Fine particulate matter induces childhood asthma attacks via extracellular vesicle-packaged let-7i-5p-mediated modulation of the MAPK signaling pathway

Fine particulate matter less than 2.5 μm in diameter (PM2.5) is a major risk factor for acute asthma attacks in children. However, the biological mechanism underlying this association remains unclear. In the present study, PM2.5-treated HBE cells-secreted extra-cellular vesicles (PM2.5-EVs) caused cytotoxicity in“horizontal” HBE cells and increased the contractility of“longitudinal” sensitive human bronchial smooth muscle cells (HBSMCs). RNA sequencing showed that let-7i-5p was significantly overexpressed inPM2.5-EVs and asthmatic plasma; additionally, its level was correlated with PM2.5 exposure in children with asthma. The combination of EV-packaged let-7i-5p and the traditional clinical biomarker IgE exhibited the best diagnostic performance (area under the curve (AUC) = 0.855, 95% CI = 0.786-0.923). Mechanistically,let-7i-5p was packaged into PM2.5-EVs by interacting with ELAVL1and internalized by both“horizontal” recipient HBE cells and “longitudinal”recipient-sensitive HBSMCs, with subsequent activation of the MAPK signaling pathway via suppression of its targetDUSP1. Furthermore, an injection of EV-packaged let-7i-5p intoPM2.5-treated juvenile mice aggravated asthma symptoms. This comprehensive study deciphered the remodeling of the extracellular environment mediated by the secretion of let-7i-5p-enriched EVs during PM2.5-induced asthma attacks and identified plasma-packaged let-7i-5p as a novel predictor of childhood asthma.

Genomic data helps to resolve the population history of Chinese crocodile lizards and provides insights into how genetic purging works in small wild populations.

The purging of deleterious alleles has been hypothesized to mitigate inbreeding depression, but its effectiveness in endangered species remains debatable. To understand how deleterious alleles are purged during population contractions, we analyzed genomes of the endangered Chinese crocodile lizard (Shinisaurus crocodilurus), which is the only surviving species of its family and currently isolated into small populations. Population genomic analyses revealed four genetically distinct conservation units and sharp declines in both effective population size and genetic diversity. By comparing the relative genetic load across populations and conducting genomic simulations, we discovered that seriously deleterious alleles were effectively purged during population contractions in this relict species, although inbreeding generally enhanced the genetic burden. However, despite with the initial purging, our simulations also predicted that seriously deleterious alleles will gradually accumulate under prolonged bottlenecking. Therefore, we emphasize the importance of maintaining a minimum population capacity and increasing the functional genetic diversity in conservation efforts to preserve populations of the crocodile lizard and other endangered species.

The decoding of haplotypic genomes of lychee provides novel insights into its domestication history and uncovers the underlying genetics of flowering regulation.

Lychee is an exotic tropical fruit with distinct flavor. The genome of cultivar ‘Feizixiao’ was assembled into 15 pseudo-chromosomes, totaling ~470 Mb. High heterozygosity (2.27%) resulted in two complete haplotypic assemblies. 13,517 allelic genes (42.4%) were differentially expressed in diverse tissues. Analyses of 72 re-sequenced lychee accessions revealed two independent domestication events. The extremely early maturing cultivars (EEMC) preferentially aligned to one haplotype were domesticated from a wild population in Yunnan, whereas the late-maturing cultivars (LMC) mostly mapped to the second haplotype were independently domesticated from a wild population in Hainan. Early maturing cultivars were likely developed in Guangdong via hybridization between EEMC and LMC individuals. Variable deletions of a 3.7 kb region encompassed by a pair of CONSTANS-like genes likely regulate fruit maturation differences among lychee cultivars. These genomic resources provide insights into the natural history of lychee domestication and will accelerate the improvement of lychee and related crops.

The objective of this research program is to identify the role of cytidine deaminase, an enzyme otherwise involved in tumor resistance to gemcitabine, is exerting in pancreatic cancer cells

Chronic DNA replication stress and genome instability are two hallmarks of cancer that fuel oncogene sis and tumor diversity. Therapeutic approaches aimed to leverage tumor-specific replication stress to intolerable levels or to expose vulnerabilities for synthetic lethality purpose have recently gained mo mentum, especially for pancreatic cancer, a disease with no cure. However, the current knowledge is limited considering the molecular mechanisms involved in the replication stress response in pancreat ic tumors. Cytidine deaminase (CDA) is involved in the pyrimidine salvage pathway for DNA and RNA synthesis. Loss of CDA induces genomic instability in Bloom Syndrome, and CDA protects tumor cells from chemotherapy with pyrimidine analogs. Here, we show that CDA is overexpressed in genetically instable pancreatic tumors, associates with DNA replication signature and is instrumental for experi mental tumor growth. In cancer cells, CDA promotes DNA replication, increases replication fork fitness for controlling replication stress and genomic stability. CDA expression is predictive of DNA-damaging drug efficacy, and targeting CDA relieves resistance to chemotherapy in patients’ models. Our findings shed a new light on the mechanisms by which pancreatic cancer cells control replication stress, and highlight targeting of CDA as a potential therapeutic intervention to defeat tumor resistance to treat ment. https://www.biorxiv.org/content/10.1101/2021.10.23.465566v1