Stimulation of antigen receptors in T and B cells leads to the activation of the Src and Syk families of protein tyrosine kinases (PTK). These PTKs subsequently phosphorylate numerous intracellular substrates, including the 95-kD protooncogene product Vav. Vav is essential for both T and B cell development and T and B cell antigen receptor-mediated signal transduction. After receptor ligation, Vav associates with phosphorylated Syk and ZAP-70 PTKs, an interaction that depends upon its SH2 domain. Here we demonstrate that a point mutation of tyrosine 315 (Y315F) in ZAP-70, a putative Vav SH2 domain binding site, eliminated the Vav- ZAP-70 interaction. Moreover, the Y315 mutation impaired the function of ZAP-70 in antigen receptor signaling. Surprisingly, this mutation also resulted in marked reduction in the tyrosine phosphorylation of ZAP-70, Vav, SLP-76, and Shc. These data demonstrate that the Vav binding site in ZAP-70 plays a critical role in antigen receptor-mediated signal transduction.

Air pollution is a serious environmental problem in China. Birth defects are particularly vulnerable to outdoor air pollution. Our study was to evaluate the association between short-term exposure to air pollutants and the risk of birth defects. Daily data including the air pollutants, meteorological characteristics, and birth records were obtained in Hefei, China, during January 2013 to December 2016. The findings showed that PM_2.5, PM₁₀, SO₂, NO₂, and O₃ exposures were positively correlated with the risk of birth defects. Maternal exposure to PM_2.5 and SO₂ during the 4th to 13th gestational weeks was observed to have a significant association with the risk of birth defects, with the maximum effect in the 7th or 8th week for PM_2.5 and the maximum effect in the 7th week for SO₂. The positively significant exposure windows were the 4th to 14th weeks for PM₁₀, the 4th to 12th weeks for NO₂, and the 26th to 35th weeks for O₃, respectively. The strongest associations were observed in the 8th week for PM₁₀, the 7th week for NO₂, and in the 31st or 32nd week for O_3. The findings of this study demonstrate that air pollutants increase the risk of birth defects among women during pregnancy in Hefei, China, which provide evidence for improving the health of pregnant women and neonates in developing countries, and uncovered potential opportunities to reduce or prevent birth defects by proactive measures during pregnancy.

We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.