Dynamic Diagnosis of Familial Prion Diseases Supports the β2-α2 Loop as a Universal Interference Target

[Background] Mutations in the cellular prion protein associated to familial prion disorders severely increase the likelihood of its misfolding into pathogenic conformers. Despite their postulation as incompatible elements with the native fold, these mutations rarely modify the native state structure. However they variably have impact on the thermodynamic stability and metabolism of PrPC and on the properties of PrPSc aggregates. To investigate whether the pathogenic mutations affect the dynamic properties of the HuPrP(125-229) α-fold and find possible common patterns of effects that could help in prophylaxis we performed a dynamic diagnosis of ten point substitutions.[Methodology/Principal Findings] Using all-atom molecular dynamics simulations and novel analytical tools we have explored the effect of D178N, V180I, T183A, T188K, E196K, F198S, E200K, R208H, V210I and E211Q mutations on the dynamics of HuPrP(125-228) α-fold. We have found that while preserving the native state, all mutations produce dynamic changes which perturb the coordination of the α2-α3 hairpin to the rest of the molecule and cause the reorganization of the patches for intermolecular recognition, as the disappearance of those for conversion inhibitors and the emergence of an interaction site at the β2-α2 loop region.[Conclusions/Significance] Our results suggest that pathogenic mutations share a common pattern of dynamical alterations that converge to the conversion of the β2-α2 loop into an interacting region that can be used as target for interference treatments in genetic diseases.This work was supported in parts by grants BFU2009-07971 from the MICINN (MG), FundaciÃ3n Cien (MG); Fondazione Cariplo (GC) and AIRC (GC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.Peer reviewe

Conceiving “personality”: Psychologist’s challenges and basic fundamentals of the Transdisciplinary Philosophy-of-Science Paradigm for Research on Individuals

Scientists exploring individuals, as such scientists are individuals themselves and thus not independent from their objects of research, encounter profound challenges; in particular, high risks for anthropo-, ethno- and ego-centric biases and various fallacies in reasoning. The Transdisciplinary Philosophy-of-Science Paradigm for Research on Individuals (TPS-Paradigm) aims to tackle these challenges by exploring and making explicit the philosophical presuppositions that are being made and the metatheories and methodologies that are used in the field. This article introduces basic fundamentals of the TPS-Paradigm including the epistemological principle of complementarity and metatheoretical concepts for exploring individuals as living organisms. Centrally, the TPS-Paradigm considers three metatheoretical properties (spatial location in relation to individuals’ bodies, temporal extension, and physicality versus “non-physicality”) that can be conceived in different forms for various kinds of phenomena explored in individuals (morphology, physiology, behaviour, the psyche, semiotic representations, artificially modified outer appearances and contexts). These properties, as they determine the phenomena’s accessibility in everyday life and research, are used to elaborate philosophy-of-science foundations and to derive general methodological implications for the elementary problem of phenomenon-methodology matching and for scientific quantification of the various kinds of phenomena studied. On the basis of these foundations, the article explores the metatheories and methodologies that are used or needed to empirically study each given kind of phenomenon in individuals in general. Building on these general implications, the article derives special implications for exploring individuals’ “personality”, which the TPS-Paradigm conceives of as individual-specificity in all of the various kinds of phenomena studied in individuals

Exploring the workings of the psyche: metatheoretical and methodological foundation

Introspection is considered a key method for exploring the workings of the psyche because psychical phenomena are accessible only by the individual him or herself. But this epistemological concept, despite its importance, remained unclear and contentious. Its scientificity is often questioned, but still introspective findings from psychophysics are widely accepted as the ultimate proof of the quantifiability of psychical phenomena. Not everything going on in individuals’ minds is considered introspection, but clear criteria that qualify explorations as introspective are still missing. This research applies the Transdisciplinary Philosophy-of-Science Paradigm for Research on Individuals (TPS-Paradigm) to metatheoretically define the peculiarities of psychical phenomena of which various kinds are differentiated and to derive therefrom basic methodological principles and criteria applicable to any investigation. Building on these foundations, the TPS-Paradigm introduces the concepts of introquestion versus extroquestion and reveals that introspection cannot be clearly differentiated from extrospection and that psychophysical experiments and some first-person perspective methods are not introspective as often assumed. The chapter explores the challenges that arise from the fact that psychical phenomena can be explored only indirectly through individuals’ behavioural and semiotic externalisations and scrutinises what, when, where and how to externalise in introquestive explorations. The basic principles and criteria elaborated also allow for determining which kind of psychical phenomenon can be explored by using which kind of method for establishing an appropriate phenomenon–methodology match