Engelmann, M. | Search bioRxiv

bioRxiv2025

Charting infant sleep cycle development using actigraphy: Longitudinal evidence for cycle lengthening within the first year of life from 35,000 hours of sleep

Sleep is marked by ultradian cycles, coinciding with the alternation of rapid eye movement (REM) and non-rapid eye movement sleep (NREM). These sleep cycles are a striking feature exhibited from infancy through adulthood, yet their underlying mechanisms and functional relevance remain elusive, calling for large-scale longitudinal studies. Here we leverage Locomotor Inactivity During Sleep (LIDS), previously established in adults as an accessible means to track sleep cycles, to chart ultradian sleep cycle dynamics within the first year of life at scale. Specifically, we analyzed > 35, 000 hours of sleep from a longitudinal dataset of 152 infants with 10 days of actigraphy at 3, 6, and 12 months of age. Using advanced signal processing techniques, we demonstrate the existence of rhythmic patterns in LIDS in infants with a cycle length of[~] 60 minutes. Cycles were not only shorter in infants than parents (- 11.8 min, 95% C.I. [- 13.8, - 9.8]) but also increased by[~] 10 min from 3 to 12 months of age, mirroring previous results in smaller samples for NREM-REM sleep cycles. This increase was found to be partially mediated by an increase in sleep bout duration with age (+1.0 min/h, [+0.9, +1.2]). Longer cycles were also found in infants still breastfed at 12 months (+2.5 min [+0.4, +4.5]) and their breastfeeding mothers (+6.7 min [+0.5, +12.9]). We also explored variations in non-rhythmic LIDS patterns in relation to endogenous and exogenous factors. Overall, our results provide evidence of a link between rhythmic patterns in limb inactivity and sleep cycles in infancy, underscoring the potential of studying these in large-scale population cohorts for developmental and health outcomes.

physiology↗

bioRxiv2021

Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements

Transcriptional profiling provides global snapshots of virus-mediated cellular reprogramming, which can simultaneously encompass pro- and antiviral components. To determine early transcriptional signatures associated with HCV infection of authentic target cells, we performed ex vivo infections of adult primary human hepatocytes (PHHs) from seven donors. Longitudinal sampling identified minimal gene dysregulation at six hours post infection (hpi). In contrast, at 72 hpi, massive increases in the breadth and magnitude of HCV-induced gene dysregulation were apparent, affecting gene classes associated with diverse biological processes. Comparison with HCV-induced transcriptional dysregulation in Huh-7.5 cells identified limited overlap between the two systems. Of note, in PHHs, HCV infection initiated broad upregulation of canonical interferon (IFN)-mediated defense programs, limiting viral RNA replication and abrogating virion release. We further find that constitutive expression of IRF1 in PHHs maintains a steady-state antiviral program in the absence of infection, which can additionally reduce HCV RNA translation and replication. We also detected infection-induced downregulation of [~]90 genes encoding components of the EIF2 translation initiation complex and ribosomal subunits in PHHs, consistent with a signature of translational shutoff. As HCV polyprotein translation occurs independently of the EIF2 complex, this process is likely pro-viral: only translation initiation of host transcripts is arrested. The combination of antiviral intrinsic and inducible immunity, balanced against pro-viral programs, including translational arrest, maintains HCV replication at a low-level in PHHs. This may ultimately keep HCV under the radar of extra-hepatocyte immune surveillance while initial infection is established, promoting tolerance, preventing clearance and facilitating progression to chronicity. IMPORTANCEAcute HCV infections are often asymptomatic and therefore frequently undiagnosed. We endeavored to recreate this understudied phase of HCV infection using explanted PHHs and monitored host responses to initial infection. We detected temporally distinct virus-induced perturbations in the transcriptional landscape, which were initially narrow but massively amplified in breadth and magnitude over time. At 72 hpi, we detected dysregulation of diverse gene programs, concurrently promoting both virus clearance and virus persistence. On the one hand, baseline expression of IRF1 combined with infection-induced upregulation of IFN-mediated effector genes suppresses virus propagation. On the other, we detect transcriptional signatures of host translational inhibition, which likely reduces processing of IFN-regulated gene transcripts and facilitates virus survival. Together, our data provide important insights into constitutive and virus-induced transcriptional programs in PHHs, and identifies simultaneous antagonistic dysregulation of pro-and anti-viral programs which may facilitate host tolerance and promote viral persistence.

immunology↗