Disruptions in sleep/wake cycles including decreased amplitude of rhythmic behaviors and fragmentation of the sleep episodes, are commonly associated with aging in humans and other mammals. While there are undoubtedly many factors contributing to these changes, a body of literature is emerging suggesting that an age-related decline in the central circadian clock in the suprachiasmatic nucleus (SCN) may be a key element responsible. To explore age-related changes in the SCN, we have carried out in vivo multiunit neural activity (MUA) recordings from the SCN of freely-moving young (3 – 5 mo) and middle-aged (13 – 18 mo) mice. Importantly, the amplitude of day-night difference in MUA was significantly reduced in the older mice. We also found that the neural activity rhythms are clearly degraded in the subparaventricular zone (SPZ), one of the main neural outputs of the SCN. Surprisingly, parallel studies indicate that the molecular clockwork in the SCN as measured by PER2 exhibited only minor deficits at this same age. Thus, the circadian output measured at the level of neural activity rhythms in the SCN is degraded by aging and this decline occurs before the disruption of key components of the molecular clockwork.

The molecular oscillations underlying the generation of circadian rhythmicity in mammals develop gradually during ontogenesis. However, the developmental process of mammalian cellular circadian oscillator formation remains unknown. In differentiated somatic cells, the transcriptional-translational feedback loops (TTFL) consisting of clock genes elicit the molecular circadian oscillation. Using a bioluminescence imaging system to monitor clock gene expression, we show here that the circadian bioluminescence rhythm is not detected in the mouse embryonic stem (ES) cells, and that the ES cells likely lack TTFL regulation for clock gene expression. The circadian clock oscillation was induced during the differentiation culture of mouse ES cells without maternal factors. In addition, reprogramming of the differentiated cells by expression of Sox2, Klf4, Oct3/4, and c-Myc genes, which were factors to generate induced pluripotent stem (iPS) cells, resulted in the re-disappearance of circadian oscillation. These results demonstrate that an intrinsic program controls the formation of the circadian oscillator during the differentiation process of ES cells in vitro. The cellular differentiation and reprogramming system using cultured ES cells allows us to observe the circadian clock formation process and may help design new strategies to understand the key mechanisms responsible for the organization of the molecular oscillator in mammals.circadian clock | induced pluripotent stem cells | real-time monitor T he circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as the sleep-wake cycle, energy metabolism, and the endocrine system (1, 2). These physiological rhythms develop gradually in the first year of life in humans (3). It is well known that the human sleep-wake rhythm is generated within a few months after birth. However, a weak circadian rhythm of core body temperature is present immediately after birth, suggesting that the development of the human circadian rhythms starts during fetal life. In fact, recent studies in rodents have suggested the appearance of circadian molecular rhythms in the suprachiasmatic nucleus (SCN) a few days before birth (4). However, little information is available on the development of the mammalian cellular circadian oscillator.In mammals, molecular oscillation of the circadian clock consists of interlocked positive and negative transcription/translation feedback loops (TTFL) involving a set of clock genes and clock-controlled output genes that link the oscillator to the clock-controlled processes (5). CLOCK and BMAL1 are basic-helix-loop-helix (bHLH) PAS transcription factors that heterodimerize and transactivate the core clock genes such as Period (Per1, -2, and -3), Cryptochrome (Cry1 and Cry2), and Rev-Erbα (2, 5, 6). PER and CRY proteins suppress the activity of the CLOCK/BMAL1, whereas REV-ERBα suppresses Bmal1 gene expression.In this study, we focused on the development of the mammalian circadian oscillator du...

A size effect on crystal structure has been investigated for barium titanate (BaTiO3) nanoparticles of 40-, 140-, and 430-nm sizes, by means of neutron and high-resolution synchrotron x-ray powder-diffraction and Raman-scattering techniques. These samples were prepared by a modified two-step thermal decomposition method from barium titanyl oxalate, resulting in very few lattice impurities. Rietveld analysis of the neutron-diffraction data for the 430-nm- and 140-nm-sized BaTiO3 particles was performed assuming a single phase of tetragonal (P4mm) structure. The axial ratio c∕a of tetragonal BaTiO3 decreases with a decrease in particle size from 430 to 140 nm. Barium titanate particles with a size of 40 nm consist of (1) tetragonal crystals (83 wt %) with a large cell volume and an axial ratio of unity c∕a=1.000(5) and of (2) a hexagonal phase (P63mmc, 17 wt %) with a large unit-cell volume. Rietveld and maximum-entropy method analyses suggest that there exist atomic displacements from the ideal site of a cubic structure and a spontaneous polarization of the tetragonal phase even in the 40-nm-sized BaTiO3 particles. The nuclear-density distribution of the 140-nm-sized particles with a high dielectric constant does not exhibit a large positional disorder, while the Ba atom of tetragonal BaTiO3 in the 40-nm-sized particles has a smaller atomic displacement parameter.

Large interplate earthquakes are often followed by postseismic slip that is considered to occur in areas surrounding the coseismic ruptures. Such spatial separation is expected from the difference in frictional and material properties in and around the faults. However, even though the 2011 Tohoku Earthquake ruptured a vast area on the plate interface, the estimation of high-resolution slip is usually difficult because of the lack of seafloor geodetic data. Here using the seafloor and terrestrial geodetic data, we investigated the postseismic slip to examine whether it was spatially separated with the coseismic slip by applying a comprehensive finite-element method model to subtract the viscoelastic components from the observed postseismic displacements. The high-resolution co- and postseismic slip distributions clarified the spatial separation, which also agreed with the activities of interplate and repeating earthquakes. These findings suggest that the conventional frictional property model is valid for the source region of gigantic earthquakes.