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Highlights d The structure of the human calpain-5 protease core (CAPN5-PC) is determined d CAPN5-PC contains three elongated loops compared to its classical counterparts d One loop contains a mutation identified in a patient with NIV (p.Gly267Ser) d The p.Gly267Ser mutation causes hyperactivity in CAPN5-PC and CAPN1/5-PC hybrids

Despite abundant evidence for the benefits of physical activity on aging trajectories, older Americans remain largely inactive. The present study was designed to examine age differences in responsiveness to financial incentives to increase walking. Grounded in socioemotional selectivity theory, we examined the effectiveness of financial incentives that varied in prosociality. Three types of incentives were presented to community-residing adults 18 -92 years of age (N ϭ 450). Participants were randomly assigned to 1 of 5 conditions: personal, loved one, charity, choice, or a no-incentive control group. Average daily step counts were measured using pedometers during a baseline week, during the incentivized period, and after the incentivized period ended. Overall, financial incentives significantly increased walking compared to a control group. Whereas personal incentives were effective regardless of age, incentives to earn for charities were starkly more effective in older adults than younger adults. Moreover, 1 week after the incentivized period ended, older participants were more likely to maintain increased step counts, whereas younger people reverted to baseline step counts. Findings suggest that financial incentives can increase walking in a wide age range and that charitable incentives may be especially effective in health interventions targeting older adults. The importance of aligning incentives with age-related goals is discussed.

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The purpose of this paper was to discuss manifestations of primary mitochondrial dysfunctions and whether the retinal pigment epithelium or the photoreceptors are preferentially affected. METHODS. A retrospective analysis was performed of patients with clinically and laboratory confirmed diagnoses of maternally inherited diabetes and deafness (MIDD) or Kearns-Sayre syndrome (KSS). Patients underwent full ophthalmic examination, full-field electroretinogram, and multimodal imaging studies, including short-wavelength autofluorescence, spectral domain-optical coherence tomography, and color fundus photography. RESULTS. A total of five patients with MIDD and four patients with KSS were evaluated at two tertiary referral centers. Mean age at initial evaluation was 50.3 years old. Nascent outer retinal tubulations corresponding with faint foci of autofluorescence were observed in two patients with MIDD. Characteristic features of this cohort included a foveal sparing phenotype observed in 13 of 18 eyes (72%), global absence of intraretinal pigment migration, and preserved retinal function on full-field electroretinogram testing in 12 of 16 eyes (75%). One patient diagnosed with MIDD presented with an unusual pattern of atrophy surrounding the parapapillary region and one patient with KSS presented with an atypical choroideremia-like phenotype. CONCLUSIONS. MIDD and KSS are phenotypically heterogeneous disorders. Several features of disease suggest that primary mitochondrial dysfunction may first affect the retinal pigment epithelium followed by secondary photoreceptor loss. Similarities between primary mitochondrial degenerations and retinal disorders, such as age-related macular degeneration may suggest a primary role of mitochondria in the pathogenesis of these oligogenic disorders.

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Preexisting immunity against Cas9 proteins in humans represents a safety risk for CRISPR–Cas9 technologies. However, it is unclear to what extent preexisting Cas9 immunity is relevant to the eye as it is targeted for early in vivo CRISPR–Cas9 clinical trials. While the eye lacks T-cells, it contains antibodies, cytokines, and resident immune cells. Although precise mechanisms are unclear, intraocular inflammation remains a major cause of vision loss. Here, we used immunoglobulin isotyping and ELISA platforms to profile antibodies in serum and vitreous fluid biopsies from human adult subjects and Cas9-immunized mice. We observed high prevalence of preexisting Cas9-reactive antibodies in serum but not in the eye. However, we detected intraocular antibodies reactive to S. pyogenes-derived Cas9 after S. pyogenes intraocular infection. Our data suggest that serum antibody concentration may determine whether specific intraocular antibodies develop, but preexisting immunity to Cas9 may represent a lower risk in human eyes than systemically.

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