PD-L1 is a ligand for PD-1 and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. Here we show PD-L1 expression negatively correlates with rates of apoptosis in human neutrophils harvested from patients with sepsis. Using co-immunoprecipitation assays on control neutrophils challenged with IFN-γ and LPS, we show PD-L1 complexes with the p85 subunit of PI3-K to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared to wild-type animals, PD-L1-deficient animals presented lower plasma levels of plasma TNF-α and IL-6 and higher IL-10 following CLP, and reduced seven-day mortality in CLP PD-L1 knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI-3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.

Enantioselective cross-electrophile reactions remain a challenging subject in metal catalysis, and with respect to data, studies have mainly focused on stereoconvergent reactions of racemic alkyl electrophiles. Here, we report an enantioselective cross-electrophile aryl-alkenylation reaction of unactivated alkenes. This method provides access to a number of biologically important chiral molecules such as dihydrobenzofurans, indolines, and indanes. The incorporated alkenyl group is suitable for further reactions that can lead to an increase in molecular diversity and complexity. The reaction proceeds under mild conditions at room temperature, and an easily accessible chiral pyrox ligand is used to afford products with high enantioselectivity. The synthetic utility of this method is demonstrated by enabling the modification of complex molecules such as peptides, indometacin, and steroids.

No abstract

Mammalian red blood cells lack nuclei. The molecular mechanisms underlying erythroblast nuclear condensation and enucleation, however, remain poorly understood. Here we show that Wdr26, a gene upregulated during terminal erythropoiesis, plays an essential role in regulating nuclear condensation in differentiating erythroblasts. Loss of Wdr26 induces anemia in zebrafish and enucleation defects in mouse erythroblasts because of impaired erythroblast nuclear condensation. As part of the glucose-induced degradation-deficient ubiquitin ligase complex, Wdr26 regulates the ubiquitination and degradation of nuclear proteins, including lamin B. Failure of lamin B degradation blocks nuclear opening formation leading to impaired clearance of nuclear proteins and delayed nuclear condensation. Collectively, our study reveals an unprecedented role of an E3 ubiquitin ligase in regulating nuclear condensation and enucleation during terminal erythropoiesis. Our results provide mechanistic insights into nuclear protein homeostasis and vertebrate red blood cell development.

Insecticide induced-hormesis is a bi-phasic phenomenon generally characterized by low-dose induction and high-dose inhibition. It has been linked to insect pest outbreaks and insecticide resistance, which have importance in the integrated pest management (IPM). In this paper, hormesis effects of four insecticides on demographic parameters and expression of genes associated with metabolic resistance were evaluated in a field collected population of the green peach aphid, Myzus persicae Sulzer. The bioassay results showed that imidacloprid was more toxic than acetamiprid, deltamethrin and lambda-cyhalothrin. After exposure to sublethal doses of acetamiprid and imidacloprid for four generations, significant prolonged nymphal duration and increased fecundity were observed. Subsequently, mean generation time (T) and gross reproductive rate (GRR) was significantly increased. Moreover, expression of CYP6CY3 gene associated with resistance to neonicotinoids was increased significantly compared to the control. For pyrethriods, across generation exposure to sublethal doses of lambda cyhalothrin and deltamethrin prolonged the immature development duration. However, the expression of E4 gene in M. persicase was decreased by deltamethrin exposure but increased by lambda cyhalothrin. Based on results, demographic fitness parameters were effected by hormetic dose and accompanied with detoxifying genes alteration, hence, which would be evaluated in developing optimized insect pest management strategies.