Complex regulatory networks influence pluripotent cell state transitions in human iPSCs.

Stem cells exist in vitro in a spectrum of interconvertible pluripotent states. Analyzing hundreds of hiPSCs derived from different individuals, we show the proportions of these pluripotent states vary considerably across lines. We discover 13 gene network modules (GNMs) and 13 regulatory network modules (RNMs), which are highly correlated with each other suggesting that the coordinated co-accessibility of regulatory elements in the RNMs likely underlie the coordinated expression of genes in the GNMs. Epigenetic analyses reveal that regulatory networks underlying self-renewal and pluripotency are more complex than previously realized. Genetic analyses identify thousands of regulatory variants that overlapped predicted transcription factor binding sites and are associated with chromatin accessibility in the hiPSCs. We show that the master regulator of pluripotency, the NANOG-OCT4 Complex, and its associated network are significantly enriched for regulatory variants with large effects, suggesting that they play a role in the varying cellular proportions of pluripotency states between hiPSCs. Our work bins tens of thousands of regulatory elements in hiPSCs into discrete regulatory networks, shows that pluripotency and self-renewal processes have a surprising level of regulatory complexity, and suggests that genetic factors may contribute to cell state transitions in human iPSC lines.

Does the Number of Comorbidities Predict Pain and Disability in Older Adults With Chronic Low Back Pain? A Longitudinal Study With 6- and 12-Month Follow-ups.

BACKGROUND AND PURPOSE: People who live longer often live with multimorbidity. Nevertheless, whether the presence of multimorbidity affects pain and disability in older adults with chronic low back pain (LBP) remains unclear. The aim of this study was to investigate whether multimorbidity predicts pain intensity and disability at 6- and 12-month follow-ups in older adults with chronic LBP. METHODS: This was a prospective, longitudinal study with 6- and 12-month follow-ups. Participants with chronic LBP (age ≥ 60 years) were recruited and interviewed at baseline, 6 months, and 12 months. Self-reported measures included the number of comorbidities, assessed through the Self-Administered Comorbidity Questionnaire, pain intensity, assessed with the 11-point Numerical Rating Scale, and disability, assessed with the Roland-Morris Disability Questionnaire. Data were analyzed using univariate and multivariate regression models. RESULTS AND DISCUSSION: A total of 220 participants were included. The number of comorbidities predicted pain intensity at 6-month (ß= 0.31 [95% CI: 0.12 to 0.50]) and 12-month (ß= 0.29 [95% CI: 0.08 to 0.50]) follow-ups. The number of comorbidities predicted disability at 6-month (ß= 0.55 [95% CI: 0.20 to 0.90]) and 12-month (ß= 0.40 [95% CI: 0.03 to 0.77]) follow-ups. CONCLUSION: The number of comorbidities at baseline predicted pain and disability at 6-month and 12-month follow-ups in older adults with chronic LBP. These results highlight the role of comorbidities as a predictive factor of pain and disability in patients with chronic LBP, emphasizing the need for timely and continuous interventions in older adults with multimorbidity to mitigate LBP-related pain and disability.

The efficacy of neuromuscular training, with minimal or no equipment, on performance of youth athletes: A systematic review with meta-analysis.

OBJECTIVES: To investigate the effects of neuromuscular training, with minimal or no equipment, on physical performance of youth athletes. DESIGN: Systematic review with meta-analysis. METHODS: MEDLINE, EMBASE, CENTRAL, CINAHL, PEDro and SportDiscuss from inception to March/2022. SELECTION CRITERIA: youth athletes (15-24years), from Olympic team sports; used neuromuscular training 2-3 times/week for, at least, 6 weeks; had a control group/usual training group; physical performance as outcomes; randomized controlled trial. DATA SYNTHESIS: Pooled estimate of standardized mean difference (SMD), and 95% confidence interval (95%CI). RESULTS: Thirty-four studies (1111 participants) were included. Results showed that neuromuscular training improved power (SMD: 0.84 [95%CI: 0.58, 1.10]; n = 805; I2 = 64%), speed (SMD: -1.12 [95%CI: -1.68, -0.57]; n = 688; I2 = 90%) and agility (SMD: -1.21 [95%CI: -1.60, -0.83]; n = 571; I2 = 76%) compared to control group, but showed no difference between groups for muscle strength (Quadriceps SMD: 0.34 [95%CI: -0.02, 0.69]; n = 132; I2 = 0%, Hamstrings: SMD: 0.64 [95%CI: -0.04, 1.33]; n = 132; I2 = 71%), balance and flexibility. CONCLUSION: Clinically, neuromuscular training with minimal equipment may be useful for teams with limited resources to improve mainly athletes' power and agility, including those interventions that were designed to injury prevention. Future high-quality studies are likely to change these estimates.

Analysis of regulatory network modules in hundreds of human stem cell lines reveals complex epigenetic and genetic factors contribute to pluripotency state differences between subpopulations.

Stem cells exist in vitro in a spectrum of interconvertible pluripotent states. Analyzing hundreds of hiPSCs derived from different individuals, we show the proportions of these pluripotent states vary considerably across lines. We discovered 13 gene network modules (GNMs) and 13 regulatory network modules (RNMs), which were highly correlated with each other suggesting that the coordinated co-accessibility of regulatory elements in the RNMs likely underlied the coordinated expression of genes in the GNMs. Epigenetic analyses revealed that regulatory networks underlying self-renewal and pluripotency have a surprising level of complexity. Genetic analyses identified thousands of regulatory variants that overlapped predicted transcription factor binding sites and were associated with chromatin accessibility in the hiPSCs. We show that the master regulator of pluripotency, the NANOG-OCT4 Complex, and its associated network were significantly enriched for regulatory variants with large effects, suggesting that they may play a role in the varying cellular proportions of pluripotency states between hiPSCs. Our work captures the coordinated activity of tens of thousands of regulatory elements in hiPSCs and bins these elements into discrete functionally characterized regulatory networks, shows that regulatory elements in pluripotency networks harbor variants with large effects, and provides a rich resource for future pluripotent stem cell research.