搜索结果：Journal of biological rhythms

Dysregulation of the serotonergic system is consistently noted in cases of psychiatric pathology. Circadian rhythm dysregulation is also a common comorbidity in psychiatric populations, and the circadian and serotonergic systems have a long history of coregulation. Despite this, it is not yet known whether serotonergic neurons house circadian molecular clocks, the transcription and translation feedback loops that drive circadian rhythms at the cellular level. To investigate this, brain tissue was extracted from adult male rats every 4 h throughout the light-dark cycle. Radiolabeled in situ hybridization was used to quantify clock gene expression in the dorsal and median raphe, the two nuclei responsible for providing the majority of serotonin to the brain. We discovered oscillatory rhythms in the expression of clock genes Bmal1, Per1, and Per2 with a period of approximately 24 h, and confirmed via fluorescent in situ hybridization that serotonergic (positive for Tph2, the rate-limiting enzyme in serotonin synthesis) neurons do express clock genes. The roughly antiphasic relationship between Bmal1 and the Per genes supports the existence of a circadian molecular clock in these cells. We next measured clock gene expression in neighboring brainstem regions that were not serotonergic, and found that although they all had similar daily clock gene expression profiles, the dorsal and median raphe had higher amplitude Bmal1 expression, and trending higher amplitude Per1 expression. This study adds to the growing list of extra-SCN (suprachiasmatic nucleus) molecular clocks reported in the brain. The prevalence of this circadian machinery, especially in regions of the brain so relevant to psychiatric health, underscores the importance of circadian rhythms to well-being. A greater understanding of the unique nature of circadian rhythms in discrete brain regions is a fruitful frontier for improving psychiatric treatment outcomes and overall health.

To estimate the role of disability mainly in the link between chronobiological factors (sleep, light exposure, and rest/activity patterns) and depressive symptoms in people with fibromyalgia (FM). A cross-sectional study was conducted on a cohort of 197 women, aged 18-65, diagnosed with FM. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI), while FM-related disability was assessed through the Fibromyalgia Impact Questionnaire (FIQ). Actigraphy data (activity and light exposure) over 10 consecutive days and sleep-related behaviors were assessed. Mediation models were performed to investigate the direct and indirect (through FIQ) effects of chronobiological parameters on depressive symptoms. A negative Direct Effect (DE) was identified between BDI scores and light interdaily stability (DE = -4.89), as well as sleep duration on free days (DE = -0.81). There were also Indirect Effects (IE) through FIQ of both intradaily variability of activity rhythms (IE = 3.02) and sleep duration on workdays (IE = -0.47) on BDI scores. Our findings offer evidence that disability due to fibromyalgia symptoms mediates the relationship between rhythm fragmentation and severity of depressive symptoms, providing insights for improved care and therapeutic interventions in fibromyalgia.

Skeletal muscle regeneration is a dynamic process diurnally regulated by circadian rhythms, which govern key myogenic factors. Previous studies have shown that the timing of muscle injury influences early regeneration outcomes, but it remains unclear whether these effects persist beyond early acute regeneration events. This study investigated whether the time of day at which muscle injury occurs alters postregeneration outcomes in mice. C57BL/6NCrl mice (n = 80) received bilateral cardiotoxin (CTX) injury to the tibialis anterior (TA) during either the rest phase (ZT2-ZT4) or active phase (ZT14-ZT16), with tissues collected at 7- or 42- days postinjury (DPI). All mice were matched with uninjured controls. Gross functional performance, assessed via rotarod and grip strength testing, demonstrated no differences between rest and active phase injury groups across repeated testing. A series of immunohistological analyses was performed to assess general fiber morphology and markers of regenerative state. Although the injury phase had largely no effect on most parameters, myofiber size distributions consistently displayed more small fibers in rest phase-injured mice, regardless of sex. Although there were notable differences in myosin isoform expression, such trends were observed at both 7 and 42 DPI, suggesting a specific morphological effect of injury timing. These findings indicate that the circadian phase at which skeletal muscle injury occurs causes a persistent influence on the size distribution of regenerating myofibers, independent of functional recovery, and highlights the need to consider time-of-day and the contribution of postinjury activity as a biological variable in muscle regeneration research.NEW & NOTEWORTHY The timing of skeletal muscle injury influences myofiber morphology postregeneration. Although functional capacity was unaffected by injury timing, muscles injured in the circadian rest phase exhibited a greater quantity of smaller myofibers compared with their active phase counterparts. This was not accompanied by differences in regenerating cell morphology or nuclear centralization. This research suggests that circadian timing of injury exerts a lasting effect on muscle regeneration, and may reflect time-of-day-specific regulation of muscle remodeling.

Circadian (24 h) rhythmicity is a nearly-ubiquitous property of eukaryotic cells, and the mechanisms that generate this rhythmicity have been studied in a number of organisms for many years. However, there are still gaps in our understanding of the generation and regulation of rhythms. Although transcription/translation feedback loops (TTFLs) are said to be essential to generating rhythmicity in eukaryotes, there are many examples of rhythmicity seen in organisms without functioning TTFLs. Our lab previously found that two genes that function in the TOR (Target of Rapamycin) pathway, vta and gtr2, are essential for non-TTFL rhythmicity in the fungus Neurospora crassa. These two mutants were also shown to dampen the output rhythm of spore-formation (conidiation) and the rhythm of the TTFL component protein FRQ, and dampen the amplitude of the underlying oscillator in strains with functioning TTFLs. Therefore, we are interested in the role of TOR in generating and/or sustaining rhythmicity in both the presence and absence of a functioning TTFL. Here we report the development and validation of an improved assay for TOR activity in Neurospora, and using this assay we demonstrate that TOR activity displays circadian rhythmicity in strains with functioning TTFLs. The period of TOR rhythmicity is affected by a long-period mutation in a TTFL component (frq7), and the TOR rhythm is dampened in the vta and gtr2 knockouts. The mean level of TOR activity (mesor) in the vta and gtr2 knockout mutants is within the range of the TOR rhythm in wild type, indicating that it is rhythmicity of TOR, not a constant level of activity, that is required to sustain output rhythmicity. These results establish Neurospora as a valuable model for investigating the role of TOR in circadian rhythmicity and implicate TOR activity as a rhythmic state variable of the circadian system.

Circadian neuronal plasticity describes daily recurring changes at the level of neuronal morphology, connectivity and synaptic processes. Disturbance of these plastic changes could result in inflexibility of an organism to adapt behavior to changing environmental cues. The mitogen activated protein kinases (MAPK)/ERK signaling pathway is involved both in circadian processes and neuronal plasticity. Ribosomal S6 kinases (RSK) act as downstream mediators of ERK signaling with apparently pleiotropic-but sometimes poorly understood- functions in the nervous system. This is illustrated by some major gaps in our understanding of the pathophysiological processes caused by RSK2 mutations in humans that lead to intellectual disabilities. Previous studies described the role of Drosophila RSK as one regulator of the molecular circadian oscillator. Here we could show that RSK kinase activity is required to control another aspect of circadian rhythmicity, the daily remodeling of the dorsal branching pattern of the small ventral lateral neurons (s-LNv) as the central pacemaker cells. Loss of RSK function resulted in more fasciculated and less branched s-LNv's in the early morning, which could affect synaptic in- or output connectivity. Increased fasciculation correlated with a reduced number of Bruchpilot sites as a marker for presynapses. Analysis of the expression of the Pigment Dispersing Factor PDF in s-LNv's, the most important signaling factor between clock neurons, revealed no evidence of changes in RSK mutants. Consistent with unaffected PDF signaling as a major output from the s-LNv's, RSK mutant flies are rhythmic. Their free-running rhythms show even a significantly higher power than those of the wild-type controls. This robustness is at the expense of flexibility to adapt their activity to variations in light conditions. Together with the known role of RSK in olfactory learning and memory processes our results suggest that RSK is required to maintain experience dependent plasticity.

The circadian system coordinates daily physiology across nearly all tissues to temporally organize metabolism and maintain homeostasis. In the brain, circadian timing regulates neural activity, cellular function, and neuroimmune signaling, which is especially important during development. Yet, the ontogeny of circadian regulation during neurodevelopment remains poorly defined. Here, we characterized time-of-day variation in core clock and neuroimmune genes across multiple brain structures during early postnatal development, alongside circulating corticosterone concentrations. Using male and female C57BL mice housed in a standard light-dark cycle [12:12 light (150 lux)/dark (0 lux)], we measured the expression of Per1, Per2, and Rev-erbα in the suprachiasmatic nucleus, hippocampus, and medial prefrontal cortex, as well as in neuroimmune tissues (choroid plexus, meninges, and isolated microglia) across postnatal days (PND) 1-24. Across development, rhythms were seen in corticosterone concentrations and all brain regions, with increased amplitudes and gene-specific phase maturation toward adult-like timing by PND 24. Notably, the choroid plexus and meninges exhibited time-of-day differences in clock gene expression by PND 10-24. In contrast, isolated microglia did not display detectable time-of-day differences in clock gene expression; however, microglial phagocytic activity varied by time of day. Together, these findings demonstrate that circadian regulation of the brain emerges during the neonatal period, and the parameters of time-of-day differences are tissue- and gene-specific during development. In addition, functional rhythms may precede or occur independent of detectable transcriptional differences. This work establishes a developmental framework for circadian-neuroimmune interactions, with important implications for neuroimmune development and vulnerability. Given the neuroimmune system's role in shaping brain development, disruptions in these temporal processes may contribute to neurodevelopmental or mood disorders.

This study investigated the independent and joint associations of rest-activity circadian rhythms (RACRs) and physical activity (PA) with all-cause and cardiovascular mortality, and explored the potential role of accelerated biological aging. We included 6621 adults from NHANES 2011-2014. RACR parameters were derived from wrist-worn ActiGraph GT3X+ data. Accelerated biological aging was assessed using Phenotypic Age Acceleration (PhenoAgeAccel) and Biological Age Acceleration (BioAgeAccel). Cox proportional hazards models were applied to investigate the associations of RACRs and PA with all-cause and cardiovascular mortality. Exploratory mediation analyses were used to explore the associations between accelerated biological aging, RACRs, and mortality risks. Over a median follow-up of 6.75&#x2009;years, 518 all-cause deaths and 165 cardiovascular deaths were recorded. Compared with weak RACRs and inadequate PA, participants with strong RACRs and adequate PA had significantly lower risks of all-cause mortality (HR: 0.35, 95% CI: 0.24 to 0.51; p&#x2009;<&#x2009;.001) and cardiovascular mortality (HR: 0.25, 95% CI: 0.14 to 0.45; p&#x2009;<&#x2009;.001). In exploratory analyses, PhenoAgeAccel accounted for an estimated 13.55% (p&#x2009;<&#x2009;.001) and 21.67% (p&#x2009;=&#x2009;.002) of the associations between RACRs and all-cause and cardiovascular mortality, respectively, while BioAgeAccel accounted for an estimated 5.06% (p&#x2009;<&#x2009;.001) and 8.06% (p&#x2009;=&#x2009;.004). Disrupted RACRs are associated with higher mortality risks that could be attenuated by adequate physical activity. Exploratory analyses suggest that the associations between RACRs and mortality may be mediated in part by accelerated biological aging, but additional studies are needed to test this hypothesis.

In adult samples, tightly-controlled laboratory studies indicate the presence of circadian rhythms in positive (and negative) affect. Naturalistic studies also suggest the presence of diurnal positive affect rhythms in adults, the characteristics (acrophase, mesor, and amplitude) of which vary by self-report circadian preference-greater evening preference is associated with later acrophase, lower mesor, and lower amplitude in positive affect. We examined the extent to which diurnal affect rhythms are associated with 4 different measures of circadian timing, including dim light melatonin onset, in a sample of high-school adolescents who reported at least one drink of alcohol in their lifetime (N&#x2009;=&#x2009;126, 17.3 &#xb1; 0.87&#x2009;years, 55.6% female). Cosinor models found support for robust diurnal rhythms in positive, but not negative, affect. The overall modeled positive affect rhythm had an acrophase at 3:39 PM, a mesor of 9.77, and an amplitude of 1.61. Later circadian timing was associated with later acrophase in positive affect rhythms across the following measures: circadian preference (3:00 PM vs 4:20 PM, p&#x2009;<&#x2009;.001), chronotype (3:20 PM vs 4:11 PM, p&#x2009;=&#x2009;.014), and actigraphy-based midsleep (3:08 PM vs 4:16 PM, p&#x2009;=&#x2009;.014). We did not find significant associations between circadian phase (dim light melatonin onset) and positive affect rhythms. We also explored weekday-weekend differences in positive affect rhythms, finding significantly higher mesor (9.71 vs 9.99, p&#x2009;=&#x2009;.004) and lower amplitude (1.69 vs 1.26, p&#x2009;=&#x2009;.008) on the weekends than weekdays. In sum, compared to their peers, adolescents with later sleep and circadian timing experience a delayed peak in positive affect during the day, which may have consequences for behavioral activation and depressed mood. These findings underscore the importance of considering the role of sleep and circadian factors in affective processes during adolescence.

The temporal organization of biological activities by circadian clocks is pivotal for the survival of organisms. Significant progress has been made in understanding the molecular foundations of animal circadian clocks through the characterization of key components, such as CLOCK, BMAL1/Cycle (CYC), Period (PER), Timeless, and Cryptochrome (CRY) in several model organisms. To determine the extent of conservation of these elements, we investigated the sequences of these genes and their paralogs across 46 animal species that encompass multiple phyla in the Metazoan kingdom to resolve the relative timing of duplication and loss events that have diversified core clock components. Using analyses of orthology and protein-protein binding predictions, we identified and characterized elements in diverse animal species. Based on these analyses, we propose a circadian molecular mechanism employed by the ancestor of all animals. We also identify derived losses and expansions of circadian elements in smaller animal clades and provide insight into the evolutionary pressures faced by their ancestors to change such an important piece of internal machinery. Our study is the first systematic analysis of the deep phylogeny of nearly all major clades of extant animals.

The Moon's motion around the Earth is complex, governed by interactions among several types of cycles that arise from different aspects of its orbit. The 29.53-day synodic cycle occurs as the Moon passes through new-moon and full-moon alignments (syzygies) with the Earth and the Sun. The 27.32-day tropical cycle occurs as the Moon moves back and forth between its northernmost and southernmost positions (standstills) relative to the plane of the Earth's equator. The 27.55-day anomalistic cycle occurs as the Moon moves back and forth from its nearest and farthest distances from the Earth (perigees and apogees). The Moon's effects on luminance and gravity at the Earth's surface are greatest at times of syzygies, standstills, and perigees. Here, based on periodogram analyses of 14.5 patient-year records of a circular, rapid cycling type of bipolar disorder, we show that onsets of mania in a given individual can recur in association with 2 or more lunar cycles simultaneously, and with conjunctions of syzygies of the synodic cycle with standstills of the tropical cycle or with perigees of the anomalistic cycle. The results are consistent with the fact that the Moon's effects at the Earth's surface are the result of interactions among all of its constituent cycles, and they highlight the potential importance of long-term longitudinal designs in studies of lunar influence.

This review summarizes recent insights into the roles of the circadian clock in regulating cancer hallmarks, with a focus on its impact on the tumor microenvironment, and highlights the translational promise of circadian-informed strategies for cancer therapy. The circadian clock is a 24-hour biological timekeeping system that aligns physiological processes with cyclic environmental cues, such as light-dark cycles. Disruptions of circadian rhythms caused by lifestyle factors, including shift work, irregular sleep patterns, and jet lag, can lead to physiological dysregulation and increased risk of various diseases including cancer, positioning the circadian clock as both a critical driver of tumorigenesis and a potential target for chronotherapies. This review provides a comprehensive overview of circadian regulation in tumorigenesis across diverse cancer types by framing its role according to established cancer hallmarks, with particular emphasis on how the circadian system shapes immune cell dynamics within the tumor microenvironment to modulate tumor progression and immune surveillance. We further discuss recent preclinical and clinical advances in chronotherapy, highlighting how aligning therapeutic interventions with biological rhythms can enhance treatment efficacy, including responses to immunotherapy. By integrating mechanistic insights with translational applications, this review bridges circadian biology and oncology, providing a framework for future chronobiology-based cancer therapies.

Adolescents experience chronic sleep restriction and developmental changes in circadian biology. Sleep aids adolescent learning and memory; the moderating effect of circadian rhythms is largely unknown. Here we examine adolescent sleep restriction, circadian biology, and memory consolidation. Adolescents were recruited for a larger experimental study. This study includes a subsample of individuals from the larger study who completed the motor sequence task (MST; added toward the end of data collection). Participants (MAGE&#x2009;=&#x2009;12.7, SD&#x2009;=&#x2009;1.8; 62.5% male) completed a self-selected 9&#x2009;h in bed sleep stabilization schedule for 19 nights followed by 7 nights of sleep restriction (6 h in bed; bedtime delayed and risetime advanced equally). In-lab dim light melatonin onset (DLMO) was assessed on the final nights of stabilization and restriction. The MST indexed overnight memory consolidation across the final night of sleep restriction. MST outcomes included the average number of correct sequences per trial, # of errors, and precision. We examined overnight improvement (morning-evening) in MST performance and associations between improvement, phase preference, DLMOStabilization, DLMORestriction, and DLMOShift (DLMOStabilization - DLMORestriction), controlling for age where statistically justified. The average number of correct sequences per MST trial improved, t(15)&#x2009;= -3.44, p&#x2009;<&#x2009;0.01, d&#x2009;=&#x2009;0.86, for the morning (12.94&#x2009;&#xb1;&#x2009;6.89) test session compared to evening (10.81&#x2009;&#xb1;&#x2009;5.69). There were no changes in errors or precision (ds&#x2009;<&#x2009;0.14, ps&#x2009;>&#x2009;0.34). Greater delays in DLMO phase (M&#x2009;&#xb1;&#x2009;SD: 10.34&#x2009;&#xb1;&#x2009;41.69&#x2009;min) were associated with greater overnight improvement in the average number of correct sequences per trial, Adj. R2&#x2009;=&#x2009;0.54, F(2, 13)&#x2009;=&#x2009;9.79, p&#x2009;<&#x2009;0.01, and errors, Adj. R2&#x2009;=&#x2009;0.21, F(1, 15)&#x2009;=&#x2009;4.94, p&#x2009;<&#x2009;0.05. Overnight improvement was not related to phase preference (Adj. R2s&#x2009;<&#x2009;0.17; ps&#x2009;>&#x2009;0.05). These data highlight context dependent benefits of sleep for adolescent memory consolidation and indicate a potential link between circadian biology and the cognitive benefits of adolescent sleep. Understanding the influence of circadian rhythms in sleep-dependent memory may inform discussions of adolescent sleep loss and learning.

Mapping of heart rhythms is influenced by the size and configuration of the mapping electrodes. Whether a recorded electrogram represents near (local) or remote activity influences diagnosis and treatment, yet is affected by mapping characteristics that are often undefined. We developed biophysical computational models to predict interactions between the recording tool and cardiac tissue in coherent and disorganized rhythms, which we validated in clinical recordings. Biophysical computational models demonstrated the ability to quantify and visualize the recording antennae for different electrode configurations. Our results show that unipolar electrograms reflected a recording antenna within 3-dimensional ellipsoids of radius 8 mm across-tissue and 2.7 mm transmurally. Bipolar electrogram antennae align with propagation direction in ellipsoids of long axis radius 1.7, 5.7, and 8.3 mm for 2, 5, and 10 mm spacing, respectively, and often extend beyond the physical extent of electrodes. Notably, omnipolar electrograms, constructed from orthogonal bipoles in a triangular configuration, retained some directional preferences of bipolar electrograms, with a complex relationship between electrode orientation and wave direction. When tested clinically on high-resolution, narrow field (grid) catheters and moderate-to-low resolution, global (basket) catheters, antennae varied more with electrode type (correlation coefficient of 0.43 unipolar, 0.05 bipolar, and 0.26 omnipolar; P<0.001) and spacing (correlation coefficient of 0.36 versus 0.42; P=0.002) than the precise electrode size. This novel computational-clinical system approach enabled us to systematically compare electrode configurations. This work may help interpret signals in complex biological rhythms, such as atrial fibrillation, and may influence the design of novel catheter configurations and signal processing approaches to identify local tissue signals.

Both active movement profiles and robust circadian rhythms are linked to improved health outcomes, yet the underlying mechanisms remain partially understood. We investigated this relationship in young adults (n&#x2009;=&#x2009;169, aged 18-30&#x2009;years) under real-world conditions using actigraphy data. We performed k-means clustering on 12 accelerometer-based features capturing magnitude, duration, frequency, and intensity distribution to derive movement behavior profiles. As a proxy of circadian rhythms integrity, we computed the Circadian Function Index (CFI), which combines intradaily variability, interdaily stability, and relative amplitude. We also assessed circadian phase and sleep quality parameters. In addition, we quantified light exposure and physical activity over 3-h daily intervals. The unsupervised algorithm identified 2 non-overlapping profiles among participants, the More Active (MA) and the Less Active (LA) profiles. MA exhibited a higher CFI (0.81&#x2009;&#xb1;&#x2009;0.06 vs 0.69&#x2009;&#xb1;&#x2009;0.06, p&#x2009;<&#x2009;0.001), which was also positively associated with early-evening physical activity, but not with light exposure. MA also showed an earlier activity-based phase indicator, the midpoint of the 5 least-active hours (L5c, 04:30&#x2009;&#xb1;&#x2009;01:03 vs 04:59&#x2009;&#xb1;&#x2009;01:15, p adj.&#x2009;=&#x2009;0.04), which was inversely associated with early-morning physical activity and late-morning light exposure. We found no differences in sleep quality between MA and LA. Our results underscore the association between movement behavior and overall circadian rhythms integrity. Importantly, these findings reinforce actigraphy as a multidimensional tool for both health research and clinical applications.

PURPOSE: Adults with Autism Spectrum Disorder (ASD) often experience significant challenges that affect their quality of life (QoL), including mental health issues, socioeconomic strain, and circadian rhythm disruptions. Chronotype, or an individual&#x2019;s biological preference for sleep-wake patterns, has been associated with well-being in neurotypical populations but remains underexplored in adults with ASD. This study aimed to investigate the association between chronotype and perceived QoL in Brazilian adults with ASD. METHODS: We conducted a cross-sectional, web-based survey as part of the SOLACE-ASD Brasil project. A total of 439 adults (&#x2265;&#x2009;18 years) with a self-reported diagnosis of ASD completed standardized questionnaires assessing chronotype (Morningness-Eveningness Questionnaire) and QoL (EUROHIS-QOL 8). Sociodemographic, behavioral, and clinical variables were also collected. Associations were examined using multiple linear regression and ANCOVA, adjusting for potential confounders. RESULTS: Intermediate chronotype was the most prevalent (40.1%), followed by evening (38.7%) and morning (21.2%) chronotypes. Overall, 60.4% of participants reported low QoL. Evening-type individuals had significantly lower overall and physical health QoL scores than morning and intermediate types. In multivariate analysis, evening chronotype, unemployment, low income, tobacco use, and physical inactivity were independently associated with lower QoL. CONCLUSION: Chronotype is an independent predictor of QoL in adults with ASD, with evening preference linked to worse outcomes. These findings highlight the importance of considering circadian biology in public health strategies and suggest that chronotype-targeted interventions could improve QoL in this population. Adults with autism spectrum disorder (ASD) often face challenges that affect their daily lives, including mental health struggles, sleep problems, and limited access to work or social support. This study explored whether a person&#x2019;s natural sleep pattern, called chronotype, is related to how they feel about their quality of life. Chronotype refers to whether someone tends to be more active in the morning, in the evening, or somewhere in between. The study included 439 adults with ASD in Brazil who answered online surveys about their daily habits, health, and well-being. Most participants reported low quality of life, especially those who preferred staying up late (evening chronotype). These individuals also had more physical health complaints. The main finding is that having an evening chronotype is linked to lower quality of life in adults with ASD, even when other factors like income, employment, and physical activity are considered. This means that sleep-wake patterns may play an important role in how adults with ASD experience daily life. These results suggest that helping adults with ASD create better sleep routines, or adjusting work and school schedules to fit their natural rhythms, might improve their well-being.

During dark adaptation, pupil size changes in association with visual adaptation processes; however, the influence of diurnal phase (daytime vs nighttime) and aging on these changes remains unclear. In this study, we examined pupil size changes during dark adaptation across the daytime and nighttime in young, middle-aged, and aged C57BL/6N mice. In young mice, pupil size reached a maximum shortly after the onset of dark adaptation and then gradually decreased during the daytime, whereas it remained dilated during the nighttime. Furthermore, dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) significantly attenuated the gradual pupillary constriction following pupil dilation during dark adaptation in the daytime, suggesting a possible involvement of dopaminergic signaling in the later phase of the response. In middle-aged mice, pupillary light reflex-evoked constriction was preserved; however, the early (rapid) phase of constriction following the initial dilation during daytime dark adaptation was impaired, whereas the later (delayed) phase remained largely comparable to that in young mice, suggesting age-related alterations in regulatory mechanisms rather than a loss of constriction capacity. Pharmacological analyses further suggested that distinct neural mechanisms may differentially contribute to these temporal phases. In aged mice, maximal pupil dilation during dark adaptation was significantly reduced during both the daytime and nighttime. In addition, aged mice exhibited distinct abnormalities in pupil dilation immediately after the onset of dark adaptation during the nighttime, indicating mechanisms that differ from those observed in middle-aged mice. Together, these results demonstrate that pupillary dynamics during dark adaptation are modulated by diurnal phase and progressively altered with aging. Thus, analysis of pupil dynamics during dark adaptation may provide a useful approach for detecting age-related changes in neural function.

Disruptions in sleep and circadian rhythms have been consistently linked to higher mortality rates in the general population. Among cancer patients, these disruptions are not only prevalent but may significantly influence prognosis. Despite this, sleep and circadian trajectories remain unexplored in the context of cancer, particularly related to prognostic outcomes in modern therapies such as immune checkpoint inhibitors (ICIs), which are rapidly transforming oncological care. In this pioneering report, we examined how trajectories of sleep and circadian rhythms relate to prognostic outcomes in patients with non-small cell lung cancer (NSCLC), offering novel insights into their potential role as modifiable biomarkers of clinical outcomes. Forty-nine treatment-na&#xef;ve NSCLC patients were enrolled in this prospective longitudinal study. Continuous 24-h recordings of circadian function (Circadian Function Index [CFI]) were collected over the first 5 months of treatment, alongside weekly assessments of insomnia severity (Insomnia Severity Index [ISI]) and estimations of total sleep time (TST) derived from sleep diaries every 3 weeks. Follow-up data, time to treatment discontinuation, disease progression, and cancer-related death were obtained from medical records. We estimated hazard ratios (HRs) for these outcomes based on ISI, TST, and CFI, analyzed as continuous variables and median-split. Cox regression analyses indicated that patients with trajectories portraying circadian robustness below the median had a higher risk of earlier progression (HR&#x2009;=&#x2009;3.75, 95% confidence interval [CI] = [1.475-9.536], p&#x2009;=&#x2009;0.005) and death (HR&#x2009;=&#x2009;3.07, 95% CI = [1.128-8.360], p&#x2009;=&#x2009;0.028). No significant associations were found between insomnia severity, TST, and the prognostic outcomes. Patients with more pronounced declines in circadian robustness demonstrated significantly elevated risks of disease progression and mortality. As the circadian rhythm is modifiable, these findings, if replicated, underscore the need for interventional studies aimed at stabilizing circadian rhythms to further explore potential improvements in patient outcomes and efficacy of cancer therapies.

Night shift work is linked to more severe coronavirus pneumonia, suggesting that host resilience to these pathogens may depend on the timing of exposure. Here, we examined how the time of day influences the severity of coronavirus pneumonia in mice, using mouse hepatitis virus-1 (MHV-1) as a natural infection model. We found that the timing of infection influenced MHV-1 severity, with the highest mortality, peak viral load, and lung inflammation occurring with midday infection, which corresponds to the mid-rest phase in mice and is comparable with nighttime in humans. The time-of-day dependence in disease severity occurred prominently in males and was sensitive to global disruption of the clock gene Bmal1. Midday infection correlated with increased MHV-1 binding to and replication within alveolar macrophages (AM). Depleting AMs with clodronate or loading them with neutral liposomes before MHV-1 infection eliminated differences in pneumonia survival and peak viral load related to the timing of infection. These data suggest an immunologic rhythm underlying coronavirus outcomes, in which oscillations in "first contact" interactions between AMs and the virus shape subsequent pneumonia severity.

The circadian clock is tightly connected to metabolism, which is evident in the various metabolic processes performed by the liver. Perturbation of these processes due to circadian dysregulation leads to liver-specific pathology. The liver is composed of multiple cell populations, each with distinct functions contributing to organ homeostasis, but the individual contributions of these populations to circadian clock function are not yet known. Single-cell RNA sequencing provides the opportunity to understand clock function and oscillating gene expression within an organ system at the individual cell population level, allowing for a better understanding of the crosstalk between the circadian clock and metabolic pathways within the liver. Previously, barriers to achieving this goal included both the complexity of generating single-cell RNA-sequencing time series data and the complexity of data analysis. Herein, we established a protocol that enabled the generation of murine liver cell population time series data, as well as a methodological approach to evaluate the core molecular clock and oscillating gene expression in individual cell populations. Using a combination of the normalized coefficient of variation, clock-correlation, and pseudobulk analyses, we found a robust and aligned circadian clock in each of the hepatic cell populations. We then employed a pseudoreplicate/pseudobulk strategy to identify oscillating gene expression, and when benchmarked against bulk RNA-sequencing data, we demonstrated that many metabolic genes were oscillating in several of the cell populations, including non-hepatocyte clusters. Finally, we identified oscillating genes unique to specific cell populations that play critical roles in liver function. The findings in this study provide a critical foundation for understanding clock function and the contributions of oscillating gene function at the individual cell population level in the liver.