wild-type SARS-CoV-2. Infectious virus was isolated from nasal secretions of delta-variant infected cats in high amounts at multiple timepoints, and viral antigen was co-localized in ACE2-expressing cells of the lungs (pneumocytes, vascular endothelium, peribronchial glandular epithelium) and strongly associated with severe pulmonary inflammation and vasculitis that were more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing of infected feline lung tissues identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, and viral protein–cytokine interactions during acute infection with SARS-CoV-2. Weighted correlation network analysis (WGCNA) of differentially expressed genes identified several distinct clusters of dysregulated hub genes that are significantly correlated with both clinical signs and lesions during acute infection. Collectively, the results of these studies help to delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.

Objective: Aging is a complicated process that triggers age‐related disease susceptibility through intercellular communication in the microenvironment. While the classic secretome of senescence‐associated secretory phenotype (SASP) including soluble factors, growth factors, and extracellular matrix remodeling enzymes are known to impact tissue homeostasis during the aging process, the effects of novel SASP components, extracellular small noncoding RNAs (sncRNAs), on human aging are not well established.Methods: Here, by utilizing 446 small RNA‐seq samples from plasma and serum of healthy donors found in the Extracellular RNA (exRNA) Atlas data repository, we correlated linear and nonlinear features between circulating sncRNAs expression and age by the maximal information coefficient (MIC) relationship determination. Age predictors were generated by ensemble machine learning methods (Adaptive Boosting, Gradient Boosting, and Random Forest) and core age‐related sncRNAs were determined through weighted coefficients in machine learning models. Functional investigation was performed via target prediction of age‐related miRNAs.Results: We observed the number of highly expressed transfer RNAs (tRNAs) and microRNAs (miRNAs) showed positive and negative associations with age respectively. Two‐variable (sncRNA expression and individual age) relationships were detected by MIC and sncRNAs‐based age predictors were established, resulting in a forecast performance where all R² values were greater than 0.96 and root‐mean‐square errors (RMSE) were less than 3.7 years in three ensemble machine learning methods. Furthermore, important age‐related sncRNAs were identified based on modeling and the biological pathways of age‐related miRNAs were characterized by their predicted targets, including multiple pathways in intercellular communication, cancer and immune regulation.Conclusion: In summary, this study provides valuable insights into circulating sncRNAs expression dynamics during human aging and may lead to advanced understanding of age‐related sncRNAs functions with further elucidation.

Beckwith-Wiedemann Syndrome (BWS) is the most common epigenetic overgrowth syndrome, caused by epigenetic alterations on chromosome 11p15. In ∼50% of patients with BWS, the imprinted region KvDMR1 (IC2) is hypomethylated. Nearly all children with BWS develop organ overgrowth and up to 28% develop cancer during childhood. The global epigenetic alterations beyond the 11p15 region in BWS are not currently known. Uncovering these alterations at the methylome, transcriptome, and chromatin architecture levels are necessary steps to improve the diagnosis and understanding of patients with BWS. Here we characterized the complete epigenetic profiles of BWS IC2 individuals together with the animal model of BWS, bovine large offspring syndrome (LOS). A novel finding of this research is the identification of two molecular subgroups of BWS IC2 individuals. Genome-wide alternations were detected for DNA methylation, transcript abundance, alternative splicing events of RNA, chromosome compartments, and topologically associating domains (TADs) in BWS and LOS, with shared alterations identified between species. Altered chromosome compartments and TADs were correlated with differentially expressed genes in BWS and LOS. Together, we highlight genes and genomic regions that have the potential to serve as targets for biomarker development to improve current molecular diagnostic methodologies for BWS.