[Photoreceptors for Entrainment of Circadian Rhythms].

In mammals, the intrinsic circadian clock regulates various physiological rhythms, including sleep-wake cycles. These circadian rhythms can be entrained to daily 24-hour light-dark cycles by virtue of photoreception within the retina. The photo-entrainment of circadian rhythms is predominantly mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). In this article, we review the mechanisms of action of ipRGC photoreception, the retinal circuit involving ipRGCs, and the heterogeneity of ipRGCs in mice.

Foxq2 determines blue cone identity in zebrafish.

Most vertebrate lineages retain a tetrachromatic visual system, which is supported by a functional combination of spectrally distinct multiple cone photoreceptors, ultraviolet (UV), blue, green, and red cones. The blue cone identity is ensured by selective expression of blue (sws2) opsin, and the mechanism is poorly understood because sws2 gene has been lost in mammalian species such as mouse, whose visual system has been extensively studied. Here, we pursued loss-of-function studies on transcription factors expressed predominantly in zebrafish cone photoreceptors and identified Foxq2 as a blue cone­specific factor driving sws2 gene expression. Foxq2 has dual functions acting as an activator of sws2 transcription and as a suppressor of UV (sws1) opsin transcription in blue cones. A wide range of vertebrate species retain both foxq2 and sws2 genes. We propose that Foxq2-dependent sws2 expression is a prevalent regulatory mechanism that was acquired at the early stage of vertebrate evolution.

The effects of endurance exercise combined with high-temperature head-out water immersion on serum concentration of brain-derived neurotrophic factor in healthy young men.

OBJECTIVES: To evaluate acute changes in serum brain-derived neurotrophic factor (BDNF) concentration following combined endurance exercise and heat stress through head-out water immersion (HOI). SETTING: Observational study with crossover design. METHODS: Ten healthy young male participants performed HOI at 40 °C (40 °C HOI) or continuous cycling at 60% of maximal oxygen uptake while immersed in 40 °C (40 °C HOI-ex) or 23 °C water (23 °C HOI-ex) for 15 min. Serum BDNF, cortisol and lactate concentrations, and core temperature (Tcore) were measured pre, immediately post, and 15 and 30 min post-immersion. RESULTS: BDNF concentration increased immediately and 15 min after 40 °C HOI-ex, but not after 40 °C or 23 °C HOI-ex. No changes in Tcore concentration were observed during 23 °C HOI-ex (Pre; 37.3 °C ± 0.3 °C, Post; 37.8 °C ± 0.2 °C, Post 15; 37.4 °C ± 0.3 °C, Post 30; 37.2 °C ± 0.2 °C). Tcore increased significantly post, post 15, and post 30 min of 40 °C HOI (Pre; 37.1 °C ± 0.4 °C, Post; 38.8 °C ± 0.5 °C, Post 15; 37.9 °C ± 0.4 °C, Post 30; 37.9 °C ± 0.2 °C) and 40 °C HOI-ex (Pre; 37.2 °C ± 0.2 °C, Post; 40.2 °C ± 0.7 °C, Post 15; 38.9 °C ± 0.5 °C, Post 30; 38.3 °C ± 0.5 °C). Tcore was higher in 40 °C HOI-ex compared with 40 °C HOI and 23 °C HOI-ex immediately post and post 15 min. Plasma lactate and cortisol were significantly higher in 40 °C HOI-ex compared with 40 °C HOI and 23 °C HOI-ex after immersion (p = 0.001). CONCLUSION: While 15 min HOI alone or thermoneutral exercise do not increase BDNF concentration, both combined may form a time-efficient strategy to acutely elevate BDNF.

Attenuation of core temperature elevation and interleukin-6 excretion during head-out hot water immersion in elderly people.

[Purpose] Previous studies have demonstrated a link between core body temperature and interleukin-6 production. Recent studies have reported that 20 minutes of head-out immersion in hot water (42°C) increased serum interleukin-6 levels in young males. This study aimed to compare the efficacy of head-out immersion in hot water (42°C) on serum interleukin-6 levels in seven elderly (66-75 years old) and eight young males (21-32 years old). [Participants and Methods] Venous blood samples were drawn at rest, immediately after head-out immersion in hot water (42°C), after 1 hour, and after 2 hours. Levels of serum interleukin-6, tumor necrosis factor-α, and high-sensitivity C-reactive protein; blood cell counts; and core temperature were measured. [Results] It was found that 20 minutes of head-out immersion in hot water (42°C) increased the core temperature in both the elderly and young participants; however, the rise in core temperature was more attenuated in elderly participants. Serum interleukin-6 levels were significantly higher in young participants 1 hour after the head-out immersion in hot water (42°C); however, serum interleukin-6 levels did not change in elderly participants. Serum tumor necrosis factor-α and high-sensitivity C-reactive protein levels remained constant throughout the study the elderly and young participants. [Conclusion] The current study demonstrated that head-out immersion in hot water (42°C) more attenuated core temperature and interleukin-6 levels in elderly participants than in young participants. We assert that these differences are likely to be related to age-related changes in core temperature regulation and muscle fibers.

Brain-specific homeobox Bsx specifies identity of pineal gland between serially homologous photoreceptive organs in zebrafish.

The pineal gland functioning as a photoreceptive organ in non-mammalian species is a serial homolog of the retina. Here we found that Brain-specific homeobox (Bsx) is a key regulator conferring individuality on the pineal gland between the two serially homologous photoreceptive organs in zebrafish. Bsx knock-down impaired the pineal development with reduced expression of exorh, the pineal-specific gene responsible for the photoreception, whereas it induced ectopic expression of rho, a retina-specific gene, in the pineal gland. Bsx remarkably transactivated the exorh promoter in combination with Otx5, but not with Crx, through its binding to distinct subtypes of PIRE, a DNA cis-element driving Crx/Otx-dependent pineal-specific gene expression. These results demonstrate that the identity of pineal photoreceptive neurons is determined by the combinatorial code of Bsx and Otx5, the former confers the pineal specificity at the tissue level and the latter determines the photoreceptor specificity at the cellular level.

Six6 and Six7 coordinately regulate expression of middle-wavelength opsins in zebrafish.

Color discrimination in the vertebrate retina is mediated by a combination of spectrally distinct cone photoreceptors, each expressing one of multiple cone opsins. The opsin genes diverged early in vertebrate evolution into four classes maximally sensitive to varying wavelengths of light: UV (SWS1), blue (SWS2), green (RH2), and red (LWS) opsins. Although the tetrachromatic cone system is retained in most nonmammalian vertebrate lineages, the transcriptional mechanism underlying gene expression of the cone opsins remains elusive, particularly for SWS2 and RH2 opsins, both of which have been lost in the mammalian lineage. In zebrafish, which have all four cone subtypes, rh2 opsin gene expression depends on a homeobox transcription factor, sine oculis homeobox 7 (Six7). However, the six7 gene is found only in the ray-finned fish lineage, suggesting the existence of another evolutionarily conserved transcriptional factor(s) controlling rh2 opsin expression in vertebrates. Here, we found that the reduced rh2 expression caused by six7 deficiency was rescued by forced expression of six6b, which is a six7-related transcription factor conserved widely among vertebrates. The compensatory role of six6b was reinforced by ChIP-sequencing analysis, which revealed a similar pattern of Six6b- and Six7-binding sites within and near the cone opsin genes. TAL effector nuclease-induced genetic ablation of six6b and six7 revealed that they coordinately regulate SWS2 opsin gene expression. Mutant larvae deficient for these transcription factors showed severely impaired visually driven foraging behavior. These results demonstrate that in zebrafish, six6b and six7 govern expression of the SWS2 and RH2 opsins responsible for middle-wavelength sensitivity, which would be physiologically important for daylight vision.

Head-out immersion in hot water increases serum BDNF in healthy males.

PURPOSE: Brain-derived neurotrophic factor (BDNF) is an important neurotrophin. The present study investigated the effects of head-out water immersion (HOI) on serum BDNF concentrations. METHODS: Eight healthy men performed 20 min head-out water immersion at 42 °C (hot-HOI) and 35 °C (neutral-HOI). These experimental trials were administered in a randomised order separated by at least 7 days. Venous blood samples were withdrawn at rest, immediately after the 20-min HOI, as well as at 15 and 30 min after the end of the HOI. Serum BDNF and S100ß, plasma cortisol, platelet and monocyte counts, and core body temperature (Tcb) were measured. RESULTS: Tcb was higher at the end of the hot-HOI and 15 min after hot-HOI (p < 0.01), but recovered to pre-HOI level at 30 min after hot-HOI. No change in Tcb was recorded during neutral-HOI. BDNF level was higher (p < 0.05) at the end of the hot-HOI and at 15 min after the end of hot-HOI, and returned to the baseline at 30 min after hot-HOI. S100ß, platelet count and monocyte count remained stable throughout the study. Cortisol level was lower at the end of the hot-HOI and returned to pre-HOI level during the recovery period. BDNF and S100ß, cortisol, and platelet and monocyte counts did not change throughout the neutral-HOI study. CONCLUSIONS: The present findings suggested that the increase in BDNF during 20-min hot-HOI was induced by hyperthermia through enhanced production, rather than by changes in permeability of the blood-brain barrier (BBB), platelet clotting mechanisms or secretion from monocytes.

Effects of physiatrist and registered therapist operating acute rehabilitation (PROr) in patients with stroke.

OBJECTIVE: Clinical evidence suggests that early mobilization of patients with acute stroke improves activity of daily living (ADL). The purpose of this study was to compare the utility of the physiatrist and registered therapist operating acute rehabilitation (PROr) applied early or late after acute stroke. SUBJECTS AND METHODS: This study was prospective cohort study, assessment design. Patients with acute stroke (n = 227) admitted between June 2014 and April 2015 were divided into three groups based on the time of start of PROr: within 24 hours (VEM, n = 47), 24-48 hours (EM, n = 77), and more than 48 hours (OM, n = 103) from stroke onset. All groups were assessed for the number of deaths during hospitalization, and changes in the Glasgow Coma Scale (GCS), National Institute of Health Stroke Scale (NIHSS), and Functional Independence Measure (FIM) at hospital discharge. INTERVENTIONS: All patients were assessed by physiatrists, who evaluated the specific needs for rehabilitation, and then referred them to registered physical therapists and occupational therapists to provide early mobilization (longer than one hour per day per patient). RESULTS: The number of deaths encountered during the PROr period was 13 (out of 227, 5.7%), including 2 (4.3%) in the VEM group. GCS improved significantly during the hospital stay in all three groups, but the improvement on discharge was significantly better in the VEM group compared with the EM and OM groups. FIM improved significantly in the three groups, and the gains in total FIM and motor subscale were significantly greater in the VEM than the other groups. CONCLUSIONS: PROr seems safe and beneficial rehabilitation to improve ADL in patients with acute stroke.

Prediction of cyclic delamination lives of plasma-sprayed hydroxyapatite coating on Ti-6Al-4V substrates with considering wear and dissolutions.

This study aims at developing the prediction model of cyclic delamination lives of plasma-sprayed HAp coating on Ti-6Al-4V substrate by considering wear by interface contacts and dissolution effect by Simulated Body Fluid (SBF). Delamination of HAp coating can lead to loosening of implants stem and final failure in vivo. In the fracture mechanism of interfaces between HAp coating with Ti substrates, only adhesive strength (interracial tensile strength) or fatigue behavior by longitudinal cracking have been observed. Cyclic delamination mechanism by considering various loading modes and corrosion effect has not been revealed yet. The interface delamination rates by cyclic loading were much higher than those by static loading tests. The result clearly demonstrated that the interface demalination behaviors are dominated not by maximum stress, but by stress range. Surface profile measurement and SEM observation also demonstrated damages by interface contact or third body wear at delamination tips of HAp coating only in the cases of compressions. The mechanisms of acceleration on the delaminations are third-body wear or wedge effect by worn particles which increased mean stress level during cyclic loading. Cyclic loading tests under SBF also revealed that cyclic delamination lives were shortened probably due to crevice corrosion at interfaces. Dissolutions at the tips of delaminations were observed by SEM images under tensile loading condition in SBF. Linearly adding the effects of wear and dissolutions into Paris law could successfully predict the delamination lives of HAp coating for various loading ratios in SBF.

Light-dependent activation of G proteins by two isoforms of chicken melanopsins.

In the chicken pineal gland, light stimuli trigger signaling pathways mediated by two different subtypes, Gt and G11. These G proteins may be activated by any of the three major pineal opsins, pinopsin, OPN4-1 and OPN4-2, but biochemical evidence for the coupling has been missing except for functional coupling between pinopsin and Gt. Here we investigated the relative expression levels and the functional difference among the three pineal opsins. In the chicken pineal gland, the pinopsin mRNA level was significantly more abundant than the others, of which the OPN4-2 mRNA level was higher than that of OPN4-1. In G protein activation assays, Gt was strongly activated by pinopsin in a light-dependent manner, being consistent with previous studies, and weakly activated by OPN4-2. Unexpectedly, illuminated OPN4-2 more efficiently activated G protein(s) that was endogenously expressed in HEK293T cells in culture. On the other hand, Gq, the closest analogue of G11, was activated only by OPN4-1 although the activity was relatively weak under these conditions. These results suggest that OPN4-1 and OPN4-2 couple with Gq and Gt, respectively. Two melanopsins, OPN4-1 and OPN4-2, appear to have acquired mutually different functions through the evolution.