Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion

BACKGROUND: The conversion of the cellular prion protein (PrP(C)) into the infectious form (PrP(Sc)) is the key event in prion induced neurodegenerations. This process is believed to involve a multi-step conformational transition from an alpha-helical (PrP(C)) form to a beta-sheet-rich (PrP(Sc)) state. In addition to the conformational difference, PrP(Sc) exhibits as covalent signature the sulfoxidation of M213. To investigate whether such modification may play a role in the misfolding process we have studied the impact of methionine oxidation on the dynamics and energetics of the HuPrP(125-229) alpha-fold. METHODOLOGY/PRINCIPAL FINDINGS: Using molecular dynamics simulation, essential dynamics, correlated motions and signal propagation analysis, we have found that substitution of the sulfur atom of M213 by a sulfoxide group impacts on the stability of the native state increasing the flexibility of regions preceding the site of the modification and perturbing the network of stabilizing interactions. Together, these changes favor the population of alternative states which maybe essential in the productive pathway of the pathogenic conversion. These changes are also observed when the sulfoxidation is placed at M206 and at both, M206 and M213. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the sulfoxidation of Helix-3 methionines might be the switch for triggering the initial alpha-fold destabilization required for the productive pathogenic conversion

Macrophage heterogeneity and renin-angiotensin system disorders

Macrophages are heterogeneous innate immune cells which are important in both the maintenance of tissue homeostasis and its disruption, by promoting tissue inflammation and fibrosis. The renin-angiotensin system is central to the pathophysiology of a large suite of diseases, which are driven in part by large amounts of tissue inflammation and fibrosis. Here, we review recent advances in understanding macrophage heterogeneity in origin and function, and how these may lead to new insights into the pathogenesis of these chronic diseases

The speech generating device (SGD) mentoring program : supporting the development of people learning to use an SGD

Mentoring in speech generating device (SGD) use by adults who use an SGD proficiently offers the potential to improve the device usage of people learning an SGD. The aim of the present study was to examine the impact of SGD mentoring on the mentees’ SGD usage. Three mentors, aged 23, 31, and 54 years, and 3mentees, aged 13, 14, and 32 years, participated. A nonconcurrent multiple baseline across participants design was used to assess the outcomes.Mentee conversation samples were analyzed for the number of total words, the number of different words, and the number of bound morphemes produced in mentoring sessions. Improvements were made in these measures across the mentees following commencement of mentoring sessions with a trained SGD mentor. These results provide preliminary evidence of SGD mentoring success.23 page(s