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Energy regulation in context: Free-living female arctic ground squirrels modulate the relationship between thyroid hormones and activity among life history stages. - Hormones and behavior
Thyroid hormones (THs), key regulators of lipid and carbohydrate metabolism, are likely modulators of energy allocation within and among animal life history stages. Despite their role in modulating metabolism, few studies have investigated whether THs vary among life history stages in free-living animals or if they exhibit stage-specific relationships to total energy expenditure and activity levels. We measured plasma total triiodothyronine (tT3) and thyroxine (tT4) at four, discrete life history stages of female arctic ground squirrels from two different populations in northern Alaska to test whether plasma THs correlate with life history stage-specific changes in metabolic rate and energy demand. We also tested whether THs explained individual variation in aboveground activity levels within life history stages. T3 peaked during lactation and was lowest during pre-hibernation fattening, consistent with known changes in basal metabolism and core body temperature. In contrast, T4 was elevated shortly after terminating hibernation but remained low and stable across other life-history stages in the active season. THs were consistently higher in the population that spent more time above-ground but the relationship between THs and activity varied among life history stages. T3 was positively correlated with activity only during lactation (r(2)=0.50) whereas T4 was positively correlated with activity immediately following lactation (r(2)=0.48) and during fattening (r(2)=0.53). Our results support the hypothesis that THs are an important modulator of basal metabolism but also suggest that the relationship between THs and activity varies among life history stages.Copyright Â© 2015 Elsevier Inc. All rights reserved.
Persistence, entrainment, and function of circadian rhythms in polar vertebrates. - Physiology (Bethesda, Md.)
Polar organisms must cope with an environment that periodically lacks the strongest time-giver, or zeitgeber, of circadian organization-robust, cyclical oscillations between light and darkness. We review the factors influencing the persistence of circadian rhythms in polar vertebrates when the light-dark cycle is absent, the likely mechanisms of entrainment that allow some polar vertebrates to remain synchronized with geophysical time, and the adaptive function of maintaining circadian rhythms in such environments.Â©2015 Int. Union Physiol. Sci./Am. Physiol. Soc.
Reproductive phenology of a food-hoarding mast-seed consumer: resource- and density-dependent benefits of early breeding in red squirrels. - Oecologia
The production of offspring by vertebrates is often timed to coincide with the annual peak in resource availability. However, capital breeders can extend the energetic benefits of a resource pulse by storing food or fat, thus relaxing the need for synchrony between energy supply and demand. Food-hoarding red squirrels (Tamiasciurus hudsonicus) breeding in the boreal forest are reliant on cones from a masting conifer for their nutrition, yet lactation is typically completed before the annual crop of cones is available for consumption such that peaks in energy supply and demand are not synchronized. We investigated the phenological response of red squirrels to annual variation in environmental conditions over a 20-year span and examined how intra- and inter-annual variation in the timing of reproduction affected offspring recruitment. Reproductive phenology was strongly affected by past resource availability with offspring born earlier in years following large cone crops, presumably because this affected the amount of capital available for reproduction. Early breeders had higher offspring survival and were more likely to renest following early litter loss when population density was high, perhaps because late-born offspring are less competitive in obtaining a territory when vacancies are limited. Early breeders were also more likely to renest after successfully weaning their first litter, but renesting predominantly occurred during mast years. Because of their increased propensity to renest and the higher survival rates of their offspring, early breeders contribute more recruits to the population but the advantage of early breeding depends on population density and resource availability.
Hibernation and circadian rhythms of body temperature in free-living Arctic ground squirrels. - Physiological and biochemical zoology : PBZ
In mammals, the circadian master clock generates daily rhythms of body temperature (T(b)) that act to entrain rhythms in peripheral circadian oscillators. The persistence and function of circadian rhythms during mammalian hibernation is contentious, and the factors that contribute to the reestablishment of rhythms after hibernation are unclear. We collected regular measures of core T(b) (every 34 min) and ambient light conditions (every 30 s) before, during, and following hibernation in free-living male arctic ground squirrels. Free-running circadian T(b) rhythms at euthermic levels of T(b) persisted for up to 10 d in constant darkness after animals became sequestered in their hibernacula in fall. During steady state torpor, T(b) was constant and arrhythmic for up to 13 d (within the 0.19Â°C resolution of loggers). In spring, males ended heterothermy but remained in their burrows at euthermic levels of T(b) for 22-26 d; patterns of T(b) were arrhythmic for the first 10 d of euthermia. One of four squirrels exhibited a significant free-running T(b) rhythm (Ï„ = 22.1 h) before emergence; this squirrel had been briefly exposed to low-amplitude light before emergence. In all animals, diurnal T(b) rhythms were immediately reestablished coincident with emergence to the surface and the resumption of surface activity. Our results support the hypothesis that clock function is inhibited during hibernation and reactivated by exposure to light, although resumption of extended surface activity does not appear to be necessary to reinitiate T(b) cycles.
Thermoregulatory changes anticipate hibernation onset by 45Â days: data from free-living arctic ground squirrels. - Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology
Hibernation is a strategy of reducing energy expenditure, body temperature (T(b)) and activity used by endotherms to escape unpredictable or seasonally reduced food availability. Despite extensive research on thermoregulatory adjustments during hibernation, less is known about transitions in thermoregulatory state, particularly under natural conditions. Laboratory studies on hibernating ground squirrels have demonstrated that thermoregulatory adjustments may occur over short intervals when animals undergo several brief, preliminary torpor bouts prior to entering multiday torpor. These short torpor bouts have been suggested to reflect a resetting of hypothalamic regions that control T(b) or to precondition animals before they undergo deep, multiday torpor. Here, we examined continuous records of T(b) in 240 arctic ground squirrels (Urocitellus parryii) prior to hibernation in the wild and in captivity. In free-living squirrels, T(b) began to decline 45 days prior to hibernation, and average T(b) had decreased 4.28 Â°C at the onset of torpor. Further, we found that 75 % of free-living squirrels and 35 % of captive squirrels entered bouts of multiday torpor with a single T(b) decline and without previously showing short preliminary bouts. This study provides evidence that adjustments in the thermoregulatory component of hibernation begin far earlier than previously demonstrated. The gradual reduction in T(b) is likely a component of the suite of metabolic and behavioral adjustments, controlled by an endogenous, circannual rhythm, that vary seasonally in hibernating ground squirrels.
Orphan drug development: an economically viable strategy for biopharma R&D. - Drug discovery today
Orphan drug incentives have stimulated research into diseases with significant unmet medical need. Although the targeting of orphan diseases is seen by industry as an attractive strategy, there are limited economic data available to support its use. In this paper we show that the revenue-generating potential of orphan drugs is as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. Moreover, we suggest that orphan drugs have greater profitability when considered in the full context of developmental drivers including government financial incentives, smaller clinical trial sizes, shorter clinical trial times and higher rates of regulatory success. The data support the targeting of rare diseases as an important component of a successful biopharma R&D strategy.Copyright Â© 2012 Elsevier Ltd. All rights reserved.
Regulation of proton-coupled folate transporter in retinal MÃ¼ller cells by the antipsoriatic drug monomethylfumarate. - Glia
Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, MÃ¼ller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by Ëœ50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.Copyright Â© 2011 Wiley Periodicals, Inc.
Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (ÏƒR1). - Investigative ophthalmology & visual science
Sigma receptor 1 (ÏƒR1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of ÏƒR1 on ocular development, structure, and function.Wild-type (ÏƒR1âº/âº), heterozygous (ÏƒR1âº/â»), and homozygous (ÏƒR1â»/â», knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement. The eyes were examined by light and electron microscopy and subjected to morphometric examination and detection of apoptosis.Cornea and lens of ÏƒR1â»/â» mice were similar to wild-type mice in morphologic appearance at all ages examined, and IOP was within normal limits. Comprehensive ERG and morphometric analyses initially yielded normal findings in the ÏƒR1â»/â» mice compared with those in the wild-type. By 12 months, however, significantly decreased ERG b-wave amplitudes and diminished negative scotopic threshold responses, consistent with inner retinal dysfunction, were detected in ÏƒR1â»/â» mice. Concomitant with these late-onset changes were increased TUNEL- and active caspase 3-positive cells in the inner retina and significant loss of cells in the ganglion cell layer, particularly in the central retina. Before these functional and structural abnormalities, there was ultrastructural evidence of axonal disruption in the optic nerve head of ÏƒR1â»/â» mice as early as 6 months of age, although there were no alterations observed in retinal vascularization in ÏƒR1â»/â» mice.These data suggest that lack of ÏƒR1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy.
Daily body temperature rhythms persist under the midnight sun but are absent during hibernation in free-living arctic ground squirrels. - Biology letters
In indigenous arctic reindeer and ptarmigan, circadian rhythms are not expressed during the constant light of summer or constant dark of winter, and it has been hypothesized that a seasonal absence of circadian rhythms is common to all vertebrate residents of polar regions. Here, we show that, while free-living arctic ground squirrels do not express circadian rhythms during the heterothermic and pre-emergent euthermic intervals of hibernation, they display entrained daily rhythms of body temperature (T(b)) throughout their active season, which includes six weeks of constant sun. In winter, ground squirrels are arrhythmic and regulate core body temperatures to within Â±0.2Â°C for up to 18 days during steady-state torpor. In spring, after the use of torpor ends, male but not female ground squirrels, resume euthermic levels of T(b) in their dark burrows but remain arrhythmic for up to 27 days. However, once activity on the surface begins, both sexes exhibit robust 24 h cycles of body temperature. We suggest that persistence of nycthemeral rhythms through the polar summer enables ground squirrels to minimize thermoregulatory costs. However, the environmental cues (zeitgebers) used to entrain rhythms during the constant light of the arctic summer in these semi-fossorial rodents are unknown.
Data logging of body temperatures provides precise information on phenology of reproductive events in a free-living Arctic hibernator. - Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology
Precise measures of phenology are critical to understanding how animals organize their annual cycles and how individuals and populations respond to climate-induced changes in physical and ecological stressors. We show that patterns of core body temperature (T (b)) can be used to precisely determine the timing of key seasonal events including hibernation, mating and parturition, and immergence and emergence from the hibernacula in free-living arctic ground squirrels (Urocitellus parryii). Using temperature loggers that recorded T (b) every 20Â min for up to 18Â months, we monitored core T (b) from three females that subsequently gave birth in captivity and from 66 female and 57 male ground squirrels free-living in the northern foothills of the Brooks Range Alaska. In addition, dates of emergence from hibernation were visually confirmed for four free-living male squirrels. Average T (b) in captive females decreased by 0.5-1.0Â°C during gestation and abruptly increased by 1-1.5Â°C on the day of parturition. In free-living females, similar shifts in T (b) were observed in 78% (nÂ =Â 9) of yearlings and 94% (nÂ =Â 31) of adults; females without the shift are assumed not to have given birth. Three of four ground squirrels for which dates of emergence from hibernation were visually confirmed did not exhibit obvious diurnal rhythms in T (b) until they first emerged onto the surface when T (b) patterns became diurnal. In free-living males undergoing reproductive maturation, this pre-emergence euthermic interval averaged 20.4Â days (nÂ =Â 56). T (b)-loggers represent a cost-effective and logistically feasible method to precisely investigate the phenology of reproduction and hibernation in ground squirrels.
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1120 W South Boulder Rd # 204 Lafayette, CO 80026
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