Rhythmic Oscillations Research Articles

Drums of Doubt: On the Rhythmical Origins of Poetic and Scientific Exploration

AbstractIn his article “Drums of Doubt: On the Rhythmical Origins of Poetic and Scientific Exploration” Caius Dobrescu argues that even though the sciences and arts of doubt have never been connected to the notion of rhythm, doubt is a form of energy, and more specifically, a form of vibration. It implies an exploratory movement that constantly expands and recoils in a space essentially experienced as uncharted territory. Poetry acquires cognitive attributes through oscillatory rhythmic patterns that are explorative and adaptive. In order to test this hypothesis, the essay focuses on the nature and functioning of free verse. This modern prosodic mutation brings about a dovetailing of the rhythmic spectrum, but also, and more significantly, a change in the very manner of understanding and experiencing rhythm. Oscillatory rhythms are broadly associable with entrainment indexes that point to the adaptation of inner physiological and behavioral rhythms to oscillatory environment stimuli. Free verse emerges from the experience of regaining an original explorative, adaptive, and orientation-oriented condition of consciousness.

The application of multiscale joint permutation entropy on multichannel sleep electroencephalography

Sleep quantification and automatic scoring of sleep stages via electroencephalogram (EEG) signals has been a challenge for years. It is crucial to investigate the correlation of brain waves by sleep EEG analysis due to the association between rhythmic oscillations of neuronal activity and neocortical synchronization. Multiscale joint permutation entropy (MJPE) had been proven to be capable of measuring the correlation between time series from the view of multiple time scales and thus can be a promising approach to address the challenge. Instead of simulation, we tested the MJPE method on a widely used open dataset of sleep EEG time series from healthy subjects and found that the correlation index obtained by MJPE had the capability of quantifying the brain wave correlations under different sleep stages, reflecting the typical sleep patterns and indicating the weakened correlation with aging. A higher level of correlation was found as the sleep stage advanced. The findings based on the MJPE results were in accordance with previous studies and existing knowledge in sleep medicine. In the second part of the study, we applied MJPE on sleep EEGs from subjects under pathological conditions (sleep apnea and sleep at high altitude). Likewise, the correlation index also properly revealed their sleep architectures, with consistent trends of the correlation through the nights. The effectiveness and practicability of the MJPE method had been verified on sleep EEGs. Therefore, the MJPE method should be encouraged to be widely used for analyzing large-scale sleep EEGs under various pathological conditions to provide insight into the mechanisms of the sleep process and neuron synchronization.

Numerical modelling of the effects of cold atmospheric plasma on mitochondrial redox homeostasis and energy metabolism

A biochemical reaction model clarifies for the first time how cold atmospheric plasmas (CAPs) affect mitochondrial redox homeostasis and energy metabolism. Fundamental mitochondrial functions in pyruvic acid oxidation, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation involving the respiratory chain (RC), adenosine triphosphate/adenosine diphosphate (ATP/ADP) synthesis machinery and reactive oxygen species/reactive nitrogen species (ROS/RNS)-mediated mechanisms are numerically simulated. The effects of CAP irradiation are modelled as 1) the influx of hydrogen peroxide (H{}_{2}O{}_{2}) to an ROS regulation system and 2) the change in mitochondrial transmembrane potential induced by RNS on membrane permeability. The CAP-induced stress modifies the dynamics of intramitochondrial H{}_{2}O{}_{2} and superoxide anions, i.e., the rhythm and shape of ROS oscillation are disturbed by H{}_{2}O{}_{2} infusion. Furthermore, CAPs control the ROS oscillatory behaviour, nicotinamide adenine dinucleotide redox state and ATP/ADP conversion through the reaction mixture over the RC, the TCA cycle and ROS regulation system. CAPs even induce a homeostatic or irreversible state transition in cell metabolism. The present computational model demonstrates that CAPs crucially affect essential mitochondrial functions, which in turn affect redox signalling, metabolic cooporation and cell fate decision of survival or death.

Synchronization: a framework for examining emotional climate in classes

This conceptual paper stems from a growing body of research examining the roles and functions of emotional climate (EC)—the collective state of students’ shared emotions—in classrooms. It suggests that EC in classrooms can be analyzed as a synchronization phenomenon. Synchronization is a natural phenomenon, in which autonomous objects that produce periodic rhythms adjust these rhythms to one another. The purpose of this article is thus twofold: to position the concept of EC within the broader context of synchronization theory; and to propose a new definition for EC that captures synchronization aspects. This paper first explains the theory of synchronization. It then critically discusses several sociological and biological theories regarding emotions, and the implications of these theories for teaching and learning. It subsequently delves into current conceptualizations of EC, and the descriptors used to characterize EC in classrooms. On the backdrop of this theoretical review, an argument is developed that humans’ produced emotions can be viewed as autonomous rhythmic oscillators that have the capacity to synchronize with one another, and that, consequently, EC can be studied as a form of synchronization within an ensemble of oscillators. Finally, a new definition of EC is proposed that integrates essential synchronization features. Overall, this paper suggests that synchronization theory can provide a framework of analysis of EC as a holistic phenomenon, not reduced to discrete emotional events. This approach may contribute to enhancing explanatory and predictive capacities in the study of EC.

Molecular Cloning and Functional Analysis of Three CONSTANS-Like Genes from Chinese Cymbidium

CONSTANS (CO) and CONSTANS-like (COL) are two centrally important flowering-related genes in the photoperiodic pathway of Cymbidium, an economically important orchid genus within the Orchidaceae. To assess how photoperiod affects flowering in three Cymbidium species, CsCOL1, CgCOL, and CeCOL were isolated and characterized from Cymbidium sinense, Cymbidium goeringii, and Cymbidium ensifolium, respectively. CsCOL1, CgCOL, and CeCOL, which contain a CCT domain and two conserved B-box zinc fingers, belong to Group Ic in the CO/COL protein family. These three genes, which were expressed in all organs, especially in the leaves, exhibited the same diurnal rhythm and were abundant in the late light period under long days (LD). However, their diurnal oscillation rhythm under short days (SD) differed. CsCOL1 was highly transcribed in the late dark period under SD. CeCOL was rapidly suppressed in the light, increased in the dark, and peaked at the end of the dark period under SD. CgCOL expression gradually increased, peaking after 4 h of darkness under SD. When CsCOL1 and CeCOL were overexpressed in Arabidopsis under LD, flowering was promoted, suggesting that CsCOL1 and CeCOL may be floral inducers in C. sinense and C. ensifolium, respectively. The overexpression of CgCOL delayed flowering in Arabidopsis, suggesting that it may act as a floral repressor in C. goeringii. This study provides greater insight into the molecular mechanisms regulating flowering time in three Cymbidium species, specifically related to photoperiod. This has practical implications for controlled flower production in potted Cymbidium greenhouse production systems.

Changes in latency of brain rhythms in response to affective information of visual stimuli

It is widely known that emotionally-arousing pictures are perceived more rapidly than non-arousing pictures, although neural underpinnings of this effect remain unclear. Using electroencephalography, we presently measured neural oscillatory rhythms of the human brain in response to various emotional images from the International Affective Picture System. We found that an oscillation frequency in the alpha-to-beta band (8–30 Hz) became higher over the parietal cortex when participants viewed emotionally-arousing than non-arousing pictures. This modulation of neural rhythms was also observed in a valence dimension; emotionally-negative pictures induced faster neural rhythm than emotionally-positive pictures. Those results were consistent with previous studies reporting a speeded perception of high-arousing and negative stimuli (e.g. snakes and spiders) and further provided neural evidence for an adaptive function of emotion to accelerate the processing of potentially-dangerous stimuli.

The protective effects of hydrogen sulfide on the myocardial ischemia via regulating Bmal1

BackgroundTo investigate the effect of hydrogen peroxide (H2S) on myocardial clock gene Bmal1 in ischemic cardiomyocytes. Materials & methodsQuantitative PCR (qPCR) was used to detect the expression of Bmal1 at the mRNA level in H9C2 rat cardiomyocytes. The protein expressions of Bax and Bcl-2, PI3K/Akt, caspase-3 were measured by western blotting. The levels of reactive oxygen species (ROS) were determined by ELISA. ResultsThe expression level of clock gene Bmal1 demonstrated a clock rhythm of periodic oscillation within 24 h. Compared with the control group, H2S treatment maintained the rhythm of the clock gene in ischemic cardiomyocytes and increased the transcription and expression levels of Bmal1. H2S increased cell survival by activating PI3K/Akt signaling pathway, inhibiting mitochondrial apoptosis signaling, and reducing intracellular oxidative stress. PI3K/Akt and Bmal1 were demonstrated to be involved in H2S protection of cardiomyocyte ischemia. Knockout of Bmal1 gene affects the degree of phosphorylation of Akt and Erk proteins, and the level of ROS production, resulting in a decrease in the protective effects of H2S. ConclusionThe expression level of Bmal1 has effects on the function of cardiomyocytes such as ROS production. The potential mechanism by which H2S regulates clock genes may be related to the effect of clock genes on protein phosphorylation levels in ischemic cardiomyocytes.

Loss of Diurnal Oscillatory Rhythms in Gut Microbiota Correlates with Changes in Circulating Metabolites in Type 2 Diabetic db/db Mice.

Our hypothesis is that diabetes leads to loss of diurnal oscillatory rhythms in gut microbiota altering circulating metabolites. We performed an observational study where we compared diurnal changes of the gut microbiota with temporal changes of plasma metabolites. Metadata analysis from bacterial DNA from fecal pellets collected from 10-month old control (db/m) and type 2 diabetic (db/db) mice every 4 h for a 24-h period was used for prediction analysis. Blood plasma was collected at a day and night time points and was used for untargeted global metabolomic analysis. Feeding and activity behaviors were recorded. Our results show that while diabetic mice exhibited feeding and activity behavior similar to control mice, they exhibited a loss of diurnal oscillations in bacteria of the genus Akkermansia, Bifidobacterium, Allobaculum, Oscillospira and a phase shift in the oscillations of g.Prevotella, proteobacteria, and actinobacteria. Analysis of the circulating metabolites showed alterations in the diurnal pattern of metabolic pathways where bacteria have been implicated, such as the histidine, betaine, and methionine/cysteine pathway, mitochondrial function and the urea cycle. Functional analysis of the differential microbes revealed that during the day, when mice are asleep, the microbes of diabetic mice were enriched in processing carbon and pyruvate metabolic pathways instead of xenobiotic degradation as was observed for control mice. Altogether, our study suggests that diabetes led to loss of rhythmic oscillations of many gut microbiota with possible implications for temporal regulation of host metabolic pathways.

Behavioral and Electrophysiological Arguments in Favor of a Relationship between Impulsivity, Risk-Taking, and Success on the Iowa Gambling Task.

The aim of the present study was to investigate the relationship between trait impulsivity, risk-taking, and decision-making performance. We recruited 20 healthy participants who performed the Iowa Gambling Task (IGT) and the Balloon Analog Risk Task (BART) to measure decision-making and risk-taking. The impulsivity was measured by the Barratt Impulsiveness Scale. Resting-state neural activity was recorded to explore whether brain oscillatory rhythms provide important information about the dispositional trait of impulsivity. We found a significant correlation between the ability to develop a successful strategy and the propensity to take more risks in the first trials of the BART. Risk-taking was negatively correlated with cognitive impulsivity in participants who were unable to develop a successful strategy. Neither risk-taking nor decision-making was correlated with cortical asymmetry. In a more exploratory approach, the group was sub-divided in function of participants’ performances at the IGT. We found that the group who developed a successful strategy at the IGT was more prone to risk, whereas the group who failed showed a greater cognitive impulsivity. These results emphasize the need for individuals to explore their environment to develop a successful strategy in uncertain situations, which may not be possible without taking risks.

The critical role of persistent sodium current in hippocampal gamma oscillations

Gamma network oscillations in the brain are fast rhythmic network oscillations in the gamma frequency range (~30-100 Hz), playing key roles in the hippocampus for learning, memory, and spatial processing. There is evidence indicating that GABAergic interneurons, including parvalbumin-expressing basket cells (PVBCs), contribute to cortical gamma oscillations through synaptic interactions with excitatory cells. However, the molecular, cellular, and circuit underpinnings underlying generation and maintenance of cortical gamma oscillations are largely elusive. Recent studies demonstrated that intrinsic and synaptic properties of GABAergic interneurons and excitatory cells are regulated by a slowly inactivating or non-inactivating sodium current (i.e., persistent sodium current, INaP), suggesting that INaP is involved in gamma oscillations. Here, we tested whether INaP plays a role in hippocampal gamma oscillations using pharmacological, optogenetic, and electrophysiological approaches. We found that INaP blockers, phenytoin (40 μM and 100 μM) and riluzole (10 μM), reduced gamma oscillations induced by optogenetic stimulation of CaMKII-expressing cells in CA1 networks. Whole-cell patch-clamp recordings further demonstrated that phenytoin (100 μM) reduced INaP and firing frequencies in both PVBCs and pyramidal cells without altering threshold and amplitude of action potentials, but increased rheobase in both cell types. These results suggest that INaP in pyramidal cells and PVBCs is required for hippocampal gamma oscillations, supporting a pyramidal-interneuron network gamma model. Phenytoin-mediated modulation of hippocampal gamma oscillations may be a mechanism underlying its anticonvulsant efficacy, as well as its contribution to cognitive impairments in epilepsy patients.

Adaptive notch filter for pathological tremor suppression using permanent magnet linear motor

Tremor is a progressive neurological disease involving involuntary rhythmic muscle movements and oscillations of the human body parts by alternating contractions of muscles. Tremor is a common symptom that can severely limit the independence of affected individuals and their ability to perform activities of daily living. In this paper, a permanent magnet linear motor (PMLM) and a notch filter with an adaptive frequency estimator are employed to suppress pathological tremor. The effects of undesired intrinsic forces exhibited by the use of PMLM were minimized by development and parameter identification of a dynamic force model. The experimental evaluation of a real-time adaptive tremor identification and suppression controller was performed in a human joints emulator using recorded signals from participants with Parkinson’s disease and essential tremor. We employed wavelet transform to analyze the tremor signals and the performance of the controller in the time-frequency domain. Experimental results showed an average tremor suppression of 30.51 dB (97.0%) and 13.89 dB (79.8%) in the first and second tremor frequency components, respectively. The average resistance induced by the orthotic mechanism against the voluntary motion was 0.36 N, and a 7.74 dB reduction with an active force compensator was observed. Compared to a servo-pneumatic actuator, a PMLM offers higher energy efficiency at a comparable suppression performance.

Higher order spectral analysis of scalp EEG activity reveals non-linear behavior during rhythmic visual stimulation

Objective. Flickering visual stimulation is known to evoke rhythmic oscillations in the electroencephalographic (EEG) activity, called steady-state visually evoked potentials (SSVEP). The presence of harmonic components in the EEG signals during SSVEP suggests the non-linearity of the visual-system response to rhythmic stimulation, but the nature of this behavior has not been deeply understood. The aim of this study is the quantitative evaluation and characterization of this non-linear phenomenon and its interference with the physiological alpha rhythm by means of spectral and higher order spectral analysis. Approach. EEG signals were acquired in a group of 12 healthy subjects during a pattern-reversal stimulation protocol at three different driving frequencies (7.5 Hz, 15 Hz and 24 Hz). Spectral power values were estimated, after Laplacian spatial filtering, to quantitatively evaluate the changes in the power of the individual alpha and stimulation frequencies related harmonic components. Bicoherence measure were employed to assess the presence of quadratic phase coupling (QPC) at each channel location. Main results. Our analysis confirmed a strong non-linear response to the rhythmic stimulus principally over the parieto-occipital channel locations and a simultaneous significant alpha power suppression during 7.5 Hz and 15 Hz stimulation. A prominent sub-harmonic component characterized the resonance behavior of the 24 Hz stimulation. Significance. The findings presented suggest that bicoherence is a useful tool for the identification of QPC interactions between stimulus-related frequency components within the same signal and the characterization of the non-linearity of SSVEP-induced harmonics generation. In addition, the applied methodology demonstrates the presence of coupled EEG rhythms (harmonics of the main oscillation) both in resting condition and during stimulation, with different characteristics in the distinct brain areas.

Next-generation sequencing identifies a novel frameshift variant in FRMD7 in a Chinese family with idiopathic infantile nystagmus.

BackgroundIdiopathic infantile nystagmus (IIN) is a high genetically heterogeneous ophthalmic disease and is often associated with pathogenic mutations in FRMD7 and GPR143, respectively. Idiopathic infantile nystagmus manifests as involuntary periodic rhythmic oscillation of the eyes in the very early life, which decreases visual acuity and affects the quality of life.Objective and MethodsThe aim of our study was to reveal a possible pathogenic variant through the investigation of a Chinese Han family with IIN with an implementation of a next‐generation sequencing method. Isolated DNA analysis was followed by Sanger sequencing validation. We also performed the detailed ophthalmological examination of family members.ResultsWe identified a novel frameshift variant in FRMD7 (NM_194277.2: c.1419_1422dup, p.Tyr475fs), which leads to a frameshift mutation since tyrosine (Tyr) at 475 codon of FRMD7 protein (p.Tyr475fs) and co‐segregates with IIN phenotype in this family.ConclusionsWe found a novel frameshift FRMD7 variant in a Chinese Han family, which may be causative variant for IIN and can further enrich the mutation spectrum and uncover the etiology of IIN.

Heterogeneous profiles of coupled sleep oscillations in human hippocampus

Cross-frequency coupling of sleep oscillations is thought to mediate memory consolidation. While the hippocampus is deemed central to this process, detailed knowledge of which oscillatory rhythms interact in the sleeping human hippocampus is lacking. Combining intracranial hippocampal and non-invasive electroencephalography from twelve neurosurgical patients, we characterized spectral power and coupling during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Hippocampal coupling was extensive, with the majority of channels expressing spectral interactions. NREM consistently showed delta–ripple coupling, but ripples were also modulated by slow oscillations (SOs) and sleep spindles. SO–delta and SO–theta coupling, as well as interactions between delta/theta and spindle/beta frequencies also occurred. During REM, limited interactions between delta/theta and beta frequencies emerged. Moreover, oscillatory organization differed substantially between i) hippocampus and scalp, ii) sites along the anterior-posterior hippocampal axis, and iii) individuals. Overall, these results extend and refine our understanding of hippocampal sleep oscillations.

Characterization of Visuomotor/Imaginary Movements in EEG: An Information Theory and Complex Network Approach

Imagined activities could actually be a cognitive basis for creative thinking. However it is still unknown how they might be related with the architecture of the brain. A recent study has proved the relevance of the imagined activity when investigating neuronal diseases, by comparing variations in the neuronal activity of patients with brain diseases and healthy subjects. One important aspect of the scientific methodologies focused on neuronal diseases is therefore to provide a trustable methodology that could allow us to distinguish between realized and imagined activities in the brain. The electroencephalogram is the result of synchronized action of the cerebrum, and our end is portraying the network dynamics through the neuronal responses when the subjects perform visuomotor and specific imaginary assignments. We use a subtle information theoretical approach accounting for the time causality of the signal and the closeness centrality of the different nodes. More specifically we perform estimations of the probability distribution of the data associated to each node using the Bandt and Pompe to account for the causality of the electroencephalographic signals. We calculate the Jensen-Shannon distance across different nodes, and then we quantify how fast the information flow would be through a given node to other nodes computing the closeness centrality. We perform a statistical analysis to compare the closeness centrality considering the different rhythmic oscillation bands for each node taking into account imagined and visuomotor tasks. Our discoveries stress the pertinence of the alpha band while performing and distinguishing the specific imaginary or visuomotor assignments.

Brain State-dependent Gain Modulation of Corticospinal Output in the Active Motor System

The communication through coherence hypothesis suggests that only coherently oscillating neuronal groups can interact effectively and predicts an intrinsic response modulation along the oscillatory rhythm. For the motor cortex (MC) at rest, the oscillatory cycle has been shown to determine the brain's responsiveness to external stimuli. For the active MC, however, the demonstration of such a phase-specific modulation of corticospinal excitability (CSE) along the rhythm cycle is still missing. Motor evoked potentials in response to transcranial magnetic stimulation (TMS) over the MC were used to probe the effect of cortical oscillations on CSE during several motor conditions. A brain-machine interface (BMI) with a robotic hand orthosis allowed investigating effects of cortical activity on CSE without the confounding effects of voluntary muscle activation. Only this BMI approach (and not active or passive hand opening alone) revealed a frequency- and phase-specific cortical modulation of CSE by sensorimotor beta-band activity that peaked once per oscillatory cycle and was independent of muscle activity. The active MC follows an intrinsic response modulation in accordance with the communication through coherence hypothesis. Furthermore, the BMI approach may facilitate and strengthen effective corticospinal communication in a therapeutic context, for example, when voluntary hand opening is no longer possible after stroke.

Tracking Transient Changes in the Neural Frequency Architecture: Harmonic Relationships between Theta and Alpha Peaks Facilitate Cognitive Performance.

The synchronization between neural oscillations at different frequencies has been proposed as a core mechanism for the coordination and integration of neural systems at different spatiotemporal scales. Because neural oscillations of different frequencies can only fully synchronize when their "peak" frequencies form harmonic relationships (e.g., f2 = f1/2), the present study explored whether the transient occurrence of harmonic cross-frequency relationship between task-relevant rhythms underlies efficient cognitive processing. Continuous EEG recordings (51 human participants; 14 males) were obtained during an arithmetic task, rest and breath focus. In two separate experiments, we consistently show that the proportion of epochs displaying a 2:1 harmonic relationship between alpha (8-14 Hz) and theta (4-8 Hz) peak frequencies (i.e., alphapeak ≈ 10.6 Hz; thetapeak ≈ 5.3 Hz), was significantly higher when cognitive demands increased. In addition, a higher incidence of 2:1 harmonic cross-frequency relationships was significantly associated with increased alpha-theta phase synchrony and improved arithmetic task performance, thereby underlining the functional relevance of this cross-frequency configuration. Notably, opposite dynamics were identified for a specific range of "nonharmonic" alpha-theta cross-frequency relationships (i.e., alphapeak/thetapeak = 1.1-1.6), which showed a higher incidence during rest compared with the arithmetic task. The observation that alpha and theta rhythms shifted into harmonic versus nonharmonic cross-frequency relationships depending on (cognitive) task demands is in line with the notion that the neural frequency architecture entails optimal frequency arrangements to facilitate cross-frequency "coupling" and "decoupling".SIGNIFICANCE STATEMENT Neural activity is known to oscillate within discrete frequency bands and the interplay between these brain rhythms is hypothesized to underlie cognitive functions. A recent theory posits that shifts in the peak frequencies of oscillatory rhythms form the principal mechanism by which cross-frequency coupling and decoupling is implemented in the brain. In line with this notion, we show that the occurrence of a cross-frequency arrangement that mathematically enables coupling between alpha and theta rhythms is more prominent during active cognitive processing (compared with rest and non-cognitively demanding tasks) and is associated with improved cognitive performance. Together, our results open new vistas for future research on cross-frequency dynamics in the brain and their functional role in cognitive processing.

Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism.

Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases.

Methionine Restriction Attenuates High-Fat Diet-Induced Gut-Brain Axis Circadian Rhythm Disorders and Cognitive Impairments (P08-052-19)

ObjectivesMethionine restriction (MR) has emerged as a promising dietary restriction on metabolic syndrome as its beneficial effects on increasing metabolic flexibility and up-regulating mitochondrial function. The circadian clock directs many aspects of metabolism and macronutrients can function as zeitgebers for the clock in a tissue-specific way. It has been demonstrated that high-fat diet could alter daily oscillations via gut-brain axis. We hypothesis that MR is a new strategy could reverse the high-fat diet induced circadian rhythm disorders and cognitive impairments. Methods3 month-old male C57BL/6 J mice were assigned to four groups based on diet: low-fat diet (0.86% methionine), low-fat diet with MR(0.17% methionine), high-fat diet, and high-fat diet with MR. After 8 weeks treatment, we employed behavioral test, transmission electron microscope, and 16S rDNA sequencing to evaluate cognitive function, rhythmic variation and the interconnection between gut microbiota and central nervous system. ResultsMR diminished HFD-induced body weight gain and restored the glucose tolerance at ZT0 (light phase) and ZT12 (dark phase). The neuroprotective effects of MR were connected with the ERK/CREB/BDNF signaling pathway and synaptic plasticity. MR changed energy metabolism via activated mTOR/ULK/AMPK signaling in brain. MR ameliorated rhythmic oscillations of clock control gene Bmal1/Per2 in gut-brain axis. Moreover, MR attenuated HFD-induced intestinal inflammatory and protected gut barrier integrity via enhancing the expression of intestinal tight junction protein. The gut microbiome was re-shaped by MR treatment, accompanied by the alteration of short chain fatty acids, the microbial products mediating systemic metabolism and has benefits on brain function. MR increased microbiota-derived butyric and isovaleric which possible synchronizers of peripheral circadian clocks. ConclusionsThe present study provided comprehensive evidence that MR attenuated obesity-induced cognitive impairment via balancing the circadian rhythm in gut-brain axis and that is a potential new therapeutic avenue for treating metabolic syndrome-related neurodegenerative diseases. Funding SourcesThis work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China. Supporting Tables, Images and/or Graphs▪

Blazar Mrk 501 shows rhythmic oscillations in its γ-ray emission

Quasi-periodic oscillations (QPO) originating from innermost regions of blazars can provide unique perspective of some of the burning issues in blazar studies including disk-jet connection, launch of relativistic jets from the central engine, and other extreme conditions near the fast rotating supermassive black holes. However, a number of hurdles associated with searching QPOs in blazars e.g., red-noise dominance, modest significance of the detection and periodic modulation lasting for only a couple of cycles, make it difficult to estimate the true significance of the detection. In this work, we report a $\sim$ 330-day QPO in the Fermi/LAT observations of the blazar Mrk 501 spanning nearly a decade. To establish consistency of the result, we adopted multiple approaches to the time series analysis and employed four widely known methods. Among these, Lomb-Scargle periodogram and weighted wavelet z-transform represent frequency domain based methods whereas epoch folding and z-transformed discrete auto-correlation function are time-domain based analysis. Power spectrum response method was followed to properly account for the red-noise, largely inherent in blazar light curves. Both local and global significance of the signal were found to be above 99\% over possible spurious detection. In the context where not many $\gamma$-ray QPOs have been reported to last more than 5 cycles, this might be one of the few instances where we witness a sub-year timescale $\gamma$-ray QPO persisting nearly 7 cycles. A number of possible scenarios linked with binary supermassive black hole, relativistic jets, and accretion disks can be invoked to explain the transient QPO.