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Objective: To better understand the pathogenesis of juvenile dermatomyositis (JDM), we examined the effect of the cytokines type I interferons (IFN I) and JAK inhibitor drugs (JAKi) on gene expression in bioengineered pediatric skeletal muscle., Methods: Myoblasts from three healthy pediatric donors were used to create three-dimensional skeletal muscle units termed myobundles. Myobundles were treated with IFN I, either IFNα or IFNβ. A subset of IFNβ-exposed myobundles was treated with JAKi tofacitinib or baricitinib. RNA sequencing analysis was performed on all myobundles., Results: Seventy-six myobundles were analysed. Principal component analysis showed donor-specific clusters of gene expression across IFNα and IFNβ-exposed myobundles in a dose-dependent manner. Both cytokines upregulated interferon response and proinflammatory genes; however, IFNβ led to more significant upregulation. Key downregulated pathways involved oxidative phosphorylation, fatty acid metabolism and myogenesis genes. Addition of tofacitinib or baricitinib moderated the gene expression induced by IFNβ, with partial reversal of upregulated inflammatory and downregulated myogenesis pathways. Baricitinib altered genetic profiles more than tofacitinib., Conclusion: IFNβ leads to more pro-inflammatory gene upregulation than IFNα, correlating to greater decrease in contractile protein gene expression and reduced contractile force. JAK inhibitors, baricitinib more so than tofacitinib, partially reverse IFN I-induced genetic changes. Increased IFN I exposure in healthy bioengineered skeletal muscle leads to IFN-inducible gene expression, inflammatory pathway enrichment, and myogenesis gene downregulation, consistent with what is observed in JDM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

People who score higher on intelligence tests tend to have larger brains. Twin studies suggest the same genetic factors influence both brain size and intelligence. This has led to the hypothesis that genetics influence intelligence partly by contributing to the development of larger brains. We tested this hypothesis using four large imaging genetics studies (combined N = 7965) with polygenic scores derived from a genome-wide association study (GWAS) of educational attainment, a correlate of intelligence. We conducted meta-analysis to test associations among participants' genetics, total brain volume (i.e., brain size), and cognitive test performance. Consistent with previous findings, participants with higher polygenic scores achieved higher scores on cognitive tests, as did participants with larger brains. Participants with higher polygenic scores also had larger brains. We found some evidence that brain size partly mediated associations between participants' education polygenic scores and their cognitive test performance. Effect sizes were larger in the population-based samples than in the convenience-based samples. Recruitment and retention of population-representative samples should be a priority for neuroscience research. Findings suggest promise for studies integrating GWAS discoveries with brain imaging to understand neurobiology linking genetics with cognitive performance., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such "geroprotective" therapies in humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972-1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.

Genome-scale mapping of pre-replication complex proteins has not been reported in mammalian cells. Poor enrichment of these proteins at specific sites may be due to dispersed binding, poor epitope availability or cell cycle stage-specific binding. Here, we have mapped sites of biotin-tagged ORC and MCM protein binding in G1-synchronized populations of Chinese hamster cells harboring amplified copies of the dihydrofolate reductase (DHFR) locus, using avidin-affinity purification of biotinylated chromatin followed by high-density microarray analysis across the DHFR locus. We have identified several sites of significant enrichment for both complexes distributed throughout the previously identified initiation zone. Analysis of the frequency of initiations across stretched DNA fibers from the DHFR locus confirmed a broad zone of de-localized initiation activity surrounding the sites of ORC and MCM enrichment. Mapping positions of mononucleosomal DNA empirically and computing nucleosome-positioning information in silico revealed that ORC and MCM map to regions of low measured and predicted nucleosome occupancy. Our results demonstrate that specific sites of ORC and MCM enrichment can be detected within a mammalian initiation zone, and suggest that initiation zones may be regions of generally low nucleosome occupancy where flexible nucleosome positioning permits flexible pre-RC assembly sites.