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Infectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infectivity in bioassays, and the essential determinants of recombinant prion infectivity remain obscure. To identify structural and functional features specifically associated with infectivity, we compared the properties of two autocatalytic recombinant PrP conformers derived from the same original template, which differ by >105-fold in specific infectivity for wild-type mice. Structurally, hydrogen/deuterium exchange mass spectrometry (DXMS) studies revealed that solvent accessibility profiles of infectious and non-infectious autocatalytic recombinant PrP conformers are remarkably similar throughout their protease-resistant cores, except for two domains encompassing residues 91-115 and 144-163. Raman spectroscopy and immunoprecipitation studies confirm that these domains adopt distinct conformations within infectious versus non-infectious autocatalytic recombinant PrP conformers. Functionally, in vitro prion propagation experiments show that the non-infectious conformer is unable to seed mouse PrPC substrates containing a glycosylphosphatidylinositol (GPI) anchor, including native PrPC. Taken together, these results indicate that having a conformation that can be specifically adopted by post-translationally modified PrPC molecules is an essential determinant of biological infectivity for recombinant prions, and suggest that this ability is associated with discrete features of PrPSc structure.

Sheaves are mathematical objects that describe the globally compatible data associated with open sets of a topological space. Original examples of sheaves were continuous functions; later they also became powerful tools in algebraic geometry, as well as logic and set theory. More recently, sheaves have been applied to the theory of contextuality in quantum mechanics. Whenever the local data are not necessarily compatible, sheaves are replaced by the simpler setting of presheaves. In previous work, we used presheaves to model lexically ambiguous phrases in natural language and identified the order of their disambiguation. In the work presented here, we model syntactic ambiguities and study a phenomenon in human parsing called garden-pathing. It has been shown that the information-theoretic quantity known as 'surprisal' correlates with human reading times in natural language but fails to do so in garden-path sentences. We compute the degree of signalling in our presheaves using probabilities from the large language model BERT and evaluate predictions on two psycholinguistic datasets. Our degree of signalling outperforms surprisal in two ways: (i) it distinguishes between hard and easy garden-path sentences (with a p -value <10−5), whereas existing work could not, (ii) its garden-path effect is larger in one of the datasets (32 ms versus 8.75 ms per word), leading to better prediction accuracies. This article is part of the theme issue 'Quantum contextuality, causality and freedom of choice'. [ABSTRACT FROM AUTHOR]

The spread of misfolded proteins may occur in many neurodegenerative diseases. Mammalian prions are currently the only misfolded proteins in which high specific biological infectivity can be produced in vitro. Using a system that generates infectious prions de novo from purified recombinant PrP and conversion cofactors palmitoyl-oleoyl-phosphatidylglycerol (POPG) and RNA, we examined by deuterium exchange mass spectrometry (DXMS) the stepwise protein conformational changes that occur during prion formation. We found that initial incubation with POPG causes major structural changes in PrP involving all three α helices and one β strand, with subsequent addition of RNA rendering the N terminus highly exposed. Final conversion into the infectious PrP(Sc) form was accompanied by globally decreased solvent exposure, with persistence of the major cofactor-induced conformational features. Thus, we report that cofactor molecules appear to induce major structural rearrangements during prion formation, initiating a dynamic sequence of conformational changes resulting in biologically active prions.

Secondary malignancies due to alkylating agents or topoisomerase II inhibitors are a concern in patients treated for primary brain tumors of the nervous system. Myelosuppression is the dose-limiting toxic effect of the alkylating agent temozolomide; reversible hematologic toxicity consisting mainly of thrombocytopenia is reported to occur in 7% of patients treated with concomitant radiotherapy and temozolomide and 14% with adjuvant temozolomide.1 However, the incidence of secondary malignancies and nonreversible hematologic disorders, such as myelodysplastic syndrome, are a rare complication of temozolomide.2