Deletions of neuraminidase and resistance to oseltamivir may be a consequence of restricted receptor specificity in recent H3N2 influenza viruses

<p>Abstract</p> <p>Background</p> <p>Influenza viruses attach to cells via sialic acid receptors. The viral neuraminidase (NA) is needed to remove sialic acids so that newly budded virions can disperse. Known mechanisms of resistance to NA inhibitors include mutations in the inhibitor binding site, or mutations in the hemagglutinin that reduce avidity for sialic acid and therefore reduce the requirement for NA activity.</p> <p>Results</p> <p>Influenza H3N2 isolates A/Oklahoma/323/03 (Fujian-like), A/Oklahoma/1992/05 (California-like), and A/Oklahoma/309/06 (Wisconsin-like) lost NA activity on passage in MDCK cells due to internal deletions in the NA-coding RNA segment. The viruses grow efficiently in MDCK cells despite diminished NA activity. The full length NA enzyme activity is sensitive to oseltamivir but replication of A/Oklahoma/323/03 and A/Oklahoma/309/06 in MDCK cells was resistant to this inhibitor, indicating that NA is not essential for replication. There was no change in HA activity or sequence after the NA activity was lost but the three viruses show distinct, quite restricted patterns of receptor specificity by Glycan Array analysis. Extensive predicted secondary structure in RNA segment 6 that codes for NA suggests the deletions are generated by polymerase skipping over base-paired stem regions. In general the NA deletions were not carried into subsequent passages, and we were unable to plaque-purify virus with a deleted NA RNA segment.</p> <p>Conclusion</p> <p>H3N2 viruses from 2003 to the present have reduced requirement for NA when passaged in MDCK cells and are resistant to NA inhibitors, possibly by a novel mechanism of narrow receptor specificity such that virus particles do not self-aggregate. These viruses delete internal regions of the NA RNA during passage and are resistant to oseltamivir. However, deletions are independently generated at each passage, suggesting that virus with a full length NA RNA segment initiates the first round of infection.</p

Conceptual and Numerical Analysis of Active Wingtip Vortex Cancellation in Propeller-Driven Electric Aircraft

As battery and electric motor technology continues to advance rapidly, propeller-driven electric aircraft are likely to become a significant part of the aviation market in the near future. One proposed design configuration for electric aircraft involves using large, wingtip- mounted propellers to actively cancel wingtip vortices, a method called active wingtip vortex cancellation (AWVC). By reclaiming part of the kinetic energy that would otherwise be lost to tip vortex formation, drag is decreased. In addition, the induced spanwise flow and upwash from the propeller causes the spanwise lift distribution to remain more uniform at the wingtips, increasing lift. Previous wind tunnel testing of this configuration characterized a significant increase in lift and decrease in drag, particularly in low-aspect-ratio configurations. This paper builds on that research by examining several test cases with a 3D, transient, viscous, sliding mesh CFD analysis in an effort to validate numerical methods for future conceptual design studies. In addition, many practical considerations regarding the implementation of this design are analyzed. Geometry from the aforementioned wind tunnel literature was reconstructed and analyzed. CFD indicated an 18.1% increase in lift and 5.1% increase in net thrust was possible solely through the phenomenon of AWVC. Furthermore, this CFD analysis matched wind tunnel data to within approximately 1%, validating the CFD approach for the analysis of more exotic configurations involving active wingtip vortex cancellation

C-5A Galaxy Systems Engineering Case Study

The C-5 Systems Engineering Case Study captures the untold story of the application of systems engineering during the concept exploration, development, and production of the USAF C-5A and C-5B aircraft. The case study examines and dissects the systems engineering process as applied by the Air Force C-5 System Program Office and the prime contractor, Lockheed, Georgia, from the program s genesis in 1957 to the last delivery of the C-5A and the beginning of the C-5B program in 1973. Numerous interviews were conducted with the principals who managed and directed the program and a story of the systems engineering process was developed. The case study traces the program s systems engineering process in translating a vision into 125 cargo transport aircraft that have served our nation proudly for the last 35 years

Final Report of the AFIT Quality Initiative: Gap Analysis and Investment Strategy Guidance

This report presents the investment strategy guidance emanating from the Air Force Institute of Technology’s (AFIT’s) Quality Initiative. This report culminates a two-year effort involving external discovery, internal discovery, gap analysis, and investment strategy guidance formulation. The overarching purpose of the Quality Initiative is to recommend investment strategy guidance with the intention of modernizing AFIT’s instructional capabilities. Although this report provides an overview of the entirety of AFIT’s quality initiative efforts, the two primary foci of this report are (1) discussing the six initiatives identified by the Gap Analysis Committee and (2) presenting investment strategy guidance

Ninth air force service command

From page 17: Like all other commands, the IX Air Force Service Command is made up of people -- people whose jobs began long before the invasion, endured right up to H-hour and beyond. There were glider pilots, engineers, clerks, mechanics, cooks, doctors, truck drivers; in fact, every conceivable job necessary for victory was filled by an expert who was willing to subordinate everything to the goal ahead. Take the transport pilots, for instance. Red-eyed, flying seemingly endless hours, they operated on a two-way schedule that carried everything from gasoline and guns and bombs to blood plasma and sulfa drugs into Normandy, then carried wounded men back to England on knock-down cots which made ambulances of the Douglas Skytrains. And they did this on schedules which sent ten planes across the Channel every hour. The achievements of the IX Air Force Service Command are many and varied-it is virtually impossible to enumerate all of them. Perhaps it would be better simply to say that it is the good right arm of the Ninth Air Force. And when service is wanted by the Ninth, it is the Service Command which provides it as quickly as possible.https://digicom.bpl.lib.me.us/ww_reg_his/1118/thumbnail.jp

A review of the role of social cognition in major depressive disorder

BACKGROUND: Social cognition - the ability to identify, perceive, and interpret socially relevant information - is an important skill that plays a significant role in successful interpersonal functioning. Social cognitive performance is recognized to be impaired in several psychiatric conditions, but the relationship with major depressive disorder is less well understood. The aim of this review is to characterize the current understanding of: (i) the different domains of social cognition and a possible relationship with major depressive disorder, (ii) the clinical presentation of social cognition in acute and remitted depressive states, and (iii) the effect of severity of depression on social cognitive performance. METHODS: Electronic databases were searched to identify clinical studies investigating social cognition in a major depressive disorder population, yielding 31 studies for this review. RESULTS: Patients with major depressive disorder appear to interpret social cognitive stimuli differently to healthy controls: depressed individuals may interpret emotion through a mood-congruent bias and have difficulty with cognitive theory of mind tasks requiring interpretation of complex mental states. Social cognitive performance appears to be inversely associated with severity of depression, whilst the bias toward negative emotions persists even in remission. Some deficits may normalize following effective pharmacotherapy. CONCLUSIONS: The difficulties with social interaction observed in major depressive disorder may, at least in part, be due to an altered ability to correctly interpret emotional stimuli and mental states. These features seem to persist even in remission, although some may respond to intervention. Further research is required in this area to better understand the functional impact of these findings and the way in which targeted therapy could aid depressed individuals with social interactions.Michael James Weightman,Tracy Michele Air and Bernhard Theodor Baun

Receptor binding specificity of recent human H3N2 influenza viruses

<p>Abstract</p> <p>Background</p> <p>Human influenza viruses are known to bind to sialic acid linked α2-6 to galactose, but the binding specificity beyond that linkage has not been systematically examined. H3N2 human influenza isolates lost binding to chicken red cells in the 1990s but viruses isolated since 2003 have re-acquired the ability to agglutinate chicken erythrocytes. We have investigated specificity of binding, changes in hemagglutinin sequence of the recent viruses and the role of sialic acid in productive infection.</p> <p>Results</p> <p>Viruses that agglutinate, or do not agglutinate, chicken red cells show identical binding to a Glycan Array of 264 oligosaccharides, binding exclusively to a subset of α2-6-sialylsaccharides. We identified an amino acid change in hemagglutinin that seemed to correlate with chicken red cell binding but when tested by mutagenesis there was no effect. Recombinant hemagglutinins expressed on Sf-9 cells bound chicken red cells but the released recombinant baculoviruses agglutinated only human red cells. Similarly, an isolate that does not agglutinate chicken red cells show hemadsorption of chicken red cells to infected MDCK cells. We suggest that binding of chicken red cells to cell surface hemagglutinin but not to virions is due to a more favorable hemagglutinin density on the cell surface. We investigated whether a virus specific for α2-6 sialyloligosaccharides shows differential entry into cells that have varying proportions of α2-6 and α2-3 sialic acids, including human A549 and HeLa cells with high levels of α2-6 sialic acid, and CHO cells that have only α2-3 sialic acid. We found that the virus enters all cell types tested and synthesizes viral nucleoprotein, localized in the nucleus, and hemagglutinin, transported to the cell surface, but infectious progeny viruses were released only from MDCK cells.</p> <p>Conclusion</p> <p>Agglutination of chicken red cells does not correlate with altered binding to any oligosaccharide on the Glycan Array, and may result from increased avidity due to density of hemagglutinin and not increased affinity. Absence of α2-6 sialic acid does not protect a cell from influenza infection and the presence of high levels of α2-6-sialic acids on a cell surface does not guarantee productive replication of a virus with α2-6 receptor specificity.</p