We conclude that ventilation with low V T , recurrent RM and sizable PEEP is the most protective ventilation strategy for healthy mice.  Virtual High-Throughput Screening Identifies Mycophenolic Acid as a Novel RNA Capping Inhibitor The RNA guanylyltransferase (GTase) is involved in the synthesis of the (m7)Gppp-RNA cap structure found at the 5′ end of eukaryotic mRNAs. GTases are members of the covalent nucleotidyl transferase superfamily, which also includes DNA and RNA ligases. GTases catalyze a two-step reaction in which they initially utilize GTP as a substrate to form a covalent enzyme-GMP intermediate. The GMP moiety is then transferred to the diphosphate end of the RNA transcript in the second step of the reaction to form the Gppp-RNA structure. In the current study, we used a combination of virtual database screening, homology modeling, and biochemical assays to search for novel GTase inhibitors. Using this approach, we demonstrate that mycophenolic acid (MPA) can inhibit the GTase reaction by preventing the catalytic transfer of the GMP moiety onto an acceptor RNA. As such, MPA represents a novel type of inhibitor against RNA guanylyltransferases that inhibits the second step of the catalytic reaction. Moreover, we show that the addition of MPA to S. cerevisiae cells leads to a reduction of capped mRNAs. Finally, biochemical assays also demonstrate that MPA can inhibit DNA ligases through inhibition of the second step of the reaction. The biological implications of these findings for the MPA-mediated inhibition of members of the covalent nucleotidyl superfamily are discussed. The synthesis and maturation of eukaryotic mRNAs are crucial events for gene expression. During mRNA synthesis, eukaryotic mRNAs undergo a series of essential modifications before being exported to the cytoplasm where they are translated into proteins [1] . These processing events include the addition of a cap structure at the 59 terminus, the splicing out of introns, the editing of specific nucleotides, and the acquisition of a poly(A) tail at the 39 terminus. The RNA cap structure found at the 59 end of mRNAs is critical for the splicing of the cap-proximal intron, the transport of mRNAs from the nucleus to the cytoplasm, and for both the stability and translation of mRNAs [2, 3] . The cap is synthesized by a series of three enzymatic reactions [4] . The first step involves the hydrolysis of the RNA 59-triphosphate end of the nascent RNA by an RNA triphosphatase to form a diphosphate end. An RNA guanylyltransferase then catalyzes a two-step reaction in which it initially utilizes GTP as a substrate to form a covalent enzyme-GMP intermediate. The GMP moiety is then transferred to the diphosphate end of the RNA transcript in the second step of the reaction to form the GpppN structure. The guanosine residue is finally methylated by an RNA (guanine-N7)-methyltransferase to form the typical m7 GpppN cap structure.