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Protein-misfolding diseases are based on a common principle of aggregation initiated by intra- and intermolecular contacts. The structural and conformational changes, induced by biochemical transformations, such as post-translational modifications (PTMs), often lead to protein unfolding and misfolding. Thus, these order-to-disorder or disorder-to-order transitions may regulate cellular function. Tau, a neuronal protein, regulates microtubule (MT) structure and overall cellular integrity. However, misfolded tau modified by PTMs results in MT destabilization, toxic tau aggregate formation, and ultimately cell death, leading to neurodegeneration. Currently, the lack of structural information surrounding tau severely limits understanding of neurodegeneration. This mini-review focuses on the current methodologies and approaches aimed at probing tau conformation and its role in various aspects of tau biochemistry. The recent applications of nuclear magnetic resonance, mass spectrometry, Förster resonance electron transfer, and molecular dynamics simulation toward structural analysis of conformational landscapes of tau will be described. The strategies developed for structural evaluation of tau may significantly improve our understanding of misfolding diseases.

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Poor fear extinction learning and recall are linked to the development of fear‐based disorders, like posttraumatic stress disorder, and are associated with aberrant activation of fear‐related neural circuitry. This includes greater amygdala activation during extinction learning and lesser hippocampal and ventromedial prefrontal cortex (vmPFC) activation during recall. Emerging data indicate that genetic variation in fatty acid amide hydrolase (FAAH C385A; rs324420) is associated with increased peripheral endocannabinoid (eCB) levels and lesser threat‐related amygdala reactivity. Preclinical studies link increased eCB signaling to better extinction learning and recall, thus FAAH C385A may protect against the development of trauma‐related psychopathology by facilitating extinction learning. However, how this FAAH variant affects fear extinction neural circuitry remains unknown. In the present study, we used a novel, immersive‐reality fear extinction paradigm paired with functional neuroimaging to assess FAAH C385A effects on fear‐related neural circuitry and conditioned fear responding (US expectancy ratings, subjective units of distress, and skin conductance responding) in healthy adults from an urban area (Detroit, MI; N = 59; C/C = 35, A‐carrier = 24). We found lesser amygdala activation in A‐allele carriers, compared to C/C homozygotes, during early extinction recall. Likewise, we found lesser dorsal anterior cingulate cortex and greater hippocampus activation in early extinction learning in A‐carriers compared to C/C homozygotes. We found no effects of FAAH C385A on vmPFC activation or behavioral fear indices. These data support and extend previous findings that FAAH genetic variation, associated with increased eCB signaling and subsequent enhanced fear extinction, may predict individual differences in successful fear learning.

The electrochemical oxidation of selected tert-butylated phenols 2,6-di-tert-butyl-4-methylphenol (1), 2,6-di-tert-butylphenol (2), 2,4,6-tri-tert-butylphenol (3), 2-tert-butylphenol (4), and 4-tert-butylphenol (5) was studied in an aprotic environment using cyclic voltammetry, square-wave voltammetry, and UV-vis spectroscopy. All compounds exhibited irreversible oxidation of the corresponding phenol or phenolate ion. Compound 2 was selectively electrochemically oxidized, while other phenol analogues underwent mostly chemical oxidation. The electrochemical oxidation of 2 produced a highly absorbing product, 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone, which was characterized by X-ray crystal diffraction. The electrochemical oxidation was monitored as a function of electrochemical parameters and concentration. Experimental and theoretical data indicated that the steric hindrance, phenoxyl radical stability, and hydrogen bonding influenced the outcome of the electrochemical oxidation. The absence of the substituent at the para position and the presence of the bulky substituents at ortho positions were structural and electrostatic requirements for the selective electrochemical oxidation.