1. Misconduct Case Study Our story so far: Peter:4 th -year grad. student makes mice lacking SLAM gene several cell types have abnormal function Sally:4 th -year grad. student moved onto Peter’s project to speed up cell function analysis 1 st experiment: SLAM affects blood-cell function 2 nd experiment:reports possibly switched samples recovers from error, same result as 1 st experiment

2. Misconduct Case Study  What are the pressures on Peter?  What are the pressures on Sally?  What are the pressures on Dr. Larson?  Is there evidence of error, negligence or misconduct?  Should Peter use Sally’s data and write the manuscript?  What are Peter’s other options?  What are Peter’s obligations as first author of the manuscript? What are Sally’s obligations as second author?  What are Dr. Larson’s obligations? Did his actions contribute to this problem?

3. Misconduct Case Study – Part 2 In order to avoid creating conflict in the lab, Peter wrote up the manuscript using Sally’s graph. The manuscript was published in Nature, and created quite a stir in the scientific community. However, in the next six months, Peter was dismayed to read several publications by competing labs that contradicted Sally’s data. It had even been suggested at a national conference that Dr. Larson’s lab had performed their experiments poorly or had misrepresented their data. Peter now felt certain that Sally had falsified her data.

4. Misconduct Case Study – Part 2  How is the situation different now?  How have Peter’s options changed?  What must be taken into consideration in making a decision at this point?  What should Peter do?  What should Dr. Larson do?

5. Influenza virus structure  Enveloped Hemagglutinin (HA) Neuraminidase (NA)  RNA genome single-stranded 8 segments, 10 genes minus-sense  NP protein associated with RNA  Polymerase (PA, PB1, PB2)  Matrix proteins (M1, M2)

6. Influenza virus replication  HA binds sialic acid Sialic acid: usually terminal carbohydrate on glycoprotein or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

7. Influenza virus replication  HA binds sialic acid  Endocytosis  Acidification of endosome  HA conformational change  Fusion  M2 proton channel  Acidification of virion  Uncoating

8. Influenza virus replication  Transported to nucleus  Viral replicase makes (+)RNA: mRNA / template  Cellular mRNA used for 5’ cap / primer

9. Influenza virus replication  Host machinery translates mRNAs  HA, NA inserted into membrane  M1, NP bind RNA  Assembly at membrane  Release by budding

10. Influenza virus replication  Neuraminidase (NA) cleaves sialic acid to release progeny sialic acid HA NA

11. Influenza “Flu season”  Concentrated indoors in winter  Lower temperature favors replication  Cycles of spread

12. Influenza Antigenic Drift

13. Pandemic Influenza  Appearance of significantly different virus  Immunologically “naïve” population  May also have enhanced pathogenicity (virulence) 1918 “Spanish flu” 500 million infected (1/3 pop) 50-100 million deaths 600,000 in 120 days in US Elevated fatality rate ½ of deaths 20-40 Avian virus?

14. Influenza Antigenic Shift  Two viruses (e.g. avian and human) infect one cell (e.g. in pig)  Reassortment of RNA segments during packaging  Result could be human virus with very different Ag

15. Fighting the Flu  Killed, whole vaccine: 2 predicted prevalent A strains, 1 B strain  FluMist: new live, attenuated vaccine  Amantidine, rimantidine: M2 inhibitors; currently too much resistance  Zanamivir, Oseltamivir: NA inhibitors