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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

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Misconduct case study
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 study1
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
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 21
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
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

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

  • HA binds sialic acid


Influenza virus replication1
Influenza virus replication or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

  • HA binds sialic acid

  • Endocytosis

  • Acidification of endosome

  • HA conformational change

  • Fusion

  • M2 proton channel

  • Acidification of virion

  • Uncoating


Influenza virus replication2
Influenza virus replication or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

  • Transported to nucleus

  • Viral replicase makes (+)RNA: mRNA / template

  • Cellular mRNA used for 5’ cap / primer


Influenza virus replication3
Influenza virus replication or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

  • Host machinery translates mRNAs

  • HA, NA inserted into membrane

  • M1, NP bind RNA

  • Assembly at membrane

  • Release by budding


Influenza virus replication4
Influenza virus replication or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

  • Neuraminidase (NA) cleaves sialic acid to release progeny

NA

sialic

acid

HA


Influenza
Influenza or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

“Flu season”

  • Concentrated indoors in winter

  • Lower temperature favors replication

  • Cycles of spread


Influenza antigenic drift
Influenza Antigenic Drift or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage


Pandemic influenza
Pandemic Influenza or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

  • 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
Influenza Antigenic Shift or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

  • 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
Fighting the Flu or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

  • 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


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