A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P.

Macrophage MMP10 Regulates TLR7-Mediated Tolerance.

Using an model of tolerance to TLR7-induced skin inflammation, we found a critical role for macrophage-derived MMP10 in mediating immune hypo-responsiveness. Cutaneous exposure to Imiquimod (IMQ), a TLR7 agonist, induced acute expression of pro-inflammatory factors (IL1β, IL6, CXCL1) and neutrophil influx equally in both wildtype and mice. However, whereas subsequent exposure (11 and 12 days later) to IMQ led to marked abrogation of pro-inflammatory factor expression in wildtype mice, mice responded similarly as they did to the first application.

A high-throughput screen of inactive X chromosome reactivation identifies the enhancement of DNA demethylation by 5-aza-2'-dC upon inhibition of ribonucleotide reductase.

Background: DNA methylation is important for the maintenance of the silent state of genes on the inactive X chromosome (Xi). Here, we screened for siRNAs and chemicals that reactivate an Xi-linked reporter in the presence of 5-aza-2'-deoxycytidine (5-aza-2'-dC), an inhibitor of DNA methyltransferase 1, at a concentration that, on its own, is not sufficient for Xi-reactivation.

Results: We found that inhibition of ribonucleotide reductase (RNR) induced expression of the reporter.

Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities.

Mutant p53 (mtp53) is an oncogene that drives cancer cell proliferation. Here we report that mtp53 associates with the promoters of numerous nucleotide metabolism genes (NMG). Mtp53 knockdown reduces NMG expression and substantially depletes nucleotide pools, which attenuates GTP-dependent protein activity and cell invasion.

The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia.

Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear.

Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication.

Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood.