Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells.

Hypercapnia, the elevation of CO2 in blood and tissues, commonly occurs in severe acute and chronic respiratory diseases, and is associated with increased risk of mortality. Recent studies have shown that hypercapnia adversely affects innate immunity, host defense, lung edema clearance and cell proliferation. Airway epithelial dysfunction is a feature of advanced lung disease, but the effect of hypercapnia on airway epithelium is unknown. Thus, in the current study we examined the effect of normoxic hypercapnia (20% CO2 for 24 h) vs normocapnia (5% CO2), on global gene expression in differentiated normal human airway epithelial cells. Gene expression was assessed on Affymetrix microarrays, and subjected to gene ontology analysis for biological process and cluster-network representation. We found that hypercapnia downregulated the expression of 183 genes and upregulated 126. Among these, major gene clusters linked to immune responses and nucleosome assembly were largely downregulated, while lipid metabolism genes were largely upregulated. The overwhelming majority of these genes were not previously known to be regulated by CO2. These changes in gene expression indicate the potential for hypercapnia to impact bronchial epithelial cell function in ways that may contribute to poor clinical outcomes in patients with severe acute or advanced chronic lung diseases.

Application of evolutionary algorithm methods to polypeptide folding: comparison with experimental results for unsolvated Ac-(Ala-Gly-Gly)5-LysH+.

We present an evolutionary method for finding the low-energy conformations of polypeptides. The application, called FOLDAWAY,is based on a generic framework and uses several evolutionary operators as well as local optimization to navigate the complex energy landscape of polypeptides. It maintains two complementary representations of the structures and uses the CHARMM force field for evaluating the energies. The method is applied to unsolvated Met-enkephalin and Ac-(Ala-Gly-Gly)(5)-Lys(+)H(+). Unsolvated Ac-(Ala-Gly-Gly)(5)-Lys(+)H(+) has been the object of recent experimental studies using ion mobility measurements. It has a flat energy landscape where helical and globular conformations have similar energies. FOLDAWAY locates several large groups of structures not found in previous molecular dynamics simulations for this peptide, including compact globular conformations, which are probably present in the experiments. However, the relative energies of the different conformations found by FOLDAWAY do not accurately match the relative energies expected from the experimental observations.