Cross-seeding Controls Aβ Fibril Populations and Resulting Function

Amyloid peptides nucleate from monomers to aggregate into fibrils through primary nucleation; pre-existing fibrils can then act as seeds for additional monomers to fibrillize through secondary nucleation. Both nucleation processes can occur simultaneously, yielding a distribution of fibril polymorphs that can generate a spectrum of neurodegenerative effects. Understanding the mechanisms driving polymorph structural distribution during both nucleation processes is important for uncovering fibril structure-function relationships, as well creating polymorph distributions in vitro that better match distributions found in vivo. Here, we explore how cross-seeding WT Aβ1-40 with Aβ1-40 mutants E22G (Arctic) and E22Δ (Osaka), as well as with WT Aβ1-42 affects the distribution of fibril structural polymorphs, and how changes in structural distribution impact toxicity. Transmission electron microscopy analysis reveals that fibril seeds derived from mutants of Aβ1-40 impart their structure to WT Aβ1-40 monomer during secondary nucleation, but WT Aβ1-40 fibril seeds do not affect the structure of fibrils assembled from mutant Aβ1-40 monomers, despite kinetics data indicating accelerated aggregation when cross-seeding of any combination of mutants. Additionally, WT Aβ1-40 fibrils seeded with mutant fibrils to produce similar structural distributions to the mutant seeds also produced similar cytotoxicity on neuroblastoma cell lines. This indicates that mutant fibril seeds not only impart their structure to growing WT Aβ1-40 aggregates, but they also impart cytotoxic properties. Our findings provide clear evidence that there is a relationship between fibril structure and phenotype on a polymorph population level, and that these properties can be passed on through secondary nucleation of succeeding generations of fibrils.

Mirativity as Expressive Meaning: The Case of adiós

The study of mirativity as a semantic-pragmatic concept is the study of the status or expectation of knowledge (DeLancey 2012; Sánchez López 2017). In Spanish, mirativity is expressed by the use of strategies such as intonation, exclamatory sentences, focus fronting, and the use of mirative particles. This paper examines the mirative particle adiós (lit. ‘to god’) in Puerto Rican Spanish. I divide the paper into two parts: first, I examine the structural distribution of adiós and its various mirative values (cf. Aikhenvald 2012); second, I look into several properties of adiós that are characteristic of expressive meaning rather than truth-conditional meaning (cf. Potts 2007). The essential function of adiós is to signal that a proposition-at-hand is new and unexpected information to the speaker. As derived from this mirative value, adiós implicates a speaker-oriented perspective and the speaker’s concomitant surprise. Aside from its mirative role in the sentence, adiós does not alter the truth-value of the sentence. For this reason, the function of Spanish mirative particles is best captured within an expressive account of meaning. As I illustrate in the analysis, the use of adiós, and other mirative particles alike, is consistent with Potts’ (2007) characteristics of expressive content: independence, non-displaceability, descriptive ineffability, and repeatability.