Multiplex influences on vigilance and biochemical variables induced by sleep deprivation.

Introduction: Sleep loss and sleep deprivation (SD) cause deleterious influences on health, cognition, mood and behaviour. Nevertheless, insufficient sleep and SD are prevalent across many industries and occur in various emergencies. The deleterious consequences of SD have yet to be fully elucidated. This study aimed to assess the extensive influences of SD on physiology, vigilance, and plasma biochemical variables. Methods: Seventeen volunteers were recruited to participate in a 32.5-h SD experiment. Multiple physiological and cognitive variables, including tympanic temperature, blood oxygen saturation (SaO2), and vigilance were recorded. Urinal/salivary samples were collected and subjected to cortisol or cortisone analysis, and plasma samples were subjected to transcriptomic analysis of circular RNA (circRNA) expression using microarray. Plasma neurotransmitters were measured by targeted metabolic analysis, and the levels of inflammatory factors were assessed by antibody microarray. Results: The volunteers showed significantly increased sleepiness and decreased vigilance during SD, and the changes in circadian rhythm and plasma biochemistry were observed. The plasma calcium (p = 0.0007) was induced by SD, while ischaemia-modified albumin (IMA, p = 0.0030) and total bile acid (TBA, p = 0.0157) decreased. Differentially expressed circRNAs in plasma were identified, which are involved in multiple signaling pathways including neuronal regulation and immunity. Accordingly, SD induced a decrease in 3-hydroxybutyric acid (3OBH, p = 0.0002) and an increase in thyroxine (T4, p < 0.0001) in plasma. The plasma anti-inflammatory cytokine IL-10 was downregulated while other ten inflammatory factors were upregulated. Conclusion: This study demonstrates that SD influences biochemical, physiological, cognitive variables, and the significantly changed variables may serve as candidates of SD markers. These findings may further our understanding of the detrimental consequence of sleep disturbance at multiple levels.

BMAL1 collaborates with CLOCK to directly promote DNA double-strand break repair and tumor chemoresistance.

Accumulating evidence indicates a correlation between circadian dysfunction and genomic instability. However, whether the circadian machinery directly regulates DNA damage repair, especially in double-strand breaks (DSBs), remains poorly understood. Here, we report that in response to DSBs, BMAL1 is activated by ATM-mediated phosphorylation at S183. Phosphorylated BMAL1 is then localized to DNA damage sites, where it facilitates acetylase CLOCK to load in the chromatin, regulating the acetylation of histone H4 (H4Ac) at DSB sites. In this way, the BMAL1-CLOCK-H4Ac axis promotes the DNA end-resection to generate single-stranded DNA (ssDNA) and the subsequent homologous recombination (HR). BMAL1 deficient cells display defective HR, accumulation of unrepaired DSBs and genome instability. Accordingly, depletion of BMAL1 significantly enhances the sensitivity of adrenocortical carcinoma (ACC) to DNA damage-based therapy in vitro and in vivo. These findings uncover non-canonical function of BMAL1 and CLOCK in HR-mediated DSB repair, which may have an implication in cancer therapeutics.