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Natural light exposure both in flux and spectrum is essential to human health due to its direct relationship with circadian rhythms. Given that light affects visual performance and circadian rhythms differently, metrics need to assess them independently. The aim of this research is to present a new parametric workflow to integrate metrics quantifying the effect of light on circadian rhythm. CircaLight is a new open-source tool for Rhino environment developed as a plugin for Grasshopper. This software enables the calculation of different metrics that quantify the effect of light, both natural and electric, on circadian rhythms, considering the influence of the spectral reflectance of inner surfaces. The CircaLight components can be integrated into Grasshopper plugins such as Solemma or Ladybug tools providing information about the Circadian Stimulus, the Equivalent Melanopic Lux and the Melanopic Photopic ratio, all of which provide current metrics related with circadian rhythms. This research evaluates the reliability of the software presented, quantifying its accuracy by means of other validated software. The results show the accuracy of this new parametric tool with an error under ±10% even in the most unfavorable scenarios.

Polyphenols play a key role in the modulation of circadian rhythms, while the cafeteria diet (CAF) is able to perturb the hepatic biological rhythm and induce important ROS production. Consequently, we aimed to elucidate whether grape seed proanthocyanidin extract (GSPE) administration recovers the CAF-induced hepatic antioxidant (AOX) misalignment and characterize the chronotherapeutic properties of GSPE. For this purpose, Fischer 344 rats were fed a standard diet (STD) or a CAF and concomitantly treated with GSPE at two time-points (ZT0 vs. ZT12). Animals were euthanized every 6 h and the diurnal rhythms of hepatic ROS-related biomarkers, hepatic metabolites, and AOX gene expression were examined. Interestingly, GSPE treatment was able to recover the diurnal rhythm lost due to the CAF. Moreover, GSPE treatment also increased the acrophase of Sod1, as well as bringing the peak closer to that of the STD group. GSPE also corrected some hepatic metabolites altered by the CAF. Importantly, the differences observed at ZT0 vs. ZT12 due to the time of GSPE administration highlight a chronotherapeutic profile on the proanthocyanin effect. Finally, GSPE could also reduce diet-induced hepatic oxidative stress not only by its ROS-scavenging properties but also by retraining the circadian rhythm of AOX enzymes.

Time-restricted feeding (TRF) is a dietary intervention that limits food intake within 8-10 hours of the active phase. For mice, it has been shown to protect from metabolic disease, as well as reduce damage and inflammation in the context of chronic illnesses. The alignment of feeding with underlying circadian rhythms optimizes the time for when tissues are metabolically active versus undergoing repair and maintenance. Using sequencing and mass spectrometry, we have curated a unique timeseries dataset of male and female mice fed a Western high-fat diet undergoing TRF. Physiologically, male and female mice responded similarly to TRF by reducing hepatic lipid storage and improve glucose tolerance, however females were not protected from gaining fat mass. Improvements to motor coordination was only observed in male mice as well. Moreover, organizing a multi- tissue and multi- omics response to TRF has highlighted that males respond more than females to temporal restrictions in feeding but the curious effect of increasing rhythmicity is observed in both sexes. Furthermore, the question of hormonal differences in females due to the estrous cycle presents another avenue to be explored, as estrogen has been implicated in protections from metabolic diseases as well. To do so, we examined differences in female transcriptome across the peak (proestrus) and trough (metestrus) of the estrous cycle. Not surprisingly, reproductive tissues such as the uterus respond more greatly than metabolic tissues like the liver to different stages of the hormonal profiles. However, the liver does seem to prioritize certain metabolic states according to the stage of the estrous cycle. Utilizing high-fat diet as a challenge, we observe that diet induces transcriptomic differences at specific stages of the estrous cycle, resulting in chronic disruption of estrous- regulated processes and eventual disruption of the reproductive cycle. In applying TRF, females on high- fat diet were observed to re

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

Scope: Polymethoxylated flavones (PMFs) are a group of natural compounds known to display a wide array of beneficial effects to promote physiological fitness. Recent studies revealed circadian clocks as an important cellular mechanism mediating preventive efficacy of the major PMF Nobiletin against metabolic disorders. Sudachitin is a PMF enriched in Citrus sudachi, and its functions and mechanism of action are poorly understood. Methods and Results: Using circadian reporter cells, we showed that Sudachitin modulated circadian amplitude and period of Bmal1 promoter-driven reporter rhythms, and real-time qPCR analysis showed that Sudachitin altered expression of core clock genes, notably Bmal1, at both transcript and protein levels. Mass-spec analysis revealed systemic exposure in vivo. In mice fed with high-fat diet with or without Sudachitin, we observed increased nighttime activity and daytime sleep, accompanied by significant metabolic improvements in a circadian time-dependent manner, including respiratory quotient, blood lipid and glucose profiles and liver physiology. Focusing on liver, RNA-sequencing and metabolomic analyses revealed prevalent diurnal alteration in both gene expression and metabolite accumulation. Conclusion: Our study elucidates Sudachitin as a new clock-modulating PMF with beneficial effects to to improve diurnal metabolic homeostasis and liver physiology, suggesting the circadian clock as a fundamental mechanism to safeguard physiological well-being.

Polyphenols play a key role in the modulation of circadian rhythms, while the cafeteria diet (CAF) is able to perturb the hepatic biological rhythm and induce important ROS production. Consequently, we aimed to elucidate whether grape seed proanthocyanidin extract (GSPE) administration recovers the CAF-induced hepatic antioxidant (AOX) misalignment and characterize the chronotherapeutic properties of GSPE. For this purpose, Fischer 344 rats were fed a standard diet (STD) or a CAF and concomitantly treated with GSPE at two time-points (ZT0 vs. ZT12). Animals were euthanized every 6 h and the diurnal rhythms of hepatic ROS-related biomarkers, hepatic metabolites, and AOX gene expression were examined. Interestingly, GSPE treatment was able to recover the diurnal rhythm lost due to the CAF. Moreover, GSPE treatment also increased the acrophase of Sod1, as well as bringing the peak closer to that of the STD group. GSPE also corrected some hepatic metabolites altered by the CAF. Importantly, the differences observed at ZT0 vs. ZT12 due to the time of GSPE administration highlight a chronotherapeutic profile on the proanthocyanin effect. Finally, GSPE could also reduce diet-induced hepatic oxidative stress not only by its ROS-scavenging properties but also by retraining the circadian rhythm of AOX enzymes.

Background Sleep irregularity has been linked to incident cardiovascular disease. Less is known about associations of sleep regularity with atherosclerosis. We examined cross-sectional associations of actigraphy-assessed sleep duration and sleep timing regularity with subclinical atherosclerosis in the community-based MESA (Multi-Ethnic Study of Atherosclerosis). Methods and Results MESA Sleep Ancillary Study participants (N=2032; mean age, 68.6±9.2 years; 37.9% White) completed 7-day wrist actigraphy. Participants underwent assessments of coronary artery calcium, carotid plaque presence, carotid intima-media thickness, and the ankle-brachial index. Sleep regularity was quantified by the 7-day with-in person SD of sleep duration and sleep onset timing. Relative risk regression models were used to calculate prevalence ratios and 95% CIs. Models are adjusted for demographics, cardiovascular disease risk factors, and other objectively assessed sleep characteristics including obstructive sleep apnea, sleep duration, and sleep fragmentation. After adjustment, compared with participants with more regular sleep durations (SD ≤60 minutes), participants with greater sleep duration irregularity (SD >120 minutes) were more likely to have high coronary artery calcium burden (>300; prevalence ratio, 1.33 [95% CI, 1.03-1.71]) and abnormal ankle-brachial index (<0.9; prevalence ratio, 1.75 [95% CI, 1.03-2.95]). Compared with participants with more regular sleep timing (SD ≤30 minutes), participants with irregular sleep timing (SD >90 minutes) were more likely to have high coronary artery calcium burden (prevalence ratio, 1.39 [95% CI, 1.07-1.82]). Associations persisted after adjustment for cardiovascular disease risk factors and average sleep duration, obstructive sleep apnea, and sleep fragmentation. Conclusions Sleep irregularity, particularly sleep duration irregularity, was associated with several measures of subclinical atherosclerosis. Sleep regularity may be a

From the very beginning of evolution on, virtually all life forms have developed in an environment where light intensity and temperature cycled at a rate of about 24h. It is therefore not surprising that rhythms of about 24h, i.e., circadian, are integrated in all processes of life, including gene expression, the biochemical processes in a cell, the complex physiology of an organism, its behavior and cognition. A complex system comprising central autonomous oscillators and peripheral slaved damped oscillators is responsible for this circadian modulation of our bodily functions, and is described in detail in other parts of this Encyclopedia. Sleep is one of the states that is under control of the body clock system; sleep is most likely to occur within a specified phase range of the circadian cycle. Homeostasis is the second important factor involved in sleep regulation; the need for sleep increases with the duration of wakefulness. The circadian and homeostatic regulatory systems interact to concertedly regulate the timing of sleep and wakefulness. With increasing age, cracks may start to appear in the functionality of this complex interacting system. For human sleep, this can result in a decreased ability to maintain uninterrupted sleep during the night and an increased probability for napping during the day. Sleep complaints indeed increase with age and are among the most disturbing subjectively judged consequences of getting older. At present, satisfactory pharmacological interventions to improve the sleep–wake rhythm on a daily basis are lacking. The present paper addresses the question whether the human sleep-wake rhythm is still sensitive to its evolutionary oldest environmental modulators or “Zeitgebers”: light and temperature. The focus moreover is on their capacity to support the sleep–wake rhythm of elderly people on a daily basis.

Virtually all organisms exhibit circadian rhythms, this includes mosquitoes. Many aspects of their biology are under the control of their circadian clocks like their vision, olfaction, host-seeking, mating, oviposition, metabolism, locomotion, and more. However, how the circadian clock regulates mosquito-host interactions and adapts to specific environmental conditions remains largely unknown, despite its importance to vector disease control. Here, we relied on a multidisciplinary, integrative, and comparative approach to shed light on the mechanisms underlying mosquitoes adaptations to various temporal niches. We use CRISPR/Cas9 to knockout timeless in Aedes aegypti and show this mutation causes an increase in their free running periods under continuous darkness conditions. External factors can also influence a vector's activity pattern like climate, light pollution, as well as host preference and availability. To investigate the influence these factors have on activity patterns, we compare the activity patterns of multiple lab rear strains of Aedes albopictus as well as two field collected populations of Aedes japonicus. Our results suggest host availability and light pollution could cause the differences in activity profiles that we observed. With vision playing an important role in both circadian rhythms, host seeking, and threat detection, we compared a nocturnal mosquito (Aedes japonicus) and a diurnal mosquito (Aedes aegypti). We introduced a looming visual stimulus in an LED arena and found Aedes aegypti to be more responsive to the looming stimulus than Aedes japonicus. Finally, the underlying mechanisms that mediate this threat detection and escape behavior were examined, revealing a possible candidate for a giant fiber neuron in Aedes aegypti. Overall these results provide novel insights into mosquito biology that have the potential to be applied towards vector control methods.

N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-quinone) is a degradation product of 6PPD, an antioxidant widely used in rubber tires. 6PPD-quinone enters aquatic ecosystems through urban stormwater runoff and has been identified as the chemical behind the urban runoff mortality syndrome in coho salmon. However, the available data suggest that the acute effects of 6PPD-quinone are restricted to a few salmonid species and that the environmental levels of this chemical should be safe for most fish. In this study, larvae of a "tolerant" fish species, Danio rerio, were exposed to three environmental concentrations of 6PPD-quinone for only 24 h, and the effects on exploratory behavior, escape response, nonassociative learning (habituation), neurotransmitter profile, wake/sleep cycle, circadian rhythm, heart rate and oxygen consumption rate were analyzed. Exposure to the two lowest concentrations of 6PPD-quinone resulted in altered exploratory behavior and habituation, an effect consistent with some of the observed changes in the neurotransmitter profile, including increased levels of acetylcholine, norepinephrine, epinephrine and serotonin. Moreover, exposure to the highest concentration tested altered the wake/sleep cycle and the expression of per1a, per3 and cry3a, circadian clock genes involved in the negative feedback loop. Finally, a positive chronotropic effect of 6PPD-quinone was observed in the hearts of the exposed fish. The results of this study emphasize the need for further studies analyzing the effects of 6PPD-quinone in "tolerant" fish species.

Scope: Polymethoxylated flavones (PMFs) are a group of natural compounds known to display a wide array of beneficial effects to promote physiological fitness. Recent studies revealed circadian clocks as an important cellular mechanism mediating preventive efficacy of the major PMF Nobiletin against metabolic disorders. Sudachitin is a PMF enriched in Citrus sudachi, and its functions and mechanism of action are poorly understood. Methods and Results: Using circadian reporter cells, we showed that Sudachitin modulated circadian amplitude and period of Bmal1 promoter-driven reporter rhythms, and real-time qPCR analysis showed that Sudachitin altered expression of core clock genes, notably Bmal1, at both transcript and protein levels. Mass-spec analysis revealed systemic exposure in vivo. In mice fed with high-fat diet with or without Sudachitin, we observed increased nighttime activity and daytime sleep, accompanied by significant metabolic improvements in a circadian time-dependent manner, including respiratory quotient, blood lipid and glucose profiles and liver physiology. Focusing on liver, RNA-sequencing and metabolomic analyses revealed prevalent diurnal alteration in both gene expression and metabolite accumulation. Conclusion: Our study elucidates Sudachitin as a new clock-modulating PMF with beneficial effects to to improve diurnal metabolic homeostasis and liver physiology, suggesting the circadian clock as a fundamental mechanism to safeguard physiological well-being.

Melatonin is a hormone responsible for regulating an organism's biological clock located in their brain. Meanwhile, exogenous melatonin can alter their sleep-wake cycle. Previous studies conducted on invertebrates found that exogenous melatonin impairs their locomotion (Yamano et al., 2001). However, the effect of melatonin on invertebrate species, specifically ants, has rarely been explored. We aimed to study the relationship between melatonin and ant locomotion and the role melatonin plays in ant circadian rhythm. We administered melatonin, ramelteon, a melatonin agonist, and luzindole, a melatonin antagonist, to different groups of Camponotus floridanus to explore the impact of exogenous melatonin on ants. We found that exogenous melatonin decreased the locomotion of ants by decreasing the ants' velocity and total distance traveled. The administration of melatonin also impacted the ants' circadian rhythm by making them more lethargic throughout a 24-hour cycle. Surprisingly, ramelteon, a vertebrate melatonin agonist, had the opposite effect. These results suggest that the use of exogenous melatonin hinders ants on an individual and societal level.

Every day, we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately nine million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children, and although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer-related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE), and perfluorooctanoic acid (PFOA) alter vincristine treatment in ALL when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on ALL cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments.

Every human body has a biological rhythm that can adapt to the environment through light exposure, food intake and exercise. When our biological rhythm is disrupted regularly, for example due to night shifts, this can lead to the development of type 2 diabetes. This thesis investigated the metabolic health effects of adjusting the timing of exercise and food intake to the biological rhythm. The thesis showed that advancing the evening meal and thereby extending the fasting period can increase night time fat oxidation in both healthy people and people at risk for type 2 diabetes. In people with type 2 diabetes, the 24-hour glucose levels and fasting glucose levels of participants with type 2 diabetes improved after they restricted their food intake to a period of 10 hours per day for 3 weeks. SGLT-2 inhibitors (a type of medication) can also cause the body to fast more, as it leads to extra urinary glucose loss. Treatment with this medication increased fat oxidation and lowered 24-hour glucose levels in participants at risk for type 2 diabetes. Furthermore, it turned out that the 24-hour rhythm in fat and glucose oxidation, but not in energy expenditure, depended on food intake. So for our metabolism it matters at what time of day we eat and especially how long we fast.

Every day, we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately nine million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children, and although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer-related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE), and perfluorooctanoic acid (PFOA) alter vincristine treatment in ALL when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on ALL cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments.

Every day, we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately nine million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children, and although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer-related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE), and perfluorooctanoic acid (PFOA) alter vincristine treatment in ALL when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on ALL cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments.

Every day, we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately nine million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children, and although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer-related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE), and perfluorooctanoic acid (PFOA) alter vincristine treatment in ALL when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on ALL cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments.

Every day, we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately nine million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children, and although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer-related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE), and perfluorooctanoic acid (PFOA) alter vincristine treatment in ALL when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on ALL cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments.

Some designs for bioregenerative life support systems to enable human space missions incorporate cyanobacteria for removal of carbon dioxide, generation of oxygen, and treatment of wastewater, as well as providing a source of nutrition. In this study, we examined the effects of the short light-dark (LD) cycle of low-Earth orbit on algal and cyanobacterial growth, approximating conditions on the International Space Station, which orbits Earth roughly every 90 min. We found that growth of green algae was similar in both normal 12 h light:12 h dark (12 h:12 h LD) and 45':45' LD cycles. Three diverse strains of cyanobacteria were not only capable of growth in short 45':45' LD cycles, but actually grew better than in 12 h:12 h LD cycles. We showed that 45':45' LD cycles do not affect the endogenous 24 h circadian rhythms of Synechococcus elongatus. Using a dense library of randomly barcoded transposon mutants, we identified genes whose loss is detrimental for the growth of S. elongatus under 45':45' LD cycles. These include several genes involved in glycogen metabolism and the oxidative pentose phosphate pathway. Notably, 45':45' LD cycles did not affect the fitness of strains that carry mutations in the biological circadian oscillator or the clock input and output regulatory pathways. Overall, this study shows that cultures of cyanobacteria could be grown under natural sunlight of low-Earth orbit and highlights the utility of a functional genomic study in a model organism to better understand key biological processes in conditions that are relevant to space travel.

There are numerous applications for deep learning in a healthcare setting including: providing more accurate diagnoses, recommending treatment plans, predicting patient outcomes, tracking patient engagement and adherence, and reducing the burden of administrative tasks. This plethora of applications has resulted in the widespread publication of deep learning algorithms applied to healthcare data. Despite numerous publications showing deep learning to be very successful in retrospective healthcare studies, very few of these algorithms are then actually incorporated into clinical practice. While there are many factors influencing the lack of algorithm deployment, one of the major reasons is a lack of trust in deep learning. This lack of trust stems in part from a lack of model interpretability and an inability to independently verify published results due to a lack of data availability. In this work, we explore generalized additive models with neural networks (GAM-NNs) as a method of improving model interpretability and we propose MOVER: Medical Informatics Operating Room Vi- tals and Events Repository a publicly available repository of medical data designed to improve visibility into deep learning algorithms in healthcare.Similarly, deep learning can be used to analyze circadian omic (e.g. transcriptomic, metabolomic, proteomic) time series data. Several studies have shown that a disruption to circadian rhythms have been linked to health problems such as cancer, diabetes, obesity, and premature aging. In order to gain clinician trust in the conclusions drawn from circadian omic analyses we propose CircadiOmics: the largest annotated repository of circadian omic time series data analyzed using deep learning. Clinicians and researchers can use CircadiOmics to not only validate the findings of their circadian omic experiments, but also to analyze multiple circadian omic experiments in aggregate.

The study of circadian rhythms in the human body using temperature measurements is the most informative way to assess the viability of the body’s rhythm-organizing systems. Pathological processes can affect circadian rhythm dynamics in damaged organs. Severe brain damage that caused the development of disorders of consciousness (DOC) (strokes, traumatic brain injury) disrupts the activity of central oscillators, by directly damaging or destroying the periphery links, and the level of preservation of circadian rhythms and the dynamics of their recovery can be informative diagnostic criteria for patient’s condition assessment. This study examined 23 patients with DOC by using a non-invasive method for obtaining body and cerebral cortex temperature to compare with healthy controls. Measurements were made with a 4 h interval for 52 h beginning at 08:00 on day 1 and ending at 08:00 on day 3. The profile of patients with DOC showed complete disruption compared to healthy controls with rhythmic patterns. The results indicate that the mechanisms for maintaining brain circadian rhythms are different from general homeostasis regulation of the body. Use of microwave radio thermometry for the identification of rehabilitation potential in patients with DOC is a promising area of investigation., source:https://www.mdpi.com/2075-4418/12/8/1777

Background: Light exposure is an important driver and modulator of human physiology, behavior and overall health, including the biological clock, sleep-wake cycles, mood and alertness. Light can also be used as a directed intervention, e.g., in the form of light therapy in seasonal affective disorder (SAD), jetlag prevention and treatment, or to treat circadian disorders. Recently, a system of quantities and units related to the physiological effects of light was standardized by the International Commission on Illumination (CIE S 026/E:2018). At the same time, biometric monitoring technologies (BioMeTs) to capture personalized light exposure were developed. However, because there are currently no standard approaches to evaluate the digital dosimeters, the need to provide a firm framework for the characterization, calibration, and reporting for these digital sensors is urgent. Objective: This article provides such a framework by applying the principles of verification, analytic validation and clinical validation (V3) as a state-of-the-art approach for tools and standards in digital medicine to light dosimetry. Results: This article describes opportunities for the use of digital dosimeters for basic research, for monitoring light exposure, and for measuring adherence in both clinical and non-clinical populations to light-based interventions in clinical trials.

Sleep and circadian rhythms disturbances (SCRD) in young people at high risk or with early onset of bipolar disorders (BD) are poorly understood. We systematically searched for studies of self, observer or objective estimates of SCRD in asymptomatic or symptomatic offspring of parents with BD (OSBD), individuals with presentations meeting recognised BD-at-risk criteria (BAR) and youth with recent onset of full-threshold BD (FT-BD). Of 76 studies eligible for systematic review, 35 (46%) were included in random effects meta-analyses. Pooled analyses of self-ratings related to circadian rhythms demonstrated greater preference for eveningness and more dysregulation of social rhythms in BAR and FT-BD groups; analyses of actigraphy provided some support for these findings. Meta-analysis of prospective studies showed that pre-existing SCRD were associated with a 40% increased risk of onset of BD, but heterogeneity in assessments was a significant concern. Overall, we identified longer total sleep time (Hedges g: 0.34; 95% confidence intervals:.1, .57), especially in OSBD and FT-BD and meta-regression analysis indicated the effect sizes was moderated by the proportion of any sample manifesting psychopathology or receiving psychotropic medications. This evolving field of research would benefit from greater attention to circadian rhythm as well as sleep quality measures.

To survive and reproduce, a cell must process information from its environment and its own internal state and respond accordingly, in terms of metabolic activity, gene expression, movement, growth, division and differentiation. These signal-response decisions are made by complex networks of interacting genes and proteins, which function as biochemical switches and clocks, and other recognizable information-processing circuitry. This theme issue of Interface Focus (in two parts) brings together articles on time-keeping and decision-making in living cells-work that uses precise mathematical modelling of underlying molecular regulatory networks to understand important features of cell physiology. Part I focuses on time-keeping: mechanisms and dynamics of biological oscillators and modes of synchronization and entrainment of oscillators, with special attention to circadian clocks.

Long non-coding RNAs (lncRNAs) are a new class of regulatory RNAs that play important roles in disease development and a variety of biological processes. Recent studies have underscored the importance of lncRNAs in the circadian clock system and demonstrated that lncRNAs regulate core clock genes and the core clock machinery in mammals. In this review, we provide an overview of our current understanding of how lncRNAs regulate the circadian clock without coding a protein. We also offer additional insights into the challenges in understanding the functions of lncRNAs and other unresolved questions in the field. We do not cover other regulatory ncRNAs even though they also play important roles; readers are highly encouraged to refer to other excellent reviews on this topic.

Altered 24-hour rest-activity rhythms may be associated with cognitive impairment in older adults, but evidence from prospective studies is limited. Nonparametric methods were used to assess actigraphy-based activity patterns in 2 496 older men. Incident cognitive impairment was assessed 4 times over 12 years using the Modified Mini-Mental State Examination (3MS) and Trails B tests, self-reported medication use, and clinical diagnosis. The highest quartile (vs the lowest) of intradaily variability and the lowest quartiles (vs the highest) of interdaily stability and relative amplitude were associated with incident cognitive impairment (hazard ratio [95% confidence interval]: 1.82 [1.31-2.53], 1.36 [0.99-1.86], and 1.85 [1.33-2.56], respectively). A larger increase in intradaily variability over 7.5 years was associated with a greater subsequent decline in 3MS scores but not in Trails B performance. In conclusion, less stable and more variable rest-activity rhythms may represent early biomarkers of cognitive impairment in older men.

Ambient temperature varies constantly. However, the period of circadian pacemakers is remarkably stable over a wide-range of ecologically- and physiologically-relevant temperatures, even though the kinetics of most biochemical reactions accelerates as temperature rises. This thermal buffering phenomenon, called temperature compensation, is a critical feature of circadian rhythms, but how it is achieved remains elusive. Here, we uncovered the important role played by the Drosophila PERIOD (PER) phosphodegron in temperature compensation. This phosphorylation hotspot is crucial for PER proteasomal degradation and is the functional homolog of mammalian PER2 S478 phosphodegron, which also impacts temperature compensation. Using CRISPR-Cas9, we introduced a series of mutations that altered three Serines of the PER phosphodegron. While all three Serine to Alanine substitutions lengthened period at all temperatures tested, temperature compensation was differentially affected. S44A and S45A substitutions caused undercompensation, while S47A resulted in overcompensation. These results thus reveal unexpected functional heterogeneity of phosphodegron residues in thermal compensation. Furthermore, mutations impairing phosphorylation of the per s phosphocluster showed undercompensation, consistent with its inhibitory role on S47 phosphorylation. We observed that S47A substitution caused increased accumulation of hyper-phosphorylated PER at warmer temperatures. This finding was corroborated by cell culture assays in which S47A slowed down phosphorylation-dependent PER degradation at high temperatures, causing PER degradation to be excessively temperature-compensated. Thus, our results point to a novel role of the PER phosphodegron in temperature compensation through temperature-dependent modulation of the abundance of hyper-phosphorylated PER. Our work reveals interesting mechanistic convergences and differences between mammalian and Drosophila temperature compensation of the circ

Patients who have undergone hematopoietic stem cell transplant (HSCT) may experience cognitive impairment that can persist after treatment. Several studies have shown that bright light therapy may improve cognition, potentially due to its effects on the circadian system via brain regions that respond preferentially to light. In this double-blind randomized controlled trial, the efficacy of bright light therapy on cognition was examined in HSCT survivors. Forty-seven HSCT survivors at an urban hospital in the United States were screened for mild cognitive impairment, randomized to either bright white light (BWL) or comparison dim red light (DRL) conditions using a block randomization approach, and instructed to use their assigned light box every morning upon awakening for 30 min for 4 weeks. Assessments occurred at baseline, the end of the second week of the intervention, the end of the intervention, and at follow-up (8 weeks later). The primary outcome was objective cognitive function as measured by a global composite score on neuropsychological tests. Secondary outcomes included cognitive performance in individual domains, self-reported cognitive function, fatigue, sleep and sleep quality, and circadian rhythm robustness. Repeated-measures linear mixed models for both objective and self-reported cognitive function indicated significant main effects for time (ps < 0.05) suggesting significant improvements in both conditions over time. Time by light condition interaction effects were not significant. Models focused on secondary outcomes yielded no significant effects. Both BWL and DRL groups demonstrated significant improvements in objective cognitive and self-reported cognitive function over time, but there was no hypothesized effect of BWL over DRL nor associations with circadian rhythm robustness. Therapeutic effects of both light conditions, practice effects, and/or placebo effects may account for the findings.Trial registration: ClinicalTrials.gov Identifier

This review focuses on summarizing current knowledge on how time-restricted feeding (TRF) and continuous caloric restriction (CR) affect central neuroendocrine systems involved in regulating satiety. Several interconnected regions of the hypothalamus, brainstem, and cortical areas of the brain are involved in the regulation of satiety. Following CR and TRF, the increase in hunger and reduction in satiety signals of the melanocortin system [neuropeptide Y (NPY), proopiomelanocortin (POMC), and agouti-related peptide (AgRP)] appear similar between CR and TRF protocols, as do the dopaminergic responses in the mesocorticolimbic circuit. However, ghrelin and leptin signaling via the melanocortin system appears to improve energy balance signals and reduce hyperphagia following TRF, which has not been reported in CR. In addition to satiety systems, CR and TRF also influence circadian rhythms. CR influences the suprachiasmatic nucleus (SCN) or the primary circadian clock as seen by increased clock gene expression. In contrast, TRF appears to affect both the SCN and the peripheral clocks, as seen by phasic changes in the non-SCN (potentially the elusive food entrainable oscillator) and metabolic clocks. The peripheral clocks are influenced by the primary circadian clock but are also entrained by food timing, sleep timing, and other lifestyle parameters, which can supersede the metabolic processes that are regulated by the primary circadian clock. Taken together, TRF influences hunger/satiety, energy balance systems, and circadian rhythms, suggesting a role for adherence to CR in the long run if implemented using the TRF approach. However, these suggestions are based on only a few studies, and future investigations that use standardized protocols for the evaluation of the effect of these diet patterns (time, duration, meal composition, sufficiently powered) are necessary to verify these preliminary observations.

Animals display a body temperature rhythm (BTR). Little is known about the mechanisms by which a rhythmic pattern of BTR is regulated and how body temperature is set at different times of the day. As small ectotherms, Drosophila exhibit a daily temperature preference rhythm (TPR), which generates BTR. Here, we demonstrate dorsal clock networks that play essential roles in TPR. Dorsal neurons 2 (DN2s) are the main clock for TPR. We find that DN2s and posterior DN1s (DN1ps) contact and the extent of contacts increases during the day and that the silencing of DN2s or DN1ps leads to a lower temperature preference. The data suggest that temporal control of the microcircuit from DN2s to DN1ps contributes to TPR regulation. We also identify anterior DN1s (DN1as) as another important clock for TPR. Thus, we show that the DN networks predominantly control TPR and determine both a rhythmic pattern and preferred temperatures.

Long non-coding RNAs (lncRNAs) are a new class of regulatory RNAs that play important roles in disease development and a variety of biological processes. Recent studies have underscored the importance of lncRNAs in the circadian clock system and demonstrated that lncRNAs regulate core clock genes and the core clock machinery in mammals. In this review, we provide an overview of our current understanding of how lncRNAs regulate the circadian clock without coding a protein. We also offer additional insights into the challenges in understanding the functions of lncRNAs and other unresolved questions in the field. We do not cover other regulatory ncRNAs even though they also play important roles; readers are highly encouraged to refer to other excellent reviews on this topic.

Background: Age-related macular degeneration, a prevalent degenerative retinal disease, is associated with non-visual and psychosocial impairments that may affect sleep. In this systematic review, we evaluated associations between age-related macular degeneration (AMD) and sleep, highlighted knowledge gaps and provided evidence-based recommendations to clinicians to enable holistic management of AMD patients. Methods: We searched PubMed, Embase and the Cochrane Central registries for papers published before May 2022. Non-English, qualitative studies and grey literature were excluded. Studies evaluating the association between AMD and sleep (including sleep disorders like insomnia and sleep apnea), and vice versa, were included. The quality of shortlisted studies was evaluated using the Newcastle Ottawa Scale. Results: Six (two case–control studies, three longitudinal cohort studies and one cross-sectional study) of 551 studies were included in this review. Four studies found that AMD was associated with increased rates of sleep apnea and poorer reported sleep quality, while five studies showed that patients with sleep apnea or insomnia were at higher risk of developing AMD. Associations between self-reported sleep quantity and AMD were conflicting. No study evaluated the relationship between AMD and sleep using objective sleep assessment tools. Conclusion: Only a limited number of studies investigated associations between AMD and sleep. These studies suggest a bidirectional relationship between AMD and sleep dysfunction yet disagree on the relationship between sleep quantity and the likelihood of AMD. Additional studies, using objective characterisation of sleep in patients with AMD are required to confirm these findings.

Detection of antigen is dependent on the expression level in tissue, fixation, antibody avidity, and specificity in combination with detection systems. Detection using primary antibodies raised in the same species is often complicated and may reduce the choice of antibodies used. In the present chapter, a protocol for multicolor immunohistochemical staining of brain tissue containing the suprachiasmatic nucleus is presented in which the use of two antibodies raised in the same species in combination with antibodies raised in other species. The primary antibodies are visualized using amplification steps including biotinylated tyramide and amplification using the EnVision-based system and tyramide and classical indirect immunohistochemistry to enhance signal to noise in order to perform confocal microscopy. Confocal microscopy using a spinning disk system creates stacks of multicolor images, which can be stitched, reconstructed in 3D, and analyzed.

Rhythm characterizes life on Earth. Daily physiological rhythms of eating and fasting, sleeping and waking, moving and resting, are common to almost all life forms which evolved under the solar light–dark cycle. Despite their ubiquity, historians of health and medicine have yet to grapple with the lived experiences of these daily rhythms in the past. This paper presents a potential new research agenda in ‘rhythmic history’ that understands rhythmicity as something which lies between biology and culture. Thinking with rhythms offers exciting opportunities to unite previously disparate historical studies of daily rhythms like eating and sleeping and opens up a new way to view the enmeshed connections between body and environment. In this paper, I take inspiration from the scientific concept of the ‘zeitgeber’ (‘time giver’), coined by the German chronobiologist Jürgen Aschoff, to frame a review of current literature relating to rhythms and explore Henry Lefebvre's notion of ‘rhythmanalysis’ as a methodological tool for historians undertaking ‘rhythmic histories’.

BackgroundOlder men with worse alignment of activity and light may have lower levels of cognition and increased rates of cognitive decline.MethodsThis cohort consisted of 1,036 older men (81.1 ± 4.6 years) from the MrOS Sleep Study (2009-2012). Light and activity levels were gathered by wrist actigraphy. Phasor analysis was used to quantify alignment of light-dark and rest-activity patterns (magnitude) and their temporal relationship (angle). Global cognitive function (Modified Mini-Mental State examination, 3MS) and executive function (Trails B test) were measured, then repeated 4.2 ± 0.8 years later. Linear regression models examined the associations of phasor magnitude and angle with cognition and cognitive decline. Models were adjusted for age, clinic, race, education and season.ResultsSmaller phasor magnitude (worse aligned light and activity patterns) was associated with lower initial level and increased decline in executive function. Compared to those with higher phasor magnitude, those with lower magnitude took an average of 11.1 seconds longer to complete the Trails B test (Quartile 1 vs. Quartile 4, p=.02). After follow-up, Trails B completion time increased an average of 5.5 seconds per standard deviation increase in phasor magnitude (95% CI 0.7-10.4, p=.03). There were no associations with phasor angle, and none with magnitude and global cognition (3MS).ConclusionsAmong older men, worse alignment of light and activity patterns was associated with worse initial performance and increased decline in executive function, but not related to global cognition. Interventions that improve alignment of light and activity may slow cognitive decline in older adults.

Circadian genes have an impact on multiple hormonal, metabolic, and immunological pathways and have recently been implicated in some infectious diseases.

Our understanding of the circadian clock function in plants has been markedly assisted by studies with the model species Arabidopsis thaliana. Molecular and genetics approaches have delivered a comprehensive view of the transcriptional regulatory networks underlying the Arabidopsis circadian system. The use of the luciferase as a reporter allowed the precise in vivo determination of circadian periods, phases, and amplitudes of clock promoter activities with unprecedented temporal resolution. An increasing repertoire of fine-tuned luciferases together with additional applications such as translational fusions or bioluminescence molecular complementation assays have considerably expanded our view of circadian protein expression and activity, far beyond transcriptional regulation. Further applications have focused on the in vivo simultaneous examination of rhythms in different parts of the plant. The use of intact versus excised plant organs has also provided a glimpse on both the organ-specific and autonomy of the clocks and the importance of long distance communication for circadian function. This chapter provides a basic protocol for in vivo high-throughput monitoring of circadian rhythms in Arabidopsis seedlings using bioluminescent reporters and a microplate luminometer.

[Resumen] El éxodo rural en Galicia ha llevado a la disminución de la persecución directa de la fauna silvestre debido a que ésta ya no representa una amenaza directa para los intereses humanos. Una de las posibles consecuencias del despoblamiento rural es la modificación de los ritmos circadianos de la fauna silvestre. Este Trabajo de Fin de Grado analiza cómo puede afectar la presencia de personas a los ritmos biológicos del tejón europeo (Meles meles) y del zorro común (Vulpes vulpes) en la dorsal gallega. Encontramos que ambas especies fueron nocturnas, evitando en el tiempo a las personas., [Resumo] O éxodo rural en Galicia levou á diminución da persecución directa da fauna silvestre debido a que esta xa non presenta unha ameaza directa para os intereses humanos. Unha das posibles consecuencias do despoboamento rural é a modificación dos ritmos circadianos da fauna silvestre. Este Traballo de Fin de Grao analiza como pode afectar a presencia de persoas aos ritmos biolóxicos do teixugo (Meles meles) e do raposo (Vulpes vulpes) na dorsal galega. Encontramos que ambas especies foron nocturnas, evitando no tempo ás persoas., [Abstract] The rural exodus in Galicia has led to a decrease in the direct persecution of wildlife because wildlife no longer represents a direct threat to human interests. One of the possible consequences of rural depopulation is the modification of wildlife circadian rhythms. This Final Degree Project analyses how the presence of people may affect the biological rhythms of the European badger (Meles meles) and the red fox (Vulpes vulpes) in the Galician dorsal. We found that both species were nocturnal, avoiding people in time.

The central pacemaker for biological rhythms in mammals is located in a 10,000-cell structure known as the suprachiasmatic nucleus (SCN) in the anterior hypothalamus (Hastings_2018, Meijer_1996). Clock cells in the suprachiasmatic nucleus work together to generate a coordinated and synchronous output that results in an intrinsic endogenous “ticking” of the biological clock at a set periodicity (Liu_1997). Circadian rhythms are generated by the daily fluctuation of a transcription-translation feedback loop between clock proteins and genes located in clock cells. Master pacemaker cells in the SCN project to peripheral pacemaker cells in various organs and tissues in the body. All biological rhythms oscillate at a set period known either as the intrinsic or endogenous period and is determined by the oscillatory speed of the transcription-translation feedback loop determined by the individual organism’s genetics (Jin_1999, Liu_1997). The endogenous period is not typically aligned optimally with the external 24-hour period of the earth’s daily rotation about its axis. The amount of time it takes for an animal to return to the same phase of its endogenous rhythm without an external natural or artificial cycle to align to is known as the free running period. Mammals do not have endogenous periods that cycle at exactly 24-hours but generally have free running periods ranging between 22 and 26 hours, with diurnal mammals typically exhibiting free running periods above 24-hours (Aschoff_1981). The difference in cycling between the endogenous period and the external 24-hour photoperiod (the period of light and dark denoting one complete rotation of the earth about its axis), eventually results in a drift and subsequent misalignment of important behaviors, which lead to negative and in some cases fatal health outcomes for living organisms (Aschoff_1981, Lewy_2009). In order to prevent misalignment and optimally time behaviors to the external photoperiod, the biological clock ev

Serotonin (5-HT) reuptake inhibitors, such as fluoxetine, are the most prescribed antidepressant for maternal depression. In this sense, it exposes mothers and the brains of infants to increased modulatory and trophic effects of serotonergic neurotransmission. 5-HT promotes essential brain changes throughout its development, which include neuron migration, differentiation and organisation of neural circuitries related to emotional, cognitive and circadian behavior. Early exposure to the SSRIs induces long-term effects on behavioral and neural serotonergic signalisation. We have aimed to evaluate the circadian rhythm of locomotor activity and the neurochemical content, neuropeptide Y (NPY) and 5-HT in three brain areas: intergeniculate leaflet (IGL), suprachiasmatic nuclei (SCN) and raphe nuclei (RN), at two zeitgebers (ZT6 and ZT18), in male and female rat's offspring early exposed (developmental period GD13-GD21) to fluoxetine (20 mg/kg). First, we have conducted daily records of the locomotor activity rhythm using activity sensors coupled to individual cages over 4 weeks. We have lastly evaluated the immunoreactivity of NPY in both SCN and IGL, as well the 5-HT expression in the dorsal and medial RN. In summary, our results showed that (1) prenatal fluoxetine affects phase entrainment of the rest/activity rhythm at ZT6 and ZT18, more in male than female specimens, and (2) modulates the NPY and 5-HT expression. Here, we show male rats are more susceptible to phase entrainment and the NPY and 5-HT misexpression compared to female ones. The sex differences induced by early exposure to fluoxetine in both the circadian rhythm of locomotor activity and the neurochemical expression into SCN, IGL and midbrain raphe are an important highlight in the present work. Thus, our results may help to improve the knowledge on neurobiological mechanisms of circadian rhythms and are relevant to understanding the "broken brains" and behavioral abnormalities of offspring early exposed

The study of circadian rhythms in the human body using temperature measurements is the most informative way to assess the viability of the body’s rhythm-organizing systems. Pathological processes can affect circadian rhythm dynamics in damaged organs. Severe brain damage that caused the development of disorders of consciousness (DOC) (strokes, traumatic brain injury) disrupts the activity of central oscillators, by directly damaging or destroying the periphery links, and the level of preservation of circadian rhythms and the dynamics of their recovery can be informative diagnostic criteria for patient’s condition assessment. This study examined 23 patients with DOC by using a non-invasive method for obtaining body and cerebral cortex temperature to compare with healthy controls. Measurements were made with a 4 h interval for 52 h beginning at 08:00 on day 1 and ending at 08:00 on day 3. The profile of patients with DOC showed complete disruption compared to healthy controls with rhythmic patterns. The results indicate that the mechanisms for maintaining brain circadian rhythms are different from general homeostasis regulation of the body. Use of microwave radio thermometry for the identification of rehabilitation potential in patients with DOC is a promising area of investigation., source:https://www.mdpi.com/2075-4418/12/8/1777

Epilepsy is one of the most common severe neurological diseases and is characterized by recurring seizures. Currently, about 70 million people worldwide live with epilepsy and over 30% of them cannot be adequately treated with medication. The unpredictability of seizures is a severely debilitating aspect of epilepsy that significantly impacts the quality of life of patients. Consequently, there is a clinical need to find new markers that are useful for seizure forecasting. High-frequency activity (HFA) is a newly proposed biomarker for epilepsy, but its predictive value in seizure forecasting remains uncertain. Emerging new evidence has shown that ambient air pollution affects the central nervous system, but little is known about its effect on epileptic seizures. The goal of this thesis is to investigate potential novel markers for improving seizure forecasting and epilepsy management. To achieve this goal, the work of this thesis addresses several key questions: How do HFA rates and locations change over time, and how do these changes correspond with seizures? Can HFA forecast seizures? Is ambient air pollution associated with the risk of epileptic seizures? By addressing these fundamental questions, this thesis aims to provide the basis for formulating an innovative approach to improve seizure forecasting and control. In the first research chapter, the spatiotemporal profiles of HFA are investigated using long-term intracranial EEG. The results show that HFA rates have post-implantation variability, periodic cycles, and patient-specific relationships with seizures. These findings caution against using HFA as a presurgical metric without testing its reliability over time and suggest that tracking and utilising cycles of HFA rates may offer an exciting new opportunity to track cycles of seizures. In the second research chapter, a real-time phase estimation approach and seizure forecasting framework are developed using instantaneous HFA rates and phases of HFA cycles

Rhythm characterizes life on Earth. Daily physiological rhythms of eating and fasting, sleeping and waking, moving and resting, are common to almost all life forms which evolved under the solar light–dark cycle. Despite their ubiquity, historians of health and medicine have yet to grapple with the lived experiences of these daily rhythms in the past. This paper presents a potential new research agenda in ‘rhythmic history’ that understands rhythmicity as something which lies between biology and culture. Thinking with rhythms offers exciting opportunities to unite previously disparate historical studies of daily rhythms like eating and sleeping and opens up a new way to view the enmeshed connections between body and environment. In this paper, I take inspiration from the scientific concept of the ‘zeitgeber’ (‘time giver’), coined by the German chronobiologist Jürgen Aschoff, to frame a review of current literature relating to rhythms and explore Henry Lefebvre's notion of ‘rhythmanalysis’ as a methodological tool for historians undertaking ‘rhythmic histories’.

Background Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, no medical treatment has been approved for the treatment of NAFLD. In our previous study, we found that PKLR could be a potential target for treatment of NALFD. Here, we investigated the effect of PKLR in in vivo model and performed drug repositioning to identify a drug candidate for treatment of NAFLD. Methods Tissue samples from liver, muscle, white adipose and heart were obtained from control and PKLR knock-out mice fed with chow and high sucrose diets. Lipidomics as well as transcriptomics analyses were conducted using these tissue samples. In addition, a computational drug repositioning analysis was performed and drug candidates were identified. The drug candidates were both tested in in vitro and in vivo models to evaluate their toxicity and efficacy. Findings The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in the liver as well as in other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drug candidates were identified as potential inhibitor of PKLR using our drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and we found that these drugs attenuate the hepatic steatosis without side effect on other tissues. Interpretation In conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which has been validated in preclinical studies., QC 20221019

Long non-coding RNAs (lncRNAs) are a new class of regulatory RNAs that play important roles in disease development and a variety of biological processes. Recent studies have underscored the importance of lncRNAs in the circadian clock system and demonstrated that lncRNAs regulate core clock genes and the core clock machinery in mammals. In this review, we provide an overview of our current understanding of how lncRNAs regulate the circadian clock without coding a protein. We also offer additional insights into the challenges in understanding the functions of lncRNAs and other unresolved questions in the field. We do not cover other regulatory ncRNAs even though they also play important roles; readers are highly encouraged to refer to other excellent reviews on this topic.

Microbial life is all around us and inside us in an unseen vast and varied ecosystem. For the past several decades, the microbiome field has attempted to characterize this microscopic web of life using next generation sequencing technology. It turns out that the number of host organism cells is generally outnumbered by the number of microbial cells that live on and within them. Moreover, these microbes collectively have two orders of magnitude more genes than their host organism. While the host organism’s genome stays constant during its life, the microbial community and its associated genes change much more frequently. Since microbial lifespans are sometimes measured in minutes, selective pressures in the host micro-environments can rapidly affect the evolution and gene content of the microorganisms present. Over the course of a lifetime, the host winds up with a unique set of microbes selected to fit their unique individual environment, from immune system quirks to specialized diets to biological rhythms. However, despite biological rhythms having always played a role in host behavior and survival, the impact of time on health has been a widely neglected realm until recently. The basic argument of this thesis is that time is an underappreciated but critical variable that impacts both experimental study design as well as host health.

Circadian alignment of rest-activity rhythms is an essential biological process that may be vulnerable to misalignment in critically ill patients. We evaluated circadian rest-activity rhythms in critically ill patients and their association with baseline (e.g. age) and clinical (e.g. mechanical ventilation status) variables, along with intensive care unit light-dark cycles. Using wrist actigraphy, we collected 48-hr activity and light exposure data from critically ill patients in a tertiary care medical intensive care unit. We evaluated circadian rest-activity rhythms using COSINOR and non-parametric circadian rhythm analysis models, and stratified these data across baseline and clinical variables. We used linear regression to evaluate the association of circadian rest-activity and light-dark exposure rhythms. In COSINOR and non-parametric circadian rhythm analysis analyses, the 34 medical intensive care unit patients completing 48-hr actigraphy recordings exhibited mean MESOR (mean activity levels of a fitted curve) and amplitudes of 0.50 ± 0.32 and 0.20 ± 0.19 movements per 30-s epoch, with high interdaily variability. Patients who were older, mechanically ventilated, sedated, restrained and with higher organ failure scores tended to exhibit greater circadian rest-activity misalignment, with three of 34 (9%) patients exhibiting no circadian rhythmicity. Circadian light-dark exposure misalignment was observed as well and was associated with rest-activity misalignment (p = 0.03). Critically ill patients in our MICU experienced profound circadian rest-activity misalignment, with mostly weak or absent rhythms, along with circadian light-dark exposure misalignment. Potentially modifiable factors contributing to rest-activity misalignment (i.e. mechanical ventilation, restraints, low daytime light levels) highlight possible targets for future improvement efforts.

Strains of the freshwater cyanobacterium Synechococcus elongatus were first isolated approximately 60 years ago, and PCC 7942 is well established as a model for photosynthesis, circadian biology, and biotechnology research. The recent isolation of UTEX 3055 and subsequent discoveries in biofilm and phototaxis phenotypes suggest that lab strains of S. elongatus are highly domesticated. We performed a comprehensive genome comparison among the available genomes of S. elongatus and sequenced two additional laboratory strains to trace the loss of native phenotypes from the standard lab strains and determine the genetic basis of useful phenotypes. The genome comparison analysis provides a pangenome description of S. elongatus, as well as correction of extensive errors in the published sequence for the type strain PCC 6301. The comparison of gene sets and single nucleotide polymorphisms (SNPs) among strains clarifies strain isolation histories and, together with large-scale genome differences, supports a hypothesis of laboratory domestication. Prophage genes in laboratory strains, but not UTEX 3055, affect pigmentation, while unique genes in UTEX 3055 are necessary for phototaxis. The genomic differences identified in this study include previously reported SNPs that are, in reality, sequencing errors, as well as SNPs and genome differences that have phenotypic consequences. One SNP in the circadian response regulator rpaA that has caused confusion is clarified here as belonging to an aberrant clone of PCC 7942, used for the published genome sequence, that has confounded the interpretation of circadian fitness research. IMPORTANCE Synechococcus elongatus is a versatile and robust model cyanobacterium for photosynthetic metabolism and circadian biology research, with utility as a biological production platform. We compared the genomes of closely related S. elongatus strains to create a pangenome annotation to aid gene discovery for novel phenotypes. The comparative genomic a

Non-alcoholic fatty liver disease (NAFLD) has rapidly emerged as the most prevalent liver disease in westernized countries, affecting approximately 1 in 3 adults in the US and roughly 25% of adults globally [1,2]. NAFLD can progress to nonalcoholic steatohepatitis (NASH), a progressive form of the disease characterized by inflammation, hepatocyte injury, and increased risk for hepatology-related morbidity and mortality [3]. It is unclear why only a subset of patients with NAFLD progress to NASH. One of the leading explanations is the “multiple parallel hits hypothesis”, which considers multiple insults such as hepatic steatosis, inflammation, and insulin resistance that act in unison to trigger the progression of NAFLD to NASH [4]. However, a very significant element of this hypothesis that is missing is circadian rhythms, which play a role in modulating every insult or “hit”. Our objective is to elucidate the role of circadian rhythms in the liver and intestines, which can be entrained by the gut microbiome, in the pathophysiology and progression of NAFLD to NASH. Previous research indicates that certain feeding patterns, such as time-restricted feeding (TRF), prevent a variety of NASH risk factors, including hepatic steatosis and circadian rhythm disruption in the liver and intestines [5,6]. We hypothesize that NASH onset results from altered gut microbiome dynamics and disrupted hepatic circadian rhythms, which can be manipulated with feeding pattern to ameliorate disease. To test this hypothesis, we used the streptozotocin + high-fat diet (STAM/HFD) murine model of NASH, which recapitulates key aspects of human NASH pathogenesis, including hepatic steatosis, inflammation, and fibrosis on a hyperglycemic background [7]. STAM/HFD mice underwent 8-hour TRF or had access to food ad libitum (adlib). Importantly, STAM/HFD mice are hypoinsulinemic and do not become insulin resistant [7]. This allowed us to specifically investigate whether TRF can prevent NASH via the m

Background: Sleep is considered an essential component related to physiological and psychological recovery in athletes and particularly in basketball, given the impact of condensed travel and game schedules on player health and performance. Objective: The aim of this systematic review is to examine studies published to date on sleep and basketball performance. Methodology: All scientific articles that reported a relationship between sleep and its possible impact on performance in basketball are included. The research processes followed the PRISMA criteria, and the relevant articles were extracted (PubMed, WOS, Scopus) as of December 31, 2021. Results: Twenty-eight articles were selected for inclusion and data extraction, with 27 demonstrating that sleep is a vital component in the recovery of basketball players and their corresponding on-court performance. Three central themes that we identified: (1) the quality and extension of sleep (the better quality and more extension of sleep, better performance and lower probability of injury); (2) influence of the players circadian rhythm (travel and game scheduling do not currently facilitate or take this into account); and (3) higher training loads and/or increased stress may jeopardize a subsequent good night’s sleep, which should be taken into account when scheduling practices and workouts. Conclusion: The current systematic review regarding sleep and basketball performance and highlights that there is a strong relationship between both variables. Collectively, the evidence supports the critical influence of sleep on player recovery and basketball performance and risk for injury.