Protease-Sensitive Conformers in Broad Spectrum of Distinct PrPSc Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate

The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrPSc) using novel conformational methods derived from a conformation-dependent immunoassay (CDI). In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrPSc, we identified an extensive array of PrPSc structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrPSc correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrPSc structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrPSc suggests that these conformers play an important role in the pathogenesis of sCJD

Bone histology provides insights into the life history mechanisms underlying dwarfing in hipparionins

Size shifts may be a by-product of alterations in life history traits driven by natural selection. Although this approach has been proposed for islands, it has not yet been explored in continental faunas. The trends towards size decrease experienced by some hipparionins constitute a good case study for the application of a life history framework to understand the size shifts on the continent. Here, we analysed bone microstructure to reconstruct the growth of some different-sized hipparionins from Greece and Spain. The two dwarfed lineages studied show different growth strategies. The Greek hipparions ceased growth early at a small size thus advancing maturity, whilst the slower-growing Spanish hipparion matured later at a small size. Based on predictive life history models, we suggest that high adult mortality was the likely selective force behind early maturity and associated size decrease in the Greek lineage. Conversely, we infer that resource limitation accompanied by high juvenile mortality triggered decrease in growth rate and a relative late maturity in the Spanish lineage. Our results provide evidence that different selective pressures can precipitate different changes in life history that lead to similar size shifts

Curvature of unsymmetric cross-ply laminates: Combined effect of thermal stresses, microcracking, viscoplastic and viscoelastic strains

Curvature of unsymmetrical [0/90] specimens caused by thermal stresses changes if the specimen is subjected to large axial strains introducing intralaminar cracks in the 90-layer. It is shown that the large curvature reduction can not be explained by cracking related stress release only. The large irreversible viscoplastic strains introduced during the axial tensile loading (with 5 min holding at high strain for crack counting) give the main contribution to the curvature change. The effect of transient viscoelasticity (VE) was found to be of minor significance. Simple approach based on effective damaged layer stiffness and constant irreversible strain is used in the framework of laminate theory to extract the viscoplastic and VE strains from experimental curvature data. The obtained fitting expressions for viscoplastic- and VE-strain development are successfully used to describe curvature change in [0/902] laminate subjected to the same test procedure. It is suggested that the used curved beam tests could be efficient to characterize the viscoplastic strain development in the thin 90-layers</p