Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a ...mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.
The circadian clock is a molecular timekeeper, present from cyanobacteria to mammals, that coordinates internal physiology with the external environment. The clock has a 24-h period however ...development proceeds with its own timing, raising the question of how these interact. Using the intestine of Drosophila melanogaster as a model for organ development, we track how and when the circadian clock emerges in specific cell types. We find that the circadian clock begins abruptly in the adult intestine and gradually synchronizes to the environment after intestinal development is complete. This delayed start occurs because individual cells at earlier stages lack the complete circadian clock gene network. As the intestine develops, the circadian clock is first consolidated in intestinal stem cells with changes in Ecdysone and Hnf4 signalling influencing the transcriptional activity of Clk/cyc to drive the expression of tim, Pdp1, and vri. In the mature intestine, stem cell lineage commitment transiently disrupts clock activity in differentiating progeny, mirroring early developmental clock-less transitions. Our data show that clock function and differentiation are incompatible and provide a paradigm for studying circadian clocks in development and stem cell lineages.
Optical atomic clocks Ludlow, Andrew D.; Boyd, Martin M.; Ye, Jun ...
Reviews of modern physics,
06/2015, Letnik:
87, Številka:
2
Journal Article
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Since 1967 the primary time standard is the cesium atomic clock, based on a hyperfine transition in the microwave domain. The development of ultrastable laser sources now allows one to operate on ...electronic transitions in the optical domain, corresponding to a 5-order-of-magnitude increase in the clock frequency. This article reviews the spectacular accuracy and stability gains that can be obtained when working with laser cooled ions or neutral atoms. It also discusses some important applications of these optical clocks, from geodesy to tests of fundamental theories to many-body physics. Optical atomic clocks represent the state of the art in the frontier of modern measurement science. In this article a detailed review on the development of optical atomic clocks that are based on trapped single ions and many neutral atoms is provided. Important technical ingredients for optical clocks are discussed and measurement precision and systematic uncertainty associated with some of the best clocks to date are presented. An outlook on the exciting prospect for clock applications is given in conclusion.
Circadian rhythms are nearly ubiquitous throughout nature, suggesting they are critical for survival in diverse environments. Organisms inhabiting largely arrhythmic environments, such as caves, ...offer a unique opportunity to study the evolution of circadian rhythms in response to changing ecological pressures. Populations of the Mexican tetra, Astyanax mexicanus, have repeatedly invaded caves from surface rivers, where individuals must contend with perpetual darkness, reduced food availability, and limited fluctuations in daily environmental cues. To investigate the molecular basis for evolved changes in circadian rhythms, we investigated rhythmic transcription across multiple independently-evolved cavefish populations. Our findings reveal that evolution in a cave environment has led to the repeated disruption of the endogenous biological clock, and its entrainment by light. The circadian transcriptome shows widespread reductions and losses of rhythmic transcription and changes to the timing of the activation/repression of core-transcriptional clock. In addition to dysregulation of the core clock, we find that rhythmic transcription of the melatonin regulator aanat2 and melatonin rhythms are disrupted in cavefish under darkness. Mutants of aanat2 and core clock gene rorca disrupt diurnal regulation of sleep in A. mexicanus, phenocopying circadian modulation of sleep and activity phenotypes of cave populations. Together, these findings reveal multiple independent mechanisms for loss of circadian rhythms in cavefish populations and provide a platform for studying how evolved changes in the biological clock can contribute to variation in sleep and circadian behavior.
A vast network of cellular circadian clocks regulates 24‐hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals ...demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light‐reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional mouse genetics suggesting that resetting of the circadian system occurs in a more “federated” and tissue‐specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions.
A network of cellular circadian clocks adapts physiology to the 24‐hour day cycle. Traditionally clock entrainment has been conceptualized in a hierarchical scheme with a light‐reset SCN pacemaker that subsequently aligns subordinate peripheral clocks. New experiments suggest that resetting of the circadian system occurs in a more “federated” fashion allowing for increased noise resistance and plasticity of circadian timekeeping under complex natural conditions.
The intrinsic skeletal muscle core clock has emerged as a key feature of metabolic control and influences several aspects of muscle physiology. Acute alcohol intoxication disrupts the core molecular ...clock, but whether chronic consumption, like that leading to alcoholic myopathy, is also a zeitgeber for skeletal muscle remains unknown. The purpose of this work was to determine whether chronic alcohol consumption dysregulates the skeletal muscle core molecular clock and clock-controlled genes (CCGs). C57BL/6Hsd female mice (14 weeks old) were fed a control (CON) or alcohol (EtOH) containing liquid diet for 6 weeks. Gastrocnemius muscles and serum were collected from CON and EtOH mice every 4-h for 24-h. Chronic alcohol consumption disrupted genes of the core clock including suppressing the rhythmic peak of expression of Bmal1, Per1, Per2, and Cry2. Genes involved in the regulation of Bmal1 also exhibited lower rhythmic peaks including Reverb α and Myod1. The CCGs, Dbp, Lpl, Hk2, and Hadh were also suppressed by alcohol. The nuclear expression patterns of MYOD1, DBP, and REVERBα were shifted by alcohol, while no change in BMAL1 was detected. Overall, these data indicate that alcohol disrupted the skeletal muscle core clock but whether these changes in the core clock are causative or a consequence of alcoholic myopathy requires future mechanistic confirmation.
Accurate measurements of different transition frequencies between atomic levels of the electronic and hyperfine structure over time are used to investigate temporal variations of the fine structure ...constant α and the proton-to-electron mass ratio μ. We measure the frequency of the (2)S1/2→(2)F7/2 electric octupole (E3) transition in (171)Yb(+) against two caesium fountain clocks as f(E3)=642,121,496,772,645.36 Hz with an improved fractional uncertainty of 3.9×10(-16). This transition frequency shows a strong sensitivity to changes of α. Together with a number of previous and recent measurements of the (2)S1/2→(2)D3/2 electric quadrupole transition in (171)Yb(+) and with data from other elements, a least-squares analysis yields (1/α)(dα/dt)=-0.20(20)×10(-16)/yr and (1/μ)(dμ/dt)=-0.5(1.6)×10(-16)/yr, confirming a previous limit on dα/dt and providing the most stringent limit on dμ/dt from laboratory experiments.
Abstract
The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such “geroprotective” therapies in ...humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972–1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71–cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.
Circadian rhythms, metabolism, and nutrition are intimately linked 1, 2, although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr ...delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants’ circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers.
•A 5-hr delay in meal times changes the phase relationship of human circadian rhythms•Plasma glucose, but not insulin or triglyceride, rhythms are delayed by late meals•Adipose PER2 rhythms are delayed by late meals•Rhythm changes occur without altered subjective or actigraphic sleep markers
Wehrens et al. measure the effect of a 5-hr meal delay on the human circadian system. Late meals delay rhythms of plasma glucose and adipose PER2 clock gene expression. Meal timing may help to reset the circadian system in cases of shift work, jet lag, and circadian rhythm disorders.
Circadian Clocks in the Immune System Labrecque, Nathalie; Cermakian, Nicolas
Journal of Biological Rhythms,
08/2015, Letnik:
30, Številka:
4
Book Review, Journal Article
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The immune system is a complex set of physiological mechanisms whose general aim is to defend the organism against non-self-bodies, such as pathogens (bacteria, viruses, parasites), as well as cancer ...cells. Circadian rhythms are endogenous 24-h variations found in virtually all physiological processes. These circadian rhythms are generated by circadian clocks, located in most cell types, including cells of the immune system. This review presents an overview of the clocks in the immune system and of the circadian regulation of the function of immune cells. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens. Consequently, alterations of circadian rhythms (e.g., clock gene mutation in mice or environmental disruption similar to shift work) lead to disturbed immune responses. We discuss the implications of these data for human health and the areas that future research should aim to address.
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