Transcript Our story so far

Misconduct Case Study
Our story so far:
Peter:
4th-year grad. student
makes mice lacking SLAM gene
several cell types have abnormal function
Sally:
4th-year grad. student
moved onto Peter’s project to speed up cell function analysis
1st experiment: SLAM affects blood-cell function
2nd experiment: reports possibly switched samples
recovers from error, same result as 1st experiment
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?
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.
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?
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)
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
Influenza virus replication
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HA binds sialic acid
Endocytosis
Acidification of endosome
HA conformational change
Fusion
M2 proton channel
Acidification of virion
Uncoating
Influenza virus replication
 Transported to nucleus
 Viral replicase makes (+)RNA: mRNA / template
 Cellular mRNA used for 5’ cap / primer
Influenza virus replication
 Host machinery translates mRNAs
 HA, NA inserted into membrane
 M1, NP bind RNA
 Assembly at membrane
 Release by budding
Influenza virus replication
 Neuraminidase (NA) cleaves sialic acid to release progeny
sialic
acid
NA
HA
Influenza
“Flu season”
 Concentrated indoors in winter
 Lower temperature favors replication
 Cycles of spread
Influenza Antigenic Drift
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?
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
Fighting the Flu
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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