Drivers of Infectious Disease Seasonality: Potential Implications for COVID-19.

Not 1 year has passed since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Since its emergence, great uncertainty has surrounded the potential for COVID-19 to establish as a seasonally recurrent disease. Many infectious diseases, including endemic human coronaviruses, vary across the year. They show a wide range of seasonal waveforms, timing (phase), and amplitudes, which differ depending on the geographical region. Drivers of such patterns are predominantly studied from an epidemiological perspective with a focus on weather and behavior, but complementary insights emerge from physiological studies of seasonality in animals, including humans. Thus, we take a multidisciplinary approach to integrate knowledge from usually distinct fields. First, we review epidemiological evidence of environmental and behavioral drivers of infectious disease seasonality. Subsequently, we take a chronobiological perspective and discuss within-host changes that may affect susceptibility, morbidity, and mortality from infectious diseases. Based on photoperiodic, circannual, and comparative human data, we not only identify promising future avenues but also highlight the need for further studies in animal models. Our preliminary assessment is that host immune seasonality warrants evaluation alongside weather and human behavior as factors that may contribute to COVID-19 seasonality, and that the relative importance of these drivers requires further investigation. A major challenge to predicting seasonality of infectious diseases are rapid, human-induced changes in the hitherto predictable seasonality of our planet, whose influence we review in a final outlook section. We conclude that a proactive multidisciplinary approach is warranted to predict, mitigate, and prevent seasonal infectious diseases in our complex, changing human-earth system.

Photoperiod-induced changes in hypothalamic de novo DNA methyltransferase expression are independent of triiodothyronine in female Siberian hamsters (Phodopus sungorus).

Many temperate zone animals engage in seasonal reproductive physiology and behavior as a strategy to maximise the propagation of the species. The hypothalamus integrates environmental cues and hormonal signalling to optimize the timing of reproduction. Recent work has revealed that epigenetic modifications, such as DNA methylation, vary across seasonal reproductive states. Multiple hormones act in the hypothalamus to permit or inhibit reproductive physiology, and the increase in thyroid hormone triiodothyronine (T3) has been implicated in the initiation of breeding in many species. The objective of this study was to examine the effect of T3 on the photoperiod-dependent regulation of reproductive physiology and hypothalamic DNA methyltransferase enzyme expression in female Siberian hamsters (Phodopus sungorus). We tested the hypothesis that T3 in short days (SD) would stimulate hypothalamic Rfrp3 and de novo DNA methyltransferase (Dnmt) expression in female Siberian hamsters. 10 weeks of SD lengths induced a decrease in body and uterine mass. Hamsters maintained in SD were found to express lower levels of GnRH, Rfrp3, Dnmt3a and Dnmt3b. Two weeks of daily T3 injections did not affect body mass, uterine mass, Gnrh, Rfrp3, Dnmt3a or Dnmt3b expression in neuroendocrine tissues. SD significantly lowered Tshß mRNA expression and T3 reduced Tshß in LD hamsters. Our data indicate sex-dependent effects of T3 for the neuroendocrine regulation of seasonal reproduction in hamsters.

Environmental and hormonal regulation of epigenetic enzymes in the hypothalamus.

Neuroendocrine structures integrate a vast range of external cues and internal signals that, in turn, result in adaptive physiological responses. Emerging data indicate that light, social cues, stress and energy balance stimulate relatively short- and long-term genomic modifications in discrete neuroendocrine structures, which are mediated by epigenetic mechanisms. Moreover, environmentally-induced fluctuations in the synthesis of local hypothalamic and circulating hormones provide an internal signal that contributes to the extensive neuroendocrine genomic plasticity. This review examines the impact of environmental stimuli and endogenous hormonal signals on the regulation of epigenetic enzymes in key neuroendocrine structures. The data discussed are predominantly derived from studies in the neuroendocrine control of seasonal reproduction and the impact of social stress in rodent models. The perspective presented considers the role of oestrogen and glucocorticoids as the primary catalysts for inducing epigenetic modifications (eg, DNA methylation) in specific neuroendocrine structures. Oestrogen and glucocorticoid actions suggest: (i) a preferential action for specific epigenetic enzymes and (ii) nucleus- and cell-specific modifications. Untangling the complex web of hormonal regulation of methylation and acetylation will enhance our understanding of short- and long-term changes in epigenetic enzymes that generate adaptive and pathological neuroendocrine responses.

Disrupted seasonal biology impacts health, food security and ecosystems.

The rhythm of life on earth is shaped by seasonal changes in the environment. Plants and animals show profound annual cycles in physiology, health, morphology, behaviour and demography in response to environmental cues. Seasonal biology impacts ecosystems and agriculture, with consequences for humans and biodiversity. Human populations show robust annual rhythms in health and well-being, and the birth month can have lasting effects that persist throughout life. This review emphasizes the need for a better understanding of seasonal biology against the backdrop of its rapidly progressing disruption through climate change, human lifestyles and other anthropogenic impact. Climate change is modifying annual rhythms to which numerous organisms have adapted, with potential consequences for industries relating to health, ecosystems and food security. Disconcertingly, human lifestyles under artificial conditions of eternal summer provide the most extreme example for disconnect from natural seasons, making humans vulnerable to increased morbidity and mortality. In this review, we introduce scenarios of seasonal disruption, highlight key aspects of seasonal biology and summarize from biomedical, anthropological, veterinary, agricultural and environmental perspectives the recent evidence for seasonal desynchronization between environmental factors and internal rhythms. Because annual rhythms are pervasive across biological systems, they provide a common framework for trans-disciplinary research.

Gonadotropin-releasing hormone plasticity: a comparative perspective.

Gonadotropin-releasing hormone 1 (GnRH1) is a key regulator of the reproductive neuroendocrine system in vertebrates. Recent developments have suggested that GnRH1 neurons exhibit far greater plasticity at the cellular and molecular levels than previously thought. Furthermore, there is growing evidence that sub-populations of GnRH1 neurons in the preoptic area are highly responsive to specific environmental and hormonal conditions. In this paper we discuss findings that reveal large variation in GnRH1 mRNA and protein expression that are regulated by social cues, photoperiod, and hormonal feedback. We draw upon studies using histochemistry and immediate early genes (e.g., c-FOS/ZENK) to illustrate that specific groups of GnRH1 neurons are topographically organized. Based on data from diverse vertebrate species, we suggest that GnRH1 expression within individuals is temporally dynamic and this plasticity may be evolutionarily conserved. We suggest that the plasticity observed in other neuropeptide systems (i.e. kisspeptin) may have evolved in a similar manner.

Variation in gonadotrophin-releasing hormone-1 gene expression in the preoptic area predicts transitions in seasonal reproductive state.

In many seasonally reproducing animals, the experience of prolonged exposure to constant photoperiods results in the induction of a state of photorefractoriness, which is defined as a lack of responsiveness to a previously stimulatory photoperiod. The physiological and genetic processes that control photorefractoriness are not well understood; however, the hallmark of photorefractoriness is an endogenous change in the physiological response to a constant photoperiod. It is already known that preoptic area (POA) gnrh1 gene expression declines during the development of refractoriness to long-day stimulation in European starlings. We employed in situ hybridisation histochemistry to characterise changes in POA gnrh1 mRNA expression during the reinstatement of photosensitivity in female starlings. Photorefractory starlings moved to short days (8L:16D) increased optical density of gnrh1 expressing cells within 10 days. Exposure to 30 short days resulted in greater visible gnrh1 cell numbers, with no detectable change in measures of ovarian follicular volume and oviduct mass. We subsequently examined the extent of gnrh1 expression in response to photostimulation after incremental periods on short day lengths. A significant long-day-induced increase in both gnrh1 expression and ovarian and oviduct mass occurred only after at least 30 short days. These findings demonstrate that the recovery of photorefractoriness involves an increase in gnrh1 mRNA expression and expands upon our previous knowledge that the development of photosensitivity is associated with an increase in both the precursor proGnRH1-GAP and GnRH1 peptides in the POA. Importantly, the change in the brain sensitivity occurs well before such changes can be detected via variation in ovarian activity.

Cloning of gonadotropin-releasing hormone I complementary DNAs in songbirds facilitates dissection of mechanisms mediating seasonal changes in reproduction.

Temperate zone animals exhibit seasonal variation in reproductive physiology. In most cases, seasonal changes in reproductive states are regulated by changes in GnRH1 secretion, rather than synthesis, from the preoptic area (POA)/anterior hypothalamus. An important exception occurs in some songbirds that become photorefractory to the stimulatory effects of long days and show profound decreases in brain GnRH1 protein content. Whether this decline reflects changes in gene expression is unknown because of past failures to measure GNRH1 mRNA levels, due in large part to the absence of available GNRH1 gene sequence in this taxon. Here, we report the first cloning of GNRH1 cDNAs in two songbirds: European starlings and zebra finches. Consistent with the size of the prepro-hormone in other avian and non-avian species, the open-reading frames predict proteins of 91 and 92 amino acids, respectively. Whereas the decapeptide in both species is perfectly conserved with chicken GnRH1, the amino acid identity in the signal peptide and GNRH associated peptide subdomains are significantly less well conserved. At the nucleotide level, the starling and zebra finch coding sequences are approximately 88% identical to each other but only approximately 70% identical to chicken GNRH1. In situ hybridization using radiolabeled cRNA probes demonstrated GNRH1 mRNA expression primarily in the POA, consistent with previous studies on the distribution of the GnRH1-immunoreactive cell bodies. Furthermore, we provide evidence for photoperiod-dependent regulation of GNRH1 mRNA in male starlings. Declines in GNRH1 mRNA levels occur in parallel with testicular involution. Thus, photorefractoriness is associated with decreases in GNRH1 gene expression in the medial POA.

Detecting change in patients with stroke using the Berg Balance Scale.

The Berg Balance Scale (BBS) was designed to help determine change in functional standing balance over time. The purpose of this paper was to estimate the minimum detectable change score (MDC) using the standard error of measure (SEM), thereby providing a means to decide if genuine change had occurred. Calculation of the agreement regarding the presence of change as determined by the MDC and clinicians' perceptions was performed to give an indication of the validity of this criterion value. Forty-eight subjects who were receiving inpatient rehabilitation after stroke were assessed on consecutive days by two raters using the BBS. The MDC analysis suggests that a change of +/- 6 BBS points is necessary to be 90% confident of genuine change. Only 25/45 subjects showed agreement between the statistically derived presence of change and clinicians' perceptions of change. The lack of agreement may relate to the validity of the SEM/MDC methodology to determine the criterion BBS value, the heterogeneity of the subjects, or the use of clinician gestalt impressions of change.

Postural responses to unilateral arm perturbation in young, elderly, and hemiplegic subjects.

OBJECTIVE: To compare postural responses during standing associated with self-paced unilateral arm flexion exhibited by young and elderly healthy subjects and subjects with hemiplegia from stroke. DESIGN AND SETTING: Descriptive cross-sectional study in a laboratory setting. PATIENTS: Ten young, 10 elderly healthy subjects, and 12 volunteers with longstanding hemiparesis following stroke were tested. The hemiplegic group had good functional balance scores on the Berg Balance Scale (BBS). MAIN OUTCOME MEASURES: The peak arm acceleration, center of pressure (CP) excursion speed, and the electromyographic activity in the posterior leg muscles (bilateral hamstrings and triceps surae) were monitored during self-initiated rapid unilateral arm flexion and during quiet stance. RESULTS: During unilateral arm flexion, the young group showed the highest arm accelerations and lowest CP excursion speeds. The variability of postural responses was largest in the elderly and hemiplegic groups with hemiplegic subjects showing the greatest CP excursion speeds for the lowest arm accelerations. The first burst of activity in ipsilateral hamstrings muscle was the same in all subjects. However, the hemiplegic group had less activation (latency and amplitude) of other posterior leg muscles. CONCLUSION: The elderly subjects had more variable responses to perturbation than the young subjects despite similar BBS scores. This may indicate that the BBS fails to detect differences in balance at the high end of the scale. Although the hemiplegic subjects demonstrated some anticipatory control of standing balance, they consistently performed poorer than elderly and young controls. The failure to coordinate postural leg muscle activity with focal movement may contribute to the instability of subjects with hemiplegia.

Standing balance during internally produced perturbations in subjects with hemiplegia: validation of the balance scale.

OBJECTIVE: To examine the concurrent validity of the Berg Balance Scale (BBS) in subjects with hemiparesis after stroke by correlating functional balance performance on the BBS with laboratory measures of balance (center of pressure [CP] and electromyographic [EMG] activity of leg musculature during rapid arm flexion and during quiet stance). DESIGN: Concurrent validation study. Consistency of performance was determined through repeat measures obtained from 13 subjects. SETTING: Laboratory. PATIENTS: Twenty-four volunteers with longstanding hemiparesis from cerebrovascular accident (CVA) were tested. MAIN OUTCOME MEASURES: BBS scores were compared with CP excursion speed during (1) self-initiated rapid unilateral arm flexion with the nonhemiplegic arm and (2) quiet stance. The peak tangential arm acceleration and the sequence of EMG events in the posterior leg muscles were monitored during the arm flexion movement. RESULTS: In the arm flexion condition, BBS performance was significantly correlated with arm acceleration and CP excursion speed (multiple regression R = .81). BBS performance was also related to the presence of anticipatory activation of ipsilateral hamstrings during the rapid arm flexion movement. BBS performance and CP excursion speed during quiet stance were also significantly related (r = .76). The initial and repeat measures were not significantly different in magnitude (paired tests of difference, p < .01). CONCLUSION: The BBS appears to reflect differing abilities to tolerate the internally produced perturbation to standing balance associated with forward arm flexion in individuals with hemiparesis from CVA.

Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform.

Using a combination of data base searching, polymerase chain reaction, and library screening, we have identified a putative K-Cl cotransporter isoform (KCC2) in rat brain that is specifically localized in neurons. A cDNA of 5566 bases was obtained from overlapping clones and encoded a protein of 1116 amino acids with a deduced molecular mass of 123.6 kDa. Over its full length, the amino acid sequence of KCC2 is 67% identical to the widely distributed K-Cl cotransporter isoform (KCC1) identified in rat brain and rabbit kidney (Gillen, C., Brill, S., Payne, J.A., and Forbush, B., III(1996) J. Biol. Chem. 271, 16237-16244) but only approximately25% identical to other members of the cation-chloride cotransporter gene family, including "loop" diuretic-sensitive Na-K-Cl cotransport and thiazide-sensitive Na-Cl cotransport. Based on analysis of the primary structure as well as homology with other cation-chloride cotransporters, we predict 12 transmembrane segments bounded by N- and C-terminal cytoplasmic regions. Four sites for N-linked glycosylation are predicted on an extracellular intermembrane loop between putative transmembrane segments 5 and 6. Northern blot analysis using a KCC2-specific cDNA probe revealed a very highly expressed approximately5.6-kilobase transcript only in brain. Reverse transcriptase-polymerase chain reaction revealed that KCC1 was present in rat primary astrocytes and rat C6 glioma cells but that KCC2 was completely absent from these cells, suggesting KCC2 was not of glial cell origin. In situ hybridization studies demonstrated that the KCC2 transcript was expressed at high levels in neurons throughout the central nervous system, including CA1-CA4 pyramidal neurons of the hippocampus, granular cells and Purkinje neurons of the cerebellum, and many groups of neurons throughout the brainstem.

The dust distribution within the inner coma of comet P/Halley 1982i: encounter by Giotto's impact detectors.

Analysis of the data from Giotto's Dust Impact Detection System experiment (DIDSY) is presented. These data represent measurement of the size of dust grains incident on the Giotto dust shield along its trajectory through the coma of comet P/Halley on 1986 March 13/14. First detection occurred at some 287000 km distance from the nucleus on the inbound leg; the majority of the DIDSY subsystems remained operational after closest approach (604 km) yielding the last detection at about 202000 km from the nucleus. In order to improve the data coverage (and especially for the smallest grains, to approximately 10(-19) kg particle mass), data from the PIA instrument has been combined with DIDSY data. Flux profiles are presented for the various mass channels showing, to a first approximation, a 1/R2 flux dependence, where R is the distance of the detection point from the cometary nucleus, although significant differences are noted. Deviations from this dependence are observed, particularly close to the nucleus. From the flux profiles, mass and geometrical area distributions for the dust grains are derived for the trajectory through the coma. Groundbased CCD imaging of the dust continuum in the inner coma at the time of encounter is also used to derive the area of grains intercepted by Giotto. The results are consistent with the area functions derived by Giotto data and the low albedo of the grains deduced from infrared emission. For the close encounter period (-5 min to +5 min), the cumulative mass distribution function has been investigated, initially in 20 second periods; there is strong evidence from the data for a steepening of the index of the mass distribution for masses greater than 10(-13) kg during passage through dust jets which is not within the error limits of statistical uncertainty. The fluences for dust grains along the entire trajectory is calculated; it is found that extrapolation of the spectrum determined at intermediate masses (cumulative mass index alpha = 0.85) is not able to account for the spacecraft deceleration as observed by the Giotto Radio Science Experiment and by ESOC tracking operations. Data at large masses (>10(-8) kg) recently analysed from the DIDSY data set show clear evidence of a decrease in the mass distribution index at these masses within the coma, and it is shown that such a value of the mass index can provide sufficient mass for consistency with the observed deceleration. The total particulate mass output from the nucleus of comet P/Halley at the time of encounter would be dependent on the maximum mass emitted if this change in slope observed in the coma were also applicable to the emission from the nucleus; this matter is discussed in the text. The flux time profiles have been converted through a simple approach to modeling of the particle trajectories to yield an indication of nucleus surface activity. There is indication of an enhancement in flux at t approximately -29 s corresponding to crossing of the dawn terminator, but the flux detected prior to crossing of the dawn terminator is shown to be higher than predicted by simple modelling. Further enhancements corresponding to jet activity are detected around +190 s and +270 s.