The circadian clock controls many physiological parameters including immune response to infectious agents, which is mediated by activation of the transcription factor NF-κB. It is widely accepted that circadian regulation is based on periodic changes in gene expression that are triggered by transcriptional activity of the CLOCK/BMAL1 complex. Through the use of a mouse model system we show that daily variations in the intensity of the NF-κB response to a variety of immunomodulators are mediated by core circadian protein CLOCK, which can up-regulate NF-κB–mediated transcription in the absence of BMAL1; moreover, BMAL1 counteracts the CLOCK-dependent increase in the activation of NF-κB–responsive genes. Consistent with its regulatory function, CLOCK is found in protein complexes with the p65 subunit of NF-κB, and its overexpression correlates with an increase in specific phosphorylated and acetylated transcriptionally active forms of p65. In addition, activation of NF-κB in response to immunostimuli in mouse embryonic fibroblasts and primary hepatocytes isolated fromClock-deficient mice is significantly reduced compared with WT cells, whereasClock-Δ19 mutation, which reduces the transactivation capacity of CLOCK on E-box–containing circadian promoters, has no effect on the ability of CLOCK to up-regulate NF-κB–responsive promoters. These findings establish a molecular link between two essential determinants of the circadian and immune mechanisms, the transcription factors CLOCK and NF-κB, respectively.

To understand entrainment of circadian systems to different photoperiods in nature, it is important to know the effects of single light pulses of different durations on the free-running system. The authors studied the phase and period responses of laboratory mice (C57BL6J//OlaHsd) to single light pulses of 7 different durations (1, 3, 4, 6, 9, 12, and 18 h) given once per 11 days in otherwise constant darkness. Light-pulse duration affected both amplitude and shape of the phase response curve. Nine-hour light pulses yielded the maximal amplitude PRC. As in other systems, the circadian period slightly lengthened following delays and shortened following advances. The authors aimed to understand how different parts of the light signal contribute to the eventual phase shift. When PRCs were plotted using the onset, midpoint, and end of the pulse as a phase reference, they corresponded best with each other when using the mid-pulse. Using a simple phase-only model, the authors explored the possibility that light affects oscillator velocity strongly in the 1st hour and at reduced strength in later hours of the pulse due to photoreceptor adaptation. They fitted models based on the 1-h PRC to the data for all light pulses. The best overall correspondence between PRCs was obtained when the effect of light during all hours after the first was reduced by a factor of 0.22 relative to the 1st hour. For the predicted PRCs, the light action centered on average at 38% of the light pulse. This is close to the reference phase yielding best correspondence at 36% of the pulses. The result is thus compatible with an initial major contribution of the onset of the light pulse followed by a reduced effect of light responsible for the differences between PRCs for different duration pulses. The authors suggest that the mid-pulse is a better phase reference than lights-on to plot and compare PRCs of different light-pulse durations.

The nutrient-sensing mTOR (mammalian Target of Rapamycin) pathway regulates cellular metabolism, growth functions, and proliferation and is involved in age-related diseases including cancer, type 2 diabetes, neurodegeneration and cardiovascular disease. The inhibition of mTOR by rapamycin, or calorie restriction, has been shown to extend lifespan and delays tumorigenesis in several experimental models suggesting that rapamycin may be used for cancer prevention. This requires continuous long-term treatment making oral formulations the preferred choice of administration route. However, rapamycin by itself has very poor water solubility and low absorption rate. Here we describe pharmacokinetic and biological properties of novel nanoformulated micelles of rapamycin, Rapatar. Micelles of Rapatar were rationally designed to increase water solubility of rapamycin to facilitate oral administration and to enhance its absorption. As a result, bioavailability of Rapatar was significantly increased (up to 12%) compared to unformulated rapamycin, which concentration in the blood following oral administration remained below level of detection. We also demonstrated that the new formulation does not induce toxicity during lifetime administration. Most importantly, Rapatar extended the mean lifespan by 30% and delayed tumor development in highly tumor-prone p53-/- mice. Our data demonstrate that water soluble Rapatar micelles represent safe, convenient and efficient form of rapamycin suitable for a long-term treatment and that Rapatar may be considered for tumor prevention.

Circadian clocks regulate the daily timing of many of our physiological, metabolic and biochemical functions. The immune system also displays circadian oscillations in immune cell count, synthesis and cytokine release, clock gene expression in cells and organs of the immune system as well as clock-controlled genes that regulate immune function. Circadian disruption leads to dysregulation of immune responses and inflammation which can further disrupt circadian rhythms. The response of organisms to immune challenges, such as allergic reactions also vary depending on time of the day, which can lead to detrimental responses particularly during the rest and early active periods. This review evaluates what is currently known in terms of circadian biology of immune response and the cross-talk between circadian and immune system. We discuss the circadian pattern of three respiratory-related inflammatory diseases, chronic obstructive pulmonary disease, allergic rhinitis and asthma. Increasing our knowledge on circadian patterns of immune responses and developing chronotherapeutic studies in inflammatory diseases with strong circadian patterns will lead to preventive measures as well as improved therapies focussing on the circadian rhythms of symptoms and the daily variation of the patients’ responses to medication.

Study Objectives:. To empirically derive and evaluate potential clusters of Insomnia Disorder through cluster analysis from polysomnography (PSG). We h