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Abstract Advancing age is associated with declines in cognitive function. Although physical activity is thought to protect against this decline, it is unclear how a short-term uptake in daily steps or a decline in day-to-day step variability may contribute to cognition among older adults. We tested associations between changes in step counts, day-to-day step variability and executive cognitive functions among older adults taking part in a physical activity intervention. Thirty-seven older adults (33 females; 71.4 ± 6.3 years) completed a 10-week personalized physical activity intervention. Participants wore a Fitbit to measure daily step counts throughout the study. They also completed a computerized Stroop task before and after the intervention. Average step counts and step count variability via average-real-variability (ARV) were determined. Compared to pre-intervention, step counts increased (p

Abstract Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline CAG expansions, somatic repeat expansions in neurons also contribute to HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as a genetic modifier of HD onset and progression, promotes somatic CAG expansions, and thus presents a potential therapeutic target. However, what extent of MSH3 protein reduction is needed to attenuate somatic CAG expansions and elicit therapeutic benefits in HD disease models is less clear. In our study, we employed potent di-siRNAs to silence mouse Msh3 mRNA expression in a dose-dependent manner in HdhQ111/+ mice and correlated somatic Htt CAG instability with MSH3 protein levels from simultaneously isolated DNA and protein after siRNA treatment. Our results reveal a linear correlation with a proportionality constant of ~ 1 between the prevention of somatic Htt CAG expansions and MSH3 protein expression in vivo, supporting MSH3 as a rate-limiting step in somatic expansions. Intriguingly, despite a 75% reduction in MSH3 protein levels, striatal nuclear HTT aggregates remained unchanged. We also note that evidence for nuclear Msh3 mRNA that is inaccessible to RNA interference was found, and that MSH6 protein in the striatum was upregulated following MSH3 knockdown in HdhQ111/+ mice. These results provide important clues to address critical questions for the development of therapeutic molecules targeting MSH3 as a potential therapeutic target for HD.

Abstract Among same-age adolescents, those who enter puberty relatively later and those who are relatively younger (e.g., born later in the year) might be at greater risk of physical activity discontinuation. This study aimed to (1) describe gender-specific discontinuation, re-engagement, and uptake rates in various types of physical activities from the age of 11 to 17 years, and (2) assess puberty timing and relative age as predictors of discontinuation from organized, unorganized, individual, and group-based physical activities. Longitudinal data from 781 (56% girls, age 10–13 years at study baseline) Canadian participants who self-reported puberty status, birthdate, and involvement in 36 physical activities every four months from 2011 to 2018 was analyzed. The incidence of discontinuation, re-engagement, and uptake in organized/unorganized and individual/group activities from grade 6 until grade 12 was described and Cox proportional hazard models were used to estimate associations of puberty timing and relative age with organized/unorganized and individual/group activity discontinuation. Results demonstrate that individual and unorganized activities are maintained longer than group-based and organized activities. Girls who started puberty earlier were more likely to discontinue organized activities than girls with average-puberty timing [Hazard ratio (HR) (95% confidence interval (CI)) 1.68 (1.05–2.69)]. Compared to boys born in the 4th quarter of the year, boys born in the 2nd quarter of the year were less likely to discontinue organized [HR (95% CI) 0.41 (0.23–0.74)], unorganized [HR (95% CI) 0.33 (0.16–0.70)], group [HR (95% CI) 0.58 (0.34–0.98)], and individual activities[HR (95% CI) 0.46 (0.23–0.91)], and boys born in the 3rd quarter were less likely to discontinue unorganized activities[HR (95% CI) 0.41 (0.19–0.88)]. This study illustrates the patterns of physical activity participation throughout adolescence. However, the generalizability of findings may be limited due to participant representation.

Abstract DNA damage is a prominent biomarker for numerous diseases, including cancer, as well as for the aging process. Detection of DNA damage routinely relies on traditional microscopy or cytometric methods. However, these techniques are typically of limited throughput and are not ideally suited for large-scale longitudinal and population studies that require analysis of large sample sets. We have developed HiIDDD (High-throughput Immune cell DNA Damage Detection), a robust, quantitative and single-cell assay that measures DNA damage by high-throughput imaging using the two major DNA damage markers 53BP1 and $$\upgamma$$ γ -H2AX. We demonstrate sensitive detection with low inter-assay variability of DNA damage in various types of freshly isolated and cryopreserved primary human immune cells, including CD4 + and CD8 + T cells, B cells and monocytes. As proof of principle, we demonstrate parallel batch processing of several immune cell types from multiple donors. We find common patterns of DNA damage in multiple immune cell types of donors of varying ages, suggesting that immune cell properties are specific to individuals. These results establish a novel high-throughput assay for the evaluation of DNA damage in large-scale studies.

Abstract Mosaic loss of chromosome Y (LOY) in immune cells is a male-specific mutation associated with increased risk for morbidity and mortality. The CD99 gene, positioned in the pseudoautosomal regions of chromosomes X and Y, encodes a cell surface protein essential for several key properties of leukocytes and immune system functions. Here we used CITE-seq for simultaneous quantification of CD99 derived mRNA and cell surface CD99 protein abundance in relation to LOY in single cells. The abundance of CD99 molecules was lower on the surfaces of LOY cells compared with cells without this aneuploidy in all six types of leukocytes studied, while the abundance of CD proteins encoded by genes located on autosomal chromosomes were independent from LOY. These results connect LOY in single cells with immune related cellular properties at the protein level, providing mechanistic insight regarding disease vulnerability in men affected with mosaic chromosome Y loss in blood leukocytes.

Abstract Among non-human mammals, exposure to androgens during critical periods of development leads to gynephilia (attraction to females), whereas the absence or low levels of prenatal androgens leads to androphilia (attraction to males). However, in humans, retrospective markers of prenatal androgens have only been associated with gynephilia among women, but not with androphilia among men. Here, we asked whether an indirect indication of prenatal androgen exposure, 2D:4D, differs between subsets of gay men delineated by anal sex role (ASR). ASR was used as a proxy for subgroups because ASR groups tend to differ in other measures affected by brain sexual differentiation, such as gender conformity. First, we replicated the finding that gay men with a receptive ASR preference (bottoms) report greater gender nonconformity (GNC) compared to gay men with an insertive ASR preference (tops). We then found that Tops have a lower (male-typical) average right-hand digit ratio than Bottoms, and that among all gay men the right-hand 2D:4D correlated with GNC, indicating that a higher (female-typical) 2D:4D is associated with increased GNC. Differences were found between non-exclusive and exclusive same-sex attraction and GNC, and ASR group differences on digit ratios do not reach significance when all non-heterosexual men are included in the analyses, suggesting greater heterogeneity in the development of non-exclusive same-sex sexual orientations. Overall, results support a role for prenatal androgens, as approximated by digit ratios, in influencing the sexual orientation and GNC of a subset of gay men.