Diurnal Rhythm Research Articles

Daily activity rhythm of sympatric ungulate species in Fanjingshan Reserve, China

Sympatric species inhabiting similar ecological niches can coexist by partitioning aspects of available ecological resources, such as temporal, spatial, and nutritional niches. Ungulates often coexist in the same habitat, resulting in temporal partitioning and divergence in foraging strategies and spatial utilization. To understand the temporal patterns of ecological differentiation and coexistence mechanisms among sympatric ungulates, we analyzed the monitoring data in Fanjingshan National Nature Reserve, Guizhou, China, from 2017 to 2022. Kernel density estimation was used to scrutinize disparities in diurnal activity patterns among four ungulates [tufted deer (Elaphodus cephalophus), Reeves' muntjac (Muntiacus reevesi), wild boar (Sus scrofa), and mainland serow (Capricornis milneedwardsii)] as well as the interspecies variances during different seasons, at diverse altitudes, and between breeding and non-breeding periods. Daily activity patterns differed significantly among four species, with those of tufted deer, Reeves' muntjac, and wild boar affected significantly by season and breeding cycle. In addition, the daily activity rhythms of four species were affected by altitude. Thus, the daily activity rhythms of these ungulates were resulted from a combination of environmental factors and interspecific competitive interactions, as well as the reproductive cycle of each species. Our results provided a scientific reference for the effective management of wildlife and forest ecosystems, and we suggest that knowledge of temporal dynamics should be integrated into conservation planning for these sympatric species.

Circadian fruit phenology: An overlooked crucial aspect of plant‐frugivore interactions

Abstract The intrinsic ability of plants to face environmental diel changes is paramount for flowering and interactions with pollinators and herbivores. Surprisingly, despite the commendable research efforts on the ecology and evolution of fruit‐frugivore interactions, very little is known about how fruit ripening and dropping vary throughout 24‐h cycle. Even less is known about the potential consequences of circadian fruit phenology on plant interactions with mutualistic and antagonistic frugivores. We illustrate for the first time how the circadian pattern of fleshy fruit dropping and its matching/mismatching with the diel activity of functionally diverse frugivores (fruit/seed predators, seed dispersers, pulp feeders) can drive the outcome of complex multispecies plant‐frugivore interactions. To that end, we used camera trapping to quantify the circadian fruit dropping of a mammal‐dispersed tree, Pyrus bourgaeana, and the diel activity patterns of its functionally diverse vertebrate frugivores during two fruiting seasons in two tree populations of Mediterranean Spain. Using a large data set (20,878 frugivore visits and 701 fruit‐dropping records), we evaluate the adaptive hypothesis that the circadian pattern of fruit dropping will match the diel activity of seed dispersers rather than that of fruit/seed predators. Fruit dropping during daytime doubled that at night‐time, being considerably consistent across and within seasons, study sites and individual trees. Specifically, overlaps between circadian patterns of fruit dropping across and within seasons (0.83 and 0.84 ± 0.02, respectively), study sites (0.95) and individual trees (0.68 ± 0.01) were always high. Whereas seed dispersers (mammalian carnivores) were mostly nocturnal, the most frequent fruit/seed predators (cervids) were mostly diurnal. Consequently, and contrary to our expectations, circadian fruit dropping was more aligned with the diel activity of overabundant fruit/seed predators than with that of carnivore seed dispersers. Our study illustrates how quantifying the circadian patterns of fruit dropping, the diel activity of functionally diverse frugivores, and the matching/mismatching between both patterns can contribute to a better understanding of multispecies plant‐frugivore interactions. Circadian fruiting phenology is an overlooked key attribute for most tropical and temperate fruiting plants, which patterns, mechanisms and outcomes must be fully investigated. Read the free Plain Language Summary for this article on the Journal blog.

Late-onset caloric restriction improves cognitive performance and restores circadian patterns of neurotrophic, clock and epigenetic factors in the hippocampus of male old rats.

Aging is a complex multifactorial process that results in a general functional decline, including cognitive impairment. Caloric restriction (CR) can positively influence the aging processes and delay cognitive decline. There is a rhythmic variation in memory and learning processes throughout the day, indicating the involvement of the circadian clock in the regulation of these processes. Despite growing evidence on the efficacy of CR, it has not yet been fully determined whether starting this strategy at an advanced age is beneficial for improving quality of life and eventually, for protection against age-related diseases. Here, we investigated the effect of late-onset CR on the temporal organization of the molecular clock machinery, molecules related to cognitive processes and epigenetic regulation, in the hippocampus of male old rats maintained under constant darkness conditions. Our results evidenced the existence of a highly coordinated temporal organization of Bmal1, Clock, Bdnf, Trkb, Dnmts, Sirt1, and Pgc-1α in the hippocampus of young adult rats. We observed that aging led to cognitive deficits and loss of circadian oscillations of all the above variables. Interestingly, CR restored circadian rhythmicity in all cases and, in addition, improved the cognitive performance of the old animals. This work would highlight the importance of the circadian clock and its synchronization with feeding signals, as the basis of the beneficial effects of CR. Thus, lifestyle modifications, such as CR, might be a powerful intervention to preserve hippocampal circadian organization and cognitive health during aging.

Genetic variants associated with chronic fatigue syndrome predict population-level fatigue severity and actigraphic measurements.

The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (CFS) is based on a constellation of symptoms which center around fatigue. However, fatigue is commonly reported in the general population by people without CFS. Does the biology underlying fatigue in patients with CFS also drive fatigue experienced by individuals without CFS? We used UK Biobank actigraphy data to characterize differences in physical activity patterns and daily temperature rhythms between participants diagnosed with CFS compared to controls. We then tested if single nucleotide variants (SNVs) previously associated with CFS are also associated with the variation of these actigraphic CFS correlates and/or subjective fatigue symptoms in the general population. Participants diagnosed with CFS (n = 295) had significantly decreased overall movement (Cohen's d = 0.220, 95% CI of -0.335 to -0.106, p-value = 2.42x10-15), lower activity amplitudes (Cohen's d = -0.377, 95% CI of -0.492 to -0.262, p-value = 1.74x10-6), and lower wrist temperature amplitudes (Cohen's d = -0.173, 95% CI of -0.288 -0.059, p-value = 0.002) compared to controls (n = 63,133). Of 30 tested SNVs associated in the literature with CFS, one was associated in the control population with subjective fatigue and one with actigraphic measurements (FDR < 0.05). The genetic overlap of CFS risk with actigraphy and subjective fatigue phenotypes suggests that some biological mechanisms underlying pathologic fatigue in CFS patients also underlie fatigue symptoms at a broader population level. Therefore, understanding the biology of fatigue in general may inform our understanding of CFS pathophysiology.

Eco-physiological approach to assessing the functional state of workers in geological prospecting expeditions during meridian movement between mid-latitudes and the Arctic region

BACKGROUND: The current challenge lies in defining the unique characteristics of compensatory and adaptive mechanisms formation, as well as the development of healthcare technologies for various forms of work in Arctic region conditions. AIM: To study associations between climate patterns and physiological responses to daily fluctuations in meteorological factors. Specifically, we aimed to investigate how these factors impact the cardiovascular system and psychophysiological well-being of workers during geological prospecting expeditions along the meridian travel between Tyumen (57° 09’ N) and Yamal (71° 11ʹ N). MATERIAL AND METHODS: A total of 115 men aged 20–40 years in mid-latitude conditions (baseline data) and during occupational relocation to the Arctic region comprised the sample. The examination included recording key indicators of the cardiovascular system (heart rate, blood pressure, mean arterial pressure, pulse pressure), ECG in standard unipolar and augmented leads, and psychophysiological assessments (evaluation of trait and state anxiety, stress diagnostics, regulation of self-control, and emotional lability). Additionally, to calculate the natural and climatic contrast of regions in Western Siberia, meteorological data and geomagnetic activity indicators were analyzed based on eight daily measurements over 12 months across 11 years using a unified system of meteorological station indicators in Tyumen and Kharasavey. RESULTS: The cardiovascular system experiences desynchronosis during meridian movement from middle latitudes to the Arctic region. This condition is influenced by the interregional climatic contrast and the differences in daily rhythm characteristics of meteorological data between the initial and final destinations. The interaction within the system of meteorological rhythms plays an important role in these variations. CONCLUSION: The established associations within the ‘meteorhythms–biorhythms’ system underscore the necessity for developing regional norms for chronophysiological parameters of a healthy individual under specific environmental and climatic conditions. It also highlights the importance of dynamic monitoring of deviations in these parameters during occupational relocations between mid-latitudes and the Arctic region across different seasons. This approach is essential for the effective monitoring of maladaptive disorders and for predicting the potential development of pathologies.

Environmental Heat Stress Decreases Sperm Motility by Disrupting the Diurnal Rhythms of Rumen Microbes and Metabolites in Hu Rams.

Heat stress (HS) has become a common stressor, owing to the increasing frequency of extreme high-temperature weather triggered by global warming, which has seriously affected the reproductive capacity of important livestock such as sheep. However, little is known about whether HS reduces sperm motility by inducing circadian rhythm disorders in rumen microorganisms and metabolites in sheep. In this study, the year-round reproduction of two-year-old Hu rams was selected, and the samples were collected in May and July 2022 at average environmental temperatures between 18.71 °C and 33.58 °C, respectively. The experiment revealed that the mean temperature-humidity index was 86.34 in July, indicating that Hu rams suffered from HS. Our research revealed that HS significantly decreased sperm motility in Hu rams. Microbiome analysis further revealed that HS reshaped the composition and circadian rhythm of rumen microorganisms, leading to the circadian disruption of microorganisms that drive cortisol and testosterone synthesis. Serum indicators further confirmed that HS significantly increased the concentrations of cortisol during the daytime and decreased the testosterone concentration at the highest body temperature. Untargeted metabolomics analysis revealed that the circadian rhythm of rumen fluid metabolites in the HS group was enriched by the cortisol and steroid synthesis pathways. Moreover, HS downregulated metabolites, such as kaempferol and L-tryptophan in rumen fluid and seminal plasma, which are associated with promotion of spermatogenesis and sperm motility; furthermore, these metabolites were found to be strongly positively correlated with Veillonellaceae_UCG_001. Overall, this study revealed the relationship between the HS-induced circadian rhythm disruption of rumen microorganisms and metabolites and sperm motility decline. Our findings provide a new perspective for further interventions in enhancing sheep sperm motility with regard to the circadian time scale.

Circadian variation pattern of sudden cardiac arrest occurred in Chinese community

BackgroundThe circadian variation pattern of sudden cardiac arrest (SCA) occurred in Chinese community including both community healthcare centres and primary hospitals remains unknown. This study analysed the circadian variation of...

Pharmacological Management of Sleep-Wake Disturbances in Delirium.

Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep-wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow-wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA-approved medications for delirium or delirium-related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non-pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re-regulation of sleep-wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision-making regarding these interventions.

Cardiovascular autonomic function in middle-aged people with long-term cervical and upper thoracic spinal cord injuries

Objectives To examine cardiovascular autonomic function in middle-aged people with long-term cervical and upper thoracic spinal cord injury (SCI) compared with the general population, and explore if the neurological level of injury (NLI) is related to cardiovascular autonomic function. Design Population-based cross-sectional study with matched controls. Setting Outpatient SCI unit in Southern Sweden. Participants Twenty-five individuals (20% women, mean age 58 years and mean time since injury 28 years, NLI C2-T6, American Spinal Injury Association Impairment Scale A-C) from the Swedish SPinal Cord Injury Study on Cardiopulmonary and Autonomic Impairment (SPICA). Matched controls were obtained from the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) at a ratio of 5:1. Interventions Not applicable. Outcome measures 24 h electrocardiography and deep breathing tests. 24 h ambulatory blood pressure (BP) monitoring and orthostatic BP tests. Results In individuals with SCI compared with controls, heart rate variability (24h mean SD of the normal-to-normal interval 112 ms vs 145 ms, P < 0.001) and diastolic orthostatic BP increase (2.0 and 9.4 mmHg, P < 0.001), were significantly lower, whereas BP variability was significantly higher (24h mean systolic SDBP 17.8 mmHg vs 15.7 mmHg, P = 0.029). Circadian patterns of heart rate variability and BP (lack of nocturnal dip) were significantly different among the individuals with SCI than controls. Higher NLI was significantly (P < 0.05) correlated with impairments to various cardiovascular autonomic function variables. Conclusions This exploratory study indicates that cardiovascular autonomic function is impaired in middle-aged people with long-term cervical and upper thoracic SCI compared with the general non-SCI population, and more pronounced with a higher NLI. Future research is needed to understand the pathophysiological mechanisms underlying these impairments, and the prognostic significance for individuals with SCI. Trial registration ClinicalTrials.gov identifier: NCT03515122.

Metabolic Rate of Goldfish (Carassius auratus) in the Face of Common Aquaculture Challenges.

This study examined the metabolic rate (MO2, oxygen consumption) of goldfish (Carassius auratus) under normal management conditions in aquaculture. Using an intermittent respirometry system, we assessed daily variations and the effects of feeding, handling, temperature increase, and anesthetics. MO2 exhibited a daily rhythm, with higher values during day. Feeding to satiety produced a 35% increase in MO2 compared to fasted animals, with a maximum peak after 3 h and returning to baseline after 7 h. Handling stress (5 min) produced a 140% MO2 peak (from 180 to 252 mg O2 kg-1 h-1), returning to the routine MO2 after 2.5 h. An increase in water temperature (+0.1 °C min-1) up to 30 °C caused MO2 to peak at 200% after 2.5 h from the start of the temperature increase. The use of common anesthetics in aquaculture (MS-222, 2-phenoxyethanol and clove oil in deep anesthesia concentration) affects MO2 during the first few minutes after anesthetic recovery, but also during the following 4 h. It can be concluded that the metabolic rate is a good indicator of the goldfish's response to aquaculture practices involving energy expenditure and stress. Thus, intermittent respirometry is a valuable non-invasive tool for understanding and improving fish welfare in aquaculture.

Experimentally Elevated Levels of Testosterone Advance Daily Onset of Activity in Short-Day Housed Male House Sparrows (Passer domesticus).

Seasonal changes in sleep/wake cycles and behaviors related to reproduction often co-occur with seasonal fluctuations in sex hormones. Experimental studies have established that fluctuations in circulating testosterone mediate circadian rhythms. However, most studies are performed under constant lighting conditions and fail to investigate the effects of testosterone on the phenotypic output of circadian rhythms, that is, chronotype (daily activity patterns under light:dark cycles). Here, we experimentally elevated testosterone with implants during short nonbreeding daylengths in male house sparrows (Passer domesticus) to test if observed seasonal changes in chronotype are directly in response to photoperiod or to testosterone. We fitted individuals with accelerometers to track activity across treatment periods. Birds experienced three treatments periods: short day photoperiods before manipulation (SD), followed by testosterone implants while still on short days (SD + T). Implants were then removed. After a decrease in cloacal protuberance size, an indicator of low testosterone levels, birds were then photostimulated on long days (LD). Blood samples were collected at night, when testosterone peaks, to compare testosterone levels to daily onset/offset activity for experimental periods. Our results indicate that experimentally elevated testosterone under short nonbreeding photoperiods significantly advanced daily onset of activity and total daily activity relative to daylength. This suggests that testosterone, independent of photoperiod, is responsible for seasonal shifts in chronotypes and daily activity rhythms. These findings suggest that sex steroid hormone actions regulate timing of daily behaviors, likely coordinating expression of reproductive behaviors to appropriate times of the day.

6437 Analysis of 17-OH-Progesterone (17OHP) and Androstenedione (A4) Profiles To Rationalise Biochemical Monitoring Of CAH Patients

Abstract Disclosure: N.R. Lawrence: None. N.P. Krone: None. J.F. Dawson: None. Z. Lang: None. W. Arlt: Advisory Board Member; Self; Diurnal. A. Brac de la Perriere: Research Investigator; Self; Diurnal. A.L. Hirschberg: Research Investigator; Self; Diurnal. A. Juul: Research Investigator; Self; Diurnal. D.P. Merke: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Prete: Research Investigator; Self; Diurnal. A.E. Taylor: None. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. M. Stikkelbroeck: Research Investigator; Self; Diurnal. P.A. Touraine: Research Investigator; Self; Diurnal. G. Collins: None. R.J. Ross: Consulting Fee; Self; Diurnal. Background: There is no consensus on how to monitor biochemical control of CAH as excess ACTH overnight is common on standard therapy. Modified-release hydrocortisone (MRHC) gives potential for improved disease control and the need to understand this impact on disease monitoring.Aim: To define the relationship between 17OHP and A4, in healthy controls and CAH patients. Methods: Analysis of 24-hour 2-hourly 17OHP and A4 endocrine profiles in patients randomised to either standard treatment or MRHC (n=122, mean age 36.3 (SD 11.6) years, 78 female, 44 male) and a population of healthy controls (n=20, age 30.0 (12.3), 13 male, 7 female). Markers were regressed, cross correlated and assessed by Bayesian Change Point analysis using R. Results: Regressing the natural logarithms of 17OHP on A4, Bayesian multiple change point analysis converged on a stable changepoint equivalent to 17OHP of 4.5 nmol/L 149 ng/dl (95%, CI:4.2 to 4.7 nmol/L, Rhat &amp;lt; 1.008). Below the 17OHP change point A4 is proportionally lower than above, with no evidence of difference between sexes or steroid preparation. The relationship between 17OHP and A4 was different for healthy subjects, who for similar levels of A4 have lower levels of 17OHP than CAH patients in nmol/L (ng/dl): A4 of 1 (29) and 10 (286) associated with 17OHP 1.5 (50) and 8.8 (291) in healthy subjects’ vs 3.3 (109) and 71.2 (2353) in CAH patients, respectively. There was no consistent rhythm in either marker in healthy patients, shown by an autocorrelation function (ACF) that falls quickly to zero. ACF approaches zero more quickly in CAH patients on MRHC than those on standard therapy who more commonly exhibit a diurnal rhythm with an 0700hrs peak. There was no lag between markers, with cross-correlation function plots symmetrical. Conclusions: The relationship between 17OHP and A4 is different in CAH than healthy controls. In CAH, high A4 suggests poor control but a low A4 may still be associated with a raised 17OHP. In CAH patients, 17OHP concentrations within the healthy subject range are associated with A4 below levels seen in healthy subjects. When elevated in CAH patients, A4 and 17OHP rise and fall together with no lag; thus, A4 does not give more information on control over time. On MRHC the biomarkers show a reduced diurnal rhythm; therefore, individual measurements taken in clinic are more likely to reflect the daily average than measurements taken when on standard therapy. Presentation: 6/1/2024

8665 Female Fertility In Patients With Classic And Non-Classic Congenital Adrenal Hyperplasia Under Modified-Release Hydrocortisone (MR-HC)

Abstract Disclosure: L. Tschaidse: None. H.F. Nowotny: None. M. Auer: None. C. Lottspeich: None. M. Bidlingmaier: None. J. Hawley: None. B.G. Keevil: None. N. Reisch: None. Background: Female patients with classic and non-classic (NC) CAH struggle with fertility, due to androgen excess, elevated progesterone and 17-hydroxyprogesterone (17OHP) levels, causing anovulation, impairment of endometrial development and menstrual irregularities. The typical approach to treating infertility often includes an increase in glucocorticoid (GC) dose. However, this poses a potential risk of side effects. Limited observational data on modified-release hydrocortisone (MR-HC), which better mimics the physiological diurnal rhythm of cortisol secretion, indicates improved fertility in female and male patients with classic CAH. Therefore, the aim of this study was to investigate fertility in women with classic and non-classic CAH before and after switching to MR-HC. Methods: 21 adult female patients with CAH (14 classic; 5 NC) with a median (range) age of 33.0 (30.0) years, premenopausal and without hormonal contraception, were enrolled in this prospective, observational, single-centre study. The data collection took place before (conventional GC preparation) and after dose-equivalent switching the medication to MR-HC. In addition to clinical parameters such as menstrual cycle and desire to conceive, the collection of morning serum and daily saliva profiles was conducted, measuring progesterone, 17OHP, androstenedione (A4), testosterone, 11-ketotestosterone (11KT) as well as 11-hydroxyandrostenedione (11OHA4). Results: Before study inclusion, 4/21 patients had an irregular cycle, 5/21 were amenorrhoeic and 10/21 patients had a desire to have children. There was no difference in median (range) hydrocortisone dose equivalent before and after switching to MR-HC (25.0 (50.0) vs. 25.0 (30.0), p=.441). Median (range) morning serum concentrations between 8-10 am were not different before and after switch to MR-HC for progesterone (5.9 (55.5) vs. 5.0 (58.8), p=.823), 17OHP (5.9 (362.1) vs. 5.7 (73.7), p=.280), A4 (2.9 (25.6) vs. 2.5 (6.9), p=.106), testosterone (0.8 (3.5) vs. 0.7 (1.5), p=.063), 11KT (0.4 (7.4) vs. 0.2 (2.6), p=.242) and 11OHA4 (0.8 (12.9) vs. 0.9 (10.4), p=.231). Concerning saliva day profiles, we found a significantly lower median (range) 17OHP level in early morning saliva (43.0 (526.9) vs. 19.4 (264.3), p=.049). 5/9 patients with menstrual irregularities reported menstrual regularisation within and 5/10 patients with a desire to have children became pregnant after switching to MR-HC. Conclusion: Our preliminary data show clinical improvement in fecundity and fertility under MR-HC in both women with classic and NC CAH without a dose increase of glucocorticoids. Under MR-HC replacement lower 17OHP concentrations in early morning saliva reflect better hormonal control over night contributing to ovulatory cycle regulation and improved fertility. Presentation: 6/1/2024

7061 Incidence of Adrenal Crisis In Congenital Adrenal Hyperplasia (CAH) Patients During A Prospective Monitored Long-Term Study Of Modified-Release Hydrocortisone (MRHC) Capsules, (Efmody)

Abstract Disclosure: R.J. Ross: Consulting Fee; Self; Diurnal. D.P. Merke: Research Investigator; Self; Diurnal. A. Mallappa: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. A. Brac de la Perriere: Research Investigator; Self; Diurnal. A.L. Hirschberg: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Prete: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. M. Quinkler: Research Investigator; Self; Diurnal. P.A. Touraine: Research Investigator; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. Background: Adrenal crisis is the leading cause of excess mortality in patients with CAH[1]. Retrospective studies report an adrenal crisis incidence of 5-10/100 patient years (PY), with mortality 0.5/100 PY2. Modified-release hydrocortisone (MRHC) capsules, (Efmody), replicate cortisol diurnal rhythm and improve androgen control in CAH compared to standard glucocorticoid therapy2. Here, we report the incidence of adrenal crisis in CAH patients from a prospective study of MRHC in CAH patients. Methods: Patients completing MRHC Ph2 and Ph3 studies were eligible to enter a single-arm, open-label extension study. Study visits occurred at baseline, weeks 4, 12, 24 and 6-monthly thereafter. The primary endpoint was the safety of MRHC over time. Adrenal crisis was defined according to Allolio 20153. MRHC doses were adjusted on the basis of an adrenal insufficiency checklist, and measurement of androstenedione (A4) and 17-hydroxyprogesterone (17-OHP) at 9am and 1pm. Results: 91 patients entered the study, mean age 37 years, 68% female, 32% male. 22 discontinued; 11 at patient request, 5 due to pregnancy, 2 undergoing fertility treatment, 2 at physician/sponsor request, 1 due to an AE (carpal tunnel syndrome), and 1 due to death (myocardial infarction). Median treatment duration was 1500 days, range 0.2 to 5.8 years. Median MRHC dose at study entry was 30mg/day, reducing to 20mg/day from 24-weeks until end of study. Signs and symptoms of adrenal insufficiency due to under-treatment were reported for 41 (45.1%) participants, most frequently fatigue which was reported at some point by 41.8% of all participants. Signs and symptoms of overtreatment were reported for 25 (27.5%) participants, most frequently sudden weight gain which was reported at some point by 16.5% of all participants. Signs and symptoms of both over- and undertreatment occurred predominantly during the first 24 weeks. The study encompassed 357 participant years, and 18 adverse events considered indicative of adrenal crisis occurred in 7 participants, giving an incidence rate of 5.043 adrenal crises / 100 PY. Conclusions: Data from this longest prospectively monitored study in CAH suggest that the incidence of adrenal crisis on MRHC is at the low end of that reported in retrospective studies and the safety profile of MRHC is otherwise similar to immediate release hydrocortisone.

Getting in the zone: Metabolite transport across liver zones.

The liver has many functions including the regulation of nutrient and metabolite levels in the systemic circulation through efficient transport into and out of hepatocytes. To sustain these functions, hepatocytes display large functional heterogeneity. This heterogeneity is reflected by zonation of metabolic processes that take place in different zones of the liver lobule, where nutrient-rich blood enters the liver in the periportal zone and flows through the mid-zone prior to drainage by a central vein in the pericentral zone. Metabolite transport plays a pivotal role in the division of labor across liver zones, being either transport into the hepatocyte or transport between hepatocytes through the blood. Signaling pathways that regulate zonation, such as Wnt/β-catenin, have been shown to play a causal role in the development of metabolic dysfunction-associated steatohepatitis (MASH) progression, but the (patho)physiological regulation of metabolite transport remains enigmatic. Despite the practical challenges to separately study individual liver zones, technological advancements in the recent years have greatly improved insight in spatially divided metabolite transport. This review summarizes the theories behind the regulation of zonation, diurnal rhythms and their effect on metabolic zonation, contemporary techniques used to study zonation and current technological challenges, and discusses the current view on spatial and temporal metabolite transport.

Missense mutation in the activation segment of the kinase CK2 models Okur-Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse.

Exome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder. Thus far, no preclinical model of this condition exists. Here we describe a knock-in mouse model that harbors the K198R mutation in the activation segment of the α subunit ofCK2. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in mice die mid-gestation while heterozygous knock-in mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous knock-in mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous knock-in mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of knock-in mice. Taken together, heterozygous knock-in mice (CK2αK198R/+) exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits, and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS.

Impact of Six Months of Three Different Modalities of Exercise on Stress in Post-Treatment Breast Cancer Survivors

Abstract: Background/Objectives: Extensive evidence suggests that exercise is physically and mentally beneficial for cancer survivors. This study reports on changes in self-reported stress, physiological biomarkers for stress (salivary cortisol), and HR-QOL constructs for fifty breast cancer survivors participating in one of three different exercise programs over 6 months. Methods: Fifty post-treatment breast cancer survivors were randomized to either therapeutic yoga-based exercise (YE), comprehensive exercise (CE) (aerobic, resistance, flexibility), or choosing (C) their own exercise activities. Participants completed the Perceived Stress Scale (PSS), Medical Outcomes Short-Form 36® (SF-36), and the Pittsburgh Sleep Quality Index (PSQI). Five samples of salivary cortisol were collected on two consecutive days. The 10 samples were used to calculate the diurnal rhythm slope. Outcome measures were repeated after six months. Results: All groups improved in HR-QOL measures of PSS; PSQI sleep quality components of latency and daytime functioning; and five of the ten SF-36 scales (Mental Component Scale, Social Functioning subscale, Mental Health subscale, Physical Component Scale, Physical Functioning subscale). Although the CE group observed the most favorable change in cortisol (−0.183), where cortisol slope changes approached significance (p = 0.057), but no significant decrease in cortisol between groups were noted. Conclusion: Our results suggest that it is the engagement of, rather than the specific type of exercise, which is associated with improved HR-QOL. However, longer-term studies with better adherence monitoring and larger sample sizes are needed to better determine clinical impact.

Daily Activity Rhythms of Animals in the Southwest Mountains, China: Influences of Interspecific Relationships and Seasons

Temporal and spatial factors regulate the interactions between apex predators, mesocarnivores, and herbivores. Prey adjust their activity patterns and spatial utilization based on predator activities; in turn, predators also adapt to the activities of their prey. To elucidate the factors influencing the daily activity rhythms of animals, 115 camera traps were established from September 2019 to June 2023 to assess the influences of interspecific relationships and seasons on the daily activity rhythms of animals in the southwest mountains of China. The species captured by the cameras included six Carnivora (such as Panthera pardus and Lynx lynx), six Artiodactyla (such as Moschus spp. and Rusa unicolor), one Primate (Macaca mulatta), and two Galliformes (Crossoptilon crossoptilon, Ithaginis cruentus). The results demonstrated that the 15 species exhibited different activity rhythms and peak activities to reduce intense resource competition. There were differences in the species’ activity rhythms in different seasons, with competition among different species being more intense in the cold season than in the warm season. In predation relationships, the overlap coefficient in the cold season exceeded that of the warm season, possibly due to the abundant resources in summer and food scarcity in winter. In competitive relationships, 15 pairs of species exhibited significantly higher overlap coefficients in the cold season compared to the warm season, possibly due to increased demands for energy during the cold period or seasonal changes in predatory behavior. By analyzing the daily and seasonal activity patterns of dominant species in the study area, temporal niche overlaps were established to compare the competition levels between species. These findings indicate that the activity rhythms of the animals in this area not only result from evolutionary adaptation but are also influenced by season, food resources, and interspecific relationships (predation and competition). Thus, efforts should be made to reduce human interference, protect food resources in the winter, and monitor animals’ interspecific relationships to protect animal diversity and maintain the stability of the ecosystem in this biodiversity hotspot in China.

Nighttime-specific differential gene expression in suprachiasmatic nucleus and habenula is associated with resilience to chronic social stress

The molecular mechanisms that link stress and biological rhythms still remain unclear. The habenula (Hb) is a key brain region involved in regulating diverse types of emotion-related behaviours while the suprachiasmatic nucleus (SCN) is the body’s central clock. To investigate the effects of chronic social stress on transcription patterns, we performed gene expression analysis in the Hb and SCN of stress-naïve and stress-exposed mice. Our analysis revealed a large number of differentially expressed genes and enrichment of synaptic and cell signalling pathways between resilient and stress-naïve mice at zeitgeber 16 (ZT16) in both the Hb and SCN. This transcriptomic signature was nighttime-specific and observed only in stress-resilient mice. In contrast, there were relatively few differences between the stress-susceptible and stress-naïve groups across time points. Our results reinforce the functional link between circadian gene expression patterns and differential responses to stress, thereby highlighting the importance of temporal expression patterns in homoeostatic stress responses.

Chronobiological Spatial Clusters of Cortical Regions in the Human Brain.

We demonstrate that different regions of the cerebral cortex have different diurnal rhythms of spontaneously occurring high-frequency oscillations (HFOs). High-frequency oscillations were assessed with standard-of-care stereotactic electroencephalography in patients with drug-resistant epilepsy. To ensure generalizability of our findings beyond patients with drug-resistant epilepsy, we excluded stereotactic electroencephalography electrode contacts lying within seizure-onset zones, epileptogenic lesions, having frequent epileptiform activity, and excessive artifact. For each patient, we evaluated twenty-four 5-minute stereotactic electroencephalography epochs, sampled hourly throughout the day, and obtained the HFO rate (number of HFOs/minute) in every stereotactic electroencephalography channel. We analyzed diurnal rhythms of the HFO rates with the cosinor model and clustered neuroanatomic parcels in a standard brain space based on similarity of their cosinor parameters. Finally, we compared overlap among resting-state networks, described in the neuroimaging literature, and chronobiological spatial clusters discovered by us. We found five clusters that localized predominantly or exclusively to the left perisylvian, left perirolandic and left temporal, right perisylvian and right parietal, right frontal, and right insular-opercular cortices, respectively. These clusters were characterized by similarity of the HFO rates according to the time of the day. Also, these chronobiological spatial clusters preferentially overlapped with specific resting-state networks, particularly default mode network (clusters 1 and 3), frontoparietal network (cluster 1), visual network (cluster 1), and mesial temporal network (cluster 2). This is probably the first human study to report clusters of cortical regions with similar diurnal rhythms of electrographic activity. Overlap with resting-state networks attests to their functional significance and has implications for understanding cognitive functions and epilepsy-related mortality.