Effects of season on sleep and skin temperature in the elderly

The effects of season on sleep and skin temperature (Tsk) in 19 healthy, elderly volunteers were investigated. Measurements were obtained in summer, winter, and fall, and activity levels were monitored using a wrist actigraph system for five consecutive days. The temperature and humidity of the bedrooms of the subjects’ homes were measured continuously for five days. During actigraphic measurement, Tsk during sleep was measured for two nights. The bedroom temperature and humidity significantly increased in summer compared to winter and fall. In summer, the total sleep time decreased (mean ± SE min; summer, 350.8 ± 15.7; winter, 426.5 ± 14.2; fall, 403.2 ± 16.4) and wakefulness increased (P < 0.003) compared to those in fall or winter. The sleep efficiency index that was derived from wrist actigraphy was significantly decreased (P < 0.001) in summer (81.4 ± 2.9%) compared with winter (91.6 ± 1.3%) or fall (90.2 ± 1.2%). The forehead Tsk significantly increased, while the chest and thigh Tsks were decreased in summer compared to those in fall or winter. These results suggest that, in the elderly, sleep is disturbed in summer more than in other seasons, and that this disturbance is related to fluctuations in Tsk.     

The Role of Temperature and Embryo Development Time in the Diel Timing of Spawning in a Coral-reef Damselfish with High-frequency Spawning Synchrony

We studied the diel timing of spawning in the demersally spawning Hawaiian damselfish, Dascyllus albisella, from mid-June to late-September 1997 at two small patch reefs in Hawaii. Our objectives were to elucidate daily timing of spawning in relation to water temperature, diel timing of hatching, and short-period spawning synchrony. Spawning occurred every 5–7 days at both reefs, with all spawning on a reef concluded either within a single day (1-day spawning) or within two successive days (2-day spawning). Spawning began in early morning and continued for most of the day. There was a significant, positive linear relationship between mean daily average water temperature (= daily average temperature averaged over the period starting from the day following the last spawning day of the preceding nest cycle till the day before the first spawning day of the current cycle) and peak spawning hour of day, for 1-day spawning, and the first and second days of 2-day spawning at both reefs. The relationship between mean daily average water temperature and peak spawning hour of day was comparable among all spawning-day classes and reefs. Hatching occurred on the fourth day of development throughout the study despite the 26.5–29.1°C change in water temperature during the study period, and hatching was restricted to within two hours after sunset. We propose that D. albisella's peak spawning time is positively correlated with increased water temperature because it maintains the benefits of synchronous spawning within two constraints: the narrow daily period of hatching, and the inverse relationship between water temperature and embryo developmental time.     

Interaction between Reelin and Notch signaling regulates neuronal migration in the cerebral cortex

Neuronal migration is a fundamental component of brain development whose failure is associated with various neurological and psychiatric disorders. Reelin is essential for the stereotypical inside-out sequential lamination of the neocortex, but the molecular mechanisms of its action still remain unclear. Here we show that regulation of Notch activity plays an important part in Reelin-signal-dependent neuronal migration. We found that Reelin-deficient mice have reduced levels of the cleaved form of Notch intracellular domain (Notch ICD) and that loss of Notch signaling in migrating neurons results in migration and morphology defects. Further, overexpression of Notch ICD mitigates the laminar and morphological abnormalities of migrating neurons in Reeler. Finally, our in vitro biochemical studies show that Reelin signaling inhibits Notch ICD degradation via Dab1. Together, our results indicate that neuronal migration in the developing cerebral cortex requires a Reelin-Notch interaction.     

The production of IL-10 by human regulatory T cells is enhanced by IL-2 through a STAT5-responsive intronic enhancer in the IL-10 locus

STAT5 molecules are key components of the IL-2 signaling pathway, the deficiency of which often results in autoimmune pathology due to a reduced number of CD4(+)CD25(+) naturally occurring regulatory T (Treg) cells. One of the consequences of the IL-2-STAT5 signaling axis is up-regulation of FOXP3, a master control gene for naturally occurring Treg cells. However, the roles of STAT5 in other Treg subsets have not yet been elucidated. We recently demonstrated that IL-2 enhanced IL-10 production through STAT5 activation. This occurred in two types of human Treg cells: a novel type of umbilical cord blood-derived Treg cell, termed HOZOT, and Tr1-like Treg cells, IL-10-Treg. In this study, we examined the regulatory mechanisms of IL-10 production in these Treg cells, focusing specifically on the roles of STAT5. By performing bioinformatic analysis on the IL-10 locus, we identified one STAT-responsive element within intron 4, designated I-SRE-4, as an interspecies-conserved sequence. We found that I-SRE-4 acted as an enhancer element, and clustered CpGs around the I-SRE-4 were hypomethylated in IL-10-producing Treg cells, but not in other T cells. A gel-shift analysis using a nuclear extract from IL-2-stimulated HOZOT confirmed that CpG DNA methylation around I-SRE-4 reduced STAT5 binding to the element. Chromatin immunoprecipitation analysis revealed the in situ binding of IL-2-activated STAT5 to I-SRE-4. Thus, we provide molecular evidence for the involvement of an IL-2-STAT5 signaling axis in the expression of IL-10 by human Treg cells, an axis that is regulated by the intronic enhancer, I-SRE-4, and epigenetic modification of this element.     

Male-Specific Expression of the Fruitless Protein is not Common to all Drosophila Species

Sex-specific behavioral patterns must be a result of sexual differences in the structure and/or function of the central nervous system (CNS). Male Drosophila melanogaster mutants for the fruitless (fru) locus exhibit enhanced male-to-male courtship. The fru mutant males are accompanied by malformation of the male-specific muscle of Lawrence (MOL), which, in wild-type males, is induced by male motoneurons innervating it. These two phenotypes are the consequences of impaired sex determination of CNS neurons. In D. melanogaster, although the fru mRNAs are transcribed in the CNS of both the male and female, the Fru protein is only translated in the male CNS. This male-specific translation of Fru was also observed in D. simulans, D. yakuba, D. pseudoobscura and D. virilis; however, in D. suzukii, the Fru protein expression was detected even in the female CNS.     

The role of histidine residues conserved in the putative ATP-binding region of macrolide 2'-phosphotransferase II

Macrolide 2'-phosphotransferase (MPH(2')) catalyzes the transfer of the gamma-phosphate of ATP to the 2'-hydroxyl group of macrolide antibiotics. In this study, H198 and H205, conserved in the ATP-binding region motif 1 in the putative amino acid sequence of MPH(2')II, were replaced by Ala to investigate their role. H205 was also subsequently replaced by Asn. H198A and H205N mutant enzymes retained more than 50% of the specific activity of the original enzyme to substrate oleandomycin. On the other hand, the specific activity of the H205A mutant enzyme was reduced to less than 1% of that of the wild enzyme. The results suggested that H205 is crucial for maintaining the catalytic activity of MPH(2')II, and Asn can substitute for His at this position.     

Design, synthesis and biological activity of amidinobicyclic compounds (derivatives of DX-9065a) as factor Xa inhibitors: SAR study of S1 and aryl binding sites

Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.     

Stimulation of cellular prion protein expression by TSH in human thyrocytes

The cellular isoform of prion protein (PrP(C)) is a cell-surface glycosyl-phosphatidylinositol-anchored protein which is ubiquitously expressed on the cell membrane. It may function as a cell receptor or as a cell adhesion molecule. Thyroid follicles, obtained from patients with Graves' disease at thyroidectomy, were cultured in F-12/RPMI-1640 medium supplemented with 0.5% fetal bovine serum and bovine thyroid stimulating hormone (bTSH). Northern blot analyses revealed that bTSH increased the steady-state expression levels of PrP mRNA in a time- and dose-dependent manner. This increase was reproduced by dibutyryl-cAMP and 12-decanoylphorbol-13-acetate. The mRNA expression was greater in thyroid follicles in suspension culture than in thyrocytes cultured in a monolayer. These findings suggest that TSH stimulates PrP mRNA expression in thyrocytes through the protein kinase A and C pathways. The greater mRNA expression in thyroid follicles than in monolayer cells suggests that PrP(C) may be involved in structure formation or maintenance of thyroid follicles.     

Effects of head cooling on human sleep stages and body temperature

The purpose of this study was to confirm the effect of head cooling on human sleep stages and body temperature. Nine healthy male volunteers with a mean age of 25 +/- 3.77 years served as subjects. The experiments were carried out under three different sets of conditions: 26 degrees C, relative humidity (RH) 50% (26/50); 32 degrees C, RH 80% (32/80); and 32 degrees C RH 80% with the use of a cooling pillow (32/80 HC). The subjects slept from 2300 hours to 0700 hours with a cotton blanket, wearing short-sleeved pyjamas and shorts on a bed, which was covered with a sheet. Electroencephalograms, electro-ouclogram, and mental electromyelograms were recorded through the night. Rectal temperature (Tre) and skin temperature (Tsk) were measured continuously. Whole-body sweat and the tympanic temperature (Tty) were measured before and after sleep. Wakefulness significantly increased at 32/80 than at 26/50; however, no significant difference was observed between 32/80 HC and 26/50. Tre and mean Tsk were higher both at 32/80 and 32/80 HC than at 26/50. The whole-body sweat loss was significantly greater and Tty in the morning was higher at 32/80 than 32/80 HC and 26/50. These results suggest that head cooling during sleep may help to decrease the whole-body sweat rate during sleep under humid heat conditions.     

Synthesis and antiviral activity of novel fluorinated 2',3'-dideoxynucleosides

A series of 5-(trifluoroethoxymethyl)-2',3'-dideoxyuridines and 5-[bis(trifluoroethoxy)-methyl]-2',3'-dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn- and anti conformations for these 5-(2,2,2-trifluoroethoxymethyl)- and 5-[bis(2,2,2-trifluoroethoxy)-methyl]- derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti-HIV-1 and anti-HIV-2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.