Induction of Mutant Sik3Sleepy Allele in Neurons in Late Infancy Increases Sleep Need

Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG δ power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function Sleepy (Slp) mutation in the salt-inducible kinase 3 (Sik3) gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG δ power and sleep amount. Since Sik3^Slp mice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in Sik3^Slp mice remain to be elucidated. Here, we generated two mouse lines, synapsin1^CreERT2 and Sik3^ex13flox mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to synapsin1^CreERT2 mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS δ power in male synapsin1^CreERT2; Sik3^ex13flox/+ mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS δ power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.SIGNIFICANCE STATEMENT The propensity to accumulate sleep need during wakefulness and to dissipate it during sleep underlies the homeostatic regulation of sleep. However, little is known about the developmental stage and cell types involved in determining the homeostatic regulation of sleep. Here, we show that Sik3^Slp allele induction in mature neurons in late infancy is sufficient to increase non-rapid eye movement sleep amount and non-rapid eye movement sleep δ power. SIK3 signaling in neurons constitutes an intracellular mechanism to increase sleep.     

Regulatory T Cells in Immunologic Self-Tolerance and Autoimmune Disease

Naturally arising CD25⁺CD4⁺ regulatory T cells play key roles in the maintenance of immunologic self-tolerance and negative control of various immune responses. The majority, if not all, of them are produced by the normal thymus as a functionally distinct T-cell subpopulation, and their generation is in part developmentally controlled. Genetic abnormality in the development and function of this population can indeed be a cause of autoimmune disease, immunopathology, and allergy in humans. This regulatory population can be exploited to prevent and treat autoimmune disease by strengthening and reestablishing immunologic self-tolerance.     

Usefulness of albumin–globulin ratio as a clinical prognostic factor in patients with thyroid cancer treated with radioiodine

Annals of Nuclear Medicine - Albumin–globulin ratio (AGR), which is calculated by dividing serum albumin by serum globulin, is considered as a cancer-related inflammation biomarker. Although...     

Effect of photo-thermal acceleration on in-office bleaching

Odontology - The purpose is to evaluate the effect of photo-thermal acceleration on in-office bleaching efficiency using a bleaching agent without photocatalysts in vitro. Artificially discolored...     

Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis–mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.     

Estrogen and non-feminizing estrogen for Alzheimer's disease

The preventive effect of estrogen on Alzheimer's disease (AD) has become clearer with many epidemiological reports. However, the therapeutic effects of estrogen have been controversial until now. In our trials, estrogen treatment showed a beneficial therapeutic effect for women with mild to moderate AD. Improvement of cognitive function was recognized during the third week from the beginning of administration and maintained as long as estrogen treatment continued. The longer the duration of HRT, the more HRT is useful for the prevention and therapy of AD. However, in most cases, administration of estrogen is discontinued because of the adverse effects on the uterus and breast. J 861 is a derivative of estradiol-17alpha, which has little effect on the sexual organs. The effects of estradiol-17beta (E2) and J 861 on neuronal function and vascular factors were investigated. J 861 was suggested to prevent both the intracellular calcium increase and peroxidation induced by amyloid beta (Abeta), more effectively than E2. The effect of J 861 may be related with both the direct non-genomic and the ER-mediated systems. J 861 showed neurotrophic effects like E2. J 861 inhibited the adhesion of monocytes to vascular endothelium, more effectively than E2. Also, J 861 suppressed the expression of adhesive factors, such as E-selectin and intercellular cell adhesion molecule-1 (ICAM-1), more effectively than E2.