Polygenic impact of morningness on the overnight dynamics of sleep spindle amplitude

Sleep spindles are thalamocortical oscillations that contribute to sleep maintenance and sleep‐related brain plasticity. The current study is an explorative study of the circadian dynamics of sleep spindles in relation to a polygenic score (PGS) for circadian preference towards morningness. The participants represent the 17‐year follow‐up of a birth cohort having both genome‐wide data and an ambulatory sleep electroencephalography measurement available ( N = 154, Mean age = 16.9, SD = 0.1 years, 57% girls). Based on a recent genome‐wide association study, we calculated a PGS for circadian preference towards morningness across the whole genome, including 354 single‐nucleotide polymorphisms. Stage 2 slow (9‐12.5 Hz, N = 186 739) and fast (12.5‐16 Hz, N = 135 504) sleep spindles were detected using an automated algorithm with individual time tags and amplitudes for each spindle. There was a significant interaction of PGS for morningness and timing of sleep spindles across the night. These growth curve models showed a curvilinear trajectory of spindle amplitudes: those with a higher PGS for morningness showed higher slow spindle amplitudes in frontal derivations, and a faster dissipation of spindle amplitude in central derivations. Overall, the findings provide new evidence on how individual sleep spindle trajectories are influenced by genetic factors associated with circadian type. The finding may lead to new hypotheses on the associations previously observed between circadian types, psychiatric problems and spindle activity.     

Associations between polymorphisms in the NR1D1 gene encoding for nuclear receptor REV-ERBα and circadian typologies

Nuclear receptor REV-ERBα, a key component of an internal timekeeping system, has been considered to be related to disrupted circadian rhythms and mood disorder. In this study, we aimed to evaluate the relationship between the genotype frequencies of single gene polymorphisms (SNPs) of the NR1D1 gene encoding REV-ERBα and circadian typologies. The classification of chronotypes and genotyping of three SNPs (rs2314339, rs2071427, rs12941497) of the NR1D1 gene were conducted in 602 healthy young adults (355 males, 247 females). A significant association was found between the genotypes of rs12941497 and three chronotype categories. These findings support the role of NR1D1 polymorphisms in the regulation of circadian rhythms.     

Expression of Clock Genes in Human Peripheral Blood Mononuclear Cells throughout the Sleep/Wake and Circadian Cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non‐SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five‐day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake‐time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi‐hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.     

The internal circadian clock increases hunger and appetite in the evening independent of food intake and other behaviors

Objective:

Despite the extended overnight fast, paradoxically, people are typically not ravenous in the morning and breakfast is typically the smallest meal of the day. We assessed whether this paradox could be explained by an endogenous circadian influence on appetite with a morning trough, while controlling for sleep/wake and fasting/feeding effects.

Design and Methods:

Twelve healthy non‐obese adults (six males; age, 20‐42 years) were studied throughout a 13‐day laboratory protocol that balanced all behaviors, including eucaloric meals and sleep periods, evenly across the endogenous circadian cycle. Participants rated their appetite and food preferences by visual analog scales.

Results:

There was a large endogenous circadian rhythm in hunger, with the trough in the biological morning (8 AM) and peak in the biological evening (8 PM; peak‐to‐trough amplitude = 17%; P = 0.004). Similarly‐phased significant endogenous circadian rhythms were present in appetites for sweet, salty and starchy foods, fruits, meats/poultry, food overall, and for estimates of how much food participants could eat (amplitudes 14‐25%; all P < 0.05).

Conclusions:

In people who sleep at night, the intrinsic circadian evening peak in appetite may promote larger meals before the fasting period necessitated by sleep, whereas the circadian morning trough would theoretically facilitate the extended overnight fast. Furthermore, the circadian decline in hunger across the night would theoretically counteract the fasting‐induced hunger increase that could otherwise disrupt sleep.     

Sleep Loss and Performance of Anaesthesia Trainees and Specialists

Fatigue risk associated with work schedules of hospital doctors is coming under increasing scrutiny, with much of the research and regulatory focus on trainees. However, provision of 24 h services involves both trainees and specialists, who have different but interdependent work patterns. This study examined work patterns, sleep (actigraphy, diaries) and performance (psychomotor vigilance task pre‐ and post‐duty) of 28 anaesthesia trainees and 20 specialists across a two‐week work cycle in two urban public hospitals. Trainees at one hospital worked back‐to‐back 12 h shifts, while the others usually worked 9 h day shifts but periodically worked a 14 h day (08:00–22:00 h) to maintain cover until arrival of the night shift (10 h). On 11% of day shifts and 23% of night shifts, trainees were working with ≥2 h of acute sleep loss. However, average sleep loss was not greater on night shifts, possibly because workload at night in one hospital often permitted some sleep. Post‐night shift performance was worse than post‐day shift performance for the median (t₍₁₃₁₎=3.57, p<0.001) and slowest 10% of reaction times (t₍₁₃₄₎=2.91, p<0.01). At the end of night shifts, poorer performance was associated with longer shift length, longer time since waking, greater acute sleep loss, and more total work in the past 24 h. Specialists at both hospitals had scheduled clinical duties during the day and were periodically scheduled on call to cover after‐hours services. On 8% of day shifts and 14% of day+call schedules, specialists were working with ≥2 h of acute sleep loss. They averaged 0.6 h less sleep when working day shifts (t_(23.5)=2.66, p=0.014) and 0.8 h less sleep when working day shifts+call schedules (t_(26.3)=2.65, p=0.013) than on days off. Post‐duty reaction times slowed linearly across consecutive duty days (median reaction time, t₍₁₃₁₎=?3.38, p<0.001; slowest 10%, t₍₁₆₀₎=?3.33, p<0.01; fastest 10%, t₍₁₃₈₎=?2.67, p<0.01). Poorer post‐duty performance was associated with greater acute sleep loss and longer time since waking, but better performance was associated with longer day shifts, consistent with circadian improvement in psychomotor performance across the waking day. This appears to be the first study to document sleep loss among specialist anaesthetists. Consistent with observations from experimental studies, the sleep loss of specialists across 12 consecutive working days was associated with a progressive decline in post‐duty PVT performance. However, this decline occurred with much less sleep restriction (< 1 h per day) than in laboratory studies, suggesting an exacerbating effect of extended wakefulness and/or cumulative fatigue associated with work demands. For both trainees and specialists, robust circadian variation in PVT performance was evident in this complex work setting, despite the potential confounds of variable shift durations and workloads. The relationship between PVT performance of an individual and the safe administration of anaesthesia in the operating theater is unknown. Nevertheless, the findings reinforce that any schedule changes to reduce work‐related fatigue need to consider circadian performance variation and the potential transfer of workload and fatigue risk between trainees and specialists.     

Long non‐coding RNA NR2F1‐AS1 promoted proliferation and migration yet suppressed apoptosis of thyroid cancer cells through regulating miRNA‐338‐3p/CCND1 axis

Thyroid cancer (TC) is a prevalent endocrine malignant cancer whose pathogenic mechanism remains unclear. The aim of the study was to investigate the roles of long non‐coding RNA (lncRNA) NR2F1‐AS1/miRNA‐338‐3P/CCND1 axis in TC progression. Differentially expressed lncRNAs and mRNAs in TC tissues were screened out and visualized by R program. Relative expression of NR2F1‐AS1, miRNA‐338‐3p and cyclin D1 (CCND1) was determined by quantitative real time polymerase chain reaction. In addition, Western blot analysis was adopted for evaluation of protein expression of CCND1. Targeted relationships between NR2F1‐AS1 and miRNA‐338‐3p, as well as miRNA‐338‐3p and CCND1 were predicted using bioinformatics analysis and validated by dual‐luciferase reporter gene assay. Besides, tumour xenograft assay was adopted for verification of the role of NR2F1‐AS1 in TC in vivo. NR2F1‐AS1 and CCND1 were overexpressed, whereas miRNA‐338‐3p was down‐regulated in TC tissues and cell lines. Down‐regulation of NR2F1‐AS1 and CCND1 suppressed proliferation and migration of TC cells yet greatly enhanced cell apoptotic rate. Silence of NR2F1‐AS1 significantly suppressed TC tumorigenesis in vivo. NR2F1‐AS1 sponged miRNA‐338‐3p to up‐regulate CCND1 expression to promote TC progression. Our study demonstrated that up‐regulation of NR2F1‐AS1 accelerated TC progression through regulating miRNA‐338‐3P/CCND1 axis.     

Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans

This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48?h (sleep vs. no-sleep nights) in 12 young males (mean?±?SD: 23?±?5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBα) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.