Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.

Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.

The breadth of animacy in memory: New evidence from prospective memory.

Studies using retrospective memory tasks have revealed that animates/living beings are better remembered than are inanimates/nonliving things (the animacy effect). However, considering that memory is foremost future oriented, we hypothesized that the animacy effect would also occur in prospective memory (i.e., memory for future intentions). Using standard prospective memory (PM) procedures, we explored this hypothesis by manipulating the animacy status of the PM targets. Study 1a reports data collected from an American sample; these results were then replicated with a Portuguese sample (Study 1b). Study 2 employed a new procedure, and data were collected from a broader English-speaking sample. In these three studies, animate (vs. inanimate) targets consistently led to a better PM performance, revealing, for the first time, that the animacy advantage extends to PM. These results strengthen the adaptive approach to memory and stress the need to consider animacy as an important variable in memory studies.

Is "earth" an animate thing? Cross-language and inter-age analyses of animacy word ratings in European Portuguese and British English young and older adults.

Animacy plays an important role in cognition (e.g., memory and language). Across languages, a processing advantage for animate words (representing living beings), comparatively to inanimate words (i.e., non-living things), has been found mostly in young adults. Evidence in older adults, though, is still unclear, possibly due to the use of stimuli not properly characterised for this age group. Indeed, whereas several animacy word-rating studies already exist for young adults, these are non-existent for older adults. This work provides animacy ratings for 500 British English and 224 European Portuguese words, rated by young and older adults from the corresponding countries. The comparisons across languages and ages revealed a high interrater agreement. Nonetheless, the Portuguese samples provided higher mean ratings of animacy than the British samples. Also, the older adults assigned, on average, higher animacy ratings than the young adults. The Age X Language interaction was non-significant. These results suggest an inter-age and inter-language consistency in whether a word represents an animate or an inanimate thing, although with some differences, emphasising the need for age- and language-specific word rating data. The animacy ratings are available via OSF: https://osf.io/6xjyv/.

Fused in sarcoma undergoes cold denaturation: Implications for phase separation.

The mediation of liquid-liquid phase separation (LLPS) for fused in sarcoma (FUS) protein is generally attributed to the low-complexity, disordered domains and is enhanced at low temperature. The role of FUS folded domains on the LLPS process remains relatively unknown since most studies are mainly based on fragmented FUS domains. Here, we investigate the effect of metabolites on full-length (FL) FUS LLPS using turbidity assays and differential interference contrast (DIC) microscopy, and explore the behavior of the folded domains by nuclear magnetic resonance (NMR) spectroscopy. FL FUS LLPS is maximal at low concentrations of glucose and glutamate, moderate concentrations of NaCl, Zn2+ , and Ca2+ and at the isoelectric pH. The FUS RNA recognition motif (RRM) and zinc-finger (ZnF) domains are found to undergo cold denaturation above 0°C at a temperature that is determined by the conformational stability of the ZnF domain. Cold unfolding exposes buried nonpolar residues that can participate in LLPS-promoting hydrophobic interactions. Therefore, these findings constitute the first evidence that FUS globular domains may have an active role in LLPS under cold stress conditions and in the assembly of stress granules, providing further insight into the environmental regulation of LLPS.

Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation.

The recent structural elucidation of ex vivo Drosophila Orb2 fibrils revealed a novel amyloid formed by interdigitated Gln and His residue side chains belonging to the prion-like domain. However, atomic-level details on the conformational transitions associated with memory consolidation remain unknown. Here, we have characterized the nascent conformation and dynamics of the prion-like domain (PLD) of Orb2A using a nonconventional liquid-state NMR spectroscopy strategy based on 13C detection to afford an essentially complete set of 13Cα, 13Cß, 1Hα, and backbone 13CO and 15N assignments. At pH 4, where His residues are protonated, the PLD is disordered and flexible, except for a partially populated α-helix spanning residues 55-60, and binds RNA oligos, but not divalent cations. At pH 7, in contrast, His residues are predominantly neutral, and the Q/H segments adopt minor populations of helical structure, show decreased mobility and start to self-associate. At pH 7, the His residues do not bind RNA or Ca2+, but do bind Zn2+, which promotes further association. These findings represent a remarkable case of structural plasticity, based on which an updated model for Orb2A functional amyloidogenesis is suggested.

Personalized Cognitive Stimulation through Personhood: A Case Report on Dementia Diagnosis Acceptance and Therapeutic Engagement.

Objectives: Dementia related cognitive impairment, as forgetting recent memories, brings several emotional challenges to patients and their families. This paper reports a case of a non-collaborative high-education level patient. who recurrently refused a set of conventional cognitive stimulation exercises, as he also was in refusal of his cognitive impairment. The aim of this report is to show the benefits of a personalized cognitive stimulation (PCS) program.Methods: A24-sessions PCS program was conceived within a person-centered care approach and in active co-creation between the therapist and the patient.Results: The results evidence the patient's increasing therapeutic engagement in the proposed activities, along with mild cognitive improvement. This procedure also promoted a diagnosis acceptance and the patient's mood stabilization. Two illustrative materials used in this tailored intervention are available as supplemental material.Conclusions: Cognitive stimulating programs benefit from tailoring and personalization. Personalization indeed helped the patient feeling engaged and increased his participation in the activities. Furthermore, his mood stabilized, and the patient accepted his cognitive impairments. Thus, PCS is a way of reaching person-centered care.Clinical implications: PCS may be used to improve patient's engagement in the stimulating activities. Also, PCS promoted the dementia diagnosis acceptance..