Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based ...autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.
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IJS, NUK, SBMB, UL, UM, UPUK
The axion insulator which may exhibit an exotic quantized magnetoelectric effect is one of the most interesting quantum phases predicted for the three-dimensional topological insulator (TI). The ...axion insulator state is expected to show up in magnetically doped TIs with magnetizations pointing inwards and outwards from the respective surfaces. Towards the realization of the axion insulator, we here engineered a TI heterostructure in which magnetic ions (Cr) are modulation-doped only in the vicinity of the top and bottom surfaces of the TI ((Bi,Sb)
Te
) film. A separation layer between the two magnetic layers weakens interlayer coupling between them, enabling the magnetization reversal of individual layers. We demonstrate the realization of the axion insulator by observing a zero Hall plateau (ZHP) (where both the Hall and longitudinal conductivity become zero) in the electric transport properties, excluding the other possible origins for the ZHP. The manifestation of the axion insulator can lead to a new stage of research on novel magnetoelectric responses in topological matter.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including ...the regulation of sleep, metabolism, and the immune system. Here, we review advances in understanding the genetic regulation of sleep through the circadian system, as well as the impact of dysregulated gene expression on metabolic function. We also review recent studies that have begun to unravel the circadian clock's role in controlling the cardiovascular and nervous systems, gut microbiota, cancer, and aging. Such circadian control of these systems relies, in part, on transcriptional regulation, with recent evidence for genome-wide regulation of the clock through circadian chromosome organization. These novel insights into the genomic regulation of human physiology provide opportunities for the discovery of improved treatment strategies and new understanding of the biological underpinnings of human disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The circadian clock mechanism in animals involves a transcriptional feedback loop in which the bHLH‐PAS proteins CLOCK and BMAL1 form a transcriptional activator complex to activate the transcription ...of the Period and Cryptochrome genes, which in turn feed back to repress their own transcription. In the mouse liver, CLOCK and BMAL1 interact with the regulatory regions of thousands of genes, which are both cyclically and constitutively expressed. The circadian transcription in the liver is clustered in phase and this is accompanied by circadian occupancy of RNA polymerase II recruitment and initiation. These changes also lead to circadian fluctuations in histone H3 lysine4 trimethylation (H3K4me3) as well as H3 lysine9 acetylation (H3K9ac) and H3 lysine27 acetylation (H3K27ac). Thus, the circadian clock regulates global transcriptional poise and chromatin state by regulation of RNA polymerase II.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular ...environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.
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The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous ...circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.
Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen ...using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.
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•High-throughput screening identified Nobiletin as a clock amplitude enhancer•Nobiletin potently protects against metabolic syndrome in a clock-dependent manner•Nobiletin remodels circadian and metabolic gene expression•Nobiletin is an agonist for the ROR nuclear receptors in the circadian oscillator
In a high-throughput chemical screen, He et al. identify the small molecule Nobiletin (NOB), a naturally occurring compound enriched in citrus peels, as a circadian clock amplitude enhancer, which protects against metabolic disease. NOB is an agonist for the ROR nuclear receptors in the circadian oscillator.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals. Individual SCN neurons in dispersed culture can generate independent circadian oscillations of clock gene expression ...and neuronal firing. However, SCN rhythmicity depends on sufficient membrane depolarization and levels of intracellular calcium and cAMP. In the intact SCN, cellular oscillations are synchronized and reinforced by rhythmic synaptic input from other cells, resulting in a reproducible topographic pattern of distinct phases and amplitudes specified by SCN circuit organization. The SCN network synchronizes its component cellular oscillators, reinforces their oscillations, responds to light input by altering their phase distribution, increases their robustness to genetic perturbations, and enhances their precision. Thus, even though individual SCN neurons can be cell-autonomous circadian oscillators, neuronal network properties are integral to normal function of the SCN.
The current-nonlinear Hall effect or second harmonic Hall voltage is widely used as one of the methods for estimating charge-spin conversion efficiency, which is attributed to the magnetization ...oscillation by spin-orbit torque (SOT). Here, we argue the second harmonic Hall voltage under a large in-plane magnetic field with an in-plane magnetization configuration in magnetic-nonmagnetic topological insulator (TI) heterostructures, Cr_{x}(Bi_{1-y}Sb_{y})_{2-x}Te_{3}/(Bi_{1-y}Sb_{y})_{2}Te_{3}, where it is clearly shown that the large second harmonic voltage is governed not by SOT but mainly by asymmetric magnon scattering without macroscopic magnetization oscillation. Thus, this method does not allow an accurate estimation of charge-spin conversion efficiency in TI. Instead, the SOT contribution is exemplified by current pulse induced nonvolatile magnetization switching, which is realized with a current density of 2.5×10^{10} A m^{-2}, showing its potential as a spintronic material.
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We report current-direction dependent or unidirectional magnetoresistance (UMR) in magnetic or nonmagnetic topological insulator (TI) heterostructures, ...Cr_{x}(Bi_{1-y}Sb_{y})_{2-x}Te_{3}/(Bi_{1-y}Sb_{y})_{2}Te_{3}, that is several orders of magnitude larger than in other reported systems. From the magnetic field and temperature dependence, the UMR is identified to originate from the asymmetric scattering of electrons by magnons. In particular, the large magnitude of UMR is an outcome of spin-momentum locking and a small Fermi wave number at the surface of TI. In fact, the UMR is maximized around the Dirac point with the minimal Fermi wave number.
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