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.

Circadian de(regulation) in physiology: implications for disease and treatment.

Time plays a crucial role in the regulation of physiological processes. Without a temporal control system, animals would be unprepared for cyclic environmental changes, negatively impacting their survival. Experimental studies have demonstrated the essential role of the circadian system in the temporal coordination of physiological processes.

Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping.

The circadian clock, a fundamental biological regulator, governs essential cellular processes in health and disease. Circadian-based therapeutic strategies are increasingly gaining recognition as promising avenues. Aligning drug administration with the circadian rhythm can enhance treatment efficacy and minimize side effects.

The Ecology of Human Sleep (EcoSleep) Cohort Study: Protocol for a longitudinal repeated measurement burst design study to assess the relationship between sleep determinants and outcomes under real-world conditions across time of year.

The interplay of daily life factors, including mood, physical activity, or light exposure, influences sleep architecture and quality. Laboratory-based studies often isolate these determinants to establish causality, thereby sacrificing ecological validity. Furthermore, little is known about time-of-year changes in sleep and circadian-related variables at high resolution, including the magnitude of individual change across time of year under real-world conditions.

Network switches and their role in circadian clocks.

Circadian rhythms are generated by complex interactions among genes and proteins. Self-sustained ∼24 h oscillations require negative feedback loops and sufficiently strong nonlinearities that are the product of molecular and network switches. Here, we review common mechanisms to obtain switch-like behavior, including cooperativity, antagonistic enzymes, multisite phosphorylation, positive feedback, and sequestration.

Coupling allows robust mammalian redox circadian rhythms despite heterogeneity and noise.

Circadian clocks are endogenous oscillators present in almost all cells that drive daily rhythms in physiology and behavior. There are two mechanisms that have been proposed to explain how circadian rhythms are generated in mammalian cells: through a transcription-translation feedback loop (TTFL) and based on oxidation/reduction reactions, both of which are intrinsically stochastic and heterogeneous at the single cell level. In order to explore the emerging properties of stochastic and heterogeneous redox oscillators, we simplify a recently developed kinetic model of redox oscillations to an amplitude-phase oscillator with 'twist' (period-amplitude correlation) and subject to Gaussian noise.

Circadian protein expression patterns in healthy young adults.

Objectives: To explore how the blood plasma proteome fluctuates across the 24-hour day and identify a subset of proteins that show endogenous circadian rhythmicity.

Methods: Plasma samples from 17 healthy adults were collected hourly under controlled conditions designed to unmask endogenous circadian rhythmicity; in a subset of 8 participants, we also collected samples across a day on a typical sleep-wake schedule. A total of 6916 proteins were analyzed from each sample using the SomaScan aptamer-based multiplexed platform.

Are circadian amplitudes and periods correlated? A new twist in the story.

Three parameters are important to characterize a circadian and in general any biological clock: period, phase and amplitude. While circadian periods have been shown to correlate with entrainment phases, and clock amplitude influences the phase response of an oscillator to pulse-like zeitgeber signals, the co-modulations of amplitude and periods, which we term , have not been studied in detail. In this paper we define two concepts: refers to amplitude-period correlations arising in ensembles of self-sustained, limit cycle clocks in the absence of external inputs, and refers to the co-modulation of an individual clock's amplitude and period in response to external zeitgebers.

Alternative polyadenylation factor CPSF6 regulates temperature compensation of the mammalian circadian clock.

A defining property of circadian clocks is temperature compensation, characterized by the resilience of their near 24-hour free-running periods against changes in environmental temperature within the physiological range. While temperature compensation is evolutionary conserved across different taxa of life and has been studied within many model organisms, its molecular underpinnings remain elusive. Posttranscriptional regulations such as temperature-sensitive alternative splicing or phosphorylation have been described as underlying reactions.

Dysfunction of circadian and sleep rhythms in the early stages of Alzheimer's disease.

Dysfunction of circadian and sleep rhythms is an early feature of many neurodegenerative diseases. Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in cognitive and psychiatric disturbances. Although it is largely unclear whether dysfunctions in sleep and circadian rhythms contribute to the etiology of AD or are a consequence of the disease, there is evidence that these conditions are involved in a complex self-reinforcing bidirectional relationship.

The impact of daylight-saving time (DST) on patients with delayed sleep-wake phase disorder (DSWPD).

Due to time zones, sun time and local time rarely match. The difference between local and sun time, which we designate by Solar Jet Lag (SoJL), depends on location within a time zone and can range from zero to several hours. Daylight saving time (DST) simply adds 1 h to SoJL, independently of the location.

Circadian rhythm disruption in critically ill patients.

Patients admitted to the intensive care unit (ICU) are in need of continuous organ replacement strategies and specialized care, for example because of neurological dysfunction, cardio-pulmonary instability, liver or kidney failure, trauma, hemorrhagic or septic shock or even preterm birth. The 24-h nursing and care interventions provided to critically ill patients significantly limit resting and/or recovery phases. Consecutively, the patient's endogenous circadian rhythms are misaligned and disrupted, which in turn may interfere with their critical condition.

A conditional mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway.

Nonsense-mediated messenger RNA (mRNA) decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in physiological control of mRNA stability have emerged, possible functions in mammalian physiology in vivo remain unclear. Here, we created a conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein.

Inter-layer and inter-subject variability of diurnal gene expression in human skin.

The skin is the largest human organ with a circadian clock that regulates its function. Although circadian rhythms in specific functions are known, rhythms in the proximal clock output, gene expression, in human skin have not been thoroughly explored. This work reports 24 h gene expression rhythms in two skin layers, epidermis and dermis, in a cohort of young, healthy adults, who maintained natural, regular sleep-wake schedules.

Ventilator-induced Lung Injury Is Modulated by the Circadian Clock.

Mechanical ventilation (MV) is life-saving but may evoke ventilator-induced lung injury (VILI). To explore how the circadian clock modulates severity of murine VILI via the core clock component BMAL1 (basic helix-loop-helix ARNT like 1) in myeloid cells. Myeloid cell BMAL1-deficient ( (lysozyme 2 promoter/enhancer driving cre recombinase expression)) or wild-type control () mice were subjected to 4 hours MV (34 ml/kg body weight) to induce lung injury.

Foundations of circadian medicine.

The circadian clock is an evolutionarily highly conserved endogenous timing program that structures physiology and behavior according to the time of day. Disruption of circadian rhythms is associated with many common pathologies. The emerging field of circadian medicine aims to exploit the mechanisms of circadian physiology and clock-disease interaction for clinical diagnosis, treatment, and prevention.

Mutational scanning identified amino acids of the CLOCK exon 19-domain essential for circadian rhythms.

Aim: In the mammalian circadian clock, the CLOCK/BMAL1 heterodimer binds to E-box enhancer elements in the promoters of its target genes to activate transcription. The classical Clock mice, the first circadian mouse mutant discovered, are behaviourally arrhythmic. In this mutant, CLOCK lacks a 51 amino acid domain corresponding to exon 19 (CLOCKΔ19), which is required for normal transactivation.

Effects of Early vs. Late Time-Restricted Eating on Cardiometabolic Health, Inflammation, and Sleep in Overweight and Obese Women: A Study Protocol for the ChronoFast Trial.

Time-restricted eating is a promising dietary strategy for weight loss, glucose and lipid metabolism improvements, and overall well-being. However, human studies demonstrated contradictory results for the restriction of food intake to the beginning (early TRE, eTRE) or to the end of the day (late TRE, lTRE) suggesting that more carefully controlled studies are needed. The aim of the ChronoFast trial study is to determine whether eTRE or lTRE is a better dietary approach to improve cardiometabolic health upon minimized calorie deficits and nearly stable body weight.

Susceptibility rhythm to bacterial endotoxin in myeloid clock-knockout mice.

Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival.