Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork

Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions

A decade of remotely sensed observations highlight complex processes linked to coastal permafrost bluff erosion in the Arctic

Eroding permafrost coasts are likely indicators and integrators of changes in the Arctic System as they are susceptible to the combined effects of declining sea ice extent, increases in open water duration, more frequent and impactful storms, sea-level rise, and warming permafrost. However, few observation sites in the Arctic have yet to link decadal-scale erosion rates with changing environmental conditions due to temporal data gaps. This study increases the temporal fidelity of coastal permafrost bluff observations using near-annual high spatial resolution (<1 m) satellite imagery acquired between 2008–2017 for a 9 km segment of coastline at Drew Point, Beaufort Sea coast, Alaska. Our results show that mean annual erosion for the 2007–2016 decade was 17.2 m yr−1, which is 2.5 times faster than historic rates, indicating that bluff erosion at this site is likely responding to changes in the Arctic System. In spite of a sustained increase in decadal-scale mean annual erosion rates, mean open water season erosion varied from 6.7 m yr−1 in 2010 to more than 22.0 m yr−1 in 2007, 2012, and 2016. This variability provided a range of coastal responses through which we explored the different roles of potential environmental drivers. The lack of significant correlations between mean open water season erosion and the environmental variables compiled in this study indicates that we may not be adequately capturing the environmental forcing factors, that the system is conditioned by long-term transient effects or extreme weather events rather than annual variability, or that other not yet considered factors may be responsible for the increased erosion occurring at Drew Point. Our results highlight an increase in erosion at Drew Point in the 21st century as well as the complexities associated with unraveling the factors responsible for changing coastal permafrost bluffs in the Arctic

Analysis of the effects of sex hormone background on the rat choroid plexus transcriptome by cDNA microarrays

The choroid plexus (CP) are highly vascularized branched structures that protrude into the ventricles of the brain, and form a unique interface between the blood and the cerebrospinal fluid (CSF), the blood-CSF barrier, that are the main site of production and secretion of CSF. Sex hormones are widely recognized as neuroprotective agents against several neurodegenerative diseases, and the presence of sex hormones cognate receptors suggest that it may be a target for these hormones. In an effort to provide further insight into the neuroprotective mechanisms triggered by sex hormones we analyzed gene expression differences in the CP of female and male rats subjected to gonadectomy, using microarray technology. In gonadectomized female and male animals, 3045 genes were differentially expressed by 1.5-fold change, compared to sham controls. Analysis of the CP transcriptome showed that the top-five pathways significantly regulated by the sex hormone background are olfactory transduction, taste transduction, metabolism, steroid hormone biosynthesis and circadian rhythm pathways. These results represent the first overview of global expression changes in CP of female and male rats induced by gonadectomy and suggest that sex hormones are implicated in pathways with central roles in CP functions and CSF homeostasis

Absolute Stereochemistry of a 4a-Hydroxyriboflavin Analogue of the Key Intermediate of the FAD-Monooxygenase Cycle

The biological action of flavoenzymes, such as flavin adenine dinucleotide (FAD)-containing monooxygenase, involves the formation of oxygenated flavin derivatives, such as 4a-hydroperoxyflavin and 4a-hydroxyflavin, in which a new center of chirality is created at the 4a position during the enzymatic reactions. So far, the absolute configuration of this center of chirality in natural 4a-oxygenated flavins has remained unknown in spite of its key importance for the diverse functions of flavoenzymes. Herein, we report the 4a-hydroxy adduct 3 of 3-benzyl-5-ethyl-10-(tetraacetyl-D-ribityl)flavinium (1), one of the key intermediates involved in the enantioselective organocatalytic oxidation of sulfides to sulfoxides. The 4a-hydroxyflavin diastereomers (+)-3 and (-)-3, separated by HPLC, were characterized by electronic circular dichroism (CD) spectroscopy. Their absolute configurations at the 4a position were, for the first time, determined by comparing experimental CD spectra with those calculated by means of time-dependent density functional theory (TDDFT) on DFT-optimized structures obtained after an extensive conformation analysis