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Abstract Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF^WT) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF^D380A) and severe (OLF^I499F) disease variants aggregate differently, with rates comparable to OLF^WTin initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF^WTurea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation. 

Abstract Solar wind drives magnetospheric dynamics through coupling with the geospace system at the magnetopause. While upstream fluctuations correlate with geomagnetic activity, their impact on the magnetopause energy transfer is an open question. In this study, we examine three‐dimensional global magnetospheric simulations using the Geospace configuration of the Space Weather Modeling Framework. We examine the effects of solar wind fluctuations during a substorm event by running the model with four different driving conditions that vary in fluctuation frequency spectrum. We demonstrate that upstream fluctuations intensify the energy exchange at the magnetopause increasing both energy flux into and out of the system. The increased energy input is reflected in ground magnetic indices. Moreover, the fluctuations impact the magnetopause dynamics by regulating the energy exchange between the polar caps and lobes and energy transport within the magnetotail neutral sheet.