The pH dependence of the redox potentials and kinetics for CO association and dissociation was determined between pH 3.0 and 13.0 at 25°C for the wild-type Coprinus cinereus fungal peroxidase and for a site-directed mutant in which Asp 245, which is H-bonded to N ␦ of the imidazole of the proximal His 183, was substituted with Asn. The determination of these functional properties allowed this information to be merged in a self-consistent fashion and to formulate for the first time a complete scheme employing the minimum number of groups required to describe the whole proton-linked behavior of both redox and ligand binding properties. The overall pH dependence can be accounted for by four redox-and ligand-linked groups. The proximal H-bond, which is strictly conserved in all peroxidases, will still be present in the site-specific mutant, but will no longer have an ionic character, and this event will bring about an alteration of redox equilibria and CO binding kinetics, envisaging a relevant role played by this H-bond also in modulating redox properties and ligand binding equilibria.
The cellular prion protein PrP C mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrP C (GDL) can also initiate neurotoxicity by inducing an intramolecular R 208 -H 140 hydrogen bond ("H-latch") between the 2-3 and 2-2 loops of PrP C . Importantly, GDL that suppresses the Hlatch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced 19 individual PrP C variants to PrP C -deficient cerebellar organotypic cultured slices using adenovirusassociated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K 27 or R 27 ) within PrP C . Alanine substitution of K 27 also prevented the toxicity of PrP C mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wildtype PrP C . K 27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.
The cellular prion protein PrPC mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrPC (GDL) can also initiate neurotoxicity by inducing an intramolecular R208-H140 hydrogen bond (H-latch) between the alpha2-alpha2 and beta2-alpha2 loops of PrPC. Importantly, GDL that suppress the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced nineteen individual PrPC variants to PrPC-deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K27 or R27) within PrPC. Alanine substitution of K27 also prevented the toxicity of PrPC mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrPC. K27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.
The recent energy crisis limits humans’ adaptation capability to climate change in indoors, making access to active air conditioning prohibitive. Since lighting systems are less energy-consuming then conditioning systems, this work focuses on visual stimuli to affect occupant’s thermal perception in the framework of the multi-domain comfort theory. Despite the Hue-Heat-Hypothesis has already been explored, validation is still missing. The following hypotheses were outlined: (i) different coloured lights lead to changes in thermal perception that are stronger under thermally comfortable conditions; (ii) visual and thermal domains synergistically interact on the overall comfort perception; (iii) skin temperature can be used as a proxy for thermal comfort. 24 volunteers were exposed to 9 scenarios combining 3 types of coloured light (white, blue, and red) with 3 temperature levels (cool, neutral, and warm conditions). Perceptual responses were collected through questionnaires and skin temperature was measured through wearable. Results support the hypothesis that bluish lights lead to cooler sensation especially in a thermally neutral environment. Skin temperature, mainly affected by ambient temperature, was not significantly related to expressed thermal comfort, apparently in contrast with previous literature results, which may highlight an interfering role of coloured lights on investigated thermal perception as cross-modal effect.
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