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Clocks & Sleep, Volume 3, Issue 3 (September 2021) – 14 articles

Cover Story (view full-size image): Despite the fundamental roles of circadian rhythms in physiology and diseases, chronotherapeutic implications for most drugs are poorly explored. In the study, an unbiased screening approach identified the Class I anti-arrhythmic drug moricizine as a novel modulator of circadian rhythms. Using experimental systems including reporter cells, tissue explants, and mice, they show that moricizine is able to lengthen circadian periods, reprogram gene expression and promote sleep. These findings illustrate a circadian mode of action for a heart disease drug, underscoring chronotherapeutic relevance in clock-related disorders. View this paper.
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Review
The Language of Dreams: Application of Linguistics-Based Approaches for the Automated Analysis of Dream Experiences
Clocks & Sleep 2021, 3(3), 495-514; https://doi.org/10.3390/clockssleep3030035 - 19 Sep 2021
Cited by 1 | Viewed by 1534
Abstract
The study of dreams represents a crucial intersection between philosophical, psychological, neuroscientific, and clinical interests. Importantly, one of the main sources of insight into dreaming activity are the (oral or written) reports provided by dreamers upon awakening from their sleep. Classically, two main [...] Read more.
The study of dreams represents a crucial intersection between philosophical, psychological, neuroscientific, and clinical interests. Importantly, one of the main sources of insight into dreaming activity are the (oral or written) reports provided by dreamers upon awakening from their sleep. Classically, two main types of information are commonly extracted from dream reports: structural and semantic, content-related information. Extracted structural information is typically limited to the simple count of words or sentences in a report. Instead, content analysis usually relies on quantitative scores assigned by two or more (blind) human operators through the use of predefined coding systems. Within this review, we will show that methods borrowed from the field of linguistic analysis, such as graph analysis, dictionary-based content analysis, and distributional semantics approaches, could be used to complement and, in many cases, replace classical measures and scales for the quantitative structural and semantic assessment of dream reports. Importantly, these methods allow the direct (operator-independent) extraction of quantitative information from language data, hence enabling a fully objective and reproducible analysis of conscious experiences occurring during human sleep. Most importantly, these approaches can be partially or fully automatized and may thus be easily applied to the analysis of large datasets. Full article
(This article belongs to the Special Issue Dream and Sleep)
Article
The Effects of General Anaesthesia and Light on Behavioural Rhythms and GABAA Receptor Subunit Expression in the Mouse SCN
Clocks & Sleep 2021, 3(3), 482-494; https://doi.org/10.3390/clockssleep3030034 - 17 Sep 2021
Viewed by 1103
Abstract
General anaesthesia (GA) is known to affect the circadian clock. However, the mechanisms that underlie GA-induced shifting of the clock are less well understood. Activation of γ-aminobutyric acid (GABA)-type A receptors (GABAAR) in the suprachiasmatic nucleus (SCN) can phase [...] Read more.
General anaesthesia (GA) is known to affect the circadian clock. However, the mechanisms that underlie GA-induced shifting of the clock are less well understood. Activation of γ-aminobutyric acid (GABA)-type A receptors (GABAAR) in the suprachiasmatic nucleus (SCN) can phase shift the clock and thus GABA and its receptors represent a putative pathway via which GA exerts its effect on the clock. Here, we investigated the concurrent effects of the inhalational anaesthetic, isoflurane, and light, on mouse behavioural locomotor rhythms and on α1, β3, and γ2 GABAAR subunit expression in the SCN of the mouse brain. Behavioural phase shifts elicited by exposure of mice to four hours of GA (2% isoflurane) and light (400 lux) (n = 60) were determined by recording running wheel activity rhythms in constant conditions (DD). Full phase response curves for the effects of GA + light on behavioural rhythms show that phase shifts persist in anaesthetized mice exposed to light. Daily variation was detected in all three GABAAR subunits in LD 12:12. The γ2 subunit expression was significantly increased following GA in DD (compared to light alone) at times of large behavioural phase delays. We conclude that the phase shifting effect of light on the mouse clock is not blocked by GA administration, and that γ2 may potentially be involved in the phase shifting effect of GA on the clock. Further analysis of GABAAR subunit expression in the SCN will be necessary to confirm its role. Full article
(This article belongs to the Section Animal Basic Research)
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Article
Nightmares in Children with Foetal Alcohol Spectrum Disorders, Autism Spectrum Disorders, and Their Typically Developing Peers
Clocks & Sleep 2021, 3(3), 465-481; https://doi.org/10.3390/clockssleep3030033 - 16 Sep 2021
Viewed by 1264
Abstract
Children with Foetal Alcohol Spectrum Disorders (FASD) and Autism Spectrum Disorders (ASD) experience significantly higher rates of sleep disturbances than their typically developing (TD) peers. Pre-sleep anxiety and waking emotional content is known to affect the content and frequency of nightmares, which can [...] Read more.
Children with Foetal Alcohol Spectrum Disorders (FASD) and Autism Spectrum Disorders (ASD) experience significantly higher rates of sleep disturbances than their typically developing (TD) peers. Pre-sleep anxiety and waking emotional content is known to affect the content and frequency of nightmares, which can be distressing to children and caregivers. This is the first study to analyse nightmare frequency and content in FASD, and to assess its association with psychometric outcomes. Using online caregiver questionnaires, we assessed reports from 277 caregivers of children with ASD (n = 61), FASD (n = 112), and TD children (n = 104) using the Children’s Sleep Habits Questionnaire (CSHQ), the Child Behaviour Checklist (CBCL), the Spence Children’s Anxiety Scale (SCAS), and the Behaviour Rating Inventory for Executive Functioning (BRIEF). Within the ASD group, 40.3% of caregivers reported their children had nightmares. Within the FASD group, 73.62% of caregivers reported their children had nightmares, and within the TD group, 21.36% of caregivers reported their children had nightmares. Correlation analysis revealed significant associations between anxiety and nightmares, maladaptive behaviour and nightmares, and executive functioning and nightmares in the TD and FASD groups, but not ASD group. This paper adds to the emerging body of work supporting the need for sleep interventions as part of clinical practice with regard to children with ASD and FASD. As a relatively niche but important area of study, this warrants much needed further research. Full article
(This article belongs to the Special Issue Dream and Sleep)
Article
The Effect of Bright Light Treatment on Rest–Activity Rhythms in People with Dementia: A 24-Week Cluster Randomized Controlled Trial
Clocks & Sleep 2021, 3(3), 449-464; https://doi.org/10.3390/clockssleep3030032 - 13 Sep 2021
Viewed by 1140
Abstract
Bright light treatment is an effective way to influence circadian rhythms in healthy adults, but previous research with dementia patients has yielded mixed results. The present study presents a primary outcome of the DEM.LIGHT trial, a 24-week randomized controlled trial conducted at nursing [...] Read more.
Bright light treatment is an effective way to influence circadian rhythms in healthy adults, but previous research with dementia patients has yielded mixed results. The present study presents a primary outcome of the DEM.LIGHT trial, a 24-week randomized controlled trial conducted at nursing homes in Bergen, Norway, investigating the effects of a bright light intervention. The intervention consisted of ceiling-mounted LED panels providing varying illuminance and correlated color temperature throughout the day, with a peak of 1000 lx, 6000 K between 10 a.m. and 3 p.m. Activity was recorded using actigraphs at baseline and after 8, 16, and 24 weeks. Non-parametric indicators and extended cosine models were used to investigate rest–activity rhythms, and outcomes were analyzed with multi-level regression models. Sixty-one patients with severe dementia (median MMSE = 4) were included. After 16 weeks, the acrophase was advanced from baseline in the intervention group compared to the control group (B = −1.02, 95%; CI = −2.00, −0.05). There was no significant difference between the groups on any other rest–activity measures. When comparing parametric and non-parametric indicators of rest–activity rhythms, 25 out of 35 comparisons were significantly correlated. The present results indicate that ambient bright light treatment did not improve rest–activity rhythms for people with dementia. Full article
(This article belongs to the Section Disorders)
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Brief Report
Consecutive Nights of Moderate Sleep Loss Does Not Affect Mood in Healthy Young Males
Clocks & Sleep 2021, 3(3), 442-448; https://doi.org/10.3390/clockssleep3030031 - 20 Aug 2021
Viewed by 1181
Abstract
Sleep loss causes mood disturbance in non-clinical populations under severe conditions, i.e., two days/nights of sleep deprivation or a week of sleep restriction with 4–5 h in bed each night. However, the effects of more-common types of sleep loss on mood disturbance are [...] Read more.
Sleep loss causes mood disturbance in non-clinical populations under severe conditions, i.e., two days/nights of sleep deprivation or a week of sleep restriction with 4–5 h in bed each night. However, the effects of more-common types of sleep loss on mood disturbance are not yet known. Therefore, the aim of this study was to examine mood disturbance in healthy adults over a week with nightly time in bed controlled at 5, 6, 7, 8 or 9 h. Participants (n = 115) spent nine nights in the laboratory and were given either 5, 6, 7, 8 or 9 h in bed over seven consecutive nights. Mood was assessed daily using the Profile of Mood States (POMS-2). Mixed-linear effects models examined the effect of time in bed on total mood disturbance and subscales of anger-hostility, confusion-bewilderment, depression-dejection, fatigue-inertia, tension-anxiety, vigour-activity and friendliness. There was no effect of time in bed on total mood disturbance (F(4, 110.42) = 1.31, p = 0.271) or any of the subscales except fatigue-inertia. Fatigue-inertia was higher in the 5 h compared with the 9 h time in bed condition (p = 0.012, d = 0.75). Consecutive nights of moderate sleep loss (i.e., 5–7 h) does not affect mood but does increase fatigue in healthy males. Full article
(This article belongs to the Special Issue Sleep, Rhythms, and Mental Health)
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Article
Chronobiotics KL001 and KS15 Extend Lifespan and Modify Circadian Rhythms of Drosophila melanogaster
Clocks & Sleep 2021, 3(3), 429-441; https://doi.org/10.3390/clockssleep3030030 - 20 Aug 2021
Cited by 1 | Viewed by 1254
Abstract
Chronobiotics are a group of drugs, which are utilized to modify circadian rhythms targeting clock-associated molecular mechanisms. The circadian clock is known as a controller of numerous processes in connection with aging. Hypothesis: KL001 and KS15 targeting CRY, affect lifespan, locomotor activity and [...] Read more.
Chronobiotics are a group of drugs, which are utilized to modify circadian rhythms targeting clock-associated molecular mechanisms. The circadian clock is known as a controller of numerous processes in connection with aging. Hypothesis: KL001 and KS15 targeting CRY, affect lifespan, locomotor activity and circadian rhythm of Drosophila melanogaster. We observed a slight (2%, p < 0.001) geroprotective effect on median lifespan (5 µM solution of KL001 in 0.1% DMSO) and a 14% increase in maximum lifespan in the same group. KS15 10 µM solution extended males’ median lifespan by 8% (p < 0.05). The statistically significant positive effects of KL001 and KS15 on lifespan were not observed in female flies. KL001 5 µM solution improved locomotor activity in young male imagoes (p < 0.05), elevated morning activity peak in aged imagoes and modified robustness of their circadian rhythms, leaving the period intact. KS15 10 µM solution decreased the locomotor activity in constant darkness and minimized the number of rhythmic flies. KL001 5 µM solution improved by 9% the mean starvation resistance in male flies (p < 0.01), while median resistance was elevated by 50% (p < 0.0001). This phenomenon may suggest the presence of the mechanism associated with improvement of fat body glucose depos’ utilization in starvation conditions which is activated by dCRY binding KL001. Full article
(This article belongs to the Section Animal Basic Research)
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Article
Seasonal Changes in Sleep Patterns in Two Saskatchewan First Nation Communities
Clocks & Sleep 2021, 3(3), 415-428; https://doi.org/10.3390/clockssleep3030029 - 11 Aug 2021
Viewed by 1202
Abstract
Sleep is crucial for maintaining the recovery and restoration of the body and brain. Less sleep is associated with poor mental and physical performance. Seasonal changes in sleep patterns can be observed. This paper examines seasonal effects on sleep timing, duration, and problems [...] Read more.
Sleep is crucial for maintaining the recovery and restoration of the body and brain. Less sleep is associated with poor mental and physical performance. Seasonal changes in sleep patterns can be observed. This paper examines seasonal effects on sleep timing, duration, and problems in two Cree First Nation communities in Saskatchewan, Canada. Data were available from a community survey of 588 adults aged 18 years and older (range: 18–78 years) with 44.2% males and 55.8% females. Results are presented using descriptive statistics and a binary logistic-regression model to identify the association between seasonal changes in sleep patterns, and demographic, social, and environmental factors. The participants reported sleeping the least during the spring and summer months and sleeping the most during the fall and winter months. This was further confirmed by sleep hours and the lower proportion of recommended hours of sleep during the spring and summer, and a higher proportion of longer sleep duration during the fall and winter months. There was no significant variation in sleeping onset and wake-up times by season. Overall, there were no significant differences in the prevalence of sleep deprivation, insomnia, and excessive daytime sleepiness by season. When stratified by age group and sex, some differences existed in the prevalence of sleep problems by season. More than two-thirds (68.6%) of the participants reported that there was a change in sleep patterns across seasons, and about 26.0% reported a very or extremely marked change in sleep patterns across seasons. Changes in sleep patterns by season were related to money left at the end of the month and damage caused by dampness in the house. Full article
(This article belongs to the Section Society)
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Article
Use of Actigraphy for a Rat Behavioural Sleep Study
Clocks & Sleep 2021, 3(3), 409-414; https://doi.org/10.3390/clockssleep3030028 - 02 Aug 2021
Viewed by 1041
Abstract
Previous studies of animal behavioural sleep is mainly divided into two study types, observation by video recording or counts by sensor, both of which require a complex environment and procedure. An actigraph unit is a commercially available product which can provide non-invasive monitoring [...] Read more.
Previous studies of animal behavioural sleep is mainly divided into two study types, observation by video recording or counts by sensor, both of which require a complex environment and procedure. An actigraph unit is a commercially available product which can provide non-invasive monitoring human rest/activity cycles. The goal of this study was to evaluate whether actigraphy can be applied for analysing behavioural sleep in rats, since no reports have described utilization of the actigraphy unit for monitoring sleep of small animals. The actigraph unit was held on the chest of eight male rats by a loose elastic belt. The rats spent two days in a normal condition, followed by two days of sleep deprivation. Total counts measured by the actigraph could be clearly divided into two phases, sleep phase and awake phase, when the rats were kept in the normal cage. Next, the rats were moved into the sleep-deviation cage, and the total counts were significantly higher during daytime, indicating the successful induction of sleep deprivation. These results showed that the actigraphy unit monitored rest/activity cycles of rats, which will contribute to making sleep behaviour experiments easier. Full article
(This article belongs to the Section Animal Basic Research)
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Review
Dream Recall/Affect and the Hypothalamic–Pituitary–Adrenal Axis
Clocks & Sleep 2021, 3(3), 403-408; https://doi.org/10.3390/clockssleep3030027 - 22 Jul 2021
Cited by 1 | Viewed by 1370
Abstract
In this concise review, we present an overview of research on dream recall/affect and of the hypothalamic–pituitary–adrenal (HPA) axis, discussing caveats regarding the action of hormones of the HPA axis (mainly cortisol and its free form, cortisol-binding globulin and glucocorticoid receptors). We present [...] Read more.
In this concise review, we present an overview of research on dream recall/affect and of the hypothalamic–pituitary–adrenal (HPA) axis, discussing caveats regarding the action of hormones of the HPA axis (mainly cortisol and its free form, cortisol-binding globulin and glucocorticoid receptors). We present results of studies regarding dream recall/affect and the HPA axis under physiological (such as waking) or pathological conditions (such as in Cushing’s syndrome or stressful situations). Finally, we try to integrate the effect of the current COVID-19 situation with dream recall/affect vis-à-vis the HPA axis. Full article
(This article belongs to the Special Issue Dream and Sleep)
Reply
Reply to Bracke et al. Comment on “Prayag et al. Light Modulation of Human Clocks, Wake, and Sleep. Clocks&Sleep 2019, 1, 193–208”
Clocks & Sleep 2021, 3(3), 398-402; https://doi.org/10.3390/clockssleep3030026 - 05 Jul 2021
Cited by 1 | Viewed by 1286
Abstract
We thank Bracke and colleagues [...] Full article
(This article belongs to the Section Impact of Light & other Zeitgebers)
Article
Habitual Sleep Duration and the Colonic Mucosa-Associated Gut Microbiota in Humans—A Pilot Study
Clocks & Sleep 2021, 3(3), 387-397; https://doi.org/10.3390/clockssleep3030025 - 01 Jul 2021
Cited by 7 | Viewed by 1579
Abstract
We examined the association between the colonic adherent microbiota and nocturnal sleep duration in humans. In a cross-sectional study, 63 polyp-free adults underwent a colonoscopy and donated 206 mucosal biopsies. The gut microbiota was profiled using the 16S rRNA gene sequencing targeting the [...] Read more.
We examined the association between the colonic adherent microbiota and nocturnal sleep duration in humans. In a cross-sectional study, 63 polyp-free adults underwent a colonoscopy and donated 206 mucosal biopsies. The gut microbiota was profiled using the 16S rRNA gene sequencing targeting the V4 region. The sequence reads were processed using UPARSE and DADA2, respectively. Lifestyle factors, including sleep habits, were obtained using an interviewer-administered questionnaire. We categorized the participants into short sleepers (<6 h per night; n = 16) and normal sleepers (6–8 h per night; n = 47) based on self-reported data. Differences in bacterial biodiversity and the taxonomic relative abundance were compared between short vs. normal sleepers, followed by multivariable analysis. A false discovery rate-adjusted p value (q value) < 0.05 indicated statistical significance. The bacterial community composition differed in short and normal sleepers. The relative abundance of Sutterella was significantly lower (0.38% vs. 1.25%) and that of Pseudomonas was significantly higher (0.14% vs. 0.08%) in short sleepers than in normal sleepers (q values < 0.01). The difference was confirmed in the multivariable analysis. Nocturnal sleep duration was associated with the bacterial community composition and structure in the colonic gut microbiota in adults. Full article
(This article belongs to the Section Human Basic Research & Neuroimaging)
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Article
No Effect of Chronotype on Sleepiness, Alertness, and Sustained Attention during a Single Night Shift
Clocks & Sleep 2021, 3(3), 377-386; https://doi.org/10.3390/clockssleep3030024 - 01 Jul 2021
Viewed by 1212
Abstract
The study’s aim was to examine the effect of chronotype on cognitive performance during a single night shift. Data were collected from 72 (36f) young, healthy adults in a laboratory study. Participants had a 9 h sleep period (03:00–12:00) followed by an 8 [...] Read more.
The study’s aim was to examine the effect of chronotype on cognitive performance during a single night shift. Data were collected from 72 (36f) young, healthy adults in a laboratory study. Participants had a 9 h sleep period (03:00–12:00) followed by an 8 h night shift (23:00–07:00). During the night shift, participants completed five test sessions, which included measures of subjective sleepiness, subjective alertness, and sustained attention (i.e., psychomotor vigilance task; PVT). Dim light melatonin onset (DLMO) was derived from saliva samples taken during the evening preceding the night shift. A tertile split of DLMO was used to determine three chronotype categories: earlier (DLMO = 20:22 ± 0:42), intermediate (DLMO = 21:31 ± 0:13), and later (DLMO = 22:54 ± 0:54). There were (a) significant main effects of test session (all p < 0.001); (b) no main effects of chronotype; and (c) no interaction effects between chronotype and test session on sleepiness, alertness, PVT response time, and PVT lapses. The results indicate that under controlled sleeping conditions, chronotype based on dim light melatonin onset did not affect nighttime performance. Differences in performance during night shift between chronotypes reported by field studies may be related to differences in the amount and/or timing of sleep before or between night shifts, rather than circadian timing. Full article
(This article belongs to the Special Issue Shift-Work and the Individual)
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Article
A Pilot Study of 24-h Motor Activity Patterns in Multiple Sclerosis: Pre-Planned Follow-Up at 2 Years
Clocks & Sleep 2021, 3(3), 366-376; https://doi.org/10.3390/clockssleep3030023 - 28 Jun 2021
Viewed by 830
Abstract
Early multiple sclerosis (MS) predictive markers of disease activity/prognosis have been proposed but are not universally accepted. Aim of this pilot prospective study is to verify whether a peculiar hyperactivity, observed at baseline (T0) in early relapsing-remitting (RR) MS patients, could represent a [...] Read more.
Early multiple sclerosis (MS) predictive markers of disease activity/prognosis have been proposed but are not universally accepted. Aim of this pilot prospective study is to verify whether a peculiar hyperactivity, observed at baseline (T0) in early relapsing-remitting (RR) MS patients, could represent a further prognostic marker. Here we report results collected at T0 and at a 24-month follow-up (T1). Eighteen RRMS patients (11 females, median Expanded Disability Status Scale-EDSS score 1.25, range EDSS score 0–2) were monitored at T0 (mean age 32.33 ± 7.51) and T1 (median EDSS score 1.5, range EDSS score 0–2.5). Patients were grouped into two groups: responders (R, 14 patients) and non-responders (NR, 4 patients) to treatment at T1. Each patient wore an actigraph for one week to record the 24-h motor activity pattern. At T0, NR presented significantly lower motor activity than R between around 9:00 and 13:00. At T1, NR were characterized by significantly lower motor activity than R between around 12:00 and 17:00. Overall, these data suggest that through the 24-h motor activity pattern, we can fairly segregate at T0 patients who will show a therapeutic failure, possibly related to a more active disease, at T1. These patients are characterized by a reduced morning level of motor activation. Further studies on larger populations are needed to confirm these preliminary findings. Full article
(This article belongs to the Section Disorders)
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Article
Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine
Clocks & Sleep 2021, 3(3), 351-365; https://doi.org/10.3390/clockssleep3030022 - 22 Jun 2021
Cited by 4 | Viewed by 1078
Abstract
Dysregulated circadian functions contribute to various diseases, including cardiovascular disease. Much progress has been made on chronotherapeutic applications of drugs against cardiovascular disease (CVD); however, the direct effects of various medications on the circadian system are not well characterized. We previously conducted high-throughput [...] Read more.
Dysregulated circadian functions contribute to various diseases, including cardiovascular disease. Much progress has been made on chronotherapeutic applications of drugs against cardiovascular disease (CVD); however, the direct effects of various medications on the circadian system are not well characterized. We previously conducted high-throughput chemical screening for clock modulators and identified an off-patent anti-arrhythmic drug, moricizine, as a clock-period lengthening compound. In Per2:LucSV reporter fibroblast cells, we showed that under both dexamethasone and forskolin synchronization, moricizine was able to increase the circadian period length, with greater effects seen with the former. Titration studies revealed a dose-dependent effect of moricizine to lengthen the period. In contrast, flecainide, another Class I anti-arrhythmic, showed no effects on circadian reporter rhythms. Real-time qPCR analysis in fibroblast cells treated with moricizine revealed significant circadian time- and/or treatment-dependent expression changes in core clock genes, consistent with the above period-lengthening effects. Several clock-controlled cardiac channel genes also displayed altered expression patterns. Using tissue explant culture, we showed that moricizine was able to significantly prolong the period length of circadian reporter rhythms in atrial ex vivo cultures. Using wild-type C57BL/6J mice, moricizine treatment was found to promote sleep, alter circadian gene expression in the heart, and show a slight trend of increasing free-running periods. Together, these observations demonstrate novel clock-modulating activities of moricizine, particularly the period-lengthening effects on cellular oscillators, which may have clinical relevance against heart diseases. Full article
(This article belongs to the Special Issue Role of Sleep and Circadian Rhythms in Health)
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