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Articles for Clocks in the News
Prof. Stu Brody, Dr. Anna Kriebs, and Dr. Drew Duglan
by: D.Duglan | Mar 2018
It has been estimated that 10% of the workforce in Western countries performs some type of night shift work, which can disrupt normal biological rhythms and has been associated with the risk of cardiovascular disease, diabetes and cancer. A recent study, published in the journal Diabetes Care, has now built upon these earlier findings, revealing that those individuals who worked irregular or rotating shifts had a 44% higher relative risk of type 2 diabetes compared to day workers. Celine Vetter and colleagues analyzed UK Biobank data for more than 270 000 people, examining the relationship between the type, as well as frequency of shift work, and disease risk. The researchers observed a dose-response effect for frequency, whereby the likelihood of having type 2 diabetes rose with increasing numbers of night shifts worked per month. Interestingly however, those individuals who worked permanent night shifts did not exhibit any increase in risk, which could suggest a long-term adaptation to this consistent schedule, although it may also be a product of other healthier lifestyle habits observed in this group. Another novel finding is that the negative effects of shift work on type 2 diabetes risk were present regardless of any genetic predispositions, with no observable interaction between genetic risk score and shift work exposure. Overall, the research highlights the potential metabolic costs of inconsistent work-life schedules that are incongruent with our biology. This is a pertinent subject for emergency service workers such as firefighters, who have recently teamed up with UCSD and Satchin Panda's Lab at the Salk Institute, in the hopes of ameliorating the deleterious effects of shift work with a circadian-based nutritional intervention.
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EurekAlert (SD Fire-Rescue collaborate with UCSD and Salk)
by: D.Duglan | Feb 2018
Poor sleep and perturbed daily activity patterns have been described extensively in patients that exhibit definitive neurodegenerative disease. However, until now, it has not been clear whether abnormal circadian rhythms exist in individuals with markers of preclinical Alzheimer’s, who otherwise display no cognitive symptoms. A recent study published in JAMA Neurology addressed precisely this question; Dr. Eric Musiek and colleagues studied wrist actigraphy data from 189 participants, in conjunction with the results of PET imaging and CSF sampling, which serve as biomarkers of amyloid plaque pathology. Those individuals who tested positive for amyloid deposition displayed significantly more circadian fragmentation, reflecting greater daytime sleep and nighttime wake. In the subset of individuals who tested negative for amyloid pathology, increased age was also associated with this rest-activity fragmentation. This work suggests that both normal aging and Alzheimer’s disease could separately drive circadian disruption, and it raises the question of whether each biological state could act through the same internal clock mechanism. While the direction of causality between disturbed sleep and Alzheimer’s onset has yet to be established, this research highlights the utility of the former as an early biomarker, which could hopefully be used in combination with other future diagnostic tools – perhaps a simple blood test.
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Scientific American (Blood Test for Alzheimer’s)
by: D.Duglan | Jan 2018
The responsiveness of plants to their photoperiod is finely integrated with their internal clock to direct growth, development and reproduction. The entrainment of their circadian oscillator by sunlight is largely mediated by the phytochrome-interacting factors (PIFs), a group of transcription factors that normally accumulate during the night phase to stimulate stem growth. Now, a new study published in the journal Current Biology has elucidated this mechanism further, highlighting the molecular components responsible for the specific timing of stem elongation in the plant Arabidopsis thaliana. Prof. Elena Monte and colleagues performed a detailed analysis of DNA-binding sites in Arabidopsis seedlings, demonstrating that specific DNA motifs interact with both PIFs and a repressive family of clock proteins called PRRs. They observed how this PIF-PRR protein interaction influenced the expression of a downstream growth factor, CDF5, and subsequently the daily timing of stem growth. Between the hours of morning and dusk, CDF5 expression was repressed by the sequential activity of different PRRs, thereby inhibiting growth. Throughout the night the process was reversed; PRR levels declined and PIFs accumulated, reaching a peak towards dawn and promoting stem growth via CDF5 induction. This work suggests an antagonistic model of growth-related gene regulation; moreover, it expands our understanding of the transcription-translation feedback loops that govern the rhythmic gating of plant physiology.
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by: A.Kriebs | Dec 2017
Fibroblasts are connective tissue cells that, among other functions, are crucial for wound healing. At the injured site, fibroblast migration, proliferation, and secretion of extracellular matrix proteins initiates the growth of new tissue. Fibroblasts are also a well-established circadian model system and synchronized cultures display robust rhythms in vitro. An analysis of rhythmically expressed proteins in these cells, performed by the O’Neill laboratory of the MRC Laboratory of Molecular Biology in Cambridge, has now found that the abundance of proteins involved in actin polymerization fluctuates with 24-hour periodicity.
The researchers asked whether circadian actin polymerization, driven by cell-intrinsic clocks, affects wound-oriented cell polarization, cell migration, and ultimately wound closure. In fact, the authors observed a striking time-of-wounding effect on the efficiency of wound healing both in cultured cells as well as in mouse skin samples. Injuries inflicted 24 hours after synchronization (in vitro) or during the active phase (in vivo) closed much more quickly compared to injuries sustained 32 hours after synchronization or during the inactive phase. This differential effect depended on functioning actin polymerization and was sustained for several days post wounding.
In further analysis of data from the International Burn Injury Database, the authors observed that burns sustained during the day time healed about twice as fast compared to burn injuries that occurred at night. This research has potential clinical relevance and indicates that patients might recover faster if surgeries are performed in sync with individual biological timing.
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Chemical & Engineering News:
by: D.Duglan | Dec 2017
The inability of an organism to entrain its circadian rhythm to the Earth’s 24-hour day is typically recognized as disadvantageous; lab animal mutants display reduced lifespan, while epidemiological reports in humans associate circadian disruption with increased risk of depression, cardiometabolic disease and cancer. However, this broad notion has just been challenged by a study of behavioral rhythms in the trashline orb-weaving spider, which were presented by lead author Darrell Moore at the recent Society for Neuroscience conference. This work, published in the Journal of Arachnology, demonstrated that these spiders have extremely short circadian cycles of between 17 and 19 hours, the shortest ever observed. Moore and colleagues caught several species of spider from the wild and measured their internal free-running period in constant darkness. While the spiders had a movement cycle of approximately 18.5 hours under these conditions, upon exposure to light the spiders reset their circadian clock by 6 hours the following day, seemingly without any noticeable jet-lag.
In terms of their natural daily activity, trashline orb-weavers remain motionless and camouflaged in their webs for most of the day, only becoming active in the remaining dark hours before sunrise. It is hypothesized that this accelerated internal clock allows them to avoid potential predators that become active after dawn. Interestingly, the authors note that unlike locomotor activity, the proclivity for web-building does not follow the same robust periodicity under constant darkness, suggesting that this behavior may at least be driven partly by the environmental factors. The molecular mechanism underlying this spider’s truncated circadian cycle remains unclear; undoubtedly now an area for further investigation. This study should also remind circadian biologists of the potential diversity of rhythms in other wild animals, and not merely those of model organisms maintained in a lab setting.
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by: D.Duglan | Nov 2017
While there is increasing appreciation for the role of tissue-specific clocks, recent work has now identified circadian oscillations in one of the major elements of our sensory perception: our sense of smell.
An exploratory study conducted by researchers at Brown University has revealed that odor detection sensitivity in adolescent teenagers varies throughout an individual’s circadian phase. Prof. Mary Carskadon and colleagues admitted 37 subjects to a controlled laboratory, where they underwent a week of 28-hour days, known as a “forced desynchrony” protocol. Unable to entrain to this 28-hour day, the method allows researchers to measure the outputs of free-running human oscillators; each subject’s circadian time was assessed by measuring melatonin levels.
Smell sensitivity to a chemical odor (rose-smelling) was then tested 6 times during the wake hours throughout each 28-hour cycle. The researchers found that on average, peak odor sensitivity in the teenagers occurred shortly after the onset of melatonin production, which would correspond to approximately 9pm. While there was significant variability between individuals’ timing of peak sensitivity, none of the subjects displayed peaks between the approximate hours of 2am and 10am.
This work has interesting implications for both our evolutionary origins and our modern lives. An improved sense of smell towards the end of the day may have been advantageous for the detection of predators, when darkness would impair visual acuity. The primary feeding period for our hunter-gatherer ancestors also likely occurred during the evening, therefore heightened olfactory sensing may have aided detection of toxins and improved flavor perception.
In a practical sense, this study may be useful for clinicians who use olfactory diagnostic tests, the results of which could vary between early morning and late afternoon measurements. It also builds on earlier work demonstrating that during sleep our odor detection ability is blunted, underscoring the importance of auditory fire alarms. This research was published in Chemical Senses and is part of a larger ongoing project investigating the relationship between sense of smell and dietary habits in teenagers.
by: A.Kriebs | Nov 2017
Healthy human physiology is robustly rhythmic, as is the timing of onset of adverse health events, including myocardial infarction, sudden cardiac death, and stroke. These observations suggest that there is an optimal time-of-day for therapeutic treatments. Finding ways to harness circadian timing to make medical interventions more effective and safer (also known as chronotherapy) has been the subject of much study, promising easy and cost effective solutions.
Now a new study published in The Lancet shows that patients stand to benefit from the simple act of scheduling their heart surgery for the afternoon rather than the morning. Patients undergoing on-pump heart surgery will experience reoxygenation injuries of the heart tissue which increase the risk for adverse cardiac events, such as myocardial infarction and acute heart failure.
To improve clinical outcomes the authors studied the occurrence of adverse events after aortic valve replacement in patients with surgery in the morning or the afternoon and found that the afternoon group fared significantly better. Ex vivo study of human biopsy samples indicated that myocardial tissue taken in the afternoon was better adapted to cope with a hypoxia-reoxygenation challenge. This coincided with differences in REV-ERBα and BMAL1 expression. Intriguingly, chemical or genetic ablation of Rev-erbα function in mouse hearts resulted in increased hypoxia-reoxygenation tolerance, implicating cardiomyocyte clock transcriptional regulation as at least partly responsible for the effect and raising the possibility of chemical intervention targeting REV-ERBα to improve patient outcomes.
Thus this study presents compelling options to improve outcomes of patients undergoing this type of surgery.
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New York Times
by: A.Kriebs and D.Duglan | Oct 2017
Ubiquitously, circadian biology literature defines the eukaryotic circadian clock as the mechanism that generates self-sustained transcription-translation feedback loops and thus drives rhythmic expression of genes with 24-hour periodicity. Now, the scientists whose work throughout the 1980s and 1990s laid the foundation for our understanding of the biological clockwork, Jeffrey Hall, Michael Rosbash and Michael Young, have been awarded the Nobel prize for Physiology or Medicine.
Using the model organism Drosophila melanogaster, the scientists studied the period gene, which had been shown to be required for normal fly biological rhythms, including circadian patterns of eclosion and locomotor activity, as well as short-term male courtship song oscillations. In 1984 Jeffrey Hall and Michael Rosbash, collaborators at Brandeis University, as well as Michael Young at Rockefeller University, independently succeeded in isolating the period gene. Subsequently, Hall and Rosbash demonstrated that the abundance of the period gene product, the PER protein, fluctuates with 24-hour periodicity, peaking during the night and hardly detectable during the day. This oscillation persisted in constant darkness. Subsequent work by the three scientists was key to identifying the molecular mechanism that generated these oscillations. Observing that mutations in the period gene affected the periodicity of its mRNA rhythms, Hall and Rosbash proposed that the PER protein itself was involved in a feedback loop regulating its own expression. In fact, work by Young led to the identification and functional characterization of an additional clock component, timeless. He showed that TIM, PER’s heterodimer partner, facilitates PER translocation into the nucleus where the complex represses period expression. Young also identified double-time. The protein kinase DOUBLE-TIME destabilizes PER, thus explaining how PER degrades during the day and how the cycle is able to renew. Homologs of Drosophila clock protein components are present in other animals and function by the same principles, therefore their work created a molecular understanding of the gears that govern circadian rhythms in other species, including humans.
These internal rhythms coordinate the timing of essential aspects of our physiology and behavior, such as the sleep-wake cycle, metabolism and immune function, as well cardiovascular, endocrine and reproductive health. This intrinsic ability to match physiological processes to fundamental environmental cues over the 24 hour day is central to an organism’s evolutionary success. However, the presence of an entrainable circadian clock can be a double-edged sword; namely in the face of modern changes to our environment. In a world of rotational shift work, jet lag and inappropriate lighting and feeding schedules, a discordance can arise between our biology and our contemporary lifestyles. These circadian stressors are now increasingly associated with the development of cardiovascular and metabolic disease, as well as the risk of cancer. An optimistic future of preventing and reversing these serious health conditions will likely involve further resolution of the molecular clock, which will no doubt be inspired by the celebrated work of these three circadian pioneers.
Michael Young, who is Vice President for Academic Affairs and Richard and Jeanne Fisher Professor in the Laboratory of Genetics at The Rockefeller University, also serves on the CCB’s external advisory board. The Young laboratory currently studies the genetic underpinnings of homeostatic sleep regulation in Drosophila, as well as the activity of the human circadian clock in cells derived from patients with sleep or depressive disorders. Most recently, this work led to the identification of a mutation in CRY1 which causes familial delayed sleep phase disorder.
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(Also follow this link to take a peek at the key publications that document these discoveries.)
by: A.Kriebs | Oct 2017
Immune function varies with the time-of-day. Circadian clocks temporally coordinate immune cell localization, cytokine and chemokine expression, as well as other processes to help organisms cope with the risk of pathogenic infection. The chances of encountering air and food borne pathogens are heightened during the active phase. In fact, studies in mice have shown that the animals are most susceptible to viral and bacterial infections during the early inactive period, when exposure to pathogens is anticipated to be low.
Now, in a new study from the lab of Nicolas Cermakian at McGill University, Silke Kiessling and her colleagues explore the time-of-day dependence of Leishmania infection - a parasite that is transmitted through female sandfly bites and resides in the host’s neutrophils and macrophages. The researchers infected mice with the parasite at different times-of-day. They observed that parasitic load was lowest when the infection took place at ZT3 (inactive period) and highest when it occurred at ZT15 (active period). To determine the cause, the team looked at the host cells targeted by the parasite and found that parasitic insult at ZT15 more strongly induced the expression of chemoattractants and resulted in increased neutrophil recruitment to the site of infection thus enhancing the efficiency of parasitic invasion. These effects were abolished when the circadian clock was ablated in bone marrow cells by knocking-out the Bmal1 gene.
This study indicates that the time of highest Leishmania infectivity corresponds to the natural time of sandfly biting behavior which occurs at dusk and continues into the night. While it is not known how this research translates to humans it raises the possibility that the Leishmania parasite benefits from the circadian gating of the immune response.
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Infectious Diseases Hub:
by: D.Duglan | Sep 2017
The make-up of our intestinal microbiota is ever-increasingly being linked to our overall metabolic health. Recent work by scientists at Southwestern Medical Center (Dallas) has revealed that the gut flora is dependent on the circadian transcription factor Nfil3 to influence body composition. The team, led by Prof. Lora Hooper, generated mice that lacked Nfil3 in intestinal epithelial cells, observing that these mice were protected against those deleterious effects of being placed on a Western-style diet; namely weight gain, hepatic fat deposition and insulin resistance. This was also replicated in other germ-free mice that completely lacked a microbiome, demonstrating the interdependence of Nfil3 and the gut flora to modulate body fat accumulation. Whilst Nfil3 has typically been associated with the circadian regulation of immune function, this latest research now defines a role for the protein in controlling lipid absorption across the intestinal lining. It remains to be seen whether this same molecular link might underlie the incidence of metabolic syndrome in humans that are subjected to circadian disruption.
Medical News Today
by: A.Kriebs | Sep 2017
Circadian clocks are crucial for maintaining metabolic health. The brain clock regulates sleep and activity cycles, as well as the timing of other behaviors, like feeding, while clocks in peripheral tissues coordinate daily rhythms of physiology and metabolism. Clocks, for example in the liver and pancreas, regulate proper responses to food consumption. Evidence suggests that meal timing, not only calorie count, affects weight gain, as discussed in the FiveThirtyEight article linked to below.
To further dissect the mechanisms underlying health benefits through restriction of food intake the laboratories of Profs. Carla Greene and Joseph Takahashi developed an automated feeder system that allows precise control of the amount, duration and timing of food availability in animal studies. Applying this system to several commonly used feeding paradigms, like temporal restriction and caloric restriction, showed that calorically restricted mice lost weight only when fed during the night, the animal’s active period, not when fed during the day. The study also revealed that calorie restriction altered running wheel activity and that activity patterns varied over the course of the study, underlining the plasticity of feeding and activity behavior. The authors hope that their new feeder system will help scientists assess the respective contributions of reduced calorie count and timing of food intake to increased longevity observed with calorie restriction regiments.
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UT Southwestern news release:
by: A.Kriebs | Sep 2017
Circadian clocks are present in virtually all tissues of the body to optimally regulate tissue specific functions, e.g. the skin circadian clock protects from UV-induced DNA damage, at least in part, by increasing the expression of DNA repair machinery during the day, when skin is exposed to sunlight.
Time-telling external stimuli that enable proper circadian synchronization to the environment include light and food availability. While light received through the eyes allows the master circadian clock in the brain to tell the time-of-day and synchronize peripheral circadian clocks, circadian oscillations, especially in metabolic organs such as the liver, can be shifted relative to brain-time through time-restricted feeding.
A new study from the laboratory of Prof. Bogi Andersen at the University of California, Irvine, now shows that the skin circadian oscillator is also sensitive to feeding time. Comparing circadian rhythms of gene expression in mice that received food at different times of the day or at night showed that skin circadian phase was shifted in response to feeding time. The authors also demonstrate that animals that feed at night, like they naturally would, are more sensitive to UVB-induced damage at night compared to the day. However, day-time feeding reverses the diurnal sensitivity to UVB-induced DNA damage. While it is unclear how these results translate to humans, this study reveals an unanticipated connection between the circadian timing cue, feeding time, and the skin circadian clock.
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UT Southwestern news release:
by: A.Kriebs | Apr 2017
The recommendation: “Early to bed, and early to rise” is not for everyone. Preference for sleep timing, or chronotype, is determined by the circadian clock. Roughly, there are morning larks and night owls. Chronotype can determine compatibility with certain social schedules and extreme chronotypes can be very disruptive to the regular day-to-day. Recently, researchers at Rockefeller University discovered the genetic underpinnings of a slow circadian clock that caused delayed sleep phase disorder (DSPD). The study from the laboratory of Prof. Michael Young, a member of the CCB advisory board, lead by Dr. Alina Patke linked the disorder to a variant of the CRY1 gene, a component of the mammalian circadian clock. The resulting protein product was missing a small portion in the C-terminal tail. This shorter CRY1 turned out to be a more potent version of the full length form effectively slowing down circadian time. While there are currently no treatment options targeting CRY1 this finding is still highly relevant and could encourage development of the same since this gene variant is likely present in one out of 75 individuals.
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by: A.Kriebs | Mar 2017
Anecdotally, a good night’s sleep is one of the most frequently prescribed remedies. In fact, sleep is crucial for physical and mental well-being. Among other things, memories are solidified during sleep. As both sleep and memory change over the course of a lifetime, researchers are exploring the interconnection between sleep, memory, and aging. Scientists at Northwestern University Medical School focused on decreasing slow wave activity, a sleep stage associated with the ability to recall factual information and experiences, in adults 60 years and older. The team of CCB advisory board member Prof. Phyllis Zee reports that sound stimulation during certain parts of the slow wave activity improved test subjects’ performance in memory tests the next day. This exciting new finding could lead to easy, non-invasive interventions to prevent age-related memory decline.
by: A.Kriebs | Feb 2017
Plants are often perceived as immobile. However, circadian biologists, dating back to the French scientist Jean-Jaques de Mairan in the 1700(s), knew that plants show daily rhythms of movement. More recently, in an elegant study, the team of Prof. Stacey Harmer from UC Davis, a CCB Associate member, showed that the east to west rotation of young sunflower plants over the course of the day is controlled by an internal circadian clock and helped the young flowers to grow bigger than their sibling plants whose movement was impeded. While young sunflowers rotated their heads to follow the sun, this behavior stopped in adult sunflowers, which faced perpetually east. Adult flowers have evolved to face the rising sun because the warmth helps them to attract pollinators. This study was published in the journal Science and featured in the Los Angles Times in August of 2016.
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LA Times article:
by: A.Kriebs | Feb 2017
The expression “to go to bed with the chickens” refers to a time when people’s sleep wake cycle was dictated by the natural day. In modern society this is no longer the case. We often stay up long after dusk, since we don’t have to rely on natural light to do our work. As a consequence our biological night, as defined by elevated levels of the sleep hormone melatonin, begins long after dark. Therefore, when it is time to rise in the morning melatonin levels may still be high, making getting out of bed a challenge. The team of Prof. Kenneth Wright from the University of Colorado, Boulder, reports that camping might help. Their unique study, published in the journal Current Biology and featured in this Los Angles Times article, shows that a weekend camping trip in the Rocky Mountains, away from electric lighting, was sufficient to shift the melatonin profile of campers more than an hour earlier compared with the control group that stayed home. Additionally, the researchers showed that the melatonin profiles mirror seasonal changes in day length. Therefore, maximizing light exposure during the day as well as minimizing it during the night is key to changing sleep patterns
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LA Times article: