A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms.

Many self-motivated and goal-directed behaviours display highly flexible, approximately 4 hour ultradian (shorter than a day) oscillations. Despite lacking direct correspondence to physical cycles in the environment, these ultradian rhythms may be involved in optimizing functional interactions with the environment and reflect intrinsic neural dynamics. Current evidence supports a role of mesostriatal dopamine (DA) in the expression and propagation of ultradian rhythmicity, however, the biochemical processes underpinning these oscillations remain to be identified. Here, we use a mathematical model to investigate D2 autoreceptor-dependent DA self-regulation as the source of ultradian behavioural rhythms. DA concentration at the midbrain-striatal synapses is governed through a dual-negative feedback-loop structure, which naturally gives rise to rhythmicity. This model shows the propensity of striatal DA to produce an ultradian oscillation characterized by a flexible period that is highly sensitive to parameter variations. Circadian (approximately 24 hour) regulation consolidates the ultradian oscillations and alters their response to the phase-dependent, rapid-resetting effect of a transient excitatory stimulus. Within a circadian framework, the ultradian rhythm orchestrates behavioural activity and enhances responsiveness to an external stimulus. This suggests a role for the circadian-ultradian timekeeping hierarchy in governing organized behaviour and shaping daily experience through coordinating the motivation to engage in recurring, albeit not highly predictable events, such as social interactions.

A review of radiation doses and associated parameters in Western Australian mining operations (2020-23).

The Western Australian mining industry is a global supplier of critical minerals, including lithium and rare earths. The lithology of these minerals is associated with elevated concentrations of naturally occurring radionuclides (NORs). An increase in the number of mines producing the minerals has witnessed a commensurate increase in the number of workers potentially exposed to the radiation from NORs. The regulatory framework in Western Australia underwent significant change in March 2022. Mining operations whose workers are likely to receive doses greater than one mSvy-1 are referenced as relevant mines and are required to submit an annual report of worker doses to the mining regulator. This research provides an overview of the new legislative framework and updates the information in Ralph and Cattani (2022) to include data derived from annual radiation doses reported by relevant mines in the period spanning 2020-21 to 2022-23. In 2022-23, 38 mining operations were identified as relevant mines, an increase of sixteen from 2020-21. The mean effective dose (ED) reported in the three-year period was 1.0 mSv, and the maximum ED was 4.9 mSv. The collective effective dose of the mine worker population reached an historical maximum of 2,339 man.mSv in 2022-23. Inhalation of long-lived alpha emitting radionuclides in dust remains the most significant contributor to worker doses. Inhalation of radon-22, radon-220 and their short-lived progeny, once considered as a negligible contributor to worker doses, is the second most significant exposure pathway. A declining trend in the number of samples collected per worker is highlighted as requiring remediation to provide confidence in the reported dose estimates. The transition to the new legislative framework for radiation protection in mines has been supported by the publication of guidance materials which have been widely endorsed by the industry. .

High Sensitivity of the Circadian Clock in the Hippocampal Dentate Gyrus to Glucocorticoid- and GSK3-Beta-Dependent Signals.

AIMS: Circadian clocks in the hippocampus (HPC) align memory processing with appropriate time of day. Our study was aimed at ascertaining the specificity of glycogen synthase kinase 3-beta (GSK3ß)- and glucocorticoid (GC)-dependent pathways in the entrainment of clocks in individual HPC regions, CA1-3, and dentate gyrus (DG). METHODS: The role of GCs was addressed in vivo by comparing the effects of adrenalectomy (ADX) and subsequent dexamethasone (DEX) supplementation on clock gene expression profiles (Per1, Per2, Nr1d1, and Bmal1). In vitro the effects of DEX and the GSK3ß inhibitor, CHIR-99021, were assessed from recordings of bioluminescence rhythms in HPC organotypic explants of mPER2Luc mice. RESULTS: Circadian rhythms of clock gene expression in all HPC regions were abolished by ADX, and DEX injections to the rats rescued those rhythms in DG. The DEX treatment of the HPC explants significantly lengthened periods of the bioluminescence rhythms in all HPC regions with the most significant effect in DG. In contrast to DEX, CHIR-99021 significantly shortened the period of bioluminescence rhythm. Again, the effect was most significant in DG which lacks the endogenously inactivated (phosphorylated) form of GSK3ß. Co-treatment of the explants with CHIR-99021 and DEX produced the CHIR-99021 response. Therefore, the GSK3ß-mediated pathway had dominant effect on the clocks. CONCLUSION: GSK3ß- and GC-dependent pathways entrain the clock in individual HPC regions by modulating their periods in an opposite manner. The results provide novel insights into the mechanisms connecting the arousal state-relevant signals with temporal control of HPC-dependent memory and cognitive functions.

Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice.

Modification of the Per2 clock gene in mPer2Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses, and altered entrainment to scheduled feeding. Mechanistic mathematical modelling predicts that enhanced protein interactions with the modified mPER2 C-terminus, combined with differential clock regulation among SCN subregions, can account for effects on circadian behavior via increased Per2 transcript and protein stability. PER2::LUC produces greater suppression of CLOCK:BMAL1 E-box activity than PER2. mPer2Luc carries a 72 bp deletion in exon 23 of Per2, and retains a neomycin resistance cassette that affects rhythm amplitude but not period. The results show that mPer2Luc acts as a circadian clock mutation illustrating a need for detailed assessment of potential impacts of c-terminal tags in genetically modified animal models.

A review of radiation doses and associated parameters in Western Australian mining operations (2018-20).

In the 2019-20 reporting period, 19 mining operations in Western Australia were identified as having workers who were likely to be exposed to ionising radiation stemming from naturally occurring radioactive materials, 17 of which, known hereinafter as reporting entities (REs), were required to submit an annual report of the dose estimates of their workforce to the mining regulatory authority. In 2018 the International Commission for Radiological Protection published the revision of the dose coefficients (DCs) for occupational intakes of radionuclides of the uranium-238 and thorium-232 decay series, in ICRP-137 and ICRP-141. The 2019-20 annual reports are the first to apply the revised DCs to estimate worker doses. The mean effective dose (ED) reported by the 17 REs increased by 32.4% to 0.94 mSv in 2019-20 from 0.71 mSv reported in 2018-19, indicating that the mean ED is approaching the 1 mSv annual dose estimate at which regulatory intervention should be considered. The mean committed effective dose (CED) from inhalation of dusts containing long-lived alpha-emitting (LLα) nuclides has increased by 35% from 0.40 mSv in 2018-19 to 0.54 mSv in 2019-20. The maximum CED from LLαincreased by 16.3% from 3.20 mSv in 2018-19 to 3.72 mSv in 2019-20. The authors consider that, in the absence of other explanations provided by the REs, the increase is largely attributable to the revised DC's published in ICRP-137 and ICRP-141, but highlight that there are significant variations between REs that make a generalised conclusion problematic. The maximum reported ED in 2019-20 was 6.0 mSv, an increase of 36.4% from 2018 to 2019 (4.4 mSv). The 2019-20 reporting period is the first time in a decade in which mine worker EDs have been elevated to the point that EDs have exceeded 5 mSv, a level at which personal monitoring and additional institutional controls are required.

A review of radiation doses and associated parameters in Western Australian mining operations that process ores containing naturally occurring radionuclides for 2018-19.

Naturally occurring radionuclides (NORs) are encountered in varying concentrations in a wide range of commodities that are mined and processed in Western Australia (WA), including mineral sands, coal, phosphate ores, sandblasting materials, and the production of bauxite, titanium dioxide pigment, copper, zinc, lead, tin, tantalum and the refining of zircon.Because they have the potential for workers to receive annual doses in excess of 1 mSv, 14 mining operations in WA are required to submit an annual report of worker doses to the regulatory authority. This research provides a summary of the workforce demographics and radiation doses reported by mining operations for the 2018-19 reporting period in order to establish a benchmark against which to compare future worker exposures. The 2018-19 data is compared to that presented in the last peer-reviewed research, published in 1994 in order to evaluate changes in worker dose profiles over the intervening period.In 1992-93, the collective effective dose received by 1496 workers across seven mining operations was 2824 man.mSv, whereas in 2018-19 it had decreased to 784 man.mSv for 1474 workers in 13 operations. The maximum committed effective dose (CED) decreased by 76%, from 18 mSv (36% of the annual limit) in 1992-93 to 4.4 mSv (22% of the derived annual limit) in 2018-19. The mean CED decreased by 49%, from 1.8 mSv in 1992-93 to 0.97 mSv in 2018-19.As a result of revised DC's published in ICRP-137 and ICRP-141, the impacts upon the mean CED per unit intake of alpha activity arising from inhalation of insoluble NORs-containing dusts, and contribution to CED from inhalation of radon, thoron and their progeny will require evaluation for individual mining operations in the WA mining industry.

Impacts of revised dose coefficients for the inhalation of NORM-containing dusts encountered in the Western Australian Mining Industry.

The aim of this paper is to evaluate the impact of recent revisions to the dose coefficients published in ICRP-137 and ICRP-141 for members of the232Th,238U and235U decay series on radiation doses received by Western Australian mine workers via the inhalation of insoluble dusts containing long-lived alpha particle emitting radionuclides.Whilst some dose coefficients for individual members of the decay series have decreased, the nett effect is that the sum of all dose coefficients in all three decay series have increased as a result of the revisions. The increase is inversely related to Activity Median Aerodynamic Diameter.Assuming the radionuclides in the inhaled dusts are in secular equilibrium, the dose conversion factors (the mean committed effective dose per unit intake of alpha activity) will increase by a factor between 1.9 and 2.9 times.In 2019, 11 mining operations in Western Australia submitted an annual report of worker radiation exposures to the regulatory authority. The reports indicate that between 35% and 60% of the committed effective doses to workers arises from inhalation of insoluble radioactive dusts. Applying an AMAD of 5 µm and a232Th decay series to238+235U decay series ratio of 10:1, committed effective doses to the workforce are greater by a factor of between 0.74 and 1.26 times from those reported in 2018-19 as a result of the revised DCs published in ICRP-137 and ICRP-141.Guidance on how to calculate doses from the inhalation of radioactive dusts is provided in the regulatory authority's Guideline 'NORM-5: Dose Assessment', which will need revision to incorporate the revised dose coefficients. The Guideline has been widely distributed outside of Western Australia, and those jurisdictions which have adopted all, or sections of it, into their legal framework for radiation protection may need to consider the impact of the revision.

Dopamine dependent setting of a circadian oscillator underlying the memory for time of day.

Animals learn and remember the time of day that significant conditions occur, and anticipate recurrence at 24-h intervals, even after only one exposure to the condition. On several place-conditioning tasks, animals show context avoidance or preference only near the time of day of the experience. The memory for time of day is registered by a circadian oscillator that is set at the time of the training. We show that manipulations of dopamine (DA) neurotransmission can set a time memory in place preference and avoidance tasks, indicating that time of day is part of the context that is learned. Single injections of the DA agonist, d-amphetamine sulfate given without further exposure to the conditioning apparatus, can reset the timing of anticipatory behavior evoked by previously acquired place-event associations. The data support a model for time memory in which DA signaling sets the phase of a circadian oscillator, which returns to the same state at regular 24-h intervals. The data also raise the possibility that some apparent impairments of memory formation or retention could reflect post-experience resetting of the optimal retrieval time rather than impairment of memory or retrieval per se.

Suprachiasmatic vasopressin and the circadian regulation of voluntary locomotor behavior.

A role for arginine vasopressin in the circadian regulation of voluntary locomotor behavior (wheel running activity) was investigated in the golden hamster, Mesocricetus auratus. Spontaneous nocturnal running was suppressed in a dose-dependent manner by systemic injections of vasopressin, and also in a concentration-dependent manner by microinjections directly into the hypothalamic suprachiasmatic nucleus. Pre-injections of a vasopressin V1 receptor antagonist into the nucleus reduced the suppression of behavior by vasopressin. Ethogram analyses revealed that peripheral drug injections predominantly increased grooming, flank marking, and sleep-related behaviors. Central injections did not induce sleep, but increased grooming and periods of 'quiet vigilance' (awake but not moving). Nocturnal behavioral profiles following either peripheral or central injections were similar to those shown by untreated animals in the hour prior to the onset of nocturnal wheel running. Site control vasopressin injections into the medial preoptic area or periaqueductal gray increased flank marking and grooming, but had no significant effect on locomotion, suggesting behavioral specificity of a vasopressin target near the suprachiasmatic nucleus. Both peripheral and central administration increased FOS-like immunoreactivity in the retinorecipient core of the suprachiasmatic nucleus. The distribution of FOS-positive cells overlapped the calbindin subregion, but was more extensive, and most calbindin-positive cells did not co-express FOS. We propose a model of temporal behavioral regulation wherein voluntary behavior, such as nocturnal locomotor activity, is inhibited by the activity of neurons in the suprachiasmatic ventrolateral core that project to the posterior hypothalamus and are driven by rhythmic vasopressin input from the dorsomedial shell.

Retention of a 24-hour time memory in Syrian hamsters carrying the 20-hour short circadian period mutation in casein kinase-1ε (ck1εtau/tau).

Circadian rhythmic expression of conditioned place avoidance (CPA) was produced in Syrian hamsters homozygous for the circadian short period mutation, tau. In constant dim red light neither the 20 h endogenous period, nor a 20 h place conditioning schedule eliminated the 24 h modulation of CPA behavior described previously for wild type (wt) hamsters and other species. Tau mutants exhibited a 20 h rhythm superimposed on the 24 h modulation. The 20 h component was removed selectively with lesions of the suprachiasmatic nucleus. Wt animals conditioned on a 20 h schedule did not produce a 20 h rhythm, but still expressed the 24 h modulation. The results show that the context entrainable oscillator (CEO) underlying memory for the timing of an unconditioned stimulus, retains a period of about 24 h regardless of clock gene background (tau mutation) and/or the conditioning schedule (24 vs 20 h). Therefore the CEO responsible for time memory is distinct from the biological clock controlling activity; the underlying circadian molecular mechanisms may differ from the ubiquitous transcription-translation feedback oscillator; and time memory itself is not classically conditioned.

Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase α3 sodium pump.

Bipolar disorder is a debilitating psychopathology with unknown etiology. Accumulating evidence suggests the possible involvement of Na(+),K(+)-ATPase dysfunction in the pathophysiology of bipolar disorder. Here we show that Myshkin mice carrying an inactivating mutation in the neuron-specific Na(+),K(+)-ATPase α3 subunit display a behavioral profile remarkably similar to bipolar patients in the manic state. Myshkin mice show increased Ca(2+) signaling in cultured cortical neurons and phospho-activation of extracellular signal regulated kinase (ERK) and Akt in the hippocampus. The mood-stabilizing drugs lithium and valproic acid, specific ERK inhibitor SL327, rostafuroxin, and transgenic expression of a functional Na(+),K(+)-ATPase α3 protein rescue the mania-like phenotype of Myshkin mice. These findings establish Myshkin mice as a unique model of mania, reveal an important role for Na(+),K(+)-ATPase α3 in the control of mania-like behavior, and identify Na(+),K(+)-ATPase α3, its physiological regulators and downstream signal transduction pathways as putative targets for the design of new antimanic therapies.

Emergence of noise-induced oscillations in the central circadian pacemaker.

Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN) of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell-autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.

Circadian rhythms in executive function during the transition to adolescence: the effect of synchrony between chronotype and time of day.

To explore the influence of circadian rhythms on executive function during early adolescence, we administered a battery of executive function measures (including a Go-Nogo task, the Iowa Gambling Task, a Self-ordered Pointing task, and an Intra/Extradimensional Shift task) to Morning-preference and Evening-preference participants (N = 80) between the ages of 11 and 14 years who were tested in the morning or afternoon. Significant Chronotype × Time of Day interactions (controlling for amount of sleep the previous night) revealed that adolescents tested at their optimal times of day performed better than those tested at their nonoptimal times. Implications for our understanding of physiological arousal, sleep, and executive function during adolescence are discussed.

A Phenomenological Mouse Circadian Pacemaker Model.

Mathematical models have been used extensively in chronobiology to explore characteristics of biological clocks. In particular, for human circadian studies, the Kronauer model has been modified multiple times to describe rhythm production and responses to sensory input. This phenomenological model comprises a single set of parameters which can simulate circadian responses in humans under a variety of environmental conditions. However, corresponding models for nocturnal rodents commonly used in circadian rhythm studies are not available and may require new parameter values for different species and even strains. Moreover, due to a considerable variation in experimental data collected from mice of the same strain, within and across laboratories, a range of valid parameters is essential. This study develops a Kronauer-like model for mice by re-fitting relevant parameters to published phase response curve and period data using total least squares. Local parameter sensitivity analysis and parameter distributions determine the parameter ranges that give a near-identical model and data distribution of periods. However, the model required further parameter adjustments to match characteristics of other mouse strains, implying that the model itself detects changes in the core processes of rhythm generation and control. The model is a useful tool to understand and interpret future mouse circadian clock experiments.

REASSESSMENT OF RADIATION EXPOSURES OF UNDERGROUND NON-URANIUM MINE WORKERS IN WESTERN AUSTRALIA.

In the 1990, radon and radon progeny was reported to contribute approximately 70% of the average 1.4 + 1.0-mSv annual dose across 26 Western Australian underground non-uranium mines. The Western Australian underground mining workforce has expanded significantly, and parameters used to calculate doses have changed significantly, warranting a review of the 1990's data. The review concludes that doses received by the contemporary mining workforce has increased on average, by 5.4%, with annual dose estimates ranging from 0.53 to 3.56 mSv, with a mean of 1.33 mSv. Doses in 12 of the 23 underground mines exceed 1 mSv and are required to comply with radiation safety legislation. It is estimated that 5400 underground workers will fall into the greater than 1-mSv category. The collective dose to the underground worker population has increased by 4.5 times from 3060 man mSv (2173 workers) to 13 669 man mSv (8597 workers).

Withdrawn: Dexamethasone resets the circadian clock in hippocampus via multiple mechanisms involving lithium-independent GSK3ß signalling.

The above article from British Journal of Pharmacology, published online as an Accepted Article on 19 August 2019 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors, the journal Editor-in-Chief Professor Amrita Ahluwalia, and John Wiley & Sons Limited. The withdrawal has been agreed owing to new findings that necessitate re-interpretation of the results.

PERSIANN Dynamic Infrared-Rain Rate (PDIR-Now): A Near-Real-Time, Quasi-Global Satellite Precipitation Dataset.

This study presents the Precipitation Estimation from Remotely Sensed Information Using Artificial Neural Networks-Dynamic Infrared Rain Rate (PDIR-Now) near-real-time precipitation dataset. This dataset provides hourly, quasi-global, infrared-based precipitation estimates at 0.04° × 0.04° spatial resolution with a short latency (15-60 min). It is intended to supersede the PERSIANN-Cloud Classification System (PERSIANN-CCS) dataset previously produced as the near-real-time product of the PERSIANN family. We first provide a brief description of the algorithm's fundamentals and the input data used for deriving precipitation estimates. Second, we provide an extensive evaluation of the PDIR-Now dataset over annual, monthly, daily, and subdaily scales. Last, the article presents information on the dissemination of the dataset through the Center for Hydrometeorology and Remote Sensing (CHRS) web-based interfaces. The evaluation, conducted over the period 2017-18, demonstrates the utility of PDIR-Now and its improvement over PERSIANN-CCS at all temporal scales. Specifically, PDIR-Now improves the estimation of rain/no-rain days as demonstrated by a critical success index (CSI) of 0.53 compared to 0.47 of PERSIANN-CCS. In addition, PDIR-Now improves the estimation of seasonal and diurnal cycles of precipitation as well as regional precipitation patterns erroneously estimated by PERSIANN-CCS. Finally, an evaluation is carried out to examine the performance of PDIR-Now in capturing two extreme events, Hurricane Harvey and a cluster of summer thunderstorms that occurred over the Netherlands, where it is shown that PDIR-Now adequately represents spatial precipitation patterns as well as subdaily precipitation rates with a correlation coefficient (CORR) of 0.64 for Hurricane Harvey and 0.76 for the Netherlands thunderstorms.

Circadian modulation of conditioned place avoidance in hamsters does not require the suprachiasmatic nucleus.

Animals possess the ability to remember both the time of day as well as the location that noxious and potentially dangerous conditions occur. A behavioral expression of this learning is demonstrated in conditioned place avoidance (CPA). CPA is strongest when the time of testing matches the time of day that the prior training had occurred, suggesting the involvement of a circadian oscillator that modulates either memory retrieval or reactivity to the conditioned environment. In these experiments we show that time of day learning persists in the absence of the central circadian clock in the suprachiasmatic nucleus (SCN), demonstrating that memory for time of day is implicit in context conditioning and may involve a circadian oscillator that is distinct from the SCN.

Removing Short Wavelengths From Polychromatic White Light Attenuates Circadian Phase Resetting in Rats.

Visible light is the principal stimulus for resetting the mammalian central circadian pacemaker. Circadian phase resetting is most sensitive to short-wavelength (blue) visible light. We examined the effects of removing short-wavelengths < 500 nm from polychromatic white light using optical filters on circadian phase resetting in rats. Under high irradiance conditions, both long- (7 h) and short- (1 h) duration short-wavelength filtered (< 500 nm) light exposure attenuated phase-delay shifts in locomotor activity rhythms by (∼40-50%) as compared to unfiltered light exposure. However, there was no attenuation in phase resetting under low irradiance conditions. Additionally, the reduction in phase-delay shifts corresponded to regionally specific attenuation in molecular markers of pacemaker activation in response to light exposure, including c-FOS, Per1 and Per2. These results demonstrate that removing short-wavelengths from polychromatic white light can attenuate circadian phase resetting in an irradiance dependent manner. These results have important implications for designing and optimizing lighting interventions to enhance circadian adaptation.