The Mind’s Presence to Itself: In Search of Non‐intentional Awareness

According to some philosophers, the mind enjoys a form of presence to itself. That is to say, in addition to being aware of whatever objects it is aware of, it is also (co-presently) aware of itself. This paper explores the proposal that we should think about this kind of experiential-presence in terms of a form of non-intentional awareness. Various candidates for the relevant form of awareness, as constituting supposed non-intentional experiential-presence, are considered and are shown to encounter significant problems. The fact that a plausible account of the non-intentional awareness which experience putatively has of itself cannot be framed with reference to such forms of awareness is grounds for scepticism concerning the cogency of non-intentional experiential presence

Insights into protein folding mechanisms from large scale analysis of mutational effects

Protein folding mechanisms are probed experimentally using single-point mutant perturbations. The relative effects on the folding (ϕ-values) and unfolding (1 - ϕ) rates are used to infer the detailed structure of the transition-state ensemble (TSE). Here we analyze kinetic data on > 800 mutations carried out for 24 proteins with simple kinetic behavior. We find two surprising results: (i) all mutant effects are described by the equation: . Therefore all data are consistent with a single ϕ-value (0.24) with accuracy comparable to experimental precision, suggesting that the structural information in conventional ϕ-values is low. (ii) ϕ-values change with stability, increasing in mean value and spread from native to unfolding conditions, and thus cannot be interpreted without proper normalization. We eliminate stability effects calculating the ϕ-values at the mutant denaturation midpoints; i.e., conditions of zero stability (ϕ0). We then show that the intrinsic variability is ϕ0 = 0.36 ± 0.11, being somewhat larger for β-sheet-rich proteins than for α-helical proteins. Importantly, we discover that ϕ0-values are proportional to how many of the residues surrounding the mutated site are local in sequence. High ϕ0-values correspond to protein surface sites, which have few nonlocal neighbors, whereas core residues with many tertiary interactions produce the lowest ϕ0-values. These results suggest a general mechanism in which the TSE at zero stability is a broad conformational ensemble stabilized by local interactions and without specific tertiary interactions, reconciling ϕ-values with many other empirical observations