The protein-only hypothesis predicts that infectious mammalian prions are composed solely of PrP Sc , a misfolded conformer of the normal prion protein, PrP C . However, protein-only PrP Sc preparations lack significant levels of prion infectivity, leading to the alternative hypothesis that cofactor molecules are required to form infectious prions. Here, we show that prions with parental strain properties and full specific infectivity can be restored from protein-only PrP Sc in vitro . The restoration reaction is rapid, potent, and requires bank vole PrP C substrate, post-translational modifications, and cofactor molecules. To our knowledge, this represents the first report in which the essential properties of an infectious mammalian prion have been restored from pure PrP without adaptation. These findings provide evidence for a unified hypothesis of prion infectivity in which the global structure of protein-only PrP Sc accurately stores latent infectious and strain information, but cofactor molecules control a reversible switch that unmasks biological infectivity.
Prions are unorthodox pathogens that cause fatal neurodegenerative diseases in humans and other mammals. Prion propagation occurs through the self-templating of the pathogenic conformer PrP Sc , onto the cell-expressed conformer, PrP C . Here we study the conversion of PrP C to PrP Sc using a recombinant mouse PrP Sc conformer (mouse protein-only recPrP Sc ) as a unique tool that can convert bank vole but not mouse PrP C substrates in vitro . Thus, its templating ability is not dependent on sequence homology with the substrate. In the present study, we used chimeric bank vole/mouse PrP C substrates to systematically determine the domain that allows for conversion by Mo protein-only recPrP Sc . Our results show that that either the presence of the bank vole amino acid residues E227 and S230 or the absence of the second N-linked glycan are sufficient to allow PrP C substrates to be converted by Mo protein-only recPrP Sc and several native infectious prion strains. We propose that residues 227 and 230 and the second glycan are part of a C-terminal domain that acts as a linchpin for bank vole and mouse prion conversion.
Introduction: Cardiopulmonary arrests (CPAs) are common in the intensive care unit (ICU). However, effects of protocol deviations on CPA outcomes in the ICU are relatively unknown. Objectives: To establish the frequency of errors of commission (EOCs) during CPAs in the ICU and their relationship with CPA outcomes. Methods: Retrospective analysis of data entered into institutional registry with inclusion criteria of age >18 years and non-traumatic cardiac arrest in the ICU. EOCs consist of administration of drugs or procedures performed during a CPA that are not recommended by ACLS guidelines. Primary outcome: relationship of EOCs with likelihood of return of spontaneous circulation (ROSC). Secondary outcomes: relationship of specific EOCs to ROSC and relationship of EOCs and CPA length on ROSC. Results: Among 120 CPAs studied, there was a cumulative ROSC rate of 66%. Cumulatively, EOCs were associated with a decreased likelihood of ROSC (OR: 0.534, 95% CI: 0.387-0.644). Specifically, administration of sodium bicarbonate (OR: 0.233, 95% CI: 0.084-0.644) and calcium chloride (OR: 0.278, 95% CI: 0.098-0.790) were the EOCs that significantly reduced likelihood of attaining ROSC. Each 5-minute increment in CPA duration and/or increase in number of EOCs corresponded to fewer patients sustaining ROSC. Conclusions: EOCs during CPAs in the ICU were common. Among all EOCs studied, sodium bicarbonate and calcium chloride seemed to have the greatest association with decreased likelihood of attaining ROSC. Number of EOCs and CPA duration both seemed to have an inversely proportional relationship with the likelihood of attaining and sustaining ROSC. EOCs represent potentially modifiable human factors during a CPA through resources such as life safety nurses.
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