Exposing 24-hour cycles in bile acids of male humans.

Bile acids are trans-genomic molecules arising from the concerted metabolism of the human host and the intestinal microbiota and are important for digestion, energy homeostasis and metabolic regulation. While diurnal variation has been demonstrated in the enterohepatic circulation and the gut microbiota, existing human data are poorly resolved, and the influence of the host circadian system has not been determined. Using entrained laboratory protocols, we demonstrate robust daily rhythms in the circulating bile acid pool in healthy male participants.

Protocol to study human gut bacterial communities and rhythmicity ex vivo using a chemostat system.

Chemostat systems can be used to cultivate complex intestinal microbial communities ex vivo. Here, we present a protocol to transfer bacteria from human fecal material into chemostat systems as well as settings to simulate infant or adult colonic conditions. We describe the experimental setup, media design, donor selection, 16S rRNA amplicon sequencing, and circadian analysis of bacterial abundance.

Diurnal rhythmicity of infant fecal microbiota and metabolites: A randomized controlled interventional trial with infant formula.

Microbiota assembly in the infant gut is influenced by diet. Breastfeeding and human breastmilk oligosaccharides promote the colonization of beneficial bifidobacteria. Infant formulas are supplemented with bifidobacteria or complex oligosaccharides, notably galacto-oligosaccharides (GOS), to mimic breast milk.

Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity.

Background And Aims: Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.

Reduced glucose concentration enhances ultradian rhythms in promoter activity .

Intrinsically driven ultradian rhythms in the hourly range are often co-expressed with circadian rhythms in various physiological processes including metabolic processes such as feeding behaviour, gene expression and cellular metabolism. Several behavioural observations show that reduced energy intake or increased energy expenditure leads to a re-balancing of ultradian and circadian timing, favouring ultradian feeding and activity patterns when energy availability is limited. This suggests a close link between ultradian rhythmicity and metabolic homeostasis, but we currently lack models to test this hypothesis at a cellular level.

Co-expression of diurnal and ultradian rhythms in the plasma metabolome of common voles (Microtus arvalis).

Metabolic rhythms include rapid, ultradian (hourly) dynamics, but it remains unclear what their relationship to circadian metabolic rhythms is, and what role meal timing plays in coordinating these ultradian rhythms in metabolism. Here, we characterized widespread ultradian rhythms under ad libitum feeding conditions in the plasma metabolome of the vole, the gold standard animal model for behavioral ultradian rhythms, naturally expressing ~2-h foraging rhythms throughout the day and night. These ultradian metabolite rhythms co-expressed with diurnal 24-h rhythms in the same metabolites and did not align with food intake patterns.

Cyclic uniaxial mechanical load enhances chondrogenesis through entraining the molecular circadian clock.

The biomechanical environment plays a key role in regulating cartilage formation, but the current understanding of mechanotransduction pathways in chondrogenic cells is incomplete. Among the combination of external factors that control chondrogenesis are temporal cues that are governed by the cell-autonomous circadian clock. However, mechanical stimulation has not yet directly been proven to modulate chondrogenesis via entraining the circadian clock in chondroprogenitor cells.

In vitro characterisation of murine pre-adipose nucleated cells reveals electrophysiological cycles associated with biological clocks.

Adipocytes are energy stores of the body which also play a role in physiological regulation and homeostasis through their endocrine activity. Adipocyte circadian clocks drive rhythms in gene expression, and dysregulation of these circadian rhythms associates with pathological conditions such as diabetes. However, although the role of circadian rhythms in adipose cells and related tissues has been studied from phsyiological and molecular perspectives, they have not yet been explored from an electrical perspective.

Pericytes' Circadian Clock Affects Endothelial Cells' Synchronization and Angiogenesis in a 3D Tissue Engineered Scaffold.

Angiogenesis, the formation of new capillaries from existing ones, is a fundamental process in regenerative medicine and tissue engineering. While it is known to be affected by circadian rhythms , its peripheral regulation within the vasculature and the role it performs in regulating the interplay between vascular cells have not yet been investigated. Peripheral clocks within the vasculature have been described in the endothelium and in smooth muscle cells.

Metabolomics Signature of Patients With Narcolepsy.

Background And Objectives: Narcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown.

A Topological Cluster of Differentially Regulated Genes in Mice Lacking PER3.

Polymorphisms in the human circadian clock gene () are associated with a wide variety of phenotypes such as diurnal preference, delayed sleep phase disorder, sleep homeostasis, cognitive performance, bipolar disorder, type 2 diabetes, cardiac regulation, cancer, light sensitivity, hormone and cytokine secretion, and addiction. However, the molecular mechanisms underlying these phenotypic associations remain unknown. knockout mice ( ) have phenotypes related to activity, sleep homeostasis, anhedonia, metabolism, and behavioral responses to light.

A Synchronized Circadian Clock Enhances Early Chondrogenesis.

Objective: Circadian rhythms in cartilage homeostasis are hypothesized to temporally segregate and synchronize the activities of chondrocytes to different times of the day, and thus may provide an efficient mechanism by which articular cartilage can recover following physical activity. While the circadian clock is clearly involved in chondrocyte homeostasis in health and disease, it is unclear as to what roles it may play during early chondrogenesis.

Design: The purpose of this study was to determine whether the rhythmic expression of the core circadian clock was detectable at the earliest stages of chondrocyte differentiation, and if so, whether a synchronized expression pattern of chondrogenic transcription factors and developing cartilage matrix constituents was present during cartilage formation.

Ten-Second Electrophysiology: Evaluation of the 3DEP Platform for high-speed, high-accuracy cell analysis.

Electrical correlates of the physiological state of a cell, such as membrane conductance and capacitance, as well as cytoplasm conductivity, contain vital information about cellular function, ion transport across the membrane, and propagation of electrical signals. They are, however, difficult to measure; gold-standard techniques are typically unable to measure more than a few cells per day, making widespread adoption difficult and limiting statistical reproducibility. We have developed a dielectrophoretic platform using a disposable 3D electrode geometry that accurately (r > 0.

Host circadian rhythms are disrupted during malaria infection in parasite genotype-specific manners.

Infection can dramatically alter behavioural and physiological traits as hosts become sick and subsequently return to health. Such "sickness behaviours" include disrupted circadian rhythms in both locomotor activity and body temperature. Host sickness behaviours vary in pathogen species-specific manners but the influence of pathogen intraspecific variation is rarely studied.

Chronic sleep restriction in the rotenone Parkinson's disease model in rats reveals peripheral early-phase biomarkers.

Parkinson's disease (PD) is a chronic disorder that presents a range of premotor signs, such as sleep disturbances and cognitive decline, which are key non-motor features of the disease. Increasing evidence of a possible association between sleep disruption and the neurodegenerative process suggests that sleep impairment could produce a detectable metabolic signature on the disease. In order to integrate neurocognitive and metabolic parameters, we performed untargeted and targeted metabolic profiling of the rotenone PD model in a chronic sleep restriction (SR) (6 h/day for 21 days) condition.

Flexible clock systems: adjusting the temporal programme.

Under natural conditions, many aspects of the abiotic and biotic environment vary with time of day, season or even era, while these conditions are typically kept constant in laboratory settings. The timing information contained within the environment serves as critical timing cues for the internal biological timing system, but how this system drives daily rhythms in behaviour and physiology may also depend on the internal state of the animal. The disparity between timing of these cues in natural and laboratory conditions can result in substantial differences in the scheduling of behaviour and physiology under these conditions.

Twenty-four-hour rhythmicity of circulating metabolites: effect of body mass and type 2 diabetes.

Metabolic profiling of individuals with type 2 diabetes mellitus (T2DM) has previously been limited to single-time-point samples, ignoring time-of-day variation. Here, we tested our hypothesis that body mass and T2DM affect daily rhythmicity and concentrations of circulating metabolites across a 24-h day in 3 age-matched, male groups-lean, overweight/obese (OW/OB), and OW/OB with T2DM-in controlled laboratory conditions, which were not confounded by large meals. By using targeted liquid chromatography/mass spectrometry metabolomics, we quantified 130 plasma metabolites every 2 h over 24 h, and we show that average metabolite concentrations were significantly altered by increased body mass (90 of 130) and T2DM (56 of 130).

High-throughput, low-loss, low-cost, and label-free cell separation using electrophysiology-activated cell enrichment.

Currently, cell separation occurs almost exclusively by density gradient methods and by fluorescence- and magnetic-activated cell sorting (FACS/MACS). These variously suffer from lack of specificity, high cell loss, use of labels, and high capital/operating cost. We present a dielectrophoresis (DEP)-based cell-separation method, using 3D electrodes on a low-cost disposable chip; one cell type is allowed to pass through the chip whereas the other is retained and subsequently recovered.

Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3 mice, but not wildtype mice.

Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are 'direct' effects of light on affect, an 'indirect' pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light.

Unmasking ultradian rhythms in gene expression.

Biological oscillations with an ultradian time scale of 1 to several hours include cycles in behavioral arousal, episodic glucocorticoid release, and gene expression. Ultradian rhythms are thought to have an extrinsic origin because of a perceived absence of ultradian rhythmicity in vitro and a lack of known molecular ultradian oscillators. We designed a novel, non-spectral-analysis method of separating ultradian from circadian components and applied it to a published gene expression dataset with an ultradian sampling resolution.

A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.

In humans, a primate-specific variable-number tandem-repeat (VNTR) polymorphism (4 or 5 repeats 54 nt in length) in the circadian gene PER3 is associated with differences in sleep timing and homeostatic responses to sleep loss. We investigated the effects of this polymorphism on circadian rhythmicity and sleep homeostasis by introducing the polymorphism into mice and assessing circadian and sleep parameters at baseline and during and after 12 h of sleep deprivation (SD). Microarray analysis was used to measure hypothalamic and cortical gene expression.

Mistimed sleep disrupts circadian regulation of the human transcriptome.

Circadian organization of the mammalian transcriptome is achieved by rhythmic recruitment of key modifiers of chromatin structure and transcriptional and translational processes. These rhythmic processes, together with posttranslational modification, constitute circadian oscillators in the brain and peripheral tissues, which drive rhythms in physiology and behavior, including the sleep-wake cycle. In humans, sleep is normally timed to occur during the biological night, when body temperature is low and melatonin is synthesized.