Regulation Of Circadian Rhythms Research Articles

Melatonin as a Potential Therapeutic Tool in Allergic Rhinitis Induced by House-Dust Mite

Melatonin is known as an important regulator of circadian rhythm in humans. In the literature, there are no studies evaluating the efficacy of melatonin in the management of allergic rhinitis (AR) or nasal polyps (Np). Np tissue was taken from nasal cavity and mucosal tissue (Mu) was taken from the nasal septal area. Melatonin (25-200nM) and Mite Allergen (2.5-12.5%) were prepared in complete media. Cell viability, apoptosis, intracellular reactive oxygen species production and gene expression levels were determined. Our results showed that there is no toxic effect of Melatonin, Mite and their combination which was given to Np-MSCs and Mu-MSCs. Melatonin significantly reduced reactive oxygen species levels in both mite-treated Np-MSCs and Mu-MSCs. Indoleamine 2,3-dioxygenase level was significantly decreased in melatonin-treated cells. Cyclooxygenase-1 level was significantly decreased in melatonin-treated healthy and allergic Np-MSCs while there was no significant difference in 100 and 150nM Melatonin-treated Mu-MSCs. Interestingly, 50nM Melatonin significantly increased Cyclooxygenase-1 level in Mu-MSCs. 50, 100 and 150nm Melatonin significantly decreased Interleukin-6 level in Mite-treated Np-MSCs. In addition, 100 and 150nM Melatonin significantly decreased Interleukin-6 level in Mite-treated Mu-MSCs. Melatonin has well-established anti-oxidant and anti-neoplastic activity, could be a promising therapeutic agent in the treatment of AR and nasal polyposis.

Drastic decline in vasoactive intestinal peptide expression in the suprachiasmatic nucleus in obese mice on a long-term high-fat diet

The suprachiasmatic nucleus (SCN) is the main region for the regulation of circadian rhythms. Although the SCN contains a heterogeneous neurochemical phenotype with a wide variety of neuropeptides, a key role has been suggested for the vasoactive intestinal neuropeptide (VIP) as a modulator circadian, reproductive, and seasonal rhythms. VIP is a 28-amino acid polypeptide hormone that belongs to the secretin-glucagon peptide superfamily and shares 68 % homology with the pituitary adenylate cyclase-activating polypeptide (PACAP). VIP acts as an endogenous appetite inhibitor in the central nervous system, where it participates in the control of appetite and energy homeostasis. In recent years, significant efforts have been made to better understand the role of VIP in the regulation of appetite/satiety and energy balance. This study aimed to elucidate the long-term effect of an obesogenic diet on the distribution and expression pattern of VIP in the SCN and nucleus accumbens (NAc) of C57BL/6 mice. A total of 15 female C57BL/6J mice were used in this study. Female mice were fed ad libitum with water and, either a standard diet (SD) or a high-fat diet (HFD) to induce obesity. There were 7 female mice on the SD and 8 on the HFD. The duration of the experiment was 365 days. The morphological study was performed using immunohistochemistry and double immunofluorescence techniques to study the neurochemical profile of VIP neurons of the SCN of C57BL/6 mice. Our data show that HFD-fed mice gained weight and showed reduced VIP expression in neurons of the SCN and also in fibres located in the NAc. Moreover, we observed a loss of neuropeptide Y (NPY) expression in fibres surrounding the SCN. Our findings on VIP may contribute to the understanding of the pathophysiological mechanisms underlying obesity in regions associated with uncontrolled intake of high-fat foods and the reward system, thus facilitating the identification of novel therapeutic targets.

FoxO3 Modulates Circadian Rhythms in Neural Stem Cells.

Both FoxO transcription factors and the circadian clock act on the interface of metabolism and cell cycle regulation and are important regulators of cellular stress and stem cell homeostasis. Importantly, FoxO3 preserves the adult neural stem cell population by regulating cell cycle and cellular metabolism and has been shown to regulate circadian rhythms in the liver. However, whether FoxO3 is a regulator of circadian rhythms in neural stem cells remains unknown. Here, we show that loss of FoxO3 disrupts circadian rhythmicity in cultures of neural stem cells, an effect that is mediated via regulation of Clock transcriptional levels. Using Rev-Erbα-VNP as a reporter, we then demonstrate that loss of FoxO3 does not disrupt circadian rhythmicity at the single cell level. A meta-analysis of published data revealed dynamic co-occupancy of multiple circadian clock components within FoxO3 regulatory regions, indicating that FoxO3 is a Clock-controlled gene. Finally, we examined proliferation in the hippocampus of FoxO3-deficient mice and found that loss of FoxO3 delayed the circadian phase of hippocampal proliferation, indicating that FoxO3 regulates correct timing of NSC proliferation. Taken together, our data suggest that FoxO3 is an integral part of circadian regulation of neural stem cell homeostasis.

Glucocorticoid receptor regulates protein chaperone, circadian clock and affective disorder genes in the zebrafish brain.

Glucocorticoid resistance is commonly observed in depression, and has been linked to reduced expression and/or function of the glucocorticoid receptor (NR3C1 in human, hereafter referred to as GR). Previous studies have shown that GR-mutant zebrafish exhibit behavioural abnormalities that are indicative of an affective disorder, suggesting that GR plays a role in brain function. We compared the brain methylomes and brain transcriptomes of adult wild-type and GR-mutant zebrafish, and identified 249 differentially methylated regions (DMRs) that are regulated by GR. These include a cluster of CpG sites within the first intron of fkbp5, the gene encoding the glucocorticoid-inducible heat shock protein co-chaperone Fkbp5. RNA-sequencing analysis revealed that genes associated with chaperone-mediated protein folding, the regulation of circadian rhythm and the regulation of metabolism are particularly sensitive to loss of GR function. In addition, we identified subsets of genes exhibiting GR-regulated transcription that are known to regulate behaviour, and are linked to unipolar depression and anxiety. Taken together, our results identify key biological processes and novel molecular mechanisms through which the GR is likely to mediate responses to stress in the adult zebrafish brain, and they provide further support for the zebrafish GR mutant as a model for the study of affective disorders.

PPARG stimulation restored lung mRNA expression of core clock, inflammation- and metabolism-related genes disrupted by reversed feeding in male mice.

The circadian rhythm system regulates lung function as well as local and systemic inflammations. The alteration of this rhythm might be induced by a change in the eating rhythm. Peroxisome proliferator-activated receptor gamma (PPARG) is a key molecule involved in circadian rhythm regulation, lung functions, and metabolic processes. We described the effect of the PPARG agonist pioglitazone (PZ) on the diurnal mRNA expression profile of core circadian clock genes (Arntl, Clock, Nr1d1, Cry1, Cry2, Per1, and Per2) and metabolism- and inflammation-related genes (Nfe2l2, Pparg, Rela, and Cxcl5) in the male murine lung disrupted by reversed feeding (RF). In mice, RF disrupted the diurnal expression pattern of core clock genes. It decreased Nfe2l2 and Pparg and increased Rela and Cxcl5 expression in lung tissue. There were elevated levels of IL-6, TNF-alpha, total cells, macrophages, and lymphocyte counts in bronchoalveolar lavage (BAL) with a significant increase in vascular congestion and cellular infiltrates in male mouse lung tissue. Administration of PZ regained the diurnal clock gene expression, increased Nfe2l2 and Pparg expression, and reduced Rela, Cxcl5 expression and IL-6, TNF-alpha, and cellularity in BAL. PZ administration at 7 p.m. was more efficient than at 7 a.m.

The Effect of Melatonin on Body Weight and the Potential use of Melatonin as an Anti-Obesity Agent

Background: obesity is a major global health problem with more than 200 million obese men and almost 300 million obese women. Melatonin is a well-known molecule for its involvement in circadian rhythm regulation and has multiple pathological actions including control of appetite, sleep wake cycle and metabolic syndrome. Aim: to estimate the effect of melatonin supplements on obese patients on a calorie restricted diet in comparison to patients on lifestyle measures only in the form of weight loss, waist circumference and sleep quality. Subjects and Method: one hundred patients with body mass index > 24 were collected, fifty patients were started on melatonin 5 mg with calorie restricted diet and they were compared to fifty patients who were kept on lifestyle measures. After twelve weeks, patients were re-assessed for weight, waist circumference and sleep duration and quality and the development of any side effects. Data analyzed using paired t test. Results: patients’ group who were treated with melatonin has shown significant reduction in body weight (91.58. Vs 92.88, p value <0.0004) and waist circumference (99.36 +- 10.73 vs 101 +-10.51, p value< 0.0064). Patients treated with melatonin show improved insomnia severity index (5.47+-0.8 vs 9.08 +-3.58, p value <0.0001). 60% of patients noticed decreased appetite,35% reported daytime sleepiness and fatigue, 25% had dizziness and 20% had mild nausea. Conclusion: Melatonin significantly reduces the body weight, waist circumference and appetite more than placebo, it has been shown to be safe supplement and helpful in patients with sleep disturbance and obesity.

Effects of melatonin implants on locomotor activity, body temperature, and growth of lambs fed a concentrate-based diet

Melatonin is involved in the regulation of circadian rhythms and is implicated in seasonal reproduction in sheep. In several physiological mechanisms, it acts as an antioxidant and an anti-inflammatory molecule, regulating energy metabolism. This work investigated the effects of melatonin implants at 30 days of age on locomotor activity (LA), body temperature, and growth of fattening female and male lambs. Sixty lambs were divided into two groups: one of which received melatonin (MEL, 15 males, 16 females) and a control group (CTR, 16 males, 14 females). In the melatonin group, two 18 mg melatonin implants were placed at 30 days of age. Lambs were fattened for 6 weeks from weaning (45 days of age) to slaughter (85 days). The feed conversion rate (FCR) was calculated based on live weight and the amount of concentrate consumed. LA was measured weekly by actigraphy, and circadian rhythmicity was calculated. Rectal (Trec) and surface temperatures (Tsur) were recorded in the last week of fattening, and subcutaneous fat thickness (FT) over the longissimus dorsi muscle was measured by ultrasound scanning. Treatment did not affect FCR, although MEL female lambs consumed significantly (P < 0.001) less concentrate than CTR lambs. Treatment and sex had a significant (P < 0.05) interaction effect on FT; specifically, FT was significantly (P < 0.05) higher in female MEL lambs (3.22 ± 0.21 mm) than in female CTR lambs (2.57 ± 0.24 mm), but FT in males did not differ between MEL (2.77 ± 0.21) and CTR (2.94 ± 0.24 mm) lambs. Overall activity was significantly (P < 0.001) lower in the MEL lambs (72.22 ± 0.10 counts/min) than in the CTR lambs (78.89 ± 0.12 counts/min). MEL lambs had a significantly (P < 0.01) lower Trec (CTR: 39.00 ± 0.07; MEL: 38.68 ± 0.10) and Tsur for all body regions evaluated than the CTR lambs. In conclusion, treatment with exogenous melatonin at 30 days of age increased food efficiency in fattening female lambs, probably, because of the lower metabolism in treated lambs, which was reflected by the lower body temperature and LA exhibited by these animals. In addition, the study has demonstrated the effect of exogenous melatonin in the growth performances of post-weaning lambs, and that its effects depend on animal sex, which suggests that treatments that target females might be most appropriate in the fattening period.

The role of the symbiotic microecosystem in cancer: gut microbiota, metabolome, and host immunome.

The gut microbiota is not just a simple nutritional symbiosis that parasitizes the host; it is a complex and dynamic ecosystem that coevolves actively with the host and is involved in a variety of biological activities such as circadian rhythm regulation, energy metabolism, and immune response. The development of the immune system and immunological functions are significantly influenced by the interaction between the host and the microbiota. The interactions between gut microbiota and cancer are of a complex nature. The critical role that the gut microbiota plays in tumor occurrence, progression, and treatment is not clear despite the already done research. The development of precision medicine and cancer immunotherapy further emphasizes the importance and significance of the question of how the microbiota takes part in cancer development, progression, and treatment. This review summarizes recent literature on the relationship between the gut microbiome and cancer immunology. The findings suggest the existence of a "symbiotic microecosystem" formed by gut microbiota, metabolome, and host immunome that is fundamental for the pathogenesis analysis and the development of therapeutic strategies for cancer.

CPEB4 - CLOCK crosstalk during temporal lobe epilepsy.

Post-transcriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large-scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element-binding protein CPEB4 was found to drive epilepsy-induced poly(A) tail changes and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood. Status epilepticus was induced in wild-type and CPEB4-deficient male mice via an intra-amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via Chromatin immunoprecipitation assay and melatonin levels via High-Performance Liquid Chromatography in plasma. Here we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4-dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post-status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post-status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug-resistant temporal lobe epilepsy. Further, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4-deficient compared to wild-type mice. Last, CPEB4-deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day. Our results reveal a new positive transcriptional-translational feedback loop (TTFL) involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep-wake cycle during epilepsy.

Is Diabetes Pre-coded in the Brain? Role of Hypothalamus, Addiction Network and Social Cognition

The hypothalamus, the master regulator of circadian rhythm, in association with peripheral clocks, play crucial roles in glucose metabolism. Impairment in cerebral sensing, uptake and processing of glucose has been suggested in various animal and human diabetic models. Diabetes Mellitus has been largely superseded by the discovery of insulin and insulin resistance. Expanding horizons of knowledge of the roles of the hypothalamus in glucose metabolism and the overlapping neural pathways of sugar addictionwith other classically described substance and behavioral addictions networks have again thrown some light on the cerebral theory of DM pathogenesis.

Transmembrane and PAS domains of the histidine kinase Hik33 as regulators of cold and light responses in the cyanobacterium Synechocystis sp. PCC 6803

The PAS (Per-ARNT-Sim) domain is a sensory protein regulatory module found in archaea, prokaryotes, and eukaryotes. Histidine and serine/threonine protein kinases, chemo- and photoreceptors, circadian rhythm regulators, ion channels, phosphodiesterases, and other cellular response regulators are among these proteins. Hik33 is a multifunctional sensory histidine kinase that is implicated in cyanobacterial responses to cold, salt, hyperosmotic, and oxidative stressors. The functional roles of individual Hik33 domains in signal transduction were investigated in this study. Synechocystis Hik33 deletion variants were developed, in which either both or a portion of the transmembrane domains and/or the PAS domain were deleted. Cold stress was applied to the mutant strains either under illumination or in the dark. The findings show that the transmembrane domains govern temperature responses, whereas PAS domain may be involved in regulation of downstream gene expression in light-dependent manner.

Clinical Neurobiology of Sleep and Wakefulness.

This article focuses on novel neuronal mechanisms of sleep and wakefulness and relates basic science developments with potential translational implications in circadian neurobiology, pharmacology, behavioral factors, and the recently integrated potential pathways of sleep-related motor inhibition. During the past decade, remarkable advances in the molecular biology of sleep and wakefulness have taken place, opening a promising path for the understanding of clinical sleep disorders. Newly gained insights include the role of astrocytes in sleep brain homeostasis through the glymphatic system, the promotion of memory consolidation during states of reduced cholinergic activity during slow wave sleep, and the differential functions of melatonin receptors involving regulation of both circadian rhythm and sleep initiation. Ongoing investigations exploring sleep and circadian rhythm disruptions are beginning to unlock pathophysiologic aspects of neurologic, psychiatric, and medical disorders. An understanding of sleep and circadian neurobiology provides coherent and biologically credible approaches to treatments, including the identification of potential targets for neuromodulation.

Bioinformatics-Based Analysis of Circadian Rhythm Regulation Mechanisms in Alzheimer's Disease.

There is a close association between Alzheimer's disease (AD) and circadian rhythms, and neuroinflammatory-related pathways are associated with both interactions. To reveal the relationship between circadian rhythm (CR) and AD at the level of genes, pathways, and molecular functions through bioinformatics. We analyzed the differential genes between AD and control groups in GSE122063 and found the important gene modules; obtained CR-related genes from GeenCard database; used Venn 2.1 database to obtain the intersection of genes of AD important modules with CR-related genes; and used STRING database and Cytoscape 3.7.1 to construct the gene protein-protein interaction network. The MCODE plugin was used to screen pivotal genes and analyze their differential expression. We trranslated with www.DeepL.com/Translator (free version) to obtain transcriptional regulatory relationships from the TRRUST database and construct a hub gene-transcription factor relationship network. A total of 42 common genes were screened from AD and CR genes, mainly involving signaling pathways such as neuroactive ligand-receptor interactions. A total of 10 pivotal genes were screened from the common genes of CR and AD, which were statistically significant in the comparison of AD and control groups (p < 0.001), and ROC analysis showed that all these pivotal genes had good diagnostic significance. A total of 36 TFs of pivotal genes were obtained. We identified AD- and CR-related signaling pathways and 10 hub genes and found strong associations between these related genes and biological processes such as inflammation.

Donor circadian clock influences the long-term survival of heart transplantation by immunoregulation.

Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection. In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group. Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.

Classification of drugs for the treatment of circadian rhythm disorders

Survey studies found that more than 3% of adults have CRSD, and about 16% of teenagers may have CRSD. Although it may be self-limiting, others will cause burden consequences. Many existing papers on drug classification focus on the classification method, or discuss some drug characteristics, but because the target range of drugs is too large, there is no way to expand each drug mentioned, and make their characteristics more detailed and clear. With the development of sleep drug research, there are a lot of reviews on the regulation of circadian rhythm, especially on the circadian rhythm disturbance, but most of them are very detailed studies on a specific drug, such as melatonin or amphetamine. The drugs used to treat circadian disorders can be classed as sedative hypnotics, stimulant stimulants, chronotropic drugs, and gives a cursory mention of other drugs that do not fall into the first three categories. Among the sedatives and hypnotics, barbiturates, benzodiazepines and other drugs include tranquilizers or non-benzodiazepines. Amphetamine, Modafinil and caffeine were mentioned in the stimulant category. The third category of drugs that is mainly described is melatonin. This paper is based on the classification of drugs that regulate circadian rhythm disorders. For each category, at least several representative drugs are proposed and their characteristics are described. It contains basic information about the drug, its properties, mechanism of action, side effects and so on. In the description of drug characteristics, there are also some parts of this article that compare drug effects horizontally. The section on stimulant function discusses how long three different drugs can help to maintain a state of arousal, Differences in side effects were also compared.

Brain Gene Expression of Foraging Behavior and Social Environment in Ceratina calcarata.

Rudimentary social systems have the potential to both advance our understanding of how complex sociality may have evolved and our understanding of how changes in social environment may influence gene expression and cooperation. Recently, studies of primitively social Hymenoptera have greatly expanded empirical evidence for the role of social environment in shaping behavior and gene expression. Here, we compare brain gene expression profiles of foragers across social contexts in the small carpenter bee, Ceratina calcarata. We conducted experimental manipulations of field colonies to examine gene expression profiles among social contexts including foraging mothers, regular daughters, and worker-like dwarf eldest daughters in the presence and absence of mother. Our analysis found significant differences in gene expression associated with female age, reproductive status, and social environment, including circadian clock gene dyw, hexamerin, and genes involved in the regulation of juvenile hormone and chemical communication. We also found that candidate genes differentially expressed in our study were also associated with division of labor, including foraging, in other primitively and advanced eusocial insects. Our results offer evidence for the role of the regulation of key developmental hormones and circadian rhythms in producing cooperative behavior in rudimentary insect societies.

Long non-coding RNAs regulate heavy metal-induced apoptosis in embryo-derived cells

Heavy metal pollution has been a worldwide prevalent problem, and particularly a threat to ecosystem integrity and animals’ health. Previous studies on the mechanisms of heavy metal toxicity have focused on protein-coding genes, whereas most genomic transcripts are long non-coding RNAs (lncRNAs). Although lncRNAs are known to play important regulatory roles in biological processes, their role in heavy metal stress regulation is still not fully understood. We here developed an insect embryo cell model for studying metal toxicity and the underlying regulatory mechanisms. We performed genome-wide screening and functional characterization of lncRNAs induced by two essential and two non-essential heavy metals in Drosophila embryo-derived S2 cells. We identified 4894 lncRNAs, of which 1410 were novel. Forty-one lncRNAs, together with 328 mRNAs, were induced by all the four heavy metals. LncRNA–mRNA co-expression network and pathway enrichment analysis showed that detoxification metabolism, circadian rhythm, and apoptosis regulation pathways were activated in response to heavy metal stress. LncRNA CR44138 was remarkably upregulated in cells exposed to the four heavy metals and was associated with the apoptosis pathway. Expression interference confirmed that CR44138 aggravated cytotoxicity-induced apoptosis in cells under heavy metals stress. This study highlights the important role of lncRNAs in regulating the cellular response to heavy metals. This study also lays the foundation for discovering the novel regulatory mechanisms and developing diagnostic biomarkers of the toxic effects of heavy metal pollutants on organisms.

Melatonin effects on sleep quality of COVID-19 patients: a protocol for systematic review and meta-analysis of randomised controlled trials with trial sequential analysis

IntroductionSleep disturbance is one of the common complaints of patients with COVID-19 infection. Melatonin is a physiological indoleamine involved in circadian rhythm regulation and it is currently used for secondary...

0035 Melanopsin genetic variants and delayed sleep phenotype – whole genome sequencing analysis

Abstract Introduction Melanopsin (OPN4) is a blue light-sensitive opsin-type G-protein coupled receptor. It is highly expressed in photosensitive retinal ganglion cells which mediate responses to light, including regulation of sleep, circadian photoentrainment, and pupillary light response. Mutations in OPN4 were shown to affect responses to light, ultimately affecting the regulation of circadian rhythms and sleep. Previously, we describe a male carrier of the OPN4 missense variant diagnosed with delayed sleep-wake phase disorder (DSWPD), with a consistent recurrent pattern of delayed sleep onset The rs143641898 [NM_033282.4:c.502C&amp;gt;T p.(Arg168Cys)] variant in the OPN4 gene that was shown in a functional study to render the OPN4 protein non-functional. Methods The analysis was conducted on whole genome sequencing samples obtained from patients with a clinical diagnosis of DSWPD. Age and sex-matched samples were used as controls. Results Here we report an enrichment of OPN4 rare coding variants, MAF&amp;lt; 1, in a set of 117 DSWPD samples as compared to 315 healthy controls. This significant enrichment likely implies that other rare pLOFs can similarly contribute to the delayed sleep phenotype. Moreover, we report a significant association of rs rs1079610, a common variant in OPN4 – with delayed bedtime in DSWPD patients. This variant has been previously reported in association with altered pupillary responses. This effect is not seen in a large set of healthy controls without DSWPD diagnosis. Conclusion The OPN4 discussed rare OPN4 variants likely increase the risk of DSWPD via its direct effect on the pathophysiology along the melanopsin axis. This study offers useful insights for the differential diagnosis and ultimately treatment of DSWPD risk in which patients carry pathogenic variants in the OPN4 gene. Support (if any)

Characterization of sleep in emerging adults with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor

Characterization of sleep in emerging adults with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor