Circadian Clock Research Articles

An integrative approach prioritizes the orphan GPR61 genomic region in tissue-specific regulation of chronotype.

Chronotype, a manifestation of circadian rhythms, affects morning or evening preferences and ease of getting-up. This study explores the genetic basis of morning chronotype and ease of getting-up, focusing on the G protein-coupled receptor locus, GPR61. We analyzed the genetic correlation between chronotype and ease of getting-up using linkage disequilibrium score regression with summary statistics from the UK Biobank (n=453,379). We prioritized shared signals between chronotype and ease of getting-up using the Human Genetic Evidence (HuGE) score. We assessed the significance of GPR61 and the lead variant rs12044778 through colocalization and in-silico analyses from ENCODE, Genotype-Tissue Expression, Hi-C, and Knockout Mouse Project databases to explore potential regulatory roles of causal genes. We identified a strong genetic correlation (Rg=0.80, P=4.9 x10 324 ) between chronotype and ease of getting-up. Twenty-three genes, including three circadian core clock components, had high HuGE scores for both traits. Lead variant rs12044778 in GPR61 was prioritized for its high HuGE score (45) and causal pleiotropy (posterior probability=0.98). This morningness variant influenced gene expression in key tissues: decreasing GPR61 in tibial nerve, increasing AMIGO1 in subcutaneous adipose, and increasing ATXN7L2 in the cerebellum. Functional knockout models showed GPR61 knockout increased fat mass and activity, AMIGO1 knockout increased activity, and ATXN7L2 knockout reduced body weight without affecting activity. Our findings reveal pleiotropic genetic factors influencing chronotype and ease of getting-up, emphasizing GPR61 's rs12044778 and nearby genes like AMIGO1 and ATXN7L2 . These insights advance understanding of circadian preferences and suggest potential therapeutic interventions. This study investigates the genetic underpinnings of chronotype preferences and ease of getting up, with a focus on the orphan G protein-coupled receptor GPR61 and the locus lead variant rs12044778. By combining genomic data with in silico functional analysis, we provide mechanistic insight into a locus for morning chronotype and ease of getting in the morning. We identified the variant rs12044778 as a key regulator of GPR61 and nearby genes AMIGO1 and ATXN7L2 influencing circadian and metabolic traits. Our findings shed light on the intricate genetic networks governing circadian rhythms, suggesting potential therapeutic targets for disorders of the circadian rhythm.

Dual roles of pear EARLY FLOWERING 4 -like genes in regulating flowering and leaf senescence

BackgroundFlowering is a critical agronomic trait in fruit tree cultivation, essential for sexual reproduction and fruit yield. Circadian clock system, governing processes such as flowering, growth, and hormone signaling, plays a key role in plant adaptability. While some clock-related genes influencing pear flowering have been studied, the role of the PbELF4 (EARLY FLOWERING 4) family remains largely unexplored.ResultsIn this study, we identified five ELF4 homologous genes within the pear (Pyrus bretschneideri) genome. Phylogenetic analysis delineated two distinct groups within the PbELF4 genes, with PbELF4a and PbELF4b clustering with AtELF4. Expression profiling across various pear tissues revealed diverse expression patterns. Diurnal rhythms of PbELF4 genes were discernible in pear leaves, suggesting potential regulatory roles. Ectopic overexpression of PbELF4a and PbELF4b in Arabidopsis significantly delayed flowering and suppressed the expression of flowering-related genes. Additionally, PbELF4b overexpression induced premature leaf senescence, evidenced by reduced chlorophyll content and increased expression of senescence-associated genes. Nuclear localization of PbELF4a and PbELF4b proteins was observed, and interaction assays revealed that PbELF4a interacted with PbELF3α.ConclusionsThese findings underscore the conserved function of PbELF4a and PbELF4b as negative regulators of flowering time, with PbELF4b also demonstrating a positive role in leaf senescence.

Neuronal Progenitors Suffer Genotoxic Stress in the Drosophila Clock Mutant per0

The physiological role and the molecular architecture of the circadian clock in fully developed organisms are well established. Yet, we have a limited understanding of the function of the clock during ontogenesis. We have used a null mutant (per0) of the clock gene period (per) in Drosophila melanogaster to ask whether PER may play a role during normal brain development. In third-instar larvae, we have observed that the absence of functional per results in increased genotoxic stress compared to wild-type controls. We have detected increased double-strand DNA breaks in the central nervous system and chromosome aberrations in dividing neuronal precursor cells. We have demonstrated that reactive oxygen species (ROS) are causal to the genotoxic effect and that expression of PER in glia is necessary and sufficient to suppress such a phenotype. Finally, we have shown that the absence of PER may result in less condensed chromatin, which contributes to DNA damage.

The correlation of shift work and CLOCK, BMAL1, and PER1 gene polymorphisms with hypertension in healthcare workers: A cross-sectional study

This study aimed to investigate the polymorphisms of circadian clock genes and the association of shift work and gene polymorphisms with hypertension in healthcare workers. This study recruited 222 healthcare workers, of whom 76 had primary hypertension (Hyp group) and 146 served as controls (Control group). General information and working hours were collected through questionnaires. Next, the identification of specific single nucleotide polymorphism (SNP) loci related to the Circadian locomotor output cycles kaput (CLOCK), brain and muscle arnt-like 1 (BMAL1), and PER1 genes was conducted by literature and PDGene database search. Venous blood samples were then collected for DNA extraction, and polymerase chain reaction-restriction fragment length polymorphism techniques were used to analyze the genotyping and allele frequency of the SNP sites. Finally, multivariate logistic regression was employed to analyze the association between various risk factors and hypertension in healthcare workers. Compared to the control group, the Hyp group had significantly higher proportions of alcohol consumption and family history of hypertension, while the average sleep duration and average exercise time were significantly lower. Shift work analysis showed that the Hyp group had a significantly lower average number of evening shifts per month while a much higher average number of night shifts per month compared to the control group. The GG genotype at the CLOCK rs1801260 locus was associated with a lower risk of hypertension (OR = 0.446), and the TT genotype of the BMAL1 rs11022775 locus also showed a similar protective effect (OR = 0.426). However, the genotype distribution of the PER1 rs2735611 locus was not significantly associated with the risk of hypertension. Multivariate regression analysis revealed that a family history of hypertension and insufficient sleep were significantly associated with the risk of hypertension, and the average number of night shifts per month was positively correlated with the risk of hypertension. Specific polymorphisms in the CLOCK and BMAL1 genes may have a protective effect against hypertension in healthcare workers, while polymorphisms in the PER1 gene are not significantly associated with the risk of hypertension. Additionally, a family history of hypertension, insufficient sleep, and shift work patterns may be significant risk factors for hypertension.

Photoperiodic control of growth and reproduction in non-flowering plants.

Photoperiodic responses shape the plant fitness to the changing environment and are important regulators of growth, development and productivity. Photoperiod sensing is one of the most important cues to track seasonal variations. It is also a major cue for reproductive success. The photoperiodic information conveyed through the combined action of photoreceptors and circadian clock orchestrates an output response in plants. Multiple responses such as hypocotyl elongation, induction of dormancy and flowering are photoperiodically-regulated in seed plants such as angiosperms. Flowering plants such as Arabidopsis or rice have served as important model systems to understand the molecular players involved in photoperiodic-signaling. However, photoperiodic responses in non-angiosperm plants have not been investigated and documented in detail. Genomic and transcriptomic studies have provided evidences on the conserved and distinct molecular mechanisms across plant kingdom. In this review, we have attempted to compile and compare the photoperiodic responses in the plant kingdom with a special focus on the non-angiosperms.

1,3-Dichloro-2-propanol Induced Renal Cell Ferroptosis via the Circadian Clock Protein BMAL1 Targeting GPX4.

1,3-Dichloro-2-propanol (1,3-DCP), a representative chloropropyl alcohol contaminant in food, has shown toxic effects on the kidney. Ferroptosis is a newly identified cell death driven by iron-dependent lipid peroxidation that is associated with renal injury. However, the role of 1,3-DCP in ferroptosis in renal cells remains unclear. In this study, we found that ferroptosis was involved in a 1,3-DCP-induced renal injury. Mechanistically, we revealed that 1,3-DCP triggered ferroptosis by inhibiting GPX4 activity and disturbing iron homeostasis in NRK-52E cells. The circadian clock is crucial in modulating physiological cellular functions through the regulation of various downstream proteins. Furthermore, our findings also showed that 1,3-DCP triggered ferroptosis through interference with the circadian clock. The data showed that the expression of GPX4 was regulated by clock core protein BMAL1. 1,3-DCP interfered with GPX4 rhythmic expression through disordering BMAL1 and led to lipid peroxidation, ultimately inducing ferroptosis. In conclusion, our study uncovered that BMAL1 was responsible for controlling GPX4 to mediate 1,3-DCP-induced ferroptosis. The BMAL1/GPX4 axis may be a potentially novel pathway for ferroptosis. Our work may offer a fresh perspective for toxicological research examining the interactions between food pollutants, circadian clock, and ferroptosis.

Proteomic insights into circadian transcription regulation: novel E-box interactors revealed by proximity labeling.

Circadian clocks (∼24 h) are responsible for daily physiological, metabolic, and behavioral changes. Central to these oscillations is the regulation of gene transcription. Previous research has identified clock protein complexes that interact with the transcriptional machinery to orchestrate circadian transcription, but technological constraints have limited the identification of de novo proteins. Here we use a novel genomic locus-specific quantitative proteomics approach to provide a new perspective on time of day-dependent protein binding at a critical chromatin locus involved in circadian transcription: the E-box. Using proximity labeling proteomics at the E-box of the clock-controlled Dbp gene in mouse fibroblasts, we identified 69 proteins at this locus at the time of BMAL1 binding. This method successfully enriched BMAL1 as well as HDAC3 and HISTONE H2A.V/Z, known circadian regulators. New E-box proteins include the MINK1 kinase and the transporters XPO7 and APPL1, whose depletion in human U-2 OS cells results in disrupted circadian rhythms, suggesting a role in the circadian transcriptional machinery. Overall, our approach uncovers novel circadian modulators and provides a new strategy to obtain a complete temporal picture of circadian transcriptional regulation.

A theoretical systems chronopharmacology approach for COVID-19: Modeling circadian regulation of lung infection and potential precision therapies.

The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgent need for innovative therapeutic approaches. Recent studies have revealed a complex interplay between the circadian clock and SARS-CoV-2 infection in lung cells, opening new avenues for targeted interventions. This systems pharmacology study investigates this intricate relationship, focusing on the circadian protein BMAL1. BMAL1 plays a dual role in viral dynamics, driving the expression of the viral entry receptor ACE2 while suppressing interferon-stimulated antiviral genes. Its critical position at the host-pathogen interface suggests potential as a therapeutic target, albeit requiring a nuanced approach to avoid disrupting essential circadian regulation. To enable precise tuning of potential interventions, we constructed a computational model integrating the lung cellular clock with viral infection components. We validated this model against literature data to establish a platform for drug administration simulation studies using the REV-ERB agonist SR9009. Our simulations of optimized SR9009 dosing reveal circadian-based strategies that potentially suppress viral infection while minimizing clock disruption. This quantitative framework offers insights into the viral-circadian interface, aiming to guide the development of chronotherapy-based antivirals. More broadly, it underscores the importance of understanding the connections between circadian timing, respiratory viral infections, and therapeutic responses for advancing precision medicine. Such approaches are vital for responding effectively to the rapid spread of coronaviruses like SARS-CoV-2.

Temporal and spatial layout of endocannabinoid system components in the mouse suprachiasmatic nucleus

Environmental light serves as the main entraining signal for the central circadian pacemaker, the suprachiasmatic nucleus of the hypothalamus (SCN). To shift clock timing with the changing environment, minute adjustments are necessary and the endocannabinoid system (ECS) acts as a neuromodulatory signaling mechanism in the SCN. These systems exert bidirectional effects on one another, still, limited knowledge exists about the role of endocannabinoids in circadian rhythm regulation. Therefore, we investigated the temporal and spatial molecular layouts of the ECS in the SCN of male and female C57BL/6J mice. We utilized laser capture microdissection and quantitative RT-PCR to investigate the ECS temporal layout in the SCN, detected 13 of 19 examined ECS components, and followed up with two 24-hour time course experiments, one under 12:12 light/dark and one under constant dark conditions. All enzymatic machinery related to endocannabinoid synthesis and degradation investigated were found present; however, only cannabinoid receptor 1 (Cnr1) was detected from the 6 ECS related receptors investigated. Cosinor analysis revealed circadian rhythms in many components in both sexes and lighting conditions. Next, we investigated the spatial localization of ECS components in the SCN with RNAscope in situ hybridization. Some genes, such as Cnr1, were more highly expressed in neurons with others, such as Fabp7, were elevated in astrocytes. Cnr1 levels were highest in neurons that do not express the neuropeptides Avp or Vip, and lowest in Vip neurons. Our results support the idea that locally regulated ECS signaling through neuronal CB1 modulates circadian clock function.

Impact of Circadian Clock PER2 Gene Overexpression on Rumen Epithelial Cell Dynamics and VFA Transport Protein Expression.

The circadian gene PER2 is recognized for its regulatory effects on cell proliferation and lipid metabolism across various non-ruminant cells. This study investigates the influence of PER2 gene overexpression on goat rumen epithelial cells using a constructed pcDNA3.1-PER2 plasmid, assessing its impact on circadian gene expression, cell proliferation, and mRNA levels of short-chain fatty acid (SCFA) transporters, alongside genes related to lipid metabolism, cell proliferation, and apoptosis. Rumen epithelial cells were obtained every four hours from healthy dairy goats (n = 3; aged 1.5 years; average weight 45.34 ± 4.28 kg), cultured for 48 h in vitro, and segregated into control (pcDNA3.1) and overexpressed (pcDNA3.1-PER2) groups, each with four biological replicates. The study examined the potential connection between circadian rhythms and nutrient assimilation in ruminant, including cell proliferation, apoptosis, cell cycle dynamics, and antioxidant activity and the expression of circadian-related genes, VFA transporter genes and regulatory factors. The introduction of the pcDNA3.1-PER2 plasmid drastically elevated PER2 expression levels by 3471.48-fold compared to controls (p < 0.01), confirming effective overexpression. PER2 overexpression resulted in a significant increase in apoptosis rates (p < 0.05) and a notable reduction in cell proliferation at 24 and 48 h post-transfection (p < 0.05), illustrating an inhibitory effect on rumen epithelial cell growth. PER2 elevation significantly boosted the expression of CCND1, WEE1, p21, and p16 (p < 0.05) while diminishing CDK4 expression (p < 0.05). While the general expression of intracellular inflammation genes remained stable, TNF-α expression notably increased. Antioxidant marker levels (SOD, MDA, GSH-Px, CAT, and T-AOC) exhibited no significant change, suggesting no oxidative damage due to PER2 overexpression. Furthermore, PER2 overexpression significantly downregulated AE2, NHE1, MCT1, and MCT4 mRNA expressions while upregulating PAT1 and VH+ ATPase. These results suggest that PER2 overexpression impairs cell proliferation, enhances apoptosis, and modulates VFA transporter-related factors in the rumen epithelium. This study implies that the PER2 gene may regulate VFA absorption through modulation of VFA transporters in rumen epithelial cells, necessitating further research into its specific regulatory mechanisms.

Effect of Intermittent Fasting on Immune Parameters and Intestinal Inflammation.

Intermittent fasting (IF), including alternate day fasting (ADF) and time-restricted feeding (TRF) or, in humans, time-restricted eating (TRE), has been associated with the prevention and improvement of diseases, including inflammatory bowel disease (IBD). This review summarizes 20 animal and human studies on the influence of IF on intestinal inflammation. In the animal studies, TRF and ADF improved histological scores, inflammatory markers, markers of oxidative stress, and microbiota composition. Apart from the studies on Ramadan fasting, there are no studies on IF in IBD patients, so human studies on IF in healthy people were included. The studies on Ramadan fasting showed almost no effects, but this particular type of fasting is not directly comparable to TRE or ADF. However, TRE and ADF appear to have anti-inflammatory effects in healthy individuals, as they significantly reduce CRP levels and inflammatory markers. TRE also improved the composition of microbiota and the circadian oscillation of clock genes. The beneficial effects of TRE and ADF in healthy people appear to depend on the number of uninterrupted days of fasting, while in animal studies improvements in colitis have been observed regardless of the duration of fasting.

Interaction Between Early Meals (Big-Breakfast Diet), Clock Gene mRNA Expression, and Gut Microbiome to Regulate Weight Loss and Glucose Metabolism in Obesity and Type 2 Diabetes.

The circadian clock gene system plays a pivotal role in coordinating the daily rhythms of most metabolic processes. It is synchronized with the light-dark cycle and the eating-fasting schedule. Notably, the interaction between meal timing and circadian clock genes (CGs) allows for optimizing metabolic processes at specific times of the day. Breakfast has a powerful resetting effect on the CG network. A misaligned meal pattern, such as skipping breakfast, can lead to a discordance between meal timing and the endogenous CGs, and is associated with obesity and T2D. Conversely, concentrating most calories and carbohydrates (CH) in the early hours of the day upregulates metabolic CG expression, thus promoting improved weight loss and glycemic control. Recently, it was revealed that microorganisms in the gastrointestinal tract, known as the gut microbiome (GM), and its derived metabolites display daily oscillation, and play a critical role in energy and glucose metabolism. The timing of meal intake coordinates the oscillation of GM and GM-derived metabolites, which in turn influences CG expression, playing a crucial role in the metabolic response to food intake. An imbalance in the gut microbiota (dysbiosis) can also reciprocally disrupt CG rhythms. Evidence suggests that misaligned meal timing may cause such disruptions and can lead to obesity and hyperglycemia. This manuscript focuses on the reciprocal interaction between meal timing, GM oscillation, and circadian CG rhythms. It will also review studies demonstrating how aligning meal timing with the circadian clock can reset and synchronize CG rhythms and GM oscillations. This synchronization can facilitate weight loss and improve glycemic control in obesity and those with T2D.

The Effect of Caffeine Exposure on Sleep Patterns in Zebrafish Larvae and Its Underlying Mechanism.

The effect of caffeine on the behavior and sleep patterns of zebrafish larvae, as well as its underlying mechanisms, has been a topic of great interest. This study aimed to investigate the impact of caffeine on zebrafish larval sleep/wake behavior and the expression of key regulatory genes such as cAMP-response element binding protein (CREB) and adenosine (ADA) in the sleep pathway. To begin, the study determined the optimal dose and duration of caffeine exposure, with the optimal doses found to be 31.25 μM, 62.5 μM, and 120 μM. Similarly, the optimal exposure time was established as no more than 120 h, ensuring a mortality rate of less than 10%. The confirmation of these conditions was achieved through the assessment of angiogenesis and the inflammatory reaction. As a result, the treatment time point of 24 h post-fertilization (hpf) was selected to examine the effects of caffeine on zebrafish larval sleep rhythm (48 h, with a light cycle of 14:10). Furthermore, the study analyzed the expression of clock genes (bmal1a, per1b, per2, per3, cry2), adenosine receptor genes (adora1a, adora1b, adora2aa, adora2ab, adora2b), and key regulatory factors (CREB and ADA). The research confirmed that caffeine could induce sleep pattern disorders, significantly upregulate adenosine receptor genes (adora1a, adora1b, adora2a, adora2ab, adora2b) (p < 0.05), and markedly decrease the total sleep time and sleep efficiency of the larvae. Additionally, the activity of ADA significantly increased during the exposure (p < 0.001), and the tissue-specific expression of CREB was also significantly increased, as assessed by immunofluorescence. Caffeine may regulate circadian clock genes through the ADA/ADORA/CREB pathway. These findings not only enhance our understanding of the effects of caffeine on zebrafish larvae but also provide valuable insights into the potential impact of caffeine on human behavior and sleep.

Interaction between time-of-day and oxytocin efficacy in mice and humans with and without gestational diabetes.

Management of labor in women with diabetes is challenging due to the high risk of peri- and postpartum complications. To avoid cesarean section and assist with labor progression, Pitocin, a synthetic oxytocin, is frequently used to induce and augment labor. However, the efficacy of Pitocin is often compromised in diabetic pregnancies, leading to increased cesarian delivery. As diabetes deregulates the body's circadian timekeeping system and the time-of-day of the first Pitocin administration contributes to labor duration, our objective was to determine how the time of day and the circadian clock gene, Bmal1 , gates oxytocin efficacy. Our studies in mice show that, compared to the rest phase of the day (lights on), the uterotonic efficacy of oxytocin is significantly increased during the active phase (lights off). Using in vitro studies, a myometrium-specific Bmal1 conditional knockout mouse model, and a mouse model of food-induced gestational diabetes, we find that Bmal1 is crucial for maintaining oxytocin receptor expression and response in the myometrium in mice. These findings also translate to humans, where oxytocin-induced human myometrial cell contraction is time-of-day dependent, and retrospective clinical data suggest that administration of Pitocin in the morning should be considered for pregnant women with gestational diabetes.

Diurnal Rhythmicity in the Rhizosphere Microbiome—Mechanistic Insights and Significance for Rhizosphere Function

ABSTRACTThe rhizosphere is a key interface between plants, microbes and the soil which influences plant health and nutrition and modulates terrestrial biogeochemical cycling. Recent research has shown that the rhizosphere environment is far more dynamic than previously recognised, with evidence emerging for diurnal rhythmicity in rhizosphere chemistry and microbial community composition. This rhythmicity is in part linked to the host plant's circadian rhythm, although some heterotrophic rhizosphere bacteria and fungi may also possess intrinsic rhythmicity. We review the evidence for diurnal rhythmicity in rhizosphere microbial communities and its link to the plant circadian clock. Factors which may drive microbial rhythmicity are discussed, including diurnal change in root exudate flux and composition, rhizosphere physico‐chemical properties and plant immunity. Microbial processes which could contribute to community rhythmicity are considered, including self‐sustained microbial rhythms, bacterial movement into and out of the rhizosphere, and microbe‐microbe interactions. We also consider evidence that changes in microbial composition mediated by the plant circadian clock may affect microbial function and its significance for plant health and broader soil biogeochemical cycling processes. We identify key knowledge gaps and approaches which could help to resolve the spatial and temporal variation and functional significance of rhizosphere microbial rhythmicity. This includes unravelling the factors which determine the oscillation of microbial activity, growth and death, and cross‐talk with the host over diurnal time frames. We conclude that diurnal rhythmicity is an inherent characteristic of the rhizosphere and that temporal factors should be considered and reported in rhizosphere studies.

Behavioural phenotypes of Dicer knockout in the mouse SCN

AbstractThe suprachiasmatic nucleus (SCN) is the master clock that directly dictates behavioural rhythms to anticipate the earth's light/dark cycles. Although post‐transcriptional regulators called microRNAs have been implicated in physiological SCN function, how the absence of the entire mature miRNome impacts SCN output has not yet been explored. To study the behavioural consequences of miRNA depletion in the SCN, we first generated a mouse model in which Dicer is inactivated in the SCN by crossing Syt10Cre mice with Dicerflox mice to study behavioural consequences of miRNA depletion in the SCN. Loss of all mature miRNAs in the SCN shortened the circadian period length by ~37 minutes at the tissue level and by ~45 minutes at the locomotor activity level. Moreover, knockout animals exhibited a reduction in the precision of the circadian rhythm with more variable activity onsets under both LD 12:12 and DD conditions. We also observed that knockouts with higher onset variations were inclined to develop ultradian rhythms under constant light. In a second mouse model, recombination of Dicerflox via Cre delivery specifically in the SCN resulted in loss of behavioural rhythms in some animals depending on the injection efficiency. Together, our observations highlight the importance of microRNAs for a physiological SCN function and their pivotal role in robust circadian oscillations.

Enlightening the blind spot of the Michaelis–Menten rate law: The role of relaxation dynamics in molecular complex formation

The century-long Michaelis–Menten rate law and its modifications in the modeling of biochemical rate processes stand on the assumption that the concentration of the complex of interacting molecules, at each moment, rapidly approaches an equilibrium (quasi-steady state) compared to the pace of molecular concentration changes. Yet, in the case of actively time-varying molecular concentrations with transient or oscillatory dynamics, the deviation of the complex profile from the quasi-steady state becomes relevant. A recent theoretical approach, known as the effective time-delay scheme (ETS), suggests that the delay from the relaxation time of molecular complex formation contributes to the substantial breakdown of the quasi-steady state assumption. Here, we systematically expand this ETS and inquire into the comprehensive roles of relaxation dynamics in complex formation. Through the modeling of rhythmic protein–protein and protein–DNA interactions and the mammalian circadian clock, our analysis reveals the effect of the relaxation dynamics beyond the time delay, which extends to the dampening of changes in the complex concentration with a reduction in the oscillation amplitude compared to the quasi-steady state. Interestingly, the combined effect of the time delay and amplitude reduction shapes both qualitative and quantitative oscillatory patterns such as the emergence and variability of the mammalian circadian rhythms. These findings highlight the downside of the routine assumption of quasi-steady states and enhance the mechanistic understanding of rich time-varying biomolecular processes.

Mineralocorticoid Receptor and Sleep Quality in Chronic Kidney Disease.

The classical function of the mineralocorticoid receptor (MR) is to maintain electrolytic homeostasis and control extracellular volume and blood pressure. The MR is expressed in the central nervous system (CNS) and is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as sleep physiology, playing a role in the non-rapid eye movement (NREM) phase of sleep. Some patients with psychiatric disorders have very poor sleep quality, and a relationship between MR dysregulation and this disorder has been found in them. In addition, the MR is involved in the regulation of the renal peripheral clock. One of the most common comorbidities observed in patients with chronic kidney disease (CKD) is poor sleep quality. Patients with CKD experience sleep disturbances, including reduced sleep duration, sleep fragmentation, and insomnia. To date, no studies have specifically investigated the relationship between MR activation and CKD-associated sleep disturbances. However, in this review, we analyzed the environment that occurs in CKD and proposed two MR-related mechanisms that may be responsible for these sleep disturbances: the circadian clock disruption and the high levels of MR agonist observed in CKD.

EARLY FLOWERING 3 alleles affect the temperature responsiveness of the circadian clock in Chinese cabbage.

Temperature is an environmental cue that entrains the circadian clock, adapting it to local thermal and photoperiodic conditions that characterize different geographic regions. Circadian clock thermal adaptation in leafy vegetables such as Chinese cabbage (Brassica rapa ssp. pekinensis) is poorly understood but essential to sustain and increase vegetable production under changing climates. We investigated circadian rhythmicity in natural Chinese cabbage accessions grown at 14, 20, and 28 °C. The circadian period was significantly shorter at 20 °C than at either 14 or 28 °C, and the responses to increasing temperature and temperature compensation (Q10) were associated with population structure. Genome-wide association studies mapping identified variation responsible for temperature compensation as measured by Q10 value for temperature increase from 20 to 28 °C. Haplotype analysis indicated that B. rapa EARLY FLOWERING 3 H1 Allele (BrELF3H1) conferred a significantly higher Q10 value at 20 to 28 °C than BrELF3H2. Co-segregation analyses of an F2 population derived from a BrELF3H1 × BrELF3H2 cross revealed that variation among BrELF3 alleles determined variation in the circadian period of Chinese cabbage at 20 °C. However, their differential impact on circadian oscillation was attenuated at 28 °C. Transgenic complementation in Arabidopsis thaliana elf3-8 mutants validated the involvement of BrELF3 in the circadian clock response to thermal cues, with BrELF3H1 conferring a higher Q10 value than BrELF3 H2 at 20 to 28 °C. Thus, BrELF3 is critical to the circadian clock response to ambient temperature in Chinese cabbage. These findings have clear implications for breeding new varieties with enhanced resilience to extreme temperatures.

REV-ERBα inhibitor rescues MPTP/MPP+-induced ferroptosis of dopaminergic neuron through regulating FASN/SCD1 signaling pathway

Circadian disruption is a risk factor for Parkinson's disease (PD). Ferroptosis, a cellular death process, assumes a pivotal role in the degeneration of dopaminergic neurons in PD. Despite its significance, the potential contribution of circadian clock proteins to PD through the modulation of ferroptosis remains elusive. Our investigation unveiled a reduction in the circadian clock protein REV-ERBα in both MPTP/MPP+ and ferroptosis models. REV-ERBα actively promotes ferroptosis by binding to the RORE cis-element and suppressing the transcription of Fasn and Scd1, two genes that inhibit ferroptosis. Notably, inhibiting REV-ERBα exhibited a discernible mitigating effect on ferroptosis and the ensuing dopaminergic neuron damage induced by MPTP/MPP+. Consequently, targeting REV-ERBα emerges as a promising strategy for inhibiting ferroptosis and presents a novel therapeutic avenue for PD.