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Cytotoxic accumulation of loosely bound mitochondrial Fe2+ is a hallmark of Friedreich's Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe2+ associated with FA or the neurological disorders Parkinson's disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe3+ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe2+ or exceptionally high affinities (i.e. ≤10-31) for non-pathologic Fe3+ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe2+-targeted therapeutics, we compared traditional Fe3+ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe2+ binding affinities (Kd's of 1-4  µM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe3+(0.46-9.59 µM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe2+ coordination using H2O. ATH434 significantly stabilized bound Fe2+ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe2+ and Fe3+ position it to sequester excess Fe2+ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores., (© The Author(s) 2024. Published by Oxford University Press.)

Empathy is the capacity to feel and understand others' mental states. In some individuals, there is an imbalance between the affective and cognitive components of empathy, which can lead to deficits. This study investigated the functional connectivity of the anterior insula (AI) and dorsomedial prefrontal cortex (dmPFC), which play key roles in empathy, in covariation with the affective and cognitive subscales of the Interpersonal Reactivity Index (IRI), as a function of age and sex, as an exploratory analysis. Seed-based functional connectivity analyses were performed on 33 healthy participants that were subdivided according to their age (16 adults and 17 adolescents) and sex (16 women and 17 men). Adolescents reported lower cognitive empathy than adults and men less affective empathy than women. The connectivity of the dmPFC and AI, in covariation with the cognitive and affective subscales of empathy, respectively, differed between adolescents and adults, but was similar in men and women. Adolescents had patterns of negative covariations between the regions of interest and many brain regions associated with the default-mode and salience networks. These findings support that lower self-report levels of empathy in certain individuals could be reflected in the functional connectivity patterns of the dmPFC and AI., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This paper introduces an innovative functional magnetic resonance imaging (fMRI) protocol to study real verbal interactions while limiting the impact of speech-related movement artefacts. This protocol is based on a sparse sampling acquisition technique and allowed participants to complete a referential communication task with a real interaction partner. During verbal interactions, speakers adjust their verbal productions depending on their interlocutors' knowledge of the referents being mentioned. These adjustments have been linked to theory of mind (ToM), the ability to infer other's mental states. We thus sought to determine if the brain regions supporting ToM would also be activated during a referential communication task in which participants have to present movie characters that vary in their likelihood of being known by their interlocutor. This pilot study establishes that the sparse sampling strategy is a viable option to study the neural correlates of referential communication while minimizing movement artefacts. In addition, the brain regions supporting ToM were recruited during the task, though specifically for the conditions where participants could adjust their verbal productions to the interlocutor's likely knowledge of the referent. This study therefore demonstrates the feasibility and relevance of a sparse-sampling approach to study verbal interactions with fMRI, including referential communication., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)