Journal of Biological Rhythms最新文献

Circadian rhythms are endogenous oscillations that occur with a 24-h periodicity and support organismal homeostasis. While the role of the circadian clock in systemic vasculature is well known, its role in pulmonary vasculature, specifically in the pulmonary endothelium, has remained unexplored. We hypothesized that the circadian clock directly regulates pulmonary endothelium to control lung inflammation. Using pulmonary artery segments and endothelial cells isolated from lungs of mPer2luciferase transgenic mice, we monitored circadian rhythms and observed that lipopolysaccharide (LPS) treatment disrupted rhythmicity. This disruption was mediated by reactive oxygen species (ROS) generated via NADPH oxidase 2 (NOX2). Remarkably, the pharmacologic inhibition of NOX2 before LPS exposure restored circadian rhythmicity in the pulmonary endothelium. In wild-type (WT) mice, LPS activated a NOX2-NLRP3 signaling axis that drove inflammation as evidenced by increased polymorphonuclear neutrophil (PMN) accumulation and intercellular adhesion molecule-1 (ICAM-1) expression on the pulmonary endothelium. In contrast, disruption of the clock using two different clock mutants (Bmal1^-/- and Cry1/2^-/-) resulted in a sustained baseline elevation of PMN and ICAM-1, which changed minimally with LPS. This effect was attributed to aberrant activation of the NLRP3 inflammasome at baseline in the clock mutants, as supported by lung transcriptomic data and reversal of the phenotype with an NLRP3 inhibitor. Importantly, these findings also reveal an intriguing bidirectional relationship: while the circadian clock modulates inflammatory responses, inflammatory stimuli in turn alter circadian rhythmicity via the NOX2 pathway. Together, our results identify a novel mechanism by which circadian control of pulmonary endothelial inflammation may be leveraged to mitigate the consequences of clock disruption in lung disease.

We present a comprehensive analysis of the historical fluctuations and rephasing of seasonal birth rates in the United Kingdom from 1955 to 2015. We analyzed monthly live-birth records for England and Wales together with national photoperiod and surface-temperature series to track the annual rhythm of human reproduction. Fast Fourier transforms confirmed a robust 12-month component across the entire record, but breakpoint tests located a sharp phase shift in 1974-1976. Before this transition, peak conceptions clustered tightly around the summer solstice and yielded a stable March birth maximum. After 1976, the rhythm decoupled: the spring peak in births collapsed, a secondary autumn peak emerged, and inter-annual phase variability more than doubled. Cross-correlation analyses showed that, up to 1974, photoperiod led birth counts by ≈11 months whereas temperature played only a minor role. Post 1976, photoperiod correlations disappeared and a weaker, inverse link with temperature persisted. Sliding-window statistics indicate that variability has narrowed again since the mid-1990s, hinting at partial re-stabilization of the seasonal pattern, now centered in late autumn conceptions. These results demonstrate that the mid-1970s marked a singular disruption of the United Kingdom's reproductive calendar, coincident with the nationwide roll-out of freely available hormonal contraception and other social shifts. The findings urge caution when pooling pre- and post-1974 cohorts in genetic or epidemiological studies-such as those using UK Biobank-to explore season-of-birth effects. More broadly, they highlight the plasticity of human annual timing and the need to disentangle biological from socio-environmental drivers of reproduction.

Time-restricted feeding (TRF), a dietary intervention that consolidates food intake to specific hours of the day, ameliorates key metabolic risk factors for metabolic-associated steatohepatitis (MASH), including adiposity, insulin resistance, and liver steatosis. However, whether TRF can directly mitigate steatohepatitis or fibrosis remains uncertain. Moreover, whether the protective effects of TRF against MASH-related complications, such as inflammation and fibrosis, depend exclusively on improvements in insulin sensitivity or involve additional mechanisms remains unknown. Here, we examine the impact of 8-hour TRF on the development of fibrosis and steatohepatitis using a streptozotocin/high-fat diet (STAM/HFD) model, which recapitulates key MASH characteristics, including steatohepatitis and fibrosis, in an insulin-deficient context. TRF does not prevent the development of MASH in STAM/HFD male mice where insulin signaling is impaired. Unlike diet-induced obesity models, which exhibit greatly perturbed feeding and circadian behaviors under HFD conditions, STAM/HFD mice did not develop obesity and maintained regular or less-pronounced disruptions to circadian behaviors. This may explain why TRF failed to produce beneficial effects in this model. These findings indicate that intact insulin signaling is likely essential for TRF to effectively protect against MASH.

Animals often show distinct activity rhythms which may align their behavior with favorable environmental conditions. In terrestrial species, daily and seasonal activity patterns are largely influenced by changes in photoperiod and temperature. However, subterranean animals experience weak or absent environmental variation due to minimal light exposure and reduced daily temperature fluctuations. Despite these conditions, many subterranean rodents display pronounced diel rhythms in physiological processes and locomotor activity, though the extent of seasonal variation remains unclear. In this study, we used radio frequency identification technology on wild groups of subterranean Damaraland mole-rats to assess their daily activity patterns. Our results show a population-wide daily activity peak around midday, which coincides with the minimum temperature at nesting depths and increasing temperature at foraging depths. The timing of this peak shifts by approximately 2 h between seasons. Neither individual nor group characteristics predicted the occurrence and timing of the activity peak, suggesting that temperature fluctuations, rather than social factors, are the main driver of seasonal variation in activity timing. Although Damaraland mole-rats remain active at low levels throughout the day, they display clear diurnal foraging rhythms at the group level that change little across seasons.

Sepsis is a syndrome caused by a dysregulated host response to pathogens, representing the leading cause of death from infection. Various murine models of sepsis have shown a time-dependent response based on the time of induction. Mice stimulated with high doses of bacterial lipopolysaccharide (LPS) at the end of the day exhibit a higher mortality rate (~80%) compared with those inoculated in the middle of the night (~30%). In this work, we assessed the differences in serum proteins of septic mice during the day and night. Through this proteomic study, we found significant variations in metabolic pathways, including glucose metabolism, which were associated with a better prognosis. Therefore, we studied the glucose response to LPS during the day and night. In this context, we found an early peak of LPS-induced glucose exclusively at the time of worse prognosis. We also observed a hypoglycemic response to LPS, which was independent of the time of sepsis induction. Finally, we performed a set of metabolic manipulations to study how hyperglycemia influences sepsis severity in mice. We observed that suppressing the glucose peak during the day, through metformin administration, reduced sepsis severity. In contrast, nocturnal glucose administration with LPS was rapidly metabolized and also decreased sepsis severity. In conclusion, sepsis severity may be influenced by the metabolic state at the time of the stimulus. Metabolic rhythms could lead to differences in early glucose management, affecting the outcome of this pathology.

The light input pathways and the molecular clock are tightly linked, with light serving as the most potent zeitgeber that entrains the clock to the external environment. Our present study focuses on the Drosophila melanogaster populations that have evolved with a precise circadian clock as a correlated response to selection for adult emergence in a narrow window of time over 335 generations. The results of our study showed that flies from populations selected for the timing of adult emergence sleep more during the night phase compared to controls. This sleep was even more enhanced when the light intensity was reduced to 1 lux under a 12 h light:12 h dark cycle. In addition, a significantly higher percentage of these flies exhibited free-running period rather than arrhythmicity compared to the control flies under constant light (1 lux). Moreover, the larvae from selected populations exhibited an increased preference toward darkness than light indicating that the effect of selection extends beyond the adult circadian light input pathway, influencing the innate circadian regulated photobehavior in larvae. We examined the transcript oscillation of the circadian photoreceptor cryptochrome (cry), along with the core clock genes period (per) and timeless (tim) in adult flies to explore the molecular basis of the evolved precise circadian clocks and to determine whether selection influences the circadian light input pathway. Flies from the selected population exhibited a phase advance in the transcript oscillation of per, tim, and cry, indicating that the molecular circadian clock and its light input pathway evolve as a correlated response to the selection for the timing of adult emergence in D. melanogaster populations.

Early childhood represents a period of profound developmental changes for sleep and circadian biology. Although the relationship between sleep and circadian timing has been well characterized in older populations, such data in young children remain limited. Here, we provide fundamental data on the relationship between endogenous circadian phase and sleep timing in a sample of preschool-aged children. Participants were 49 healthy children ages 3.1 to 6.0 years (M = 4.44 years, SD = 0.69 years, 27 female). After 7 days of maintaining a consistent, parent-selected sleep schedule, children completed an in-home, dim-light circadian assessment. Saliva samples were collected in 30-min intervals throughout the evening to determine the timing of children's dim-light melatonin onset (DLMO). Children's DLMOs occurred an average of 35.0 ± 35.3 min before their bedtimes, with parent-selected bedtime occurring before DLMO for 18.4% of children. Children with later DLMOs had significantly later bedtimes (r = 0.65), sleep onset times (r = 0.74), midsleep times (r = 0.74), and wake times (r = 0.66) (all p < 0.001). For every hour later that DLMO occurred, average bedtime and sleep onset time were 28.0 and 33.4 min later, respectively. In addition, children with later DLMOs had higher scores on a parent-reported measure of chronotype (r = 0.56, p < 0.001), indicating greater eveningness. No association between DLMO time and sleep duration or social jetlag was observed. These data extend previous findings in toddlers, demonstrating a consistent relationship between circadian phase and sleep timing, as well as chronotype, throughout early childhood.

In the cyanobacterial circadian clock, a core oscillator comprising the proteins KaiA, KaiB, and KaiC keeps time based on a rhythmic phosphorylation of KaiC, and histidine protein kinases relay temporal information from the KaiABC complex to regulate gene expression. The kinases SasA and CikA engage directly with the oscillator and are responsible for modulating the phosphorylation and dephosphorylation throughout the circadian day of the response-regulator transcription factor RpaA; the phosphorylation state of RpaA in turn determines circadian gene expression. We recently showed that either CikA or SasA can drive rhythmic phosphorylation and DNA binding of RpaA in an in vitro system. However, when SasA is absent in vivo, a bioluminescence reporter gene shows a very low expression and amplitude rhythm, indicating CikA kinase activity is not sufficient to activate gene expression. We questioned why CikA cannot serve as a robust kinase for RpaA in the absence of SasA in the cell. Here, we investigated post-translational modifications of CikA and found KaiC-dependent phosphorylation sites of CikA that dramatically affect its activity. Phosphomimetic mutants of these sites showed that the phosphorylated version of CikA is not functional. Our data show that inverse correlation of KaiC levels and these inhibitory phosphorylation sites can explain the lower CikA activity in a SasA knockout background. We conclude that these phosphorylation sites act as a rheostat for CikA activity and are regulated by KaiC levels.