Background/aimsBest-corrected visual acuity (BCVA) is the most common primary endpoint in treatment trials for choroideremia (CHM) but the long-term natural history of BCVA is unclear.MethodsWe searched in seven databases to identify studies that reported BCVA of untreated eyes with CHM. We sought individual-level data and performed segmented regression between BCVA and age. For eyes followed longitudinally, we introduced a horizontal translation factor to each dataset to account for different ages at onset of a rapid BCVA decline.ResultsWe included 1004 eyes from 23 studies. BCVA of the right and left eyes was moderately correlated (r=0.60). BCVA as a function of age followed a 2-phase decline (slow followed by rapid decline), with an estimated transition age of 39.1 years (95% CI 33.5 to 44.7). After the introduction of horizontal translation factors to longitudinal datasets, BCVA followed a 2-phase decline until it reached 0 letters (r2=0.90). The BCVA decline rate was 0.33 letters/year (95% CI −0.38 to 1.05) before 39 years, and 1.23 letters/year (95% CI 0.55 to 1.92) after 39 years (p=0.004).ConclusionBCVA in eyes with CHM follows a 2-phase linear decline with a transition age of approximately 39 years. Future trials enrolling young patients may not be able to use BCVA as a primary or sole endpoint, but rather, may need to employ additional disease biomarkers that change before age 39. BCVA may still have utility as a primary endpoint for patients older than 39 years who have measurable BCVA decline rates.

Summary Much evidence has shown that reactive oxygen species (ROS) regulate several plant hormone signaling cascades, but little is known about the real‐time kinetics and the underlying molecular mechanisms of the target proteins in the brassinosteroid (BR) signaling pathway. In this study, we used single‐molecule techniques to investigate the true signaling timescales of the major BR signaling components BRI1‐EMS‐SUPPRESSOR 1 (BES1) and BRASSINOSTEROID INSENSITIVE 2 (BIN2) of Arabidopsis thaliana. The rate constants of BIN2 associating with ATP and phosphorylating BES1 were determined to be 0.7 ± 0.4 mM−1 s−1 and 2.3 ± 1.4 s−1, respectively. Interestingly, we found that the interaction of BIN2 and BES1 was oxygen‐dependent, and oxygen can directly modify BIN2. The activity of BIN2 was switched on via modification of specific cysteine (Cys) residues, including C59, C95, C99 and C162. The mutation of these Cys residues inhibited the BR signaling outputs. These findings demonstrate the power of using single‐molecule techniques to study the dynamic interactions of signaling components, which is difficult to be discovered by conventional physiological and biochemical methods.

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