Role for Circadian Clock Genes in Seasonal Timing: Testing the Bünning Hypothesis

A major question in chronobiology focuses around the “Bünning hypothesis” which implicates the circadian clock in photoperiodic (day-length) measurement and is supported in some systems (e.g. plants) but disputed in others. Here, we used the seasonally-regulated thermotolerance of Drosophila melanogaster to test the role of various clock genes in day-length measurement. In Drosophila, freezing temperatures induce reversible chill coma, a narcosis-like state. We have corroborated previous observations that wild-type flies developing under short photoperiods (winter-like) exhibit significantly shorter chill-coma recovery times (CCRt) than flies that were raised under long (summer-like) photoperiods. Here, we show that arrhythmic mutant strains, per⁰¹, tim⁰¹ and Clk^Jrk, as well as variants that speed up or slow down the circadian period, disrupt the photoperiodic component of CCRt. Our results support an underlying circadian function mediating seasonal daylength measurement and indicate that clock genes are tightly involved in photo- and thermo-periodic measurements.     

Comparative study of the AT1 receptor prodrug antagonist candesartan cilexetil with other sartans on the interactions with membrane bilayers

Drug–membrane interactions of the candesartan cilexetil (TCV-116) have been studied on molecular basis by applying various complementary biophysical techniques namely differential scanning calorimetry (DSC), Raman spectroscopy, small and wide angle X-ray scattering (SAXS and WAXS), solution ¹H and ¹³C nuclear magnetic resonance (NMR) and solid state ¹³C and ³¹P (NMR) spectroscopies. In addition, ³¹P cross polarization (CP) NMR broadline fitting methodology in combination with ab initio computations has been applied. Finally molecular dynamics (MD) was applied to find the low energy conformation and position of candesartan cilexetil in the bilayers. Thus, the experimental results complemented with in silico MD results provided information on the localization, orientation, and dynamic properties of TCV-116 in the lipidic environment. The effects of this prodrug have been compared with other AT₁ receptor antagonists hitherto studied. The prodrug TCV-116 as other sartans has been found to be accommodated in the polar/apolar interface of the bilayer. In particular, it anchors in the mesophase region of the lipid bilayers with the tetrazole group oriented toward the polar headgroup spanning from water interface toward the mesophase and upper segment of the hydrophobic region. In spite of their localization identity, their thermal and dynamic effects are distinct pointing out that each sartan has its own fingerprint of action in the membrane bilayer, which is determined by the parameters derived from the above mentioned biophysical techniques.     

Versatile regulation of cytosolic Ca2+ by vanilloid receptor I in rat dorsal root ganglion neurons

Analysis of small dorsal root ganglion (DRG) neurons revealed novel functions for vanilloid receptor 1 (VR1) in the regulation of cytosolic Ca(2+). The VR1 agonist capsaicin induced Ca(2+) mobilization from intracellular stores in the absence of extracellular Ca(2+), and this release was inhibited by the VR1 antagonist capsazepine but was unaffected by the phospholipase C inhibitor xestospongins, indicating that Ca(2+) mobilization was dependent on capsaicin receptor binding and was not due to intracellular inositol-1,4,5-trisphosphate generation. Confocal microscopy revealed extensive expression of VR1 on endoplasmic reticulum, consistent with VR1 operating as a Ca(2+) release receptor. The main part of the capsaicin-releasable Ca(2+) store was insensitive to thapsigargin, a selective endoplasmic reticulum Ca(2+)-ATPase inhibitor, suggesting that VR1 might be predominantly localized to a thapsigargin-insensitive endoplasmic reticulum Ca(2+) store. In addition, VR1 was observed to behave as a store-operated Ca(2+) influx channel. In DRG neurons, capsazepine attenuated Ca(2+) influx following thapsigargin-induced Ca(2+) store depletion and inhibited thapsigargin-induced inward currents. Conversely, transfected HEK-293 cells expressing VR1 showed enhanced Ca(2+) influx and inward currents following Ca(2+) store depletion. Combined data support topographical and functional diversity for VR1 in the regulation of cytosolic Ca(2+) with the plasma membrane-associated form behaving as a store-operated Ca(2+) influx channel and endoplasmic reticulum-associated VR1 possibly functioning as a Ca(2+) release receptor in sensory neurons.     

Simple sleep questions can predict 12-year mortality in a rural population

Sleep and Biological Rhythms - There is apt evidence in favor of a significant association between sleep and mortality. So far, most studies examine sleep problems using comprehensive,...     

Mental Representation of Arm Motion Dynamics in Children and Adolescents

Motor imagery, i.e., a mental state during which an individual internally represents an action without any overt motor output, is a potential tool to investigate action representation during development. Here, we took advantage of the inertial anisotropy phenomenon to investigate whether children can generate accurate motor predictions for movements with varying dynamics. Children (9 and 11 years), adolescents (14 years) and young adults (21 years) carried-out actual and mental arm movements in two different directions in the horizontal plane: rightwards (low inertia) and leftwards (high inertia). We recorded and compared actual and mental movement times. We found that actual movement times were greater for leftward than rightward arm movements in all groups. For mental movements, differences between leftward versus rightward movements were observed in the adults and adolescents, but not among the children. Furthermore, significant differences between actual and mental times were found at 9 and 11 years of age in the leftward direction. The ratio R/L (rightward direction/leftward direction), which indicates temporal differences between low inertia and high inertia movements, was inferior to 1 at all ages, except for the mental movements at 9 years of age, indicating than actual and mental movements were shorter for the rightward than leftward direction. Interestingly, while the ratio R/L of actual movements was constant across ages, it gradually decreased with age for mental movements. The ratio A/M (actual movement/mental movement), which indicates temporal differences between actual and mental movements, was near to 1 in the adults'' groups, denoting accurate mental timing. In children and adolescents, an underestimation of mental movement times appeared for the leftward movements only. However, this overestimation gradually decreased with age. Our results showed a refinement in the motor imagery ability during development. Action representation reached maturation at adolescence, during which mental actions were tightly related to their actual production.