SUMMARY
Host factors required for viral replication are ideal drug targets because they are less likely than viral proteins to mutate under drug-mediated selective pressure. Although genome-wide screens have identified host proteins involved in influenza virus replication, limited mechanistic understanding of how these factors affect influenza has hindered potential drug development. We conducted a systematic analysis to identify and validate host factors that associate with influenza virus proteins and affect viral replication. After identifying over one thousand host factors that co-immunoprecipitate with specific viral proteins, we generated a network of virus-host protein interactions based on the stage of the viral lifecycle affected upon host factor down-regulation. Using compounds that inhibit these host factors, we validated several proteins, notably Golgi-specific brefeldin A resistant guanine nucleotide exchange factor (GBF1) and JAK1, as potential antiviral drug targets. Thus, virus-host interactome screens are powerful strategies to identify targetable host factors and guide antiviral drug development.
SummaryNeonates with Pierre Robin or Treacher-Collins syndrome are at risk of upper airway obstruction and may require surgical fixation of the tongue to the mandible. Such neonates are at high risk of hypoxia during induction of anesthesia and thus awake fiberoptic intubation would be required. We experienced neonates in whom awake fiberoptic intubation could not be carried out, because of severe hypoxia. Awake insertion of the laryngeal mask solved this problem. A 1-month-old neonate with Pierre Robin syndrome and another with Treacher-Collins syndrome were scheduled for surgical fixation of the tongue to the mandible, for constant upper airway obstruction. In both patients, awake fiberoptic intubation was attempted but abandoned, because SpO 2 rapidly decreased during the attempts. Awake insertion of the laryngeal mask relieved upper airway obstruction and facilitated oxygenation. Fiberoptic intubation through the laryngeal mask was easily achieved. Anesthesia was then induced. No hypoxia occurred after insertion of the laryngeal mask. In a further two neonates with Treacher-Collins syndrome and in one neonate with Pierre Robin syndrome, awake fiberoptic intubation through the laryngeal mask was also successful. We believe that in neonates with predicted difficult intubation, who are at risk of upper airway obstruction and awake fiberoptic intubation could aggregate hypoxia, awake insertion of the laryngeal mask can be useful in facilitating oxygenation (by relieving upper airway obstruction) and in facilitating fiberoptic intubation.
Caseinolytic protease was isolated and purified, with high yield, from culture supernatant of Bacteroides gingivalis 381 by procedures including acetone fractionation, gel filtration on Sepharose CL‐6B, solubilization with 0.8% 1‐O‐N‐octyl‐β‐D‐glucopyranoside and affinity chromatography on arginine‐Sepharose 4B. By the affinity chromatography, the protease was separated into three isoenzymes, one of which was unadsorbed on the arginine‐Sepharose 4B, but the other two of which were adsorbed and eluted with the buffer at a different concentration of arginine. Caseinolytic activities of the latter two were highly dependent on dithiothreitol and were inhibited by both thiol‐blocking reagents and some microbial protease inhibitors; but such inhibition was not found in the former isoenzyme. The higher the affinity of the enzyme to arginine‐Sepharose, the stronger the thiol dependency and the inhibition by these inhibitors. Phosphoramidone and ethylenediamine tetraacetate had no effect on the activity of any of the three peaks, indicating that the enzyme is not a metaloprotease. Besides the enzymehydrolyzed synthetic substrates of trypsin, such as BApNA, TAME, substrates of chymotrypsin and kallikrein were also hydrolyzed. The salivary and egg‐white lysozymes were also degraded by this enzyme. These findings suggest that the protease produced by B. gingivalis may play a role as a periodontopathogen not only in directly destroying periodontal tissues but also in weakening the oral antibacterial mechanism.
These results demonstrate that the inhibitory effect of propofol on ketamine-induced c-Fos expression in the PC/RS is mediated by GABAA receptor activation, and suggests that ketamine-induced psychoneuronal adverse effects may be suppressed by propofol via the activation of GABAA receptors.
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