Structural Features of Antiviral APOBEC3 Proteins are Linked to Their Functional Activities

Human APOBEC3 (A3) proteins are cellular cytidine deaminases that potently restrict the replication of retroviruses by hypermutating viral cDNA and/or inhibiting reverse transcription. There are seven members of this family including A3A, B, C, DE, F, G, and H, all encoded in a tandem array on human chromosome 22. A3F and A3G are the most potent inhibitors of HIV-1, but only in the absence of the virus-encoded protein, Vif. HIV-1 utilizes Vif to abrogate A3 functions in the producer cells. More specifically, Vif, serving as a substrate receptor, facilitates ubiquitination of A3 proteins by forming a Cullin5 (Cul5)-based E3 ubiquitin ligase complex, which targets A3 proteins for rapid proteasomal degradation. The specificity of A3 degradation is determined by the ability of Vif to bind to the target. Several lines of evidence have suggested that three distinct regions of A3 proteins are involved in the interaction with Vif. Here, we review the biological functions of A3 family members with special focus on A3G and base our analysis on the available structural information

Modeling circadian and sleep-homeostatic effects on short-term interval timing

Short-term interval timing i.e., perception and action relating to durations in the seconds range, has been suggested to display time-of-day as well as wake dependent fluctuations due to circadian and sleep-homeostatic changes to the rate at which an underlying pacemaker emits pulses; pertinent human data being relatively sparse and lacking in consistency however, the phenomenon remains elusive and its mechanism poorly understood. To better characterize the putative circadian and sleep-homeostatic effects on interval timing and to assess the ability of a pacemaker-based mechanism to account for the data, we measured timing performance in eighteen young healthy male subjects across two epochs of sustained wakefulness of 38.67 h each, conducted prior to (under entrained conditions) and following (under free-running conditions) a 28 h sleep-wake schedule, using the methods of duration estimation and duration production on target intervals of 10 and 40 s. Our findings of opposing oscillatory time courses across both epochs of sustained wakefulness that combine with increasing and, respectively, decreasing, saturating exponential change for the tasks of estimation and production are consistent with the hypothesis that a pacemaker emitting pulses at a rate controlled by the circadian oscillator and increasing with time awake determines human short-term interval timing; the duration-specificity of this pattern is interpreted as reflecting challenges to maintaining stable attention to the task that progressively increase with stimulus magnitude and thereby moderate the effects of pacemaker-rate changes on overt behavior

Angiotensin II type 2 receptors facilitate reinnervation of phenol-lesioned vascular calcitonin gene-related peptide (CGRP)-containing nerves in rat mesenteric arteries

The present study was designed to investigate involvement of angiotensin (Ang) II type 2 receptors (AT2 receptors) in restoration of perivascular nerve innervation injured by topical phenol treatment. Male Wistar rats underwent in vivo topical application of 10% phenol around the superior mesenteric artery. After phenol treatment, animals were subjected to immunohistochemistry of the third branch of small arteries, Western blot analysis of AT2 receptor protein expression in dorsal root ganglia (DRG) and studies of mesenteric neurogenic vasoresponsiveness. Ang II (750 ng/kg/day), nerve growth factor (NGF; 20 μg/kg/day) and PD123,319 (AT2 receptor antagonist; 10 mg/kg/day) were intraperitoneally administered for 7 days using osmotic mini-pumps immediately after topical phenol treatment. Losartan (AT1 receptor antagonist) was administered in drinking water (0.025%). Phenol treatment markedly reduced densities of both calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI)- and neuropeptide Y (NPY)-LI-containing fibers. NGF restored densities of both nerve fibers to the Sham control level. Coadministration of Ang II and losartan significantly increased the density of CGRP-LI-fibers but not NPY-LI-fibers compared with saline control. The increase of the density of CGRP-LI-fibers by coadministration of Ang II and losartan was suppressed by adding PD123,319. Coadministration of Ang II and losartan ameliorated reduction of CGRP nerve-mediated vasodilation of perfused mesenteric arteries caused by phenol treatment. The AT2 receptor protein expression detected in DRG was markedly increased by NGF. These results suggest that selective stimulation of AT2 receptors by Ang II facilitates reinnervation of mesenteric perivascular CGRP-containing nerves injured by topical phenol application in the rat.</p

COVID-19-mandated social restrictions unveil the impact of social time pressure on sleep and body clock

© The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/In humans, sleep regulation is tightly linked to social times that assign local time to events, such as school, work, or meals. The impact of these social times, collectively-social time pressure, on sleep has been studied epidemiologically via quantification of the discrepancy between sleep times on workdays and those on work-free days. This discrepancy is known as the social jetlag (SJL). COVID-19-mandated social restrictions (SR) constituted a global intervention by affecting social times worldwide. We launched a Global Chrono Corona Survey (GCCS) that queried sleep-wake times before and during SR (preSR and inSR). 11,431 adults from 40 countries responded between April 4 and May 6, 2020. The final sample consisted of 7517 respondents (68.2% females), who had been 32.7 ± 9.1 (mean ± sd) days under SR. SR led to robust changes: mid-sleep time on workdays and free days was delayed by 50 and 22 min, respectively; sleep duration increased on workdays by 26 min but shortened by 9 min on free days; SJL decreased by ~ 30 min. On workdays inSR, sleep-wake times in most people approached those of their preSR free days. Changes in sleep duration and SJL correlated with inSR-use of alarm clocks and were larger in young adults. The data indicate a massive sleep deficit under pre-pandemic social time pressure, provide insights to the actual sleep need of different age-groups and suggest that tolerable SJL is about 20 min. Relaxed social time pressure promotes more sleep, smaller SJL and reduced use of alarm clocks.info:eu-repo/semantics/publishedVersio

Outdoor daylight exposure and longer sleep promote wellbeing under COVID‐19 mandated restrictions

© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.Light is an important regulator of daily human physiology in providing time-of-day information for the circadian clock to stay synchronised with the 24-hr day. The coronavirus disease 2019 (COVID-19) pandemic led to social restrictions in many countries to prevent virus spreading, restrictions that dramatically altered daily routines and limited outdoor daylight exposure. We previously reported that sleep duration increased, social jetlag decreased, and mid-sleep times delayed during social restrictions (Global Chrono Corona Survey, N = 7,517). In the present study, we investigated in the same dataset changes in wellbeing and their link to outdoor daylight exposure, and sleep-wake behaviour. In social restrictions, median values of sleep quality, quality of life, physical activity and productivity deteriorated, while screen time increased, and outdoor daylight exposure was reduced by ~58%. Yet, many survey participants also reported no changes or even improvements. Larger reductions in outdoor daylight exposure were linked to deteriorations in wellbeing and delayed mid-sleep times. Notably, sleep duration was not associated with outdoor daylight exposure loss. Longer sleep and decreased alarm-clock use dose-dependently correlated with changes in sleep quality and quality of life. Regression analysis for each wellbeing aspect showed that a model with six predictors including both levels and their deltas of outdoor daylight exposure, sleep duration and mid-sleep timing explained 5%-10% of the variance in changes of wellbeing scores (except for productivity). As exposure to daylight may extenuate the negative effects of social restriction and prevent sleep disruption, public strategies during pandemics should actively foster spending more daytime outdoors.info:eu-repo/semantics/publishedVersio

Novel CLOCK and NR1D2 variants in 64 sighted Japanese individuals with non-24-hour sleep-wake rhythm disorder

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Reactions of excited-state benzophenone ketyl radical in a room-temperature ionic liquid

金沢大学理工研究域自然システム学系The photochemistry of the benzophenone ketyl radical in D1 excited state, BPH(D1), was studied by means of two-color dual-pulse laser flash photolysis (355 and 532 nm) in a room-temperature ionic liquid, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (Bmim-TFSA), and in methanol. Upon excitation with the 532 nm pulse, BPH(D1) emitted strong fluorescence. The transient absorption and fluorescence spectra of BPH(D1) were measured with nanosecond and sub-nanosecond time resolution, respectively. The observed Stokes shift was 1700 cm-1 in Bmim-TFSA, and this shift was close to that in acetonitrile. The fluorescence lifetime of BPH(D1) was determined to be 5 ns in Bmim-TFSA, and again the value was close to that in acetonitrile. The rate constant of the reaction of BPH(D1) with CCl4 in Bmim-TFSA was determined to be (2.1 ± 0.4) × 109 M-1 s-1, which was 10 times the rate constant calculated on the basis of the bulk viscosity of Bmim-TFSA. The results are discussed in terms of the effective microscopic viscosity of the ionic liquid that was recently reported for the cage effect. © 2010 the Owner Societies

Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis

Although Rho regulates cytokinesis, little was known about the functions in mitosis of Cdc42 and Rac. We recently suggested that Cdc42 works in metaphase by regulating bi-orient attachment of spindle microtubules to kinetochores. We now confirm the role of Cdc42 by RNA interference and identify the mechanisms for activation and down-regulation of Cdc42. Using a pull-down assay, we found that the level of GTP-Cdc42 elevates in metaphase, whereas the level of GTP-Rac does not change significantly in mitosis. Overexpression of dominant-negative mutants of Ect2 and MgcRacGAP, a Rho GTPase guanine nucleotide exchange factor and GTPase activating protein, respectively, or depletion of Ect2 by RNA interference suppresses this change of GTP-Cdc42 in mitosis. Depletion of Ect2 also impairs microtubule attachment to kinetochores and causes prometaphase delay and abnormal chromosomal segregation, as does depletion of Cdc42 or expression of the Ect2 and MgcRacGAP mutants. These results suggest that Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis

Prevalence of childhood obstructive sleep apnea syndrome and its role in daytime sleepiness

ObjectivesTo investigate childhood obstructive sleep apnea syndrome (OSAS) and its role in daytime sleepiness among school-age children.MethodsA questionnaire survey was conducted with 25,211 children aged 6–15 (mean, 10.39) years attending 148 elementary and 71 middle schools in 10 prefectures across Japan and their parents. Questions concerned 4 sleep habit items (bedtime, sleep onset latency, wake time after sleep onset, wake-up time) and 4 sleep disorder items (loud snoring, snorts/gasps, breathing pauses, seems very sleepy in the daytime). Total sleep time (TST) was calculated with sleep habits. Severe possible OSAS (p-OSAS) was defined as having loud snoring, snorts and gasps, or breathing pauses “frequently” (≥ 5 times per week), and mild p-OSAS was rated as having any of these “sometimes” (2–4 times per week). Severe daytime sleepiness was defined as seeming very sleepy “frequently” and mild daytime sleepiness as seeming very sleepy “sometimes”.ResultsMean prevalence of mild to severe p-OSAS and severe p-OSAS in children across all grade levels was 9.5% and 1.6%, respectively. p-OSAS was particularly prevalent in children at lower elementary levels, decreasing with advancing grade levels. Prevalence of mild and severe daytime sleepiness was 6.1% and 0.9%, respectively, among all children (7.0%). Prevalence of daytime sleepiness increased with advancing grade levels, particularly in middle-school level. Average TST was 8.4 ± 2.2 h in both elementary and middle-school levels, and decreased as grades advanced, particularly in middle-school levels. Multivariate logistic regression analysis showed that middle-school level, TST < 8 h, and p-OSAS were independent factors for daytime sleepiness. Strong correlations were found between severe daytime sleepiness and severe p-OSAS or TST < 6 h, and between daytime sleepiness and loud snoring or breathing pauses.Conclusionp-OSAS may be an independent factor influencing daytime sleepiness in school-age children. Loud snoring and breathing pauses could be clinical markers for children with severe daytime sleepiness

Risk factors for low adherence to methylphenidate treatment in pediatric patients with attention-deficit/hyperactivity disorder

Poor adherence is a major concern in the treatment of attention-deficit/hyperactivity disorder (ADHD). The objective of this study was to evaluate factors linked to early interruption of and low adherence to treatment with osmotic-release oral system methylphenidate hydrochloride (OROS-MPH) in pediatric patients with ADHD. A total of 1353 young people (age 6–17 years) with a diagnosis of ADHD who newly started OROS-MPH were extracted from the pharmacoepidemiological data of 3 million people in Japan. The cohort was retrospectively surveyed every month for 12 months. Ten possible risk factors were extracted from the data and analyzed by multivariable logistic regression. Sensitivity analysis was conducted to ensure the robustness of the analysis. The results revealed that treatment adherence was generally poor, with a tendency for discontinuation in the early stage. Multivariable logistic regression results showed that adherence is reduced by female sex, lower starting dose, and concomitant atomoxetine or hypnotics. These findings may help clinicians to predict the risk of poor adherence in the early stage of treatment and improve not only patients’ symptoms, but also their quality of life