Synthesis and DNA binding properties of dioxime-peptide nucleic acids

Peptide nucleic acids (PNAs) C- or N-modified with dioxime ligands were prepared by solid-phase synthesis using iron(II)-clathrochelates as protected dioxime building blocks. These PNA bind complementary DNA sequence specifically, though with much reduced affinity in comparison with nonmodified PNA. The dioxime-PNA conjugates bind Cu2+ and Ni2+ at microM concentration.     

It works: combinatorial biosynthesis for generating novel glycosylated compounds

Combinatorial biosynthesis is a valuable method to generate novel glycosylated natural products. By coexpression of deoxysugar gene cassettes and genes from the staurosporine biosynthetic gene cluster it has now been applied to the generation of novel staurosporine derivatives. The work of Salas and co-workers is highlighted in this article.     

Microbial mechanosensation

Because bacterial mechanosensitive channels have been cloned, purified, crystallized and subjected to a genetic, biochemical and physical scrutiny, they have become the current structural models of mechanosensation to atomic detail. The key observation, supported by recent mutagenesis studies, is that these channels receive stretch force directly through the lipid bilayer at the interface levels bearing highest tension. Indeed, simulations of mechanosensitive channels steered by strategically applied bilayer stretch forces show channel opening. Our understanding of the gating energetics and trajectory are continually being refined by the combination of approaches applied. In addition, new microbial mechanosensitive channels from the TRP family have been characterized in yeasts. Unified by fundamental biophysical principles of gating, mechanosensitive channels provide broad insight into protein-membrane interactions and the role of hydrophobic hydration in gating.     

Upregulation of cardioprotective SUR2A by sub-hypoxic drop in oxygen

The effects of hypoxia on gene expression have been vigorously studied, but possible effects of small changes in oxygen tension have never been addressed. SUR2A is an atypical ABC protein serving as a regulatory subunit of sarcolemmal ATP-sensitive K⁺ (K_ATP) channels. Up-regulation of SUR2A is associated with cardioprotection and improved physical endurance. Here, we have found that a 24 h-long exposure to slightly decreased ambient fractional concentration of oxygen (20% oxygen), which is an equivalent to oxygen tension at 350 m above sea level, significantly increased levels of SUR2A in the heart despite that this drop of oxygen did not affect levels of O₂, CO₂ and hematocrit in the blood or myocardial levels of ATP, lactate and NAD/NADH/NAD⁺. Hearts from mice exposed to 20% oxygen were significantly more resistant to ischaemia-reperfusion when compared to control ones. Decrease in fractional oxygen concentration of just 0.9% was associated with phosphorylation of ERK1/2, but not Akt, which was essential for up-regulation of SUR2A. These findings indicate that a small drop in oxygen tension up-regulates SUR2A in the heart by activating ERK signaling pathway. This is the first report to suggest that a minimal change in oxygen tension could have a profound signaling effect.     

Electrochemical screening of the indole/quinolone derivatives as potential protein kinase CK2 inhibitors

An electrochemical method based on the bioorganometallic Fc-ATP cosubstrate for kinase-catalyzed phosphorylation reactions was used for monitoring casein kinase 2 (CK2) phosphorylations in the absence and presence of five indole/quinolone-based potential inhibitors. Fc-phosphorylation of immobilized peptide RRRDDDSDDD on Au surfaces resulted in a current density at approximately 460 ± 10 mV. An electrochemical redox signal was significantly decreased in the presence of inhibitors. In addition, the electrochemical signal was concentration dependent with respect to the potential inhibitors 1 to 5, which proved to be viable CK2 drug targets with estimated IC₅₀ values in the nanomolar range.     

Early-Life Socioeconomic Status and the Prevalence of Breast Cancer in Later Life

Knowledge of mechanisms linking early-life social environment and breast cancer remains limited. We explore direct and indirect effects of early-life socioeconomic status (SES) on breast cancer prevalence in later life. Using 50-year data from the Wisconsin Longitudinal Study (N = 4,275) and structural equation modeling, we found a negative direct effect of early-life SES, indicating that women from higher-SES family background had lower breast cancer prevalence than women from lower-SES families. Additionally, early-life SES has a positive indirect effect on breast cancer via women's adult SES and age at first birth. Were it not for their higher SES in adulthood and delayed childbearing, women from higher-SES families of origin would have had lower breast cancer prevalence than women from lower-SES families. Yet, early-life SES is associated positively with adult SES and age at first birth, and women's higher adult SES and delayed childbearing are related to higher breast cancer prevalence.