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378 Sentences With "circadian clock"

How to use circadian clock in a sentence? Find typical usage patterns (collocations)/phrases/context for "circadian clock" and check conjugation/comparative form for "circadian clock". Mastering all the usages of "circadian clock" from sentence examples published by news publications.

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Exercise has many benefits for the circadian clock and sleep cycle.
The body operates on a biological schedule known as the circadian clock.
For one: As we age, our internal circadian clock appears to break down.
Melatonin helps set the overall pace of the master circadian clock in the body.
" Before their discoveries, he said, "the nature of the circadian clock was a great mystery.
Sunlight is a natural zeitgeber, or environmental cue that resets the circadian clock, he said.
This endogenous hormone is controlled by the circadian clock, while also influencing it in turn.
Usually, at nighttime, our circadian clock sends a signal that tells us to release melatonin overnight.
The circadian clock is a concept that scientists use to measure our internal sense of time.
"Our body contains a circadian clock, which helps to keep time for many biological functions," he said.
So with irregular sleepers, melatonin is released later in the night, pushing the circadian clock later as well.
"If you catch up during weekends, you habitually eat later, because the circadian clock is shifting," Polotsky said.
They found that mutations in an unknown gene disrupted flies' circadian clock and named the gene "period," or per.
On my nightstand, you will find a shrine of sorts, a ritual offering to my own broken circadian clock.
According to Gehrman, melatonin's ability to shift the circadian clock is stronger than its ability to promote immediate sleep.
First, a new schedule throws the body's "circadian clock"—the inbuilt mechanism that regulates waking and sleeping—out of alignment.
"We recommend resetting the circadian clock at least partially toward the destination time zone before flying," the study's authors write.
So understanding the circadian clock and its variations isn't just important for sleep problems, Dr. LeBourgeois said in an email.
A greater understanding of how our circadian clock impacts on our seasonal cycles is something we could all benefit from.
Is it possible to strengthen your circadian clock to increase psychological resilience, rather than remedy depressive symptoms by forgoing sleep?
One is that it can change the timing of the circadian clock — but it's just not that effective at doing it.
Personal genomics company 23andMe recently made a deal with Reset Pharmaceuticals to develop new sleep meds based on the body's circadian clock.
In addition, they enjoyed learning about normalizing infant sleep, understanding how sleep works, and attending to their baby's circadian clock and sensory needs.
"The circadian clock is the central conductor of the many clocks that are found in nearly all tissues of your body," Zeitzer said.
Still, the experiment was designed to test the effect of the circadian clock, and that is not the only factor involved in smell sensitivity.
The idea is to get up for the day halfway through the usual sleep period, which shifts the circadian clock to an earlier time.
It's that my circadian clock tells me it's time for bed when the sun is rising and time to wake up as it's setting.
This way I could leave my cell phone in the other room, and not poison my circadian clock with light after a certain hour.
The circadian clock responds to external cues, meaning it can be managed with a carefully maintained sleep regimen and exposure to bright light during the day.
In particular, the program explains sleep regulators such as the circadian clock and sleep pressure and encourages parents to respond to babies' "cues" for eating and sleeping.
To learn what impact a person's circadian clock has on different diseases, we need really large studies—and a big one just came out in Nature Communications.
In "The Circadian Clock in Your Nose," Veronique Greenwood writes: When people tell you, "wake up and smell the roses," they might be giving you bad advice.
The ones I talked to also disagreed on when to take it — depending on whether they thought melatonin was better for sleep promotion or circadian clock resetting.
Photoreceptors nested at the back of our eyes known as ipRGCs are especially sensitive to blue light, and therefore perfectly primed to help calibrate the circadian clock.
It's part of a larger project that will also look at genetic interventions that amp up the circadian clock by operating on the DNA that controls it directly.
One of the most popular suggestions from the research community, however, is that our nasal mucus, like other parts of our body, operates according to a circadian clock.
But many unknowns remain: For example, just how does the young sunflower weave together light signals, the circadian clock and growth rates to reorient its head every night?
"This is what the predictive function of a circadian clock is," says Anna Wirz-Justice, professor at the Centre for Chronobiology at the University of Basel in Switzerland.
We also need light from the side striking the back of the eye — preferably from a natural source like a window — to entrain our body's internal circadian clock.
"There are blue light photoreceptors in the retina that directly communicate with the brain circadian clock," Tosini, who was not involved in the ANSES report, wrote in an email.
Conducting genetic tests on tissue samples, the team learned that the 287 genes linked to the circadian clock were more active in the afternoon samples than the morning samples.
Unlike other bioluminescent organisms, fungi emit a constant light, possibly to attract spore-transporting insects, that dims and intensifies according to a circadian clock that still isn't quite understood.
If you are a lark or an owl is partially driven by differences in our DNA—but it's still fuzzy exactly how your unique circadian clock might influence your health.
Research into altering the circadian clock to produce powerful antidepressant benefits could lead to the development of drugs that might mimic the effect of sleep deprivation, but without its obvious drawbacks.
One idea is that some people's eyes are less sensitive to light, so once light levels fall below a certain threshold, they struggle to synchronize their circadian clock with the outside world.
A circadian clock ticks in every cell of your body, including your brain cells, and they are coordinated by an area of the brain called the suprachiasmatic nucleus, which responds to light.
Then, the cycles of the reindeers' circadian clock have their highest highs and lowest lows, perhaps driving the animals to forage what is available during the day and prepare for what's ahead.
Though they may not agree on much else when it comes to sleep patterns, experts do agree that sunlight is one of the most significant cues that keeps the circadian clock in check.
Mander says it's been widely shown that there's a shift when you hit adolescence: The circadian clock becomes a bit more delayed, so teens want to stay up later and get up later.
For nine days, they followed a strict schedule to allow researchers to focus on the circadian clock, which helps control wake and sleep, but also influences other processes in the body, including metabolism.
Research at New York University and the University of Washington into the circadian clock — a process shared across organisms from plants to humans — could eventually unlock secrets in agriculture, medicine, and human aging.
There are several theories, none of them definitive, but most relate to the circadian clock—the roughly 21980-hour oscillation in our behavior and biology that influences when we feel hungry, sleepy, or active.
The circadian clock of the average teen is naturally shifted up to four hours later than an adult, meaning that a teen's biology pressures them to go to bed later and wake up later.
These cells, called ipRGCs, are particularly sensitive to blue light, connect to a number of different brain areas, and seem to feed into our circadian clock, our sleep centers, and even some mood-regulating areas.
"Tasimelteon is the first drug that was approved to regulate the circadian clock, other drugs that were tried for other circadian disorders didn't affect the clock—they affected the symptoms and the sleepiness," he says.
More broadly, the authors write, their study and others like it could suggest a better way to prevent and treat medical problems, like obesity and diabetes, that are associated with disruption to the circadian clock.
"Nearly all species have an internal or circadian clock which has evolved to allow us to interact with the outside world," said Steven W. Lockley, a sleep expert and associate professor at Harvard Medical School.
Then a colleague, a sleep neurologist, approached them with an intriguing case: a woman whose circadian clock seemed to be set four hours early, which caused her to go to sleep around 7:30 p.m.
"There is work that shows disrupting the cellular clock—or, the molecular 'gears' of the circadian clock—can increase depressive-like and manic-like behaviors, as well as cognitive function in mice and rats," Karatsoreos says.
According to the team, its discovery could have far reaching clinical applications, particularly for those with sleep disorders such as jet lag, seasonal affective disorder, and other disorders which mess with the suprachiasmatic nucleus' circadian clock.
We're all equipped with a circadian clock, which is that internal 24-hour timer that naturally tells us when to sleep, and the best way to getting rest and feeling rested is to keep this consistent.
Cocooned in his five-hundred-square-foot apartment in Atlanta, the windows blacked out so that his circadian clock would not be affected by natural light, he slept, ate, exercised, socialized, and worked in virtual reality.
A study just published in Cell found that people who stay up late and have trouble getting up in the morning have a genetic mutation that slows their circadian clock, which regulates patterns of sleeping and waking.
"If you do all the right things and get on the right schedule quickly, you can successfully shift your circadian clock one hour in one day, and you'll be fine in a day or two," Oexman said.
Through these cells, bright light seems to affect our mood and alertness in several ways—suppression of melatonin and synchronization of the circadian clock, for instance—but researchers believe they have another, more direct impact on mood.
"The results make sense — the circadian clock affects virtually every organ system in the body," writes Dr. Leslie Vosshall, a researcher at Rockefeller University who studies smell and was not involved in the study, in an email.
Averaged together, however, the results showed that overall the circadian clock does affect smell, and that the times when the children's noses were most sensitive tended to correspond to the evening, with an average peak of 9 p.m.
"This is the first time that the circadian clock within individual skin cells has been shown to determine how effectively they respond to injuries," said John O'Neill, who co-led the research at Britain's Medical Research Council Laboratory of Molecular Biology.
Stacey Harmer, a professor of plant biology at UC Davis and a senior author on the paper, stated in a press release that there appear to be two growth mechanisms at play: the first providing basic growth and the other controlled by a circadian clock and light.
I can't tell the difference between depression and February "Before the cell paper was published [in 2002], a lot of people — including me, to be honest — just made the assumption that the depressive effects of light are [caused by] disruption to the circadian clock," Hattar told me.
"A general piece of advice, not only for patients with diabetes but for everyone, is to try to live our lives in harmony with our circadian clock as much as possible," said Andrew Coogan, senior author of the study and a researcher at the National University of Ireland, Maynooth.
By giving corticosteroids, a class of steroid hormones, to mice with hay fever whose symptoms were worst in the morning and early evening, they were able to "reset the nasal circadian clock," bringing a better understanding of how these symptoms change throughout the day, and what effect external factors may have.
"In the last 10 years we've come to recognize that there are circadian clocks or oscillators in every cell in the body, and if you're misaligned with your circadian clock, that's going to affect all kinds of functions," said Dr. Judith Owens, the director of sleep medicine at Boston Children's Hospital and the lead author of the new study.
Peroxiredoxins have been implicated in the 24-hour internal circadian clock of many organisms.
Recent experiments have found that the oscillations in the cell cycle and circadian rhythms of Synechococcus are linked together through a one way mechanism. The circadian clock gates cells division, only allowing it to proceed at certain phases. The cell cycle does not appear to have any effect on the circadian clock though. When binary fission occurs, the daughter cells inherit the mother cell's circadian clock and are in phase with the mother cell.
LHY and CCA1 have similar patterns of expression, which is capable of being induced by light.Lu, S. X. , and S. M., Andronis. "CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL Function Synergistically in the Circadian Clock of Arabidopsis" Plant Physiology Vol. 150. (2009): 834–843.
Steven Reppert and colleagues have made seminal contributions that provide insight into the mammalian circadian clock mechanism.
Young, Martin. "Anticipating anticipation: pursuing identification of cardiomyocyte circadian clock function." Journal of Applied Physiology. 107.4 (2009): 1339-1347. Web.
LHY (late elongated hypocotyl) also has a Myb domain and functions early in the morning. Both LHY and CCA1 have similar patterns of expression, which could be induced by light.Lu, S. X. , and S. M., Andronis. "CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL Function Synergistically in the Circadian Clock of Arabidopsis" Plant Physiology Vol. 150.
These kinases then phosphorylate CREB in a circadian manner that further regulates downstream gene expression. The phosphorylated CREB recognizes the cAMP Response Element and serves as a transcription factor for Per1 and Per2, two genes that regulate the mammalian circadian clock. This induction of PER protein can entrain the circadian clock to light/dark cycles inhibits its own transcription via a transcription- translation feedback loop which can advance or delay the circadian clock. However, the responsiveness of PER1 and PER2 protein induction is only significant during the subjective night.
Gene expression is regulated by a circadian clock and the organism can effectively anticipate transitions between the light and dark phases.
These, along with the remaining PRR proteins PRR7 and PRR5 are involved in suppressing CCA1 and LHY levels, which increase during the night."Mapping the Core of the Arabidopsis Circadian Clock Defines the Network Structure of the Oscillator." Mapping the Core of the Arabidopsis Circadian Clock Defines the Network Structure of the Oscillator. W. Huang. Science. Vol.
Other studies with rats found that expression of DNMT3B and other methylation enzymes oscillate with the circadian clock and may be regulated by the circadian clock. Another methylation associated factor, MECP2, is phosphorylated by the superchiasmatic nucleus in response to light signaling. In a group of subjects that died from a variety of causes, there was partial methylation at the PER2, PER3, CRY1, and TIM promoters which are important genes in controlling the circadian clock. The methylation of CRY1 varied within an individual's tissues and between two individuals, however the difference between individuals may have been due to methamphetamine exposure.
Oxyntomodulin has been linked to entrainment of the liver's circadian clock. Oxyntomodulin has been investigated as a blood-glucose regulation agent in connection with diabetes.
Martha Merrow (born 1957) is an American chronobiologist. She currently chairs the Institute of Medical Psychology at the Ludwig Maximilian University of Munich. Her career focuses primarily on investigating the molecular and genetic mechanisms of the circadian clock. Since joining the Ludwig Maximilian University in 1996, Merrow has investigated molecular and genetic mechanisms of the circadian clock as well as daily human behavior and medical psychology.
Later work revealed that Bmal1 is the only clock gene without which the circadian clock fails to function in humans. BMAL1 functions as a positive element in the circadian clock. It forms a heterodimer with CLOCK to initiate transcription of target genes that contain E-box sequences, such as Period and Cryptochrome in mice. The BMAL1:CLOCK complex is suppressed by the buildup of the PER:CRY heterodimers.
Eskin has also researched the role of the circadian clock in glutaminergic synaptic plasticity. Although it was known that the brain's circadian clock could influence physiological outputs such as sleep and wakefulness, metabolic rate, and body temperature, Eskin suggested that the circadian clock may play another role as a regulator for memory formation. He and his lab have shown that an aplysia's ability to form long-term memory is dependent on the time of day, namely that aplysia are able to form long-term memories during the day, but are unable to at night. This was done via regulation of several factors, including neurotransmitter release, MAPK signaling, and immediate early gene expression.
As a junior fellow in the Harvard Society of Fellows, Truman studied the underlying mechanisms of silkmoth eclosion, mainly focusing on the role of the circadian clock in driving time of day rhythms in eclosion. Truman demonstrated that eclosion rhythms persist in Hyalophora cecropia moths that have had their compound eyes, corpora cardiaca, and corpora allata surgically removed. Eclosion rhythms were only abolished with the removal of the brain, indicating that the circadian clock is located within the brain. Further experiments involving brain transplantation and selective illumination of different parts of the body revealed that the circadian photoreceptors, which are responsible for receiving light information to entrain the circadian clock, are also located in the brain.
More brain transplant experiments in Hyalophora cecropia and Antheraea pernyi showed that both entrained and free-running eclosion rhythms can be rescued in debrained moths that have had brains transplanted into their abdomens. These restored eclosion rhythms in the debrained moths matched in phase angle with the eclosion rhythms observed in the donor moths prior to brain transplantation. These results confirmed Truman's previous findings that the circadian clock is located within the brain and that the factor mediating eclosion behavior is hormonal. Similar experiments focusing on the role of the circadian clock in regulating flight rhythms confirmed that extraretinal photoreceptors in the brain are responsible for entraining a brain-based circadian clock.
His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.
The two genes Cry1 and Cry2 code for the two cryptochrome proteins CRY1 and CRY2. In insects and plants, CRY1 regulates the circadian clock in a light-dependent fashion, whereas, in mammals, CRY1 and CRY2 act as light-independent inhibitors of CLOCK-BMAL1 components of the circadian clock. In plants, blue-light photoreception can be used to cue developmental signals. Besides chlorophylls, cryptochromes are the only proteins known to form photoinduced radical-pairs in vivo.
Millar hypothesized that this model could be used to isolate mutants in the plant circadian clock. In 1995, Millar and colleagues used this luciferase model to identify mutant Arabidopsis plants with abnormal cycling patterns. Millar's group found cab2 expression to oscillate with a shorter period in toc1 mutant plants compared to wild type plants.W. Huang, "Mapping the core of the Arabidopsis circadian clock defines the network structure of the oscillator", Science, 2012, .
These time-based preferences have been shown to be tied to a circadian clock in some insects. In the absence of external cues honeybees will still show a shift in preference for a reward depending on time strongly implicating an internal time-keeping mechanism, i.e. the circadian clock, in modulating the learned preference. Moreover, not only can bees remember when a particular site is rewarding but they can also remember at what times multiple different sites are profitable.
The findings suggest that the Zn2+ ion facilitates the reduction of an intramolecular disulfide bond on CRY1 so that it can bind PER2 more effectively, which would make the circadian clock zinc sensitive.
Red2 (DsRed2) dsRNA. These results suggest that in the cricket, tim plays some role in fine-tuning of the free-running period but may not be essential for oscillation of the circadian clock.
In case of the fungus Neurospora crassa, the circadian clock is controlled by two light- sensitive domains, known as the white-collar-complex (WCC) and the LOV domain vivid (VVD-LOV). WCC is primarily responsible for the light-induced transcription on the control-gene frequency (FRQ) under day-light conditions, which drives the expression of VVD-LOV and governs the negative feedback loop onto the circadian clock. By contrast, the role of VVD-LOV is mainly modulatory and does not directly affect FRQ.
In eukaryotes, about 10–20% of the genes are rhythmically expressed (as gauged by rhythms of mRNA abundance). However, in cyanobacteria, a much larger percentage of genes are controlled by the circadian clock. For example, one study has shown that the activity of essentially all promoters is rhythmically regulated. The mechanism by which this global gene regulation is mechanistically linked to the circadian clock is not known, but it may be related to rhythmic changes in the topology of the entire cyanobacterial chromosome.
The frq locus was discovered by Jerry F. Feldman. Feldman had been a graduate student with Colin Pittendrigh at Princeton and went to CalTech in 1967 to begin genetic screens for circadian clock mutants. The screening was aided by recent work that improved the expression of the rhythm in Neurospora. Colin Pittendrigh and his colleagues had confirmed in 1959 that the daily cycle of asexual development, described in Neurospora crassa earlier by Brandt, was in fact due to regulation by a circadian clock.
The Late Elongated Hypocotyl gene (LHY), is an oscillating gene found in plants that functions as part of their circadian clock. LHY encodes components of mutually regulatory negative feedback loops with Circadian Clock Associated 1 (CCA1) in which overexpression of either results in dampening of both of their expression. This negative feedback loop affects the rhythmicity of multiple outputs creating a daytime protein complex. LHY was one of the first genes identified in the plant clock, along with TOC1 and CCA1.
In future studies of silkmoth eclosion, Truman went on to confirm the role of EH in mediating ecdysis. Later studies also implicated a brain-based circadian clock as the regulator controlling the release of EH.
Achim Kramer (born May 18, 1968) is a German chronobiologist and biochemist. He is the current head of Chronobiology at Charité – Universitätsmedizin Berlin in Berlin, Germany. Kramer's primary research interests include post- translational modifications of circadian clock proteins and the function of the circadian clock in the immune system. Some of his work includes identifying phosphorylation regions on mPER2 (mammalian PER2) and their implications for familial advanced sleep phase syndrome (FASPS), identifying circadian rhythms in macrophages, and investigating the necessity of heme degradation for circadian rhythms.
Assaying expression of known circadian clock genes in the Ovtm mutants, they observed a marked decrease in PER1 and PER2 protein and mRNA levels in the brain and a significant decrease in cry2 mRNA levels only. Takahashi and his colleagues proposed that FBXL3 is a target site for protein degradation on the CRY2 protein, which would explain relatively normal CRY2 protein levels. Negative feedback by other elements of the circadian clock could then lead to the roughly 26-hour free-running period observed in Ovtm mice.
Eskin's current research focuses on long-term memory formation. His lab focuses on the role of the circadian clock and the regulation of glutamate uptake in synaptic plasticity, using aplysia and rats as model organisms primarily.
The importance of the circadian clock in the function of this time-compensated sun compass system has led to investigation into the molecular basis of the clock mechanism in monarchs, resulting in a well-defined model of both central and secondary clocks. Similarly to Drosophila and mammals, the core mechanism of the monarch circadian clock relies on a transcriptional-translational auto-regulatory negative feedback loop that drives rhythms in the mRNA and protein levels of core circadian clock components. However, the monarch mechanism has been found to be unique because it diverges from other clock mechanisms in the functions of its elements, some which reflect that of a Drosophila clock and some which reflect that of a mammalian clock. The most unique aspect of the monarch clock mechanism is that it involves two cryptochrome proteins – CRY1 and CRY2 – with differing functions.
The circadian clock refers to a biological mechanism that governs multiple biological processes causing them to display an endogenous, entrainable oscillation of about 24 hours. These rhythms have been widely observed in plants, animals, fungi and cyanobacteria.
This is one of the first pieces of evidence for a peripheral self-sustaining circadian clock. In 1998, he proposed the translational transcriptional feedback loop model of the circadian clock in flies, analogous to other labs that proposed a same model in mammals and fungi. Kay discovered that cryptochrome is the circadian photoreceptor that directly acts with and sequesters TIM in response to light. Kay did one of the pioneering microarray analyses to study clock controlled genes (ccg), and revealed tissue-specific nature of circadian rhythms by analyzing the ccg of heads and bodies separately.
A defect in the human homologue of the Drosophila "period" gene was identified as a cause of the sleep disorder FASPS (Familial advanced sleep phase syndrome), underscoring the conserved nature of the molecular circadian clock through evolution. Many more genetic components of the biological clock are now known. Their interactions result in an interlocked feedback loop of gene products resulting in periodic fluctuations that the cells of the body interpret as a specific time of the day. It is now known that the molecular circadian clock can function within a single cell; i.e.
Reppert and colleagues have focused on a novel circadian clock mechanism and its role in time-compensated sun compass orientation, a major navigational strategy that butterflies use during their fall migration. Using clock-shift experiments, they showed that the circadian clock must interact with the sun compass to enable migrants to maintain a southerly flight direction as the sun moves daily across the sky. Reppert collaborated with Eli Shlizerman at the University of Washington and Daniel Forger at the University of Michigan to propose a working mathematical model of the time-compensated sun compass.
Missra, Anamika; Ernest, Ben; Lohoff, Tim; Jia, Qidong; Satterlee, James; Ke, Kenneth; Arnim, Albrecht G. von. "The Circadian Clock Modulates Global Daily Cycles of mRNA Ribosome Loading". The Plant Cell. 27 (9): 2582–2599. doi:10.1105/tpc.15.00546.
Biological rhythms, including cycles related to sleep and wakefulness, mood, and cognitive performance, are synchronized with the body's internal circadian clock. The best way to observe the workings of this clock is to experimentally deprive individuals of external cues like light and social interaction and allow the body to experience a "free-running" environment – that is, one in which there are no zeitgebers to influence the body's rhythms. Under these circumstances, the circadian clock alone modulates the body's biological rhythms. Normally however, external cues like light-dark cycles and social interactions also exert an influence on the body's rhythms.
Modern experimental approaches using systems biology have identified many novel components in biological clocks that suggest an integrative view on how organisms maintain circadian oscillation. Recently, Baggs et al. developed a novel strategy termed "Gene Dosage Network Analysis" (GDNA) to describe network features in the human circadian clock that contribute to an organism's robustness against genetic perturbations. In their study, the authors used small interfering RNA (siRNA) to induce dose-dependent changes in gene expression of clock components within immortalized human osteosarcoma U2OS cells in order to build gene association networks consistent with known biochemical constraints in the mammalian circadian clock.
Moore noted technical limitations of the time as the reason for not continuing his study of the RHT. Moore returned to his investigation into the role of the RHT after establishing the SCN’s role as the master circadian clock. In 1988, Moore, along with Ralph F. Johnson and Lawrence P. Morin, established the role of the RHT as a light entrainment pathway of the SCN and thus a critical element of the circadian clock. This was demonstrated through an experiment in which Moore and his colleagues performed a selective transection of the RHT in the hamster and rat.
Price's research centers around the molecular mechanisms of circadian rhythms, using Drosophila melanogaster as model organisms. He is specifically interested in the role of protein kinases in clock function, and using forward genetics screens Price has contributed to the identification and characterization of many critical elements of the Drosophila circadian clock. The molecular circadian clock of D. melanogaster can be described as a feedback loop of transcription and translation, in which the proteins CLOCK and CYCLE act as transcriptional activators of the period and timeless genes. Their protein products, PER and TIM, respectively, dimerize and translocate to the nucleus after phosphorylation by DBT.
Presently, Turek's research interests revolve around the genetic, molecular, and neural basis for sleep and circadian rhythms. He focuses most of his attention on the role of sleep and circadian clock systems for energy balance, obesity, premature birth, gastrointestinal function, and depression specifically. The Turek laboratory investigates cellular events involved in the entrainment, generation, and expression of circadian rhythms arising from a biological clock located in the suprachiasmatic nucleus of the hypothalamus; the genetics of the circadian clock system; the molecular genetic mechanisms underlying the sleep-wake cycle; the effects of advanced age on the expression of behavioral and endocrine rhythms and on the expression of circadian clock genes; the links between sleep, circadian rhythms, and energy metabolism; the role of melatonin in sleep and circadian rhythms; and other topics regarding sleep and circadian rhythms. Turek's lab spends much of their time working on rodents, but they have also established working relationships with academic researchers.
Simplified Representation of Neurospora Circadian Clock. WC-1 and WC-2 (WCC) act as positive activators of frq transcription. FRQ protein binds to an RNA helicase, FRH, and to CK1 forming a complex. This complex interacts with WCC, promoting phosphorylation of WCC.
Additionally, both short and long period mutants fixed around 40% more carbon when exogenous periods matched their endogenous rhythms, consistent with the hypothesis of circadian resonance. Millar's experiments demonstrated one possible mechanism that has selected for circadian clock function during plant evolution.
Circadian Clock Associated 1 (CCA1) is a gene that is central to the circadian oscillator of angiosperms. It was first identified in Arabidopsis thaliana in 1993. CCA1 interacts with LHY and TOC1 to form the core of the oscillator system. CCA1 expression peaks at dawn.
Cyanobacteria displays a circadian clock system in which three protein oscillators, KaiA, KaiB, and KaiC, constitute a system known as a post-translational oscillator (PTO) that facilitates the oscillation of the larger transcription translation negative feedback loop (TTFL). The TTFL drives gene expression and replenishes KaiA, KaiB, and KaiC, while the PTO constitutes the core of the circadian clock of cyanobacteria. This Kai core confers circadian rhythmicity to ATP hydrolysis activity and kinase/phosphatase activity, both of which are temperature compensated. Additionally, KaiB and KaiC, but not KaiA, have a circadian rhythm of 24 hours in experimental conditions, such as free-running in conditions of constant light.
One way to rationalize this is to assume that many are "slaves" to the frequency/white collar oscillator; they do not possess all of the characteristics of a circadian clock on their own because this is supplied by the FWO. However, rhythms in clock-controlled gene-16 (ccg-16) are coupled to the FWO but function autonomously, demonstrating that Neurospora crassa contains at least 2 potential pacemakers, but only one that can be reset by light and temperature while maintaining temperature compensation. The FRQ-less oscillator has never been proven to affect the true circadian clock. The mechanism and significance for FRQ-less oscillators (FLO) are still under research.
BHLHE41/DEC2 and BHLHE40/DEC1 share 97% homology in the BHLH domain. After the identification of the BHLHE41 gene, Dr. Ken-Ichi Honma's lab characterized its role as a regulator in the mammalian circadian clock. The role of BHLHE41 in other pathways is still being fully characterized.
Short sequence repeats also provide rapid evolutionary change to surface proteins in pathenogenic bacteria; this may allow them to keep up with immunological changes in their hosts. Length changes in short sequence repeats in a fungus (Neurospora crassa) control the duration of its circadian clock cycles.
This rhythm of activation was present both with and without environmental light exposure, providing the first evidence for the suprachiasmatic nucleus as an endogenous circadian clock. This research was pivotal in confirming circadian rhythm regulation by the suprachiasmatic nucleus, and aided new techniques to study neural mechanisms.
Czeisler has spent over 40 years researching the relationship between human sleep and the physiology of the human circadian clock and teaching a course at Harvard College on Circadian Biology for undergraduate and graduate students."MCB 186. Circadian Biology: From Cellular Oscillators to Sleep Regulation." Harvard: FAS Registrar's Office.
Other forms of FASPS are caused by mutations that alter the Casein kinase 1 gene. Doubletime mutations in Drosophila alter the phosphorylation and degradation of PER protein. This affects the regularity in period of the organism. This discovery solidified doubletime as a necessary part of the circadian clock.
Cryptochromes are another type of photoreceptor that is important in photoperiodism. Cryptochromes absorb blue light and UV-A. Cryptochromes entrain the circadian clock to light. It has been found that both cryptochrome and phytochrome abundance relies on light and the amount of cryptochrome can change depending on day-length.
In the evening, they enter the nucleus to inhibit the transcription of their mRNA. In 1996, Sehgal's laboratory showed that degradation in TIM levels caused by a pulse of light resets the circadian clock. Later, they showed that specific phosphatases control stability of PER and TIM in daily cycles.
CCA1 only has one Myb domain, whereas other plant and mammalian proteins could have multiple Myb domains. The presence of only one Myb domain in CCA1 shows its importance influence in the circadian clock. LUX is also an important Myb transcription factor that is necessary for CCA/LHY transcription.
LPL is controlled transcriptionally and posttranscriptionally. The circadian clock may be important in the control of Lpl mRNA levels in peripheral tissues. LPL isozymes are regulated differently depending on the tissue. For example, insulin is known to activate LPL in adipocytes and its placement in the capillary endothelium.
With Kay's group, Millar identified roles for the ELF3 and ELF4 genes in the plant circadian system. Plants with loss-of-function mutations in elf3 exhibited arrhythmicity in constant light conditions but not in constant darkness, suggesting that elf3 was necessary for proper control of the clock by light. Additionally, Millar and colleagues showed that ELF3 and its paralog ELF4 are necessary for the proper rhythmic expression of two other important genes involved in the plant circadian clock, Circadian Clock Associated 1 (CCA1) and Late Elongated Hypocotyl (LHY).C. McClung, "Plant Circadian Rhythms", The Plant Cell, 2006, These early efforts greatly contributed to efforts to understand the mechanisms underlying the function of the plant circadian oscillator.
This is the first (and so far, only) example of the reconstitution of a circadian clock in vitro. The output of this oscillator to rhythms of gene expression may be mediated by one or both of the following mechanisms: (1) the Biochemical Cascade Model that implicates the globally acting transcription factors, RpaA and B. RpaA seems to be coupled to the central KaiABC oscillator by histidine kinase SasA through a two-component signaling pathway, and/or the (2) Chromosome/Nucleoid Hypothesis, in which the circadian clock orchestrates dramatic circadian changes in DNA topology, which causes a change in the transcription rates. The behavior of heterologous promoters from other bacteria when expressed in cyanobacteria support the latter hypothesis.
These findings indicate that degradation of monoamines is regulated by the circadian clock. It is very likely that the described clock-mediated regulation of monoamines is relevant for humans, because single-nucleotide polymorphisms in Per2, Bmal1, and Npas2 are associated in an additive fashion with seasonal affective disorder or winter depression.
Interactions with CK1δ have also been detected for the development-associated factors LEF-1 (lymphocyte enhancer factor-1) and the proneural basic helix-loop-helix (bHLH) transcription factor Atoh1. Finally, interaction of CK1δ with PER and CRY circadian clock proteins have been demonstrated, facilitating nuclear translocation of PERs and CRYs.
Kramer's current projects include improving BodyTime (a method for identifying an individual's chronotype with a single blood sample), analyzing the coupling between peripheral circadian oscillators, and live cell imaging of circadian clock proteins. Along with being an important contributor to the field of chronobiology, he is also a certified piano teacher.
The mammalian period 1 and period 2 genes play key roles in photoentrainment of the circadian clock to light pulses. This was first seen in 1999 when Akiyama et al. showed that mPer1 is necessary for phase shifts induced by light or glutamate release. Two years later, Albrecht et al.
The three components of an Eskinogram: Input, Oscillator, and Output. Eskin developed the Eskinogram as a heuristic that provides a mechanism for understanding circadian clock pathways. It presents a clock pathway as having three components: input, oscillator, and output. Further modifications to this core model can be made for more complex systems.
These methods and discoveries were published in and featured on the cover of Science magazine in February 1995. Millar's luciferase experiments have contributed immensely to the current understanding of the circadian clock in plants. Specifically, Millar's work in 1995 and 2012 have been integral in the development of the repressilator model in plants.
He reported disruption of circadian rhythm in cognitive judgment of short-time intervals in shift workers. He proposed a model for optimization of human shift work. He reported that shift work might reduce human longevity. He reported disruption of circadian clock in cancer patients and suggested implementation of patient- specific chronotherapeutic protocol.
CCA1 is generally a more significant component of this oscillator. Light induces its transcription, and mRNA levels peak at dawn along with LHY.Kangisser, Shlomit, Esther Yakir, and Rachel M. Green. "Proteasomal regulation of the CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) stability is part of the complex control of CCA1" Plant Signaling & Behavior Vol.
Biochemical imaging revealed the assembly and disassembly of various Kai complexes that form during circadian clock oscillations. During the process, KaiA and KaiB bind to sites on KaiC; the model determines that KaiC then becomes KaiAC when KaiA stimulates autophosphorylation, which then transforms into KaiBC, KaiABC, and then returns to KaiC as the cycle continues.
Melatonin secretion is controlled by the endogenous circadian clock, but can also be suppressed by bright light. One study looked at whether some people could be predisposed to SAD based on personality traits. Correlations between certain personality traits, higher levels of neuroticism, agreeableness, openness, and an avoidance-oriented coping style, appeared to be common in those with SAD.
Aihara, Kohei, and Satoshi Naramoto. "Increase in vascular pattern complexity caused by mutations in LHY and CCA1 in Arabidopsis thaliana under continuous light" Plant Biotechnology Vol. 31. (2014): 43-47 However they retain some circadian function in light/dark cycles, showing that Arabidopsis circadian clock is not completely dependent on CCA1 and LHY activity.Alabadi, David, and Marcelo J. Yanovsky.
He has spent most of his career back in his alma mater, the Autonomous University of Nuevo León, and his research, mostly focused on Human Growth Factor and epidemiology, also extends from personalized medicine to circadian clock restriction. He is now professor and Director of National Research at the Monterrey Institute of Technology and Higher Education.
Phase response curves for light and for melatonin administration In humans and animals, there is a regulatory system that governs the phase relationship of an organism's internal circadian clock to a regular periodicity in the external environment (usually governed by the solar day). In most organisms, a stable phase relationship is desired, though in some cases the desired phase will vary by season, especially among mammals with seasonal mating habits. In circadian rhythm research, a PRC illustrates the relationship between a chronobiotic's time of administration (relative to the internal circadian clock) and the magnitude of the treatment's effect on circadian phase. Specifically, a PRC is a graph showing, by convention, time of the subject's endogenous day along the x-axis and the amount of the phase shift (in hours) along the y-axis.
Cyclosa Turbinata is unique in that its locomotor and web-building activity cause it to have an exceptionally short-period circadian clock, about 19 hours. Current research is being conducted to understand how web-building behavior may be regulated by this endogenous circadian control in this species. In an experiment where C. turbinata spiders were placed into chambers with periods of 19, 24 , or 29 hours of evenly split light and dark, none of the spiders exhibited decreased longevity in their own circadian clock. These findings contradicted all previous research into circadian resonance and suggest that C. turbinata do not suffer the same costs of extreme desynchronization as do other species of animals. C.Turbinata are also unique in their collection of prey carcasses along a so-called ‘trashline’ on their web.
PER1 expression may have significant effects on the cell cycle. Cancer is often a result of unregulated cell growth and division, which can be controlled by circadian mechanisms. Therefore, a cell's circadian clock may play a large role in its likelihood of developing into a cancer cell. PER1 is a gene that plays an important role in such a circadian mechanism.
By spring, groups leave their winter grounds to go to the calving grounds. A reindeer can swim easily and quickly, normally at about but, if necessary, at and migrating herds will not hesitate to swim across a large lake or broad river. As an adaptation to their Arctic environment, they have lost their circadian rhythm.Arctic Reindeer Go Off the Circadian Clock . Wired.
Nocturnin is a human hydrolase enzyme that is involved in metabolism and its expression is controlled by the rhythmic circadian clock. It is encoded by the NOCT gene located on chromosome 4. Nocturnin contains a c-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family. A study in January 2019, demonstrated that NADP+ and NADPH are the direct targets of Nocturnin.
The primary molecular mechanism behind an oscillating gene is best described as a transcription/translation feedback loop. This loop contains both positive regulators, which increase gene expression, and negative regulators, which decrease gene expression. The fundamental elements of these loops are found across different phyla. In the mammalian circadian clock, for example, transcription factors CLOCK and BMAL1 are the positive regulators.
This is consistent with a previous observation that mice lacking active TRPV3 are likely to spend more time in cooler cage locations than wild-type mice, and have wavier hair. Also, several alterations in circadian clock genes were found, perhaps needed to cope with the extreme polar variation in length of daylight. Similar mutations are known in other Arctic mammals, such as reindeer.
The internal circadian clock, located in the hypothalamus of the brain, generates a signal that normally is slightly longer (occasionally shorter) than 24 hours, on average 24 hours and 11 minutes. This slight deviation is, in almost everyone, corrected by exposure to environmental time cues, especially the light–dark cycle, which reset the clock and synchronize (entrain) it to the 24-hour day. Morning light exposure resets the clock earlier, and evening exposure resets it later, thereby bracketing the rhythm to an average 24-hour period. If people who do not have non-24-hour sleep-wake disorder are deprived of external time cues (living in a cave or artificial time-isolated environment with no light), their circadian rhythms will "free- run" with a cycle of a little more (occasionally less) than 24 hours, expressing the intrinsic period of each individual's circadian clock.
The circadian clock that is currently understood for mammals begins when light activates BMAL1 and CLK to bind via their PAS domains. That activator complex regulates Per1, Per2, and Per3 which all have PAS domains that are used to bind to cryptochromes 1 and 2 (CRY 1,2 family). The following mammalian genes contain PAS binding domains: Per1, Per2, Per3, Cry1, Cry2, Bmal, Clk, Pasd1.
Phosphorylation of PER2 is believed to be regulated by a phosphoswitch mechanism. Specifically, PER2 requires an initial priming phosphorylation in order to be phosphorylated and subsequently degraded by CK1δ and/or CK1ε. In this manner, temporally sequenced phosphorylations of PER2 act to delay its degradation rate and may provide insight into how the circadian clock is temperature compensated. CK1δ and/or CK1ε may provide the priming activity.
Translation in plants is tightly regulated as in animals, however, it is not as well understood as transcriptional regulation. There are several levels of regulation including translation initiation, mRNA turnover and ribosome loading. Recent studies have shown that translation is also under the control of the circadian clock. Like transcription, the translation state of numerous mRNAs changes over the diel cycle (day night period).
The luminescence occurs as a brief (0.1 sec) blue flash (max 476 nm) when stimulated, usually by mechanical disturbance. Therefore, when mechanically stimulated—by boat, swimming, or waves, for example—a blue sparkling light can be seen emanating from the sea surface. Dinoflagellate bioluminescence is controlled by a circadian clock and only occurs at night. Luminescent and nonluminescent strains can occur in the same species.
Rev-erbα expression is also regulated at the post-translational level: it is phosphorylated on the amino terminus by glycogen synthase kinase (GSK 3β), which contributes to its protein stability. It has been shown that lithium, which inhibits GSK3β, can de-stabilize Rev-erbα protein and affect its function in the circadian clock. This may partly explain lithium’s therapeutic effect on circadian diseases such as bipolar disorder.
The Arabidopsis central oscillator contains several proteins that reciprocally repress genes encoding each other to achieve a negative feedback loop necessary to generate circadian rhythms controlling many clock outputs.Hemmes, H., and R., Jang. "Circadian Clock Regulates Dynamic Chromatin Modifications Associated with Arabidopsis CCA1/LHY and TOC1 Transcriptional Rhythms" Plant and Cell Physiology Vol. 53(12). (2016–2029) CCA1 is a key component of this oscillator.
This blood test provides information about an individual's chronotype. This personal chronotype identification method, what Kramer and colleagues call BodyTime, is currently being used to improve patients’ quality of sleep. The project is ongoing, aiming to advance chronomedicine. Along with optimizing the BodyTime project, Kramer is currently investigating coupling between peripheral circadian oscillators and is working on live cell imaging of circadian clock proteins.
Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.
Her focus is on the circadian clock in Neurospora and its application to the genetic mechanisms of the clock in other organisms. Loros, along with Jay Dunlap and Patricia J. DeCoursey, co-authored the text book "Chronobiology: Biological Timekeeping " which was published on June 1, 2004. The text chronicles the field of chronobiology by exploring both past and current discoveries and their relevance to modern society.
The monarch was the first butterfly to have its genome sequenced. The 273-million base pair draft sequence includes a set of 16,866 protein-coding genes. The genome provides researchers insights into migratory behavior, the circadian clock, juvenile hormone pathways and microRNAs that are differentially expressed between summer and migratory monarchs. More recently, the genetic basis of monarch migration and warning coloration has been described.
The FASP site on PER2 is a key target of this priming kinase activity. Mutations to this site can affect the ability of PER2 to receive a priming phosphorylation, leading to a lengthening or shortening of period. Other studies have suggested that down stream phosphorylation of PER2 leads to stabilizing interactions that decrease the degradation rate of PER. This is thought to increase the period of the circadian clock.
Research using VPAC2 knockout mice implicate it in the function of the circadian clock, growth, basal energy expenditure and male reproduction. VIPR2 and/or PAC1 receptor activation is involved in cutaneous active vasodilation in humans. Splice variants may modify the immunoregulatory contributions of the VIP-VIPR2 axis. VIPR2 may contribute to autoregulation and/or coupling within the suprachiasmatic nucleus (SCN) core and to control of the SCN shell.
Likely, mPER3 binds to other proteins using this domain. However, while PER1/2 have been shown to be important in the transcription-translation feedback loop involved in the intracellular circadian clock, the influence of PER3 in this loop has not yet been fully elucidated, given that mPER3 does not appear to be functionally redundant to mPER1 and mPER2. mPer3 may not be a member of the core clock loop at all.
Inhibition of m6A methylation via pharmacological inhibition of cellular methylations or more specifically by siRNA-mediated silencing of the m6A methylase Mettl3 led to the dramatic elongation of the circadian period. In contrast, overexpression of Mettl3 in vitro led to a shorter period. These observations clearly demonstrated the importance of RNA- level post-transcriptional regulation of the circadian clock, and concurrently established the physiological role of (m6A) RNA methylation.
The circadian clock in plants has completely different components to those in the animal, fungus or bacterial clocks. The plant clock does have a conceptual similarity to the animal clock in that it consists of a series of interlocking transcriptional feedback loops. The genes involved in the clock show their peak expression at a fixed time of day. The first genes identified in the plant clock were TOC1, CCA1 and LHY.
The PER/TIM heterodimer negatively regulates transcription of period (per) and timeless (tim) genes. Within this negative feedback loop, first the PER/TIM heterodimers form in the cytoplasm, accumulate, and then translocate to the nucleus. The complex then blocks the positive transcription factors clock (CLK) and cycle (CYC), thereby repressing the transcription of per. As part of the circadian clock, timeless is essential for entrainment to light-dark (LD) cycles.
Circadian clock of mammals However, mTim is shown to be necessary for embryonic development in mice, indicating a different gene function than in Drosophila. This suggests a divergence between mammalian clocks and the Drosophila clock. Moreover, mammalian tim is more orthologous to the Tim-2 (Timeout) paralog of the Drosophila Timeless gene than the actual gene itself. Like tim-2, the mamallian orthologs has a C-terminal PARP1-binding (PAB) domain.
The process is similar to the mechanism of stomatal closure. Common examples for pulvinar movements include the night closure movement of legume leaves and the touch response of the sensitive plant (Mimosa pudica). Nyctinastic movements (sleep movements) are controlled by the circadian clock and light signal transduction through phytochrome. Thigmonastic movements (touch response) appear to be regulated through electrical and chemical signal transduction spreading the stimulus throughout the plant.
Deuterium has been shown to lengthen the period of oscillation of the circadian clock when dosed in rats, hamsters, and Gonyaulax dinoflagellates. In rats, chronic intake of 25% D2O disrupts circadian rhythmicity by lengthening the circadian period of suprachiasmatic nucleus-dependent rhythms in the brain's hypothalamus. Experiments in hamsters also support the theory that deuterium acts directly on the suprachiasmatic nucleus to lengthen the free-running circadian period.
The laboratories of Paul H. Taghert, Jeff Hall, and Michael Rosbash identified a null allele of the pdf gene. In addition, they utilized the GAL4/UAS system to knock out first pdf and then the entire pdf neuron. They found that the pdf and pdf neuron knockouts resulted in the destruction of some behavioral rhythms, but not all of them. They thus concluded that PDF is likely a circadian clock output.
A basic helix-loop-helix (bHLH) is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors. bHLH transcription factors are often important in development or cell activity. For one, BMAL1-Clock is a core transcription complex in the molecular circadian clock. Other genes, like c-Myc and HIF-1, have been linked to cancer due to their effects on cell growth and metabolism.
Several studies have demonstrated a connection between molecular components of the circadian clock and psychiatric disorders, particularly drug abuse. Genetic association studies in humans have implicated CK1ε/CK1δ in the development of addictions to methamphetamine, heroin, and alcohol. Moreover, mouse studies reveal a link between CK1ε/CK1δ activity and the stimulant effect produced by methamphetamine. Additionally, inhibition of CK1ε/CK1δ in rodents has been shown to decrease alcohol and opiate relapse behavior during withdrawal.
Functions include neuroendocrine regulation, regulation of the circadian rhythm, control of the autonomic nervous system, and the regulation of fluid, and food intake. The circadian rhythm is controlled by two main cell groups in the hypothalamus. The anterior hypothalamus includes the suprachiasmatic nucleus and the ventrolateral preoptic nucleus which through gene expression cycles, generates a roughly 24 hour circadian clock. In the circadian day an ultradian rhythm takes control of the sleeping pattern.
Additionally, KaiB sequesters KaiA, which promotes KaiC dephosphorylation. In addition, “In Vitro Regulation of Circadian phosphorylation rhythm of cyanobacterial clock protein KaiC, KaiA, and KaiB,” shows the entrainment mechanism of cellular circadian clock with circadian rhythm in response to intracellular levels of KaiA and the other Kai proteins. KaiA ratios to KaiB and KaiC express a circadian rhythm and guides phosphorylation of KaiC based on KaiA ratios that can entrain in different light dark conditions.
KMT2D is partially functionally redundant with KMT2C in the liver as well. Heterozygous Kmt2d+/- mice exhibit enhanced glucose tolerance and insulin sensitivity and increased serum bile acid. KMT2C and KMT2D are significant epigenetic regulators of the hepatic circadian clock and are co- activators of the circadian transcription factors retinoid-related orphan receptor (ROR)-α and -γ. In mice, KMT2D also acts as a coactivator of PPARγ within the liver to direct over-nutrition induced steatosis.
PER2 is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian clock, which regulates the daily rhythms of locomotor activity, metabolism, and behavior. Circadian expression of these genes and their encoded proteins in the suprachiasmatic nucleus. Human PER2 is involved human sleep disorder and cancer formation.
In mammals, mPER2 forms a heterodimer with mPER1, mCRY1, and mCRY2 by binding to PAS domains. The heterodimer acts to inhibit their own transcription by suppressing the CLOCK/BMAL1 complex resulting in a negative feedback loop. This negative feedback loop is essential for maintaining a functioning circadian clock. A disruption of either both mPER1 and mPER2 genes together or both mCRY genes causes behavioural arrhythmicity when the double-knockout animals are placed in constant conditions.
The Neurospora circadian clock was discovered in 1959, when Pittendrigh et al. first described timing patterns in the asexual development of spores. They noticed that in the region of the growing front, mycelia laid down between the late night to early morning formed aerial hyphae, whereas those laid down at other times did not. This aerial growth pattern at subjective circadian times served as tentative support for the presence of circadian oscillators.
Ameloblasts are cells which secrete the enamel proteins enamelin and amelogenin which will later mineralize to form enamel, the hardest substance in the human body. Ameloblasts control ionic and organic compositions of enamel. It is theorized that a circadian clock (24-hour) probably regulates enamel production on a daily cycle by the ameloblasts (similar to osteoblasts in production of bone tissue). Ameloblasts adjust their secretory and resorptive activities to maintain favorable conditions for biomineralization.
The protein encoded by this gene belongs to the acetyltransferase superfamily. It is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for the function of the circadian clock that influences activity and sleep. This enzyme is regulated by cAMP-dependent phosphorylation that promotes its interaction with 14-3-3 proteins and thus protects the enzyme against proteasomal degradation.
As noted above, the MT1 receptor has been shown to have a hand in phase shifting but this role is secondary to that of the MT2 receptor. In experiments involving MT1 KO mice (and WT as a control) both WT and MT1 KO groups exhibited phase shifting activity. On the flip side, MT2 KO mice were not able to phase shift suggesting that the MT2 receptor is necessary for phase shifting the internal circadian clock.
This gave evidence to support that having a mammalian circadian clock is a favorable trait that has been naturally selected for. In an outdoor enclosure, DeCoursey released white-tailed antelope ground squirrels which had various levels of SCN lesioned. The squirrels displaying the most activity during the night had the highest amount of lesioning. This research has helped further our understanding of sleep related issues affecting humans such as jet lag or insomnia.
Neurospora crassa is not only a model organism for the study of phenotypic types in knock-out variants, but a particularly useful organism widely used in computational biology and the circadian clock. It has a natural reproductive cycle of 22 hours and is influenced by external factors such as light and temperature. Knock out variants of wild type N. crassa are widely studied to determine the influence of particular genes (see Frequency (gene)).
The navigation of the fall migration of the Eastern North American monarch butterfly (Danaus plexippus) to their overwintering grounds in central Mexico uses a time-compensated sun compass that depends upon a circadian clock in their antennae. Also, circadian rhythm is also known to control mating behavior in certain moth species such as Spodoptera littoralis, where females produce specific pheromone that attracts and resets the male circadian rhythm to induce mating at night.
Pittendrigh and Daan published a set of five papers reporting their findings on the properties of nocturnal rodents' circadian pacemakers. Below are some major findings: One-pulse system Instead of shining light on rodents for a long continuous period (e.g. 12hr) to represent "daytime", Pittendrigh showed that a 15 minutes light pulse shone during the subjective night is enough to cause phase shift in animals. This supports the non-parametric property of the circadian clock.
Initially, the role of CKIε within the circadian clock of mammals was discovered as the result of a mutation in hamsters. The tau mutation in the Syrian golden hamster was the first to show a heritable abnormality of circadian rhythms in mammals. Hamsters with the mutation exhibit a shorter period than the wild-type. Heterozygotes have a period of about 22h while the period of homozygotes is even shorter, at about 20h.
The frequency (frq) gene encodes the protein frequency (FRQ) that functions in the Neurospora crassa circadian clock. The FRQ protein plays a key role in circadian oscillator, serving to nucleate the negative element complex in the auto regulatory transcription-translation negative feedback-loop (TTFL) that is responsible for circadian rhythms in N. crassa. Similar rhythms are found in mammals, Drosophila and cyanobacteria. Recently, FRQ homologs have been identified in several other species of fungi.
In 2014, Li et al. showed that PDF synchronizes circadian clock neurons by increasing levels of cAMP and cAMP-mediated protein kinase A (PKA). Increasing cAMP and PKA stabilized levels of the period protein PER in Drosophila, which slows the clock speed in PDF receptor (PDFR) containing neurons. A light pulse caused more PER degradation in flies with pdf-null neurons than flies with wild-type neurons, indicating that PDF inhibits light- induced PER degradation.
Bears entering torpor in a simulated den with no light expressed normal but low functioning rhythms. The same was observed in wild bears denning in natural areas. The function of circadian rhythms in black, brown, and polar bears suggest that their system of torpor is evolutionarily advanced. Jansen, H. T., Leise, T., Stenhouse, G., Pigeon, K., Kasworm, W., Teisberg, J., ... & Robbins, C. T. (2016). The bear circadian clock doesn’t ‘sleep’during winter dormancy.
Although chronotype varies from individual to individual, as determined by rhythmic expression of clock genes, people with typical circadian clock function will be able to entrain to environmental cues. For example, if a person wishes to shift the onset of a biological activity, like waking time, light exposure during the late subjective night or early subjective morning can help advance one's circadian cycle earlier in the day, leading to an earlier wake time.
The Rev-ErbA proteins are members of the nuclear receptor family of intracellular transcription factors. There are two forms of the receptor, alpha and beta, each encoded by a separate gene ( and respectively). The rev- Erb-α gene is highly unusual in that it is encoded on the opposite strand of the alpha-thyroid hormone receptor (TR) gene. The rev-Erb-α protein is a key regulatory component of the circadian clock.
BHLHE41 is expressed in the suprachiasmatic nucleus with levels peaking during subjective day. The gene encodes for a transcription factor that belongs to the Hairy/Enhancer of Split (Hes) subfamily of basic helix-loop-helix factor genes which encode transcriptional repressors that function as downstream targets to regulate cell fate during tissue development. BHLHE41 acts as a transcriptional repressor and as a regulator of the Circadian clock. In the clock, the transcriptional factors Clock and Bmal form a heterodimer.
PDF, 30(11):1484-1501. Among blind people, the cause is the inability to register, and therefore to entrain to, light cues. The many blind people who do entrain to the 24-hour light/dark cycle have eyes with functioning retinas including operative non-visual light-sensitive cells, ipRGCs. These ganglion cells, which contain melanopsin, convey their signals to the "circadian clock" via the retinohypothalamic tract (branching off from the optic nerve), linking the retina to the pineal gland.
Rev-erbβ has been implicated in the control of lipid and energy homoeostasis in skeletal muscle. Rev-erbβ is also a circadian regulated gene; its mRNA displays rhythmic expression in vivo and in serum-synchronized cell cultures. However, it is currently unknown to what extent Rev-erbβ contributes to oscillations of the core circadian clock. However it has been shown heme suppresses hepatic gluconeogenic gene expression and glucose output through the related Rev-erbα receptor which mediates gene repression.
Okamura's team has also looked into the relationship between the circadian clock and the cell cycle. They performed DNA arrays and Northern blots to characterize the molecular differences in M-phase entry and found that cyclin B1 and cdc2 were positively correlated. They also found that wee1, the gene for a kinase that inhibits mitosis by inactivating CDC2/cyclin B, was negatively correlated to M-phase. Their research showed that mouse hepatocyte proliferation is under circadian control.
Susan Golden, Carl H. Johnson and Takao Kondo were the individuals who found that the minimal cyanobacteria clock consists of 3 proteins: KaiA, KaiB, and KaiC. (Note: kai means cycle in Japanese.) The experiment performed by Kondo consisted of attaching the luciferase gene and performing mutagenesis. This was the first identification of possible genes that could reconstitute a biological clock within cyanobacteria, of which KaiA was included. Cyanobacteria were the first prokaryotes reported to have a circadian clock.
There are 3 mutations of 19 mutants (single amino substitutions) found in kaiA found from direct sequencing of the cluster. Thus, the cluster as well as the Kai proteins have necessary functions for the circadian clock of Synechococcus. IPTG induced overexpression of kaiA led to arrhythmicity, demonstrating that rhythmicity requires the expression of kaiA as well as the other genes. Mutagenesis of kaiA reveals that there are rarely short-period mutations, but an abundance of long period mutations.
Entrainment of the mammalian circadian clock is established via light induction of PER. Light excites melanopsin-containing photosensitive retinal ganglion cells which signal to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract (RHT). Excitation of the RHT signals the release of glutamate which is received by NMDA receptors on SCN, resulting in a calcium influx into the SCN. Calcium induces the activity of Ca2+/calmodulin-dependent protein kinases, resulting in the activation of PKA, PKC, and CK2.
The core mammalian circadian clock is a negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock. This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1. Transactivation of Bmal1 is regulated through the upstream ROR/REV-ERB Response Element (RRE) in the Bmal1 promoter, to which RORα and REV-ERBα bind. This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of RORα and REV-ERBα.
Other opsins found in humans include encephalopsin (or panopsin, opsin-3), melanopsin (opsin-4), neuropsin (opsin-5) and peropsin. Melanopsin is involved in the light entrainment of the circadian clock in vertebrates. Encephalopsins and neuropsins are highly expressed in nerve cells and brain tissue, but so far their function is unknown. Peropsin binds all-trans retinal (microbial-type chromophore) and might function as a photoisomerase to return retinal to the 11-cis isomer form needed in visual perception.
In 2005, Tei, G. Lundkvist, Y. Kwak, E. Davis, and G. Block proposed that the molecular clock was linked to neurons' membrane potential via voltage-dependent regulation of Ca2+ influx, as well as secondary action of intracellular Ca2+ on gene transcription. Additionally, the same study found that removal of Ca2+ from the medium, as well as blocking the Ca2+ channels, stopped the SCN's circadian clock, while hyperpolarization of a K+ medium led to altered rhythms in the SCN.
Homozygous flies lose their circadian rhythm. Furthermore, the same researchers demonstrated that these mutant flies express low levels of PER and TIM proteins, indicating that Clock functions as a positive element in the circadian loop. While the mutation affects the circadian clock of the fly, it does not cause any physiological or behavioral defects. The similar sequence between Jrk and its mouse homolog suggests common circadian rhythm components were present in both Drosophila and mice ancestors.
The typical period length of free-running Drosophila is 23.9 hours, requiring adaptations to the 24-hour environmental cycle. Adaptation first begins with exposure to light. This process leads to the rapid degradation of the TIM protein, allowing organisms to entrain at dawn to environmental cycles. Circadian clock of drosophila In light-dark cycles, TIM protein level decreases rapidly in late night/early morning, followed by the similar but more gradual changes in PER protein level.
Studies have shown similarities to Drosophila, Neurospora, and mammalian clock models in that the kaiABC regulation of the cyanobacteria slave circadian clock is also based on a transcription translation feedback loop (TTFL). KaiC protein has both auto- kinase and auto-phosphatase activity and acts as the circadian regulator in both the PTO and the TTFL. KaiC has been found to not only suppress kaiBC when overexpressed, but also suppress circadian expression of all genes in the cyanobacterial genome.
The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment. The external stimulus used to entrain a rhythm is called the Zeitgeber, or "time giver". Travel across time zones illustrates the ability of the human biological clock to adjust to the local time; a person will usually experience jet lag before entrainment of their circadian clock has brought it into sync with local time. # The rhythms exhibit temperature compensation.
In other words, they maintain circadian periodicity over a range of physiological temperatures. Many organisms live at a broad range of temperatures, and differences in thermal energy will affect the kinetics of all molecular processes in their . In order to keep track of time, the organism's circadian clock must maintain roughly a 24-hour periodicity despite the changing kinetics, a property known as temperature compensation. The Q10 Temperature Coefficient is a measure of this compensating effect.
The simplest known circadian clocks are bacterial circadian rhythms, exemplified by the prokaryote cyanobacteria. Recent research has demonstrated that the circadian clock of Synechococcus elongatus can be reconstituted in vitro with just the three proteins (KaiA, KaiB, KaiC) of their central oscillator. This clock has been shown to sustain a 22-hour rhythm over several days upon the addition of ATP. Previous explanations of the prokaryotic circadian timekeeper were dependent upon a DNA transcription/translation feedback mechanism.
This is caused by two nuclear receptors, REV-ERB and ROR, which suppresses and activates Bmal1 transcription, respectively. In addition to these feedback loops, post- translational modifications also play a role in changing the characteristics of the circadian clock, such as its period. Without any type of feedback repression, the molecular clock would have a period of just a few hours. Casein kinase members CK1ε and CK1δ were both found to be mammalian protein kinases involved in circadian regulation.
Hogenesh has pushed for the chronobiology community to create Wikipedia pages about genes through a project called Gene Wiki. The result has been the creation of pages about genes involved in the circadian clock such as ARNTL, as well as pages about chronobiologists like Ingeborg Beling. He has also been instrumental in creating the Gene Atlas. This project uses a database run by Hogenesch called the Circa database that lists time of activity of genes in different tissues.
These data propose the existence of a novel circadian clock unique to some non-drosophilid insects that possesses mechanisms characteristic of both the Drosophila and the mammalian clocks. Other insects, such as bees and ants, possess only a vertebrate-like CRY, and their circadian clocks are even more vertebrate like. Drosophila is the only known insect that does not possess a vertebrate-like CRY. In 2008, Reppert discovered the necessity of Cry for light-dependent magnetoreception responses in Drosophila.
In 1986, frq was cloned by Jay Dunlap and his colleagues using a strategy that involved a long chromosome walk and successful application of the then-untried strategy of rescuing an arrhythmic behavioral mutant through transformation of exogenous DNA arising from the chromosome walk. The success of this strategy and of the cloning of a clock gene sparked interest in further research and understanding of the N. crassa circadian clock. The expression of frq was later shown to rhythmically cycle; furthermore, when strains of Neurospora were engineered in which frq expression could be driven from a region distinct from the resident wild type gene, it was found that FRQ repressed its own expression and that no level of constant expression could support a circadian clock. These experiments were the first to manipulate the expression of a clock gene through means that did not themselves affect the clock and established that autoregulatory negative feedback giving rise to cyclical clock gene expression lay at the core of the circadian oscillator.
Simplified Representation of Neurospora Circadian Clock Reflecting its role as a core clock protein, deletion of the frq gene results in arrhythmicity, and in Neurospora, the only function of FRQ is in the circadian clock. The frq gene can be activated from two distinct cis- acting sequences in its promoter, a distal site, the clock-box, used in the context of circadian regulation, and a site close to the principal transcription start site that is used for light-induced expression (the proximal light-regulatory element or PLRE). These frq transcripts both have capacity to encode two FRQ proteins, a long form of 989 amino acids (lFRQ) and a short form of 890 amino acids (sFRQ); both lFRQ and sFRQ are required for strong rhythmicity although the clock is able to persist at certain temperatures, albeit with a weaker rhythmicity, with just one of the proteins present. The choice of which protein is made is the result of temperature- dependent splicing of the primary transcript such that it includes or excludes the ATG start codon for lFRQ.
A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. Generally, the PAS domain acts as a molecular sensor, whereby small molecules and other proteins associate via binding of the PAS domain. Due to this sensing capability, the PAS domain has been shown as the key structural motif involved in protein-protein interactions of the circadian clock, and it is also a common motif found in signaling proteins, where it functions as a signaling sensor.
In 2005, she was recruited to Harvard University to be the director of the (FAS) Center for Systems Biology and a Professor of Molecular and Cellular Biology and Chemistry and Chemical Biology. Her research is focused on gene regulation and the biology of a three-protein circadian clock. In 2012, she was elected to be HHMI's new Vice President and Chief Scientific Officer leading the HHMI Investigator Program succeeding Jack Dixon. She will continue to maintain her lab at Harvard.
In 1997, Hajime Tei, Yoshiyuki Sakaki, and Hitoshi Okamura discovered the mammalian period gene PER1 in mice and humans. They also discovered PER2, PER3, and the mammalian homolog of the Drosophila gene timeless. They found that Per1 is light-inducible and can phase shift the circadian clock by light. Okamura worked with Jay Dunlap, a chronobiologist specializing in circadian rhythms in Neurospora, to show that mammalian clocks are similar to neurospora clocks in their use of induction to phase shift.
The protein product of the gene interacts with both CLOCK and NPAS2 to bind to E-box sequences in regulated promoters and activate their transcription. Although Arntl2 is not required for normal function of the mammalian circadian oscillator, it may play an important role in mediating the output of the circadian clock. Perhaps because of this, there is relatively little published literature on the role of Arntl2 in regulation of physiology. Arntl2 is a candidate gene for human type 1 diabetes.
It is a key component of a circadian molecular pathway that regulates many behavioral activities, including conidiation. WC-1 and WC-2, an interacting partner of WC-1, comprise the White Collar Complex (WCC) that is involved in the Neurospora circadian clock. WCC is a complex of nuclear transcription factor proteins, and contains transcriptional activation domains, PAS domains, and zinc finger DNA-binding domains (GATA). WC-1 and WC-2 heterodimerize through their PAS domains to form the White Collar Complex (WCC).
KaiB is a gene located in the highly-conserved kaiABC gene cluster of various cyanobacterial species. Along with KaiA and KaiC, KaiB plays a central role in operation of the cyanobacterial circadian clock. Discovery of the Kai genes marked the first-ever identification of a circadian oscillator in a prokaryotic species. Moreover, characterization of the cyanobacterial clock demonstrated the existence of transcription-independent, post-translational mechanisms of rhythm generation, challenging the universality of the transcription-translation feedback loop model of circadian rhythmicity.
A sleeping cat Sleep in non-human animals refers to a behavioral and physiological state characterized by altered consciousness, reduced responsiveness to external stimuli, and homeostatic regulation. Sleep is observed in mammals, birds, reptiles, amphibians, and some fish, and, in some form, in insects and even in simpler animals such as nematodes. The internal circadian clock promotes sleep at night for diurnal organisms (such as humans) and in the day for nocturnal organisms (such as rodents). Sleep patterns vary widely among species.
Golden studies the endogenous rhythms of cyanobacteria, a group of prokaryotes shown to have circadian clocks. She transformed Synechococcus elongatus, one of the better studied models, with a luciferase reporter gene and showed circadian rhythm in bioluminescence. This was used to discover the cyanobacterial clock, based on three proteins, KaiA, KaiB, and KaiC. In collaboration with Carl H. Johnson and Takao Kondo, she demonstrated circadian rhythms in S. elongatus PCC 7942, the only model organism for a prokaryotic circadian clock.
Hardin's current research centers on the function of the circadian clock in Drosophila melanogaster. One of Hardin's main research topics is understanding the mechanism behind the circadian rhythms in olfaction and gustatory physiology. His research also focuses on understanding the role of post-translational regulatory mechanisms in the feedback loop that set a 24-hour rhythm. Lastly, his lab has been working on identifying if the interlocked loops in the feedback mechanism function as a circadian oscillator or a clock output.
In 1994, Price, together with Amita Sehgal, identified the timeless gene through forward genetics mutagenesis screens. A mutant Drosophila line was generated displaying arrythmia in time of eclosion and per mRNA cycling, reliable phase markers for the Drosophila circadian clock. Price and Seghal mapped the mutations to chromosome 2 and termed the novel gene timeless. Leslie Vosshall, one of their collaborators, later noted that tim mutants were unable to localize PER protein to the nucleus, suggesting an interaction between PER and TIM.
Hypophosphorylated CLK then accumulates, binds to the E-boxes of per and tim and activates their transcription once again. This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock. A similar model is found in mice, in which BMAL1 dimerizes with CLOCK to activate per and cryptochrome (cry) transcription. PER and CRY proteins form a heterodimer which acts on the CLOCK-BMAL heterodimer to repress the transcription of per and cry.
Her current research focuses on the physiological and behavioral aspects of circadian rhythms, She has studied how the retina moves in response to the daily rhythm. Also, as mentioned above, her work on chipmunks has helped uncover the adaptive value of the circadian clock in the wild. She has done experiment related to the adaptive value of clocks on antelope squirrels and golden-mantled squirrels. This research furthers our understanding of sleep related issues affecting humans such as jet lag or insomnia.
In 1968, Menaker provided evidence for the existence of extra-retinal photoreceptors that were sufficient for photoentrainment by measuring rhythmic locomotor behavior as the output signal of the house sparrows (Passer domesticus) circadian clock. He demonstrated that photoentrainment could occur in the absence of optic neurons, evidence for the presence of an extra-retinal photoreceptor(s) coupled to the House Sparrow circadian clock.Bellingham, James, and Russell G. Foster. Opsins and mammalian photoentrainment. Cell and Tissue Research 309.1 (2002): 57-71.
A circadian rhythm is a natural, internal process that regulates the sleep- wake cycle and repeats on each rotation of the Earth roughly every 24 hours. It can refer to any biological process that displays an endogenous, entrainable oscillation of about 24 hours. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in plants, animals, fungi, and cyanobacteria. The term circadian comes from the Latin circa, meaning "around" (or "approximately"), and diēm, meaning "day".
Research from the University of New Hampshire gives insight into the circadian rhythm of Atlantic horseshoe crabs. For example, several studies have looked into the effect of a circa tidal rhythm on the locomotion of this species. While it has been known for a while that a circadian clock system controls eye sensitivity, scientists discovered a separate clock system for locomotion. When a sample of Atlantic horseshoe crabs were exposed to artificial tidal cycles in the lab, circa tidal rhythms were observed.
The precise mechanism of action of lithium is still unknown, and it is suspected that it acts at various points of the neuron between the nucleus and the synapse. Lithium is known to inhibit the enzyme GSK-3B. This improves the functioning of the circadian clock—which is thought to be often malfunctioning in people with bipolar disorder—and positively modulates gene transcription of brain-derived neurotrophic factor (BDNF). The resulting increase in neural plasticity may be central to lithium's therapeutic effects.
Some examples are keeping a journal, restricting the time spent awake in bed, practicing relaxation techniques, and maintaining a regular sleep schedule and a wake-up time. Behavioral therapy can assist a patient in developing new sleep behaviors to improve sleep quality and consolidation. Behavioral therapy may include, learning healthy sleep habits to promote sleep relaxation, undergoing light therapy to help with worry-reduction strategies and regulating the circadian clock. Music may improve insomnia in adults (see music and sleep).
Where spatially separated populations are phase-synchronized, the synchronization is thought to be due to the process of entrainment, that is, the synchronization of a circadian clock with the external environment. The cause of the outbreak cycle is not known with certainty. There are a large number of natural mortality agents which could be responsible for population cycling, including parasitoids, predators, starvation, disease, and severe weather. Most infestations subside after one or two years as a result of a combination of these factors.
There are many systems that have been used to study robustness. In silico models have been used to model RNA secondary structure, protein lattice models, or gene networks. Experimental systems for individual genes include enzyme activity of cytochrome P450, B-lactamase, RNA polymerase, and LacI have all been used. Whole organism robustness has been investigated in RNA virus fitness, bacterial chemotaxis, Drosophila fitness, segment polarity network, neurogenic network and bone morphogenetic protein gradient, C. elegans fitness and vulval development, and mammalian circadian clock.
Examples are the closing of the petals of a flower at dusk and the sleep movements of the leaves of many legumes. The earliest recorded observation of this behavior in plants dates back to 324 BC when Androsthenes, a companion to Alexander the Great, noted the opening and closing of tamarind tree leaves from day to night. Nyctinastic movements are associated with diurnal light and temperature changes and controlled by the circadian clock and the light receptor phytochrome. This is the plant sleeping.
Single loss-of- function mutants in both genes result in seemingly identical phenotypes, but LHY cannot fully rescue the rhythm when CCA1 is absent, indicating that they may only be partially functionally redundant. Under constant light conditions, CCA1 and LHY double loss-of-function mutants fail to maintain rhythms in clock-controlled RNAs.Green, RM. "Loss of the circadian clock-associated protein 1 in Arabidopsis results in altered clock-regulated gene expression." Proc Natl Acad Sci U S A. Vol. 96.
In addition to characterizing transciptomes present in various organisms, Hogenesch has also spent time throughout his career determining which genes were regulated on a circadian schedule. Working with his colleagues he has determined that mRNA in plants, flies, mice, and humans all shows extensive circadian regulation. In mammals up to 43% of all genes are regulated according to a circadian clock. Transcription for circadianly regulated mRNA shows regular peaks in morning and evening, which then has implications for the regulation of drug targets.
How the species manages to return to the same overwintering spots over a gap of several generations is still a subject of research; the flight patterns appear to be inherited, based on a combination of the position of the sun in the skyGugliotta, Guy (2003): Butterflies Guided By Body Clocks, Sun Scientists Shine Light on Monarchs' Pilgrimage . Washington Post, May 23, 2003, page A03. Retrieved 2006-JAN-07. and a time- compensated Sun compass that depends upon a circadian clock that is based in their antennae.
It is still unclear how the transcription-translation feedback loop maintains periodicity and how it is flexible to environmental changes. Since these proteins are essential for the organism to adapt to the environment, understanding the genes are imperative in circadian biology. In cyanobacterium Synechococcus elongates (PCC 7942) kaiA, kaiB, and kaiC are the necessary components that compose the circadian clock. The TTO model of cyanobacteria is questionable due to the finding that phosphorylation of KaiC oscillates regardless of transcription/translation of the kaiBC operon.
March 7, 2011.Joseph S. Takahashi, Hee-Kyung Hong, Caroline H. Ko & Erin L. McDearmon "The genetics of mammalian circadian order and disorder: implications for physiology and disease" Nature Reviews Genetics 9, 764-775 (October 2008) Czeisler's research interests encompass many areas including body temperature rhythms and the effects of melatonin on humans (2011). Czeisler investigates how the physiological system works to reset the circadian pacemaker. His team discovered that light transduced by non-visual input (melanopsin activation) could reset the circadian clock in patients without sight.
PER1 and PER2 are necessary for molecular timekeeping and light responsiveness in the master circadian clock in the SCN, but little data is shown on the concrete function for PER3. PER3 was found to be important for endogenous timekeeping in specific tissues and those tissue-specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3 double knockout (-/-) mice. PER3 may have a stabilizing effect on PER1 and PER2, and this stabilizing effect may be reduced in the PER3-P415A/H417R polymorphism.
Short-term memory, however, has not been shown to vary based on time of day. The mechanism by which this occurs is not currently understood, but Eskin and his lab have continued to study the circadian characteristics of glutamate uptake in synaptic plasticity in order to learn more about the mechanism by which memory formation is controlled by a circadian clock. Furthermore, such information will be useful for chronobiology as a whole in helping explain how a biological clock regulates its outputs to produce rhythm.
This resulted in 353 CpG sites being chosen for the age prediction, and the model had a MAD of 3.6 years. There is evidence for specific methylation sites to be associated with the circadian clock, meaning a sample could have a time of day associated with their death through methylation marks. In whole blood from humans, plasma homocysteine and global DNA methylation change in levels throughout the day. Homocysteine levels peak in the evening and are at their lowest overnight while DNA methylation follows an inverse pattern.
"Circadian and Sleep Control of Hormonal Secretions", in Turek & Zee (eds.), Regulation of Sleep and Circadian Rhythms, pp. 397–425. According to the Hobson & McCarley activation-synthesis hypothesis, proposed in 1975–1977, the alternation between REM and non-REM can be explained in terms of cycling, reciprocally influential neurotransmitter systems. Sleep timing is controlled by the circadian clock, and in humans, to some extent by willed behavior. The term circadian comes from the Latin circa, meaning "around" (or "approximately"), and diem or dies, meaning "day".
Constant routine protocols have been criticized due to evidence that the conditions necessary for the protocol themselves influence the circadian clock. Sleep deprivation and constant dim lighting may mask the endogenous clock or affect circadian phase. For example, it has been demonstrated previously that sleep deprivation itself has an effect on heart rate rhythms as measured by EEG. In addition, it has been suggested that sleep deprivation and the constant routine protocol may themselves effect the circadian phase of the participant, based on research done in hamsters.
The oscillator genes and proteins involved in the mammalian circadian oscillator In mammals, circadian clock genes behave in a manner similar to that of flies. CLOCK (circadian locomotor output cycles kaput) was first cloned in mouse and BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1) is the primary homolog of Drosophila CYC. Three homologs of PER (PER1, PER2, and PER3) and two CRY homologs (CRY1 and CRY2) have been identified. TIM has been identified in mammals; however, its function is still not determined.
The first TTFL model was proposed for Arabidopsis in 2001 and included two MYB transcription factors, LATE ELONGATED HYPOCOTYL (LHY), CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), and TIMING OF CAB EXPRESSION 1 (TOC1). CCA1 and LHY are expressed in the morning, and interact together to repress the expression of TOC1. CCA1 and LHY expression decreases in the darkness, allowing for TOC1 to express and negatively regulate CCA1 and LHY expression. CCA1 and LHY can also bind to their own promoter to repress their own transcription.
In Drosophila, there are two main players in the generation of circadian rhythms: the period (per) gene and timeless (tim). These two genes are responsible for the oscillations in protein levels, RNA levels, and transcription rates that occur in flies. Another essential component of this circadian clock mechanism is that the PER protein contains a PAS domain, which has been demonstrated to mediate the interactions between transcription factors. These transcription factors also contain the well-characterized basic helix-loop-helix (bHLH) DNA-binding domains.
Carla Beth Green (born 1962) is an American neurobiologist and chronobiologist. She is a professor in the Department of Neuroscience and a Distinguished Scholar in Neuroscience at the University of Texas Southwestern Medical Center. She is the former president of the Society for Research on Biological Rhythms (SRBR), as well as a satellite member of the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan. Her research involves the circadian clock and how it controls rhythmic processes within the cell using molecular mechanisms.
Vrille (vri) is a bZIP transcription factor found on chromosome 2 in Drosophila melanogaster. Vrille mRNA and protein product (VRI) oscillate predictably on a 24-hour timescale and interact with other circadian clock genes to regulate circadian rhythms in Drosophila. It is also a regulator in embryogenesis; it is expressed in multiple cell types during multiple stages in development, coordinating embryonic dorsal/ventral polarity, wing-vein differentiation, and ensuring tracheal integrity. It is also active in the embryonic gut but the precise function there is unknown.
S. elongatus has a circadian clock with an oscillator based only on three proteins, KaiA, KaiB, and KaiC where rhythm is generated based on KaiC phosphorylation and dephosphorylation in vitro. Photosynthesis is used to send light information, leading to clock-controlled outputs affecting transcription. This 24-hour rhythm can be recreated in vitro with the addition of ATP. The ratio of ATP/ADP fluctuates during the course of the day, and is sensed by KaiC, which phosphorylates or de-phosphorylates based on this signal.
He conducted an experiment using rats in which he established several control groups and a test group. Using a Halasz knife and his microsurgery experience gained in prior laboratory work, Moore lesioned the SCN of the mice in the test group. The resulting arrhythmicity in corticosterone levels in these mice compared to the control group’s maintained rhythmicity, revealed the SCN’s function as the master circadian clock. This experiment laid the foundation for numerous other studies into better understanding the role of the SCN in mammalian circadian functions.
In 1990, Schwartz et al. began the process of investigating the mechanism of the circadian clock in the suprachiasmatic nucleus by looking at c-Fos, considered the first known suprachiasmatic nucleus clock gene. In order to begin determining the molecular processes that lead to photic entrainment, Schwartz and others analyzed the photic and temporal regulation of the suprachiasmatic nucleus-localized transcriptional regulatory protein c-Fos. They found in albino rats that Fos has altered immunoreactive levels in a phase-dependent manner when exposed to light.
Per mRNA levels peaked at the beginning of the subjective night followed by a peak in PER protein levels about 6 hours later. Mutated per genes affected the cycling of per mRNA. From this experimental data, Rosbash, Hall, and Hardin hypothesized that PER protein is involved in a negative feedback loop that controls per mRNA levels, and that this transcription-translation feedback loop is a central feature of the Drosophila circadian clock. They also looked at two other single missense period mutations, perS and perL1.
More-or-less independent circadian rhythms are found in many organs and cells in the body outside the suprachiasmatic nuclei (SCN), the "master clock". Indeed, neuroscientist Joseph Takahashi and colleagues stated in a 2013 article that "almost every cell in the body contains a circadian clock." For example, these clocks, called peripheral oscillators, have been found in the adrenal gland, oesophagus, lungs, liver, pancreas, spleen, thymus, and skin.Id. There is also some evidence that the olfactory bulb and prostate may experience oscillations, at least when cultured.
In the pinealocyte cells of the pineal gland, aralkylamine N-acetyltransferase is involved in the conversion of serotonin to melatonin. It is the penultimate enzyme in the melatonin synthesis controlling the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for seasonal reproduction, modulates the function of the circadian clock in the suprachiasmatic nucleus, and influences activity and sleep. Due to its important role in circadian rhythm, AANAT is subjected to extensive regulation that is responsive to light exposure (see Regulation).
Dr. Kondo is best known for his discoveries surrounding the molecular basis of the cyanobacteria circadian clock. Prior to Kondo's work in the late 1980s, controversy surrounding the existence of a biological clock in bacteria. Since bacteria divide rapidly and several times per day, it was thought that there was no necessity to evolve a biological clock in bacteria. Promoter-trap and microarray analysis performed by Kondo in the cyanobacteria Synechococcus revealed that many, if not all, genes displayed a rhythmic, circadian component to their expression.
These birds also have timing mechanisms that provide avians with the distance required to travel in order to reach their destination. To regulate the migration patterns of these birds, the mammalian circadian clock is utilized. This clock allows birds to determine when the appropriate time is to migrate, which location will best help them regulate their metabolism, and whether land or water travel will be most advantageous. Tidal migration is the use of tides by organisms to move periodically from one habitat to another.
Specifically, CKIε has been shown to reduce the half-life of mPER1, one of the three mammalian PER homologs. In addition, nuclear localization of the mPER proteins is related to phosphorylation, adding another essential role to the activity of the CKIε protein. Overall, the genetic similarity of dbt and CKIε is not the end of the story; the roles they play within the circadian clock in their respective systems are almost identical. Both are involved with periodic phosphorylation, regulating the oscillations of the circadian clocks.
Cullin 3 is a component of Cullin-RING E3 ubiquitin ligases complexes (CRLs) which are involved in protein ubiquitylation and represent a part of ubiquitin–proteasome system (UPS). Added ubiquitin moieties to the lysine residue by CRLs then target the protein for the proteasomal degradation. Cullin-RING E3 ubiquitin ligases are involved in many cellular processes responsible for cell cycle regulation, stress response, protein trafficking, signal transduction, DNA replication, transcription, protein quality control, circadian clock and development. Deletion of CUL3 gene in mice causes embryonic lethality.
Research has revealed that Bmal1 is the only clock gene without which the circadian clock fails to function in humans. Bmal1 has also been identified as a candidate gene for susceptibility to hypertension, diabetes, and obesity, and mutations in Bmal1 have been linked to infertility, gluconeogenesis and lipogenesis problems, and altered sleep patterns. BMAL1, according to genome-wide profiling, is estimated to target more than 150 sites in the human genome, including all of the clock genes and genes encoding for proteins that regulate metabolism.
Currently, the International Classification of Sleep Disorders (ICSD-3) lists 6 disorders under the category of circadian rhythm sleep disorders. CRSDs can be categorized into two groups based on their underlying mechanisms: The first category is composed of disorders where the endogenous oscillator has been altered, known as intrinsic type disorders. This category will be referred to as the intrinsic disorder type. The second category consists of disorders in which the external environment and the endogenous circadian clock are misaligned, called extrinsic type CRSDs.
Also, other conserved regions exist both up- and downstream of this domain. dNF1, like its human counterpart, is mainly expressed in the developing and adult nervous system and primarily controls the MAPK RAS/ERK signaling pathway. Through the use of several mutant null alleles of dNF1 that have been generated, its role has been progressively elucidated. dNF1 functions to regulate organism growth and whole-body size, synaptic growth, neuromuscular junction function, circadian clock and rhythmic behaviors, mitochondrial function, and associative learning and long-term memory.
In 2015, Robertson-Anderson attended a Gordon and Betty Moore Foundation Scialog program, where she met Jenny Ross and became interested in cytoskeleton scaffolding proteins. Robertson-Anderson was awarded a W. M. Keck Foundation grant to develop autonomous materials based on cytoskeleton proteins that can use biologically-derived components, such as circadian clock proteins, to perform mechanical work. The circadian oscillator system is taken from cyanobacteria, and turns on and off in the presence of phosphate molecules. The proteins can function on the outside of living cells.
As stated above, the majority of patients with non-24 are totally blind. The failure of entrainment is explained by the loss of photic input to the circadian clock. Non-24 is rare among visually impaired patients who retain at least some light perception; even minimal light exposure can synchronize the body clock. A few cases have been described in which patients are subjectively blind, but are normally entrained and have an intact response to the suppressing effects of light on melatonin secretion, indicating preserved neural pathways between the retina and hypothalamus.
Type A cytokinin response regulators can act as negative regulators of cytokinin signaling by either competing with type-B positive regulators or by regulating the pathway through direct and indirect interactions with other pathway mechanisms. Type A cytokinin response regulators are also likely involved in other processes. One example is light signal transduction: ARR3 and ARR4 are involved in the synchronization of the circadian clock of Arabidopsis thaliana with external time and photoperiod. Moreover, ARR6 is implied in the control of Arabidopsis thaliana disease- resistance and cell wall composition.
In 1981, Steve Kay earned his bachelor's degree in Biochemistry at University of Bristol, UK. He stayed there in the Trevor Griffiths lab and received his PhD in 1985 exploring the light regulation of chlorophyll synthesis in plants. Kay learned that light changed gene expression, and that circadian clock was also regulating transcription on a daily basis. He would later spend more than two decades pursuing these circadian clocks. Following Griffiths' advice, Kay moved to the United States and worked as a postdoc in the Nam-Hai Chua lab at Rockefeller University.
Genes whose transcription is regulated by CREB include: c-fos, BDNF, tyrosine hydroxylase, numerous neuropeptides (such as somatostatin, enkephalin, VGF, corticotropin- releasing hormone), and genes involved in the mammalian circadian clock (PER1, PER2). CREB is closely related in structure and function to CREM (cAMP response element modulator) and ATF-1 (activating transcription factor-1) proteins. CREB proteins are expressed in many animals, including humans. CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain and has been shown to be integral in the formation of spatial memory.
Michael Greenberg first demonstrated the role of CREB in the mammalian circadian clock in 1993 through a series of experiments that correlated phase-specific light pulses with CREB phosphorylation. In vitro, light during the subjective night increased phosphorylation of CREB rather than CREB protein levels. In vivo, phase shift-inducing light pulses during the subjective night correlated with CREB phosphorylation in the SCN. Experiments by Gunther Schutz in 2002 demonstrated that mutant mice lacking the Ser142 phosphorylation site failed to induce the clock regulatory gene mPer1 in response to a light pulse.
In 1997, Hall was a part of group with Susan Renn, Jae Park, Michael Rosbash, and Paul Taghert that discovered genes that are a part of the TTFL are expressed in cells throughout the body. Despite these genes being identified as necessary genes to the circadian clock, there was a variety of levels of expressions in various parts of the body; this variation was observed on the cellular level. Hall succeeded in entraining separate tissues to different light-dark cycles at the same time. Hall didn't discover the element that synchronizes cells until 2003.
These plants are either long-short-day plants (LSDP) or short-long- day plants (SLDP). LSDPs flower after a series of long days followed by short days whereas SLDPs flower after a series of short days followed by long days. Each plant has a different length critical photoperiod, or critical night length. Modern biologists believe that it is the coincidence of the active forms of phytochrome or cryptochrome, created by light during the daytime, with the rhythms of the circadian clock that allows plants to measure the length of the night.
There is no cure for ONH; however, many therapeutic interventions exist for the care of its symptoms. These may include hormone therapy for hypopituitarism, occupational, physical, and/or speech therapy for other issues, and services of a teacher for students with blindness/visually impairment. Special attention should be paid to early development of oral motor skills and acclimation to textured foods for children with texture aversion, or who are otherwise resistant to eating. Sleep dysfunction can be ameliorated using melatonin in the evening in order to adjust a child's circadian clock.
Phosphorylation stabilizes WCC and promotes its export to the cytoplasm, effectively down-regulating frq transcription. The White Collar Complex (WCC), the heterodimer of WC-1 and WC-2, acts as a positive element in the circadian clock. WCC serves as an activator of frq gene transcription by binding to two DNA promotor elements in the nucleus: the Clock box (C box) and the Proximal Light-Response Element (PLRE). PLRE is required for maximal light induction, while the C box is required for both maximal light induction and maintaining circadian rhythmicity in constant darkness.
New York: Alfred A. Knopf.pp. 259-278. His work and ideas ran counter to the prevailing trend in chronobiology at the time, which was focused on the development of the endogenous and bio-chemical model of the circadian clock. Brown envisioned the biological clock as being a duality in which an internal responder to subtle information from the environment is overlain by an endogenous timing mechanism. Brown's research program which diverged from the mainstream, was ignored by his peers. A paper published in Science magazine in 1957Cole, Lamont C. Biological Clock in the Unicorn.
For a long time it was thought the transcriptional activation/repression cycles driven by the transcriptional regulators constituting the circadian clock was the main driving force for circadian gene expression in mammals. More recently, however, it was reported that only 22% of messenger RNA cycling genes are driven by de novo transcription. RNA-level post-transcriptional mechanisms driving rhythmic protein expression were later reported, such as mRNA polyadenylation dynamics. Fustin and co-workers identified methylation of internal adenosines (m6A) within mRNA (notably of clock transcripts themselves) as a key regulator of the circadian period.
The autoregulatory feedback loops in clocks take about 24 hour to complete a cycle and constitute a circadian molecular clock. This generation of the ~24-hour molecular clock is governed by post- translational modifications such as phosphorylation, sumoylation, histone acetylation and methylation, and ubiquitination. Reversible phosphorylation regulates important processes such as nuclear entry, formation of protein complexes and protein degradation. Each of these processes significantly contributes to keeping the period at ~24 hours and lends the precision of a circadian clock by affecting the stability of aforementioned core clock proteins.
In addition to retina this receptor is expressed on the osteoblasts and is increased upon their differentiation. MT2 regulates proliferation and differentiation of osteoblasts and regulates their function in depositing bone. MT2 signaling seems also involved in the pathogenesis of type 2 diabetes. Activation of the MT2 receptor promotes vasodilation which lowers body temperature in the extremities upon daytime administration. The most notable of the functions that are largely mediated by the MT2 receptor is that of phase shifting the internal circadian clock to entrain to the Earth's natural light-dark cycle.
In this case we can see how CLK and CYC are the positive regulators (yellow and green) and PER and TIM are the negative (red and blue) regulators that each play a role in the circadian clock. Secondary feedback loops interact with this primary feedback loop. CLOCKWORK ORANGE (CWO) binds the E-boxes to act as a direct competitor of CYC-CLK, therefore inhibiting transcription. PAR-DOMAIN PROTEIN 1 ε (PDP1ε) is a feedback activator and VRILLE (VRI) is a feedback inhibitor of the Clk promoter, and their expression is activated by dCLK-dCYC.
The research of Takahashi has led to many developments in understanding how the circadian clock of mammals affects physiology and relationships with the environment. In 1993, Takahashi and Michael Greenberg studied the mechanisms of mammalian suprachiasmatic nuclei entrainment to environmental light cycles. They explored the relationship between phosphorylated cyclic adenosine monophosphate response element binding protein (CREB) and c-fos transcription, a protein previously indicated as a component of the photic entrainment pathway. Using immunoprecipitation, Takahashi and Greenberg were able to show that light induced CREB phosphorylation occurs only during the subjective night.
Green's lab has focused heavily on a class of proteins known as cryptochromes, which are blue light receptor proteins found in both plants and animals. Cryptochrome proteins are essential for the proper functioning of the circadian clock in insects and mammals, and for proper development in plants. Cryptoproteins regulate the circadian clocks of plants, insects, and mammals in different ways. Green has worked extensively with an amphibian, the African clawed frog (or Xenopus laevis), as well as mammalian CRY1 and CRY2, to try and uncover the mysteries of these essential transcriptional repressors.
Green's research on cryptochromes began in 2003, when she and colleagues investigated the role of cryptochrome in suppressing the activation of other circadian clock genes such as CLOCK and BMAL1. They revealed that the deletion of Cryptochrome's C-terminal domain resulted in proteins unable to suppress activation of these genes. This result indicates that the C-terminal is not the domain of suppression of CLOCK/BMAL1, but is essential only for nuclear localization. Green has also studied the relationship between the suprachiasmatic nucleus and peripheral circadian oscillators, in which cryptochrome plays a key role.
In 2013, Price's lab identified a noncanonical FK506-binding protein named Bride of Double-time (BDBT), which interacts with DBT protein kinase. In his experiment, RNA interference (RNAi), which reduced BDBT expression, resulted in long periods and arrhythmicity of locomotion, as well as high levels of hypophosphorylated nuclear PER and phosphorylated DBT. These results demonstrated a role for BDBT in the circadian clock. When BDBT was overexpressed, Price found that the phosphorylation and DBT-dependent degradation of PER increased, suggesting that BDBT stimulates DBT circadian activity toward PER.
These time-dependent microbial changes are associated with differences in the transcription of circadian clock genes involved in circadian rhythm. One mouse study showed that altering clock gene transcription by disrupting circadian rhythm, such as through sleep deprivation, potentially has a direct effect on the composition of the gut microbiome. Another study found that mice that could not produce the CLOCK protein, made by a clock gene, were more likely to develop depression. Stress and sleep disturbances can lead to greater gut mucosal permeability via activation of the HPA axis.
They were eventually able to localize the gene region causing this rescue, and observed circadian rhythmicity in upstream promotor activity of kaiA and kaiB, as well as in the expression of kaiA and kaiBC messenger RNA. They determined abolishing any of the three kai genes would cause arrhythmicity in the circadian clock and reduce kaiBC promoter activity. KaiC was later found to have both autokinase and autophosphatase activity. These findings suggested that circadian rhythm was controlled by a TTFL mechanism, which is consistent with other known biological clocks.
Following work done by post-doctoral fellow, Paul Hardin, in discovering that period mRNA and its associated protein (PER) had fluctuating levels during the circadian cycle, in 1990 they proposed a Transcription Translation Negative Feedback Loop (TTFL) model as the basis of the circadian clock. Following this proposal, they looked into the elements that make up other parts of the clock. In May 1998, Rosbash et al. found a homolog for mammalian Clock that performed the same function of activating the transcription of per and tim that they proceeded to call dClock.
Reddy's research group discovered the existence of circadian clocks in human red blood cells (erythrocytes) in 2011. This was a seminal finding for the field because before this study it was not thought that mammals could have a circadian clock without DNA, RNA production, or protein production. Thus, the red cell oscillations might be considered a type of biochemical or chemical oscillation, over a long (24 hour) time scale. Sir Christopher Dobson lauded the findings, and commented that this was akin to well established short period oscillations that occur in chemical systems.
Animals as diverse as insects and vertebrates share a similar genetic clock system. The circadian clock is influenced by light but continues to operate even when light levels are held constant and no other external time-of-day cues are available. The clock genes are expressed in many parts of the nervous system as well as many peripheral organs, but in mammals, all of these "tissue clocks" are kept in synchrony by signals that emanate from a master timekeeper in a tiny part of the brain called the suprachiasmatic nucleus.
NONO is involved with many nuclear processes and binds to both DNA and RNA. As with all proteins of the DBHS familprotein is described as a multifunctional nuclear protein. The NONO protein has been shown to be implicated in many biological functions including, pre-mRNA splicing; activation of transcription; termination of transcription; DNA unwinding and pairing and maintaining correct circadian clock function. NONO has been identified to bind with Rasd1 protein, in resulting dimer Rasd1 may act to modulate the function of NONO to down regulate the expression of the CREB genes, NR4A1 and Nr4A2.
Recent research on cycle has largely focused on the role of circadian rhythmicity in other processes. In 2012, it was reported that aging reduces transcriptional oscillations of core clock genes in the fly head including cycle. Wild type Drosophila show low activity of the CLOCK/CYCLE protein dimer in the morning, and it was recently found that lowering levels of these proteins can affect neuronal signaling. Research from 2012 on sleep architecture and nutrition found that circadian clock mutants, including cyc01 still maintained a normal diet response without circadian rhythmicity.
His early work with mollusks investigated the structure and function of basal retinal neurons (BRN) in circadian photoentrainment. He was the first to discover a cell-autonomous circadian pacemaker and concluded that BRNs are both necessary and sufficient for photoentrainment. Later in his career, Block explored the molecular basis of circadian rhythms in mammals, and found that calcium flux was necessary for circadian rhythmicity. His most recent research, which he is still working on today, is largely focused on the effect that aging has on the circadian clock.
Diamondback moths are known to fly in a straight trajectory which is not dependent on the angle of the sun's rays. Tests have been performed to interfere with the biological clock of certain species by keeping them in the dark and then observing if they would choose for other flight paths. The conclusion was that some species did, and others did not. Research on monarchs demonstrates that with removal of antennae, the location of the circadian clock, individuals do not localize in any one direction during flight as they do with antennae intact.
JARID1A has been shown to interact with Estrogen receptor alpha, LMO2 and Retinoblastoma protein. JARID1A is a major component of the circadian clock, the upregulation of which at the end of the sleep phase blocks HDAC1 activity. Blocking HDAC1 activity results in an upregulation of CLOCK and BMAL1 and consequent upregulation of PER proteins. The PSF (polypyrimidine tract-binding protein-associated splicing factor) within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription.
The Arntl gene was originally discovered in 1997 by two groups of researchers, John B. Hogenesch et al. in March under the name Mop3 and Ikeda and Nomura in April as part of a superfamily of PAS domain transcription factors. In 1998, Hogenesch's additional characterization of MOP3 revealed that its role as the partner of bHLH-PAS transcription factor CLOCK was essential to mammalian circadian clock function. The MOP3 protein, as it was originally known by the Hogenesch group, was found to dimerize with MOP4, CLOCK, and hypoxia-inducible factors.
Forager bees also assess the quality of nectar by comparing the length of time it takes to unload the forage: a longer unloading time indicates higher quality nectar. They compare their own unloading time to the unloading time of other foragers present in the hive, and adjust their recruiting behavior accordingly. For instance, honey bees reduce the duration of their waggle dance if they judge their own yield to be inferior. Scientists have demonstrated that anesthesia disrupts the circadian clock and impairs the time perception of honey bees, as observed in humans.
The principal role of SHP appears to be repression of other nuclear receptors through association to produce a non-productive heterodimer. The protein has also been identified as a mediating factor in the metabolic circadian clock Research shows that it interacts with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation. In addition, interaction with estrogen receptors has been demonstrated, leading to inhibition of function. Studies suggest that the protein represses nuclear hormone receptor-mediated transactivation via two separate steps: competition with coactivators and the direct effects of its transcriptional repressor function.
The importance of m6A methylation for physiological processes was recently demonstrated. Inhibition of m6A methylation via pharmacological inhibition of cellular methylations or more specifically by siRNA-mediated silencing of the m6A methylase Mettl3 led to the elongation of the circadian period. In contrast, overexpression of Mettl3 led to a shorter period. The mammalian circadian clock, composed of a transcription feedback loop tightly regulated to oscillate with a period of about 24 hours, is therefore extremely sensitive to perturbations in m6A-dependent RNA processing, likely due to the presence of m6A sites within clock gene transcripts.
People with a circadian rhythm that is quite near to 24 hours may be able to sleep on a conventional, socially acceptable schedule, that is, at night. Others, with a "daily" cycle upwards of 25 hours or more, may need to adopt a sleep pattern that is congruent with their free-running circadian clock: by daily shifts in their sleep times, which often results in satisfactory sleep but with negative social and occupational consequences. The disorder also occurs in sighted people for reasons that are not well understood. Their circadian rhythms are not normal, often running to more than 25 hours.
The circadian rhythms of individuals with non-24 can resemble those of experimental subjects living in a time-isolated environment even though they are living in normal society. The circadian clock modulates many physiological rhythms. The most easily observed of these is the propensity for sleep and wake; thus, people with non-24 experience symptoms of insomnia and daytime sleepiness (similar to "jet lag") when their endogenous circadian rhythms drift out of synchrony with the social/solar 24-hour day, but they conform to a conventional schedule. Eventually, their circadian rhythms will drift back into normal alignment, when symptoms temporarily resolve.
In 2020, Gibson started her independent lab and became an assistant professor at Stanford University in the Department of Psychiatry and Behavioral Sciences, the Stanford Center for Sleep Sciences and Medicine, and Stanford University Medical School. She is also a member of Bio-X at Stanford and the Maternal and Child Health Research Institute. Gibson's lab explores the cellular and molecular mechanisms that modulate glial cells in the central nervous system. Combining her postdoctoral and graduate work, Gibson has a particular interest in how the circadian clock regulates the biology of glial cells in the brain.
It was at the Nam-Hai Chua lab working with another postdoc named Ferenc Nagy that Kay stumbled upon the discovery that the chlorophyll binding gene CAB was regulated by a circadian clock. In 1989, Kay was appointed to his first faculty position as an Assistant Professor at Rockefeller University. While there, he collaborated with Michael W. Young to identify fly PER gene homologues, which did not exist. Kay then developed glowing Arabidopsis thaliana plants to screen for circadian rhythm mutants, with the help of his student Andrew Millar , and subsequently identified TOC1, the first clock gene identified in plants.
Taghert and colleagues have identified the ~150 circadian clock neurons in the adult Drosophila melanogaster brain. Two distinct regions, the small and large ventral lateral neurons (LNv), express the neuropeptide pigment dispersing factor (PDF) and contribute to circadian locomotor activity rhythms. Taghert's group has made several contributions including the identification of mutants for the PDF neuropeptide gene - this revealed a specific behavioral syndrome indicating important contributions by this neuropeptide to normal circadian control of locomotor activity. This was the first genetic study identifying secreted substances (and not just clock elements) as critical proteins for circadian neurophysiology.
Studies in animals and plants suggest that cryptochromes play a pivotal role in the generation and maintenance of circadian rhythms. Similarly, cryptochromes play an important role in the entrainment of circadian rhythms in plants. In Drosophila, cryptochrome (dCRY) acts as a blue-light photoreceptor that directly modulates light input into the circadian clock, while in mammals, cryptochromes (CRY1 and CRY2) act as transcription repressors within the circadian clockwork. Some insects, including the monarch butterfly, have both a mammal-like and a Drosophila-like version of cryptochrome, providing evidence for an ancestral clock mechanism involving both light-sensing and transcriptional-repression roles for cryptochrome.
In 1990, while in collaboration with Michael Rosbash and Paul Hardin, Hall discovered that the Period protein (PER) played a role in suppressing its own transcription. While the exact role of PER was unknown, Hall, Rosbash, and Hardin were able to develop a negative transcription- translation feedback loop model (TTFL) that serves as a central mechanism of the circadian clock in Drosophila. In this original model, per expression led to an increase of PER. After a certain concentration of PER, the expression of per decreased, causing PER levels to decrease, once again allowing per to be expressed.
The phosphorylation of the WCC stabilizes WCC, preventing it from binding and activating frq transcription. Protein phosphatases PP2A and PP4 are known to counterbalance kinase activity and support the reactivation and nuclear entry of WCC. FRQ has also been shown to interact with WC-2 in vitro, and a partial loss-of-function allele of wc-2 yields Neurospora with a long period length and altered temperature compensation, which is a key characteristic of circadian pacemakers. Only WC-1 is required for transient light-induction, but both WC-1 and WC-2 are required for the circadian clock to run.
Researchers have shown that the 24-hour circadian clock also influences cognitive performance in a wide variety of paradigms, including serial search, verbal reasoning, working memory tasks, suppressing wrong answers, and manual dexterity. Performance on these tasks varies over the course of a day, with each type of task having a unique daily rhythm. For example, the best time to perform a working memory task tends to be midday, while immediate memory is best in the morning, and simple processing is ideally performed in the evening. In addition, individual differences among participants can have an effect on daily rhythms in performance.
Evidence for a genetic basis of circadian rhythms in higher eukaryotes began with the discovery of the period (per) locus in Drosophila melanogaster from forward genetic screens completed by Ron Konopka and Seymour Benzer in 1971. Through the analysis of per circadian mutants and additional mutations on Drosophila clock genes, a model encompassing positive and negative autoregulatory feedback loops of transcription and translation has been proposed. Core circadian 'clock' genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms. Similar models have been suggested in mammals and other organisms.
In 2007, he became a researcher at the Scripps Institute with Steve Kay, and continued with the lab when it moved to University of California San Diego (UCSD) for five additional years. While in Kay's lab, he was influenced by fellow researcher Takato Imaizumi to study ELF3 in plants. Nusinow then became a principal investigator at the Donald Danforth Plant Science Center and an adjunct professor at Washington University in St. Louis in 2012. He now studies to understand how the circadian clock is integrated with environmental signals to control growth, development, and physiology in order to improve the productivity in plants.
The sun plays an integral role in the monarchs’ migratory patterns: they travel during the day and use a circadian clock based on the sun's position in the sky to orient themselves. This clock mechanism is time compensated, where each butterfly entrains to the light-dark cycle of its surroundings and thereby knows how to interpret the changing light patterns throughout the day. Various studies have shown this behavior both in natural systems and laboratory settings. Yet there remains much to be researched about the underlying mechanisms for interpreting the orientation and timing cues that lead to the migratory patterns of the monarchs.
Across species, proteins involved in the TTFL contain common structural motifs such PAS domains, involved in protein-protein interactions, and bHLH domains, involved in DNA binding. Once enough modified protein products accumulate in the cytoplasm, they are transported into the nucleus where they inhibit the positive element from the promoter to stop transcription of clock genes. The clock gene is thus transcribed at low levels until its protein products are degraded, allowing for positive regulatory elements to bind to the promoter and restart transcription. The negative feedback loop of the TTFL has multiple properties important for the cellular circadian clock.
In 2001, Green found Noc homologues in other species such as mice with a high degree coding sequence similarity. Since expanding these studies into mice, they have shown that mouse Nocturnin mRNA is also rhythmic and expressed in many circadian clock-containing tissues. Interestingly, Green's group has shown that though Noc is not directly involved in regulating the master clock gene expression, it is required for oscillator output functions thereby contributing to circadian physiology. The rhythmic expression of nocturnin (Noc) is seen throughout the body, notably in tissues crucial for metabolism like the liver and intestine.
Robert Y. Moore (born December 5, 1931) is an American neurologist with interests in disorders of biological rhythms, movement disorders, and behavioral neurology. He is credited with discovering the function of the suprachiasmatic nucleus (SCN) as the circadian clock, as well as, describing its organization. He is also credited with establishing the role of the mammalian retinohypothalamic tract (RHT) as a photic entrainment pathway. Moore cin 2017 serves as a professor of neurology, with a secondary in psychiatry and neuroscience at the University of Pittsburgh, and as co- director of the National Parkinson Foundation Center of Excellence at the University of Pittsburgh.
Pseudo-response regulator (PRR) refers to a group of genes that are important in the plant circadian oscillator. There are four primary PRR proteins (PRR9, PRR7, PRR5 and TOC1/PRR1) that perform the majority of interactions with other proteins within the circadian oscillator, and another (PRR3) that has limited function. These genes are all paralogs of each other, and all repress the transcription of Circadian Clock Associated 1 (CCA1) and Late Elongated Hypocotyl (LHY) at various times throughout the day. The expression of PRR9, PRR7, PRR5 and TOC1/PRR1 peak around morning, mid-day, afternoon and evening, respectively.
Before this, codon bias prevented effective usage of firefly luciferase in Neurospora, problematic as firefly luciferase serves as a reporter to measure transcription in cells. By modifying the firefly luciferase gene, Loros was able to achieve several orders more of light production in Neurospora, revolutionizing transcription measurements in N. cell cultures. Moreover, her modification to this reporter allowed the FRQ/WCC feedback loop to be monitored in real time without disturbing the overt rhythms of the system. This in turn provided the tool to distinguish between oscillators not directly in the clock and the circadian clock itself.
Timeless does not appear to be essential for oscillation of the circadian clock for all insects. In wild type Gryllus bimaculatus, tim mRNA shows rhythmic expression in both LD and DD (dark-dark cycles) similar to that of per, peaking during the subjective night. When injected with tim double-stranded RNA (dstim), tim mRNA levels were significantly reduced and its circadian expression rhythm was eliminated. After the dstim treatment, however, adult crickets showed a clear locomotor rhythm in constant darkness, with a free-running period significantly shorter than that of control crickets injected with Discosoma sp.
In 1998, researchers identified a mouse homolog and a human homolog of the Drosophila timeless gene. The exact role of TIM in mammals is still unclear,. Recent work on the mammalian timeless (mTim) in mice has suggested that the gene may not play the same essential role in mammals as in Drosophila as an necessary function of the circadian clock. While Tim is expressed in the Suprachiasmatic Nucleus (SCN) which is thought to be the primary oscillator in humans, its transcription does not oscillate rhythmically in constant conditions, and the TIM protein remains in the nucleus.
From these data, the MCTQ offers methods to make up for sleep debt (if any), and offers suggestions on what to do to wake up earlier or sleep later. This Chronotype Questionnaire is important because it delves into the social aspects of circadian rhythms. By testing behavior rather than directly testing genetic factors, the MCTQ may offer new information regarding how the influences of external factors (like geographic location or seasons) or things such as obesity or social jetlag, may relate to genetic predispositions of circadian rhythms.The search for circadian clock components in humans: new perspectives for association studies.
Kondo was born in 1948 in Kariya, Aichi, Japan, and received his B.S. in 1970 and his Ph.D. in Biology in 1977 from Nagoya University."生物時計のブラックボックスを開く" Biography of Dr. Takao Kondo He was appointed as an assistant professor at the National Institute for Basic Biology in Okazaki, Aichi, Japan in 1978. Kondo began work as a visiting scholar at Harvard University in 1985, then continued his work abroad at Vanderbilt University between 1990 and 1991. It was at Vanderbilit University that Kondo began his research on the circadian clock of cyanobacteria.
Smith studies the metabolism in plants of starch and sucrose – the carbohydrate products of photosynthesis that fuel plant growth. Her research has uncovered metabolic pathways responsible for the synthesis and degradation of starch granules in plants. She showed that these processes in leaves are subject to complex control by the circadian clock over the day-night cycle, ensuring the availability of carbohydrate to fuel metabolism during the night. Her focus is now on the mechanisms underlying this control, and the way in which carbohydrate availability is integrated with other sources of information to determine rates and patterns of growth and development in plants.
Colin Stephenson Pittendrigh (October 13, 1918 – March 19, 1996) "Colin Pittendrigh, 'Father of biological clock,' dies at 77", March 25, 1996, accessed April 9, 2011. was a British-born biologist who spent most of his adult life in the United States. Pittendrigh is regarded as the "father of the biological clock," and founded the modern field of chronobiology alongside Jürgen Aschoff and Erwin Bünning. He is known for his careful descriptions of the properties of the circadian clock in Drosophila and other species, and providing the first formal models of how circadian rhythms entrain (synchronize) to local light-dark cycles.
He obtained his first degree of botany at University of Durham, and was assigned to wartime service as a biologist in Trinidad during World War II where he studied malaria transmission by mosquitoes. After the war, he attended Columbia University to study for his Ph.D. He later joined the faculty of Princeton University and started his chronobiology research. He also co-chaired a Mars exploration project at NASA from 1964 to 1966. The defining principle that Pittendrigh developed throughout his career was that the properties of the circadian clock are independent from those of the behaviors it controls.
Pdf is conserved across Bilateria and homologs have been identified in organisms such as mosquitos and C.elegans. A common misconception is that the PDF gene is found in vertebrates, such as rodents, chimpanzees, and humans. Pdf has also been studied in the cricket Gryllus bimaculatus; studies proved that pdf is not necessary for generating the circadian rhythm, but involved in control of nocturnal behavior, entrainment, and the fine-tuning of the free-running period of the circadian clock. Using liquid chromatography in conjunction with several biological assays, PDF, was also isolated in the insect Leucophaea maderae, a cockroach.
Regarding sleep, normal circadian function allows people to maintain balance rest and wakefulness that allows people to work and maintain alertness during the day's activities, and rest at night. Some misconceptions regarding circadian rhythms and sleep commonly mislabel irregular sleep as a circadian rhythm sleep disorder. In order to be diagnosed with CRSD, there must be either a misalignment between the timing of the circadian oscillator and the surrounding environment, or failure in the clock entrainment pathway. Among people with typical circadian clock function, there is variation in chronotypes, or preferred wake and sleep times, of individuals.
Rogulja found that cyclin A (CycA) and its regulator cyclin A1 promote sleep in Drosophila. Fascinatingly, CycA is only expressed in 40-50 neurons in the fly brain, intermingled with circadian clock neurons suggesting that interactions with their cellular neighbors are important in allowing the circadian cycle to influence sleep. When Rogulja artificially reduced expression of CycA in these neurons, she found that Drosophila had hard times falling asleep and reduced responses to sleep deprivation. Further, since CycA is a cell cycle regulator that is highly conserved across species, Rogulja and her colleagues propose the importance of CycA in sleep regulation beyond drosophila.
In March, 1997, Hogenesch was a neuroscience graduate student at Northwestern University in the laboratory of Christopher Bradfield, when he discovered five transcription factors in the basic helix-loop-helix-PAS (bHLH-PAS) domain superfamily during his thesis work. These transcription factors were initially named MOP1-5. Hogenesch’s later characterization of MOP3, better known as BMAL1 or ARNTL, revealed in 1998 that its role as a partner of the bHLH-PAS transcription factor CLOCK was essential to the function of the mammalian circadian clock. BMAL1 and CLOCK are now the two most well recognized bHLH-PAS domain transcription factors.
In 2003, Reppert began investigating the functional and evolutionary properties of the CRY protein in the monarch butterfly. He identified two Cry genes in the monarch, Cry1 and Cry2. His work demonstrated that the monarch CRY1 protein is functionally analogous to Drosophila CRY, the blue-light photoreceptor necessary for photoentrainment in the fly. He also demonstrated that monarch CRY2 is functionally analogous to vertebrate CRYs and that monarch CRY2 acts as a potent transcriptional repressor in the circadian clock transcriptional translation feedback loop of the butterfly, as his group previously showed for the two mouse CRYs.
In other words, melatonin has most effect when it is taken at times when natural melatonin is not normally present, thus during the day: when taken in the morning, melatonin causes phase delays (shifts to a later time), and when taken in the afternoon/evening it causes phase advances (shifts to an earlier time). However, for a sleep phase delayed person, the time of biological morning and biological afternoon/evening might differ depending on the circadian clock shift in the affected person. This means that if melatonin is taken during the usual bedtime and wake-up time (i.e., usual nighttime), it may have no effect.
While a precise 24-hour circadian clock is found in many organisms, it is not universal. Organisms living in the high arctic or high antarctic do not experience solar time in all seasons, though most are believed to maintain a circadian rhythm close to 24 hours, such as bears during torpor. Much of the earth's biomass resides in the dark biosphere, and while these organisms may exhibit rhythmic physiology, for these organisms the dominant rhythm is unlikely to be circadian. For east-west migratory organisms—and especially those organisms that circumnavigate the globe—the absolute 24-hour phase might deviate over months, seasons, or years.
Selective gene knockdown of known components of the human circadian clock demonstrates both active compensatory mechanisms and redundancy are used to maintain function of the clock. How these self- sustained cellular clocks achieve multicellular integration is largely obscure, but astrocytes alone can drive the molecular oscillations in the SCN and circadian behavior in mice. Several mammalian clock genes have been identified and characterized through experiments on animals harboring naturally occurring, chemically induced, and targeted knockout mutations, and various comparative genomic approaches. The majority of identified clock components are transcriptional activators or repressors that modulate protein stability and nuclear translocation, and create two interlocking feedback loops.
In 2015 through 2016, Nusinow and his colleagues identified a protein that was repeatedly associated with the evening complex in AP-MS analysis of the plant circadian clock. Nusinow found that the protein, which he named PCH1 (Photoperiodic Control of Hypocotyl), was an important regulator for the growth of the hypocotyl (the stem of a seedling) during germination. PCH1 reduces hypocotyl growth during long nights by preferentially binding and stabilizing the active form of phytochrome B (phyB), prolonging its activity. PhyB in turn forms photobodies in the nucleus, where it interacts with molecules of the evening complex (EC) to cause downstream inhibition of hypocotyl growth.
In 2011, Green's lab concluded that transcriptional and post-transcriptional processes are necessary to generate robust circadian rhythms of mRNA expression, but understandings of circadian post-transcriptional mechanisms lag far behind understandings of clock regulation at the transcriptional level. This was found to be due to the lack of well-developed methodologies to find post- transcriptionally regulated genes on a large scale. The authors believe that development of such methods is likely to lead to the discovery of many more genes and mechanisms that are under post-transcriptional control. Green's findings are cited in more recent developments on post-transcriptional control of the mammalian circadian clock.
Merrow is well known for her work on the entrainment of circadian clocks in both humans and the fungus Neurospora crassa. She has also worked to describe circadian clocks in mutant or model genetic organisms lacking clear circadian phenotypes. Merrow worked with colleagues Till Roenneberg and Anna Wirz-Justice to develop the Munich ChronoType Questionnaire ((MCTQ)), which assesses human chronotypes. Those with early chronotypes may be referred to as “larks” while those with late chronotypes may be referred to as “owls.” Merrow’s molecular chronobiology lab at Ludwig Maximilian University of Munich uses nematodes, yeast, fungi, and human tissue cultures to study the circadian clock in simple systems.
In 1972 in his laboratory at the University of Chicago, Moore and Victor B. Eichler demonstrated the suprachiasmatic nucleus (SCN), a small region of the brain in the hypothalamus located directly above the optic chiasm, was necessary for circadian rhythms, i.e. it was a circadian clock. While the SCN had been a known component of the brain for nearly one hundred years, previously, its function had been unknown. After being limited in his research of the RHT by the technology at the time, Moore decided to test the SCN’s role in circadian rhythms by using a biochemical assay to show the effects of SCN ablation on corticosterone rhythms.
The timeless gene is an essential component of the molecular circadian clock in Drosophila. It acts as part of an autoregulatory feedback loop in conjunction with the period (per) gene product as noted in collaborative studies performed by the labs of Michael W. Young and Amita Sehgal. Further studies by the labs of Young, Sehgal, Charles Weitz, and Michael Rosbash indicated that timeless protein (TIM) and period protein (PER) form a heterodimer that exhibits circadian rhythms in wild type Drosophila. Researchers in Rosbash's lab also showed that tim mRNA levels and TIM protein levels have circadian rhythms that are similar to those of the period (per) mRNA and its product.
But the retina also contains specialized ganglion cells that are directly photosensitive, and project directly to the SCN, where they help in the entrainment (synchronization) of this master circadian clock. These cells contain the photopigment melanopsin and their signals follow a pathway called the retinohypothalamic tract, leading to the SCN. If cells from the SCN are removed and cultured, they maintain their own rhythm in the absence of external cues. The SCN takes the information on the lengths of the day and night from the retina, interprets it, and passes it on to the pineal gland, a tiny structure shaped like a pine cone and located on the epithalamus.
At the same time, Michael W. Young's team reported similar effects of per, and that the gene covers 7.1-kilobase (kb) interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA. They went on to discover the key genes and neurones in Drosophila circadian system, for which Hall, Rosbash and Young received the Nobel Prize in Physiology or Medicine 2017. Joseph Takahashi discovered the first mammalian circadian clock mutation (clockΔ19) using mice in 1994. However, recent studies show that deletion of clock does not lead to a behavioral phenotype (the animals still have normal circadian rhythms), which questions its importance in rhythm generation.
Red and blue light are absorbed through several phytochromes and cryptochromes. One phytochrome, phyA, is the main phytochrome in seedlings grown in the dark but rapidly degrades in light to produce Cry1. Phytochromes B–E are more stable with , the main phytochrome in seedlings grown in the light. The cryptochrome (cry) gene is also a light- sensitive component of the circadian clock and is thought to be involved both as a photoreceptor and as part of the clock's endogenous pacemaker mechanism. Cryptochromes 1–2 (involved in blue–UVA) help to maintain the period length in the clock through a whole range of light conditions.
He also mapped the toc1 gene to chromosome 5. These methods and discoveries were published in and featured on the cover of Science magazine in February 1995. Partially because the initial studies of clock genes were conducted in Drosophila in the 1970s and then in mammals, it was originally thought that the plant circadian clock functioned similarly to the mammalian clock. In mammals, positive and negative regulatory elements act in feedback loops to drive circadian oscillations; namely, Per and Cry genes are activated by positive elements CLOCK and BMAL to produce proteins that, when phosphorylated, act as negative elements to inhibit the CLOCK:BMAL complex from its activating function.
It is also important for energy metabolism as BMAL1 modulates the regulation of hepatic metabolites, the secretion of insulin and proliferation of pancreatic islets, and adipocyte differentiation and lipogenesis. Curiously, global KO of BMAL1 has no effect on food anticipatory activity (FAA) in mice but in BMAL1 deletions in certain regions in the hypothalamus outside the SCN eliminate FAA. Knockout studies have demonstrated that BMAL1 is a key mediator between the circadian clock and the immune system response. By loss of Ccl2 regulation, BMAL1 KO in myeloid cells results in hindered monocyte recruitment, pathogen clearance, and anti-inflammatory response (consistent with the arthropathy phenotype).
This makes it difficult to reset to 24 hours daily, just like it is difficult for people with a rhythm close to 24 hours to try to reset to 25 hours daily. The majority of people with non-24 are totally blind, and the failure of entrainment is explained by an absence of light (photic) input to reset the circadian clock. Their brains may have normal circadian clocks that do not receive input from the eyes about environmental light levels, as the clocks require a functioning retina, optic nerve, and visual processing center. This makes the sleep pattern variable from one day to the next, with different wake-up time and bedtime everyday.
Kay's research on intercellular networks has the potential to contribute to drug therapies by identifying compounds that affect the circadian pathways. His findings and analyses of this mammalian oscillator contribute to our medical understanding of how the clock controls downstream processes and holds clinical significance as a variety of diseases and biological processes are involved, such as aging, immune response, and metabolism. For instance, diabetes and the circadian clock may correlate based on the findings of circadian expression in the liver and glucose output. Using a cell-cased circadian phenotypic screen, Kay and a team of chronobiologist researchers identified a small molecule, KL001, that interacts with cryptochrome to prevent ubiquitin-dependent degradation, which results in a longer circadian period.
For the adaptation of cyanobacteria, circadian clock genes exhibit forms of significant importance since they regulate fundamental physical processes such as regulation of nitrogen fixation, cell division, and photosynthesis. Early KaiA research was conducted in the 1998 research article, “Expression of a Gene Cluster kaiABC as a Circadian Feedback Process in Cyanobacteria,” where it details the functions of the gene cluster and KaiA in that it sustains the oscillations by enhancing Kai C expression. KaiA was discovered while studying the clock mutations in Synechococcus by using bacteria luciferase as a reporter on clock controlled gene expression. This was the first instance where scientists first proposed a mechanism and a naming system for KaiA and the kaiABC gene cluster.
The Kai proteins that comprise the PTO generate a circadian clock of oscillating phosphorylation/dephosphorylation with a period of around 24 hours. The KaiC protein is an enzyme with two specific phosphorylation sites, Threonine 432 and Serine 431, which express rhythmicity in phosphorylation/dephosphorylation, depending on KaiA and KaiB activity. KaiA stimulates the phosphorylation of KaiC until KaiB sequesters KaiA, initiating dephosphorylation in a determined sequence on Threonine 432 and Serine 431: KaiA stimulates autophosphorylation by KaiC on Threonine 432, and Serine 431 then follows this mechanism of phosphorylation. When both Threonine 432 and Serine 431 are phosphorylated, KaiB binds to KaiC and this complex, KaiBC, then proceeds to block the effect of KaiA.
A 2007 survey of over 55,000 people found that chronotypes tend to follow a normal distribution, with extreme morning and evening types on the far ends. There are studies that suggest genes determine whether a person is a lark or an evening person in the same way it is implicated in people's attitude toward authority, unconventional behavior, as well as reading and television viewing habits. For instance, there is the case of the Per2 gene on chromosome 2, which was discovered in the early 1990s by Urs Albrecht and colleagues at the University of Fribourg in Switzerland. This gene regulates the circadian clock and a variant of it was found in families that demonstrated advanced sleep-phase syndrome.
Thus, while transcriptional regulation generates rhythmic RNA levels, regulated posttranslational modifications control protein abundance, subcellular localization, and repressor activity of PER and CRY. Proteins responsible for post-translational modification of clock genes include casein kinase family members (casein kinase 1 delta (CSNK1D) and casein kinase 1 epsilon (CSNK1E) and the F-box leucine-rich repeat protein 3 (FBXL3). In mammals, CSNK1E and CSNK1D are critical factors that regulate the core circadian protein turnover. Experimental manipulation on either of these proteins results in dramatic effects on circadian periods, such as altered kinase activities and cause shorter circadian periods, and further demonstrates the importance of the post-translational regulation within the core mechanism of the circadian clock.
Employing multiple doses of siRNA powered their quantitative PCR to uncover several network features of the circadian clock, including proportional responses of gene expression, signal propagation through interacting modules, and compensation through gene expression changes. Proportional responses in downstream gene expression following siRNA-induced perturbation revealed levels of expression that were actively altered with respect to the gene being knocked down. For example, when Bmal1 was knocked down in a dose-dependent manner, Rev-ErbA alpha and Rev-ErbA beta mRNA levels were shown to decrease in a linear, proportional manner. This supported previous findings that Bmal1 directly activates Rev-erb genes and further suggests Bmal1 as a strong contributor to Rev-erb expression.
While neural processing may occur in the monarch's brain, research indicates that the actual circadian clock underlying the migratory patterns is located in the butterfly's antennae. Butterflies with their antennae removed showed no consistent group orientation in their migratory patterns: first exposed to a consistent light-dark cycle prior to release, antennae-less monarchs would show consistent individual directional flight, but no clear cardinal directionality as a group, unlike intact monarchs. Painting the antennae black, thereby causing a free running circadian rhythm, led to altered orientation patterns as well. Examination of various genes and proteins involved in circadian rhythms showed that the antennae exhibited their own circadian fluctuations, even when removed from the butterfly and studied in vitro.
These responses help the MT2 receptor accomplish its role in phase shifting the circadian clock by adjusting the sensitivity and availability of the population of MT2 to melatonin. This desensitization and/or internalization is characteristic of many GPCRs. Often, binding of melatonin to MT2 and subsequent desensitization can lead to the internalization of that receptor which decreases the availability of membrane bound melatonin receptor which will prevent additional melatonin from having as robust of an effect as the initial application. Since there are regular rhythms in both of these receptor subtypes, the internalization and resulting decrease in receptor availability following administration of typical levels of melatonin will effectively shift the phase of this rhythm in MT2.
In addition to researching post- translation modifications of clock proteins, Kramer has also studied the function of the circadian clock in the immune system. He has shown how TNF-α and IL-6 secretion by lipopolysaccharide (LPS)-stimulated murine splenic macrophages display circadian rhythms that are not dependent on either variations in glucocorticoid concentrations or the circadian changes that occur in the cellular constitution of the spleen. This exhibits how the molecular clock in immune cells can remain functional regardless of systemic cues. Kramer was also able to show that approximately 8% of the macrophage transcriptome in mice exhibits circadian oscillation, including genes (such as JUN and FOS) that are involved in LPS-induced responses.
In 1971, Ron Konopka, a geneticist at the California Institute of Technology, discovered the Period gene, which he found to be involved in the circadian clock of Drosophila. In 1999, Paul Hardin discovered that per mRNA underwent strong circadian oscillations by exposing isolated wild-type per mRNA to a series of light-dark (LD) cycles followed by cycles of constant darkness (DD). As a post-doctorate in the lab of chronobiologist Dr. Michael Rosbash, Hardin specifically noted that per mRNA levels in Drosophila brains fluctuate about 10-fold in a typical 24-hour light-dark cycle. Hardin further demonstrated that wild-type protein, PER, can rescue rhythmicity in the mRNA of an arrhythmic mutant of the per gene.
Schwartz has also researched the effect of social forces on circadian rhythms. His research, conducted with Matthew J. Paul ad Premananda Indic suggests that cohabitation affects the onset of rhythmicity in hamsters, and that changing the speed of the circadian clock is one mechanism by which social factors could alter daily rhythms. In a 2013 paper co-authored with Guy Bloch, Erik D. Herzog and Joel D. Levine, Schwartz shows that social cues may be critical to the adaptive function of circadian rhythms, and can affect them from colony, to organismal, to cellular levels. As of 2017, Schwartz is not running a research lab as he is helping with education at Dell Medical School, University of Texas at Austin.
After joining the faculty of the Giesel School of Medicine, Loros continued her post-doc research into the regulation of messenger RNA by circadian clocks. Through sequential rounds of subtractive hybridization, Loros found 2 such genes that are responsible for transcription in morning specific cultures of Neurospora. Loros named these two, unlinked, genes ccg-1 and ccg-2, with the initialisms standing for clock-controlled genes, a term which, now prevalent in the circadian clock dialogue, Loros claims to have coined herself. Moreover, her work on the negative feedback loop involved in the FRQ pathway demonstrated that the phosphorylation of negative elements of the clock are not as important in controlling the period as once thought.
Hastings’ PhD work introduced him to biological clocks, in the context of tidal and semi-lunar rhythms in the marine isopod crustacean Eurydice pulchra (Leach). With a post- doctoral position in Cambridge (Department of Anatomy, supervisor Joe Herbert) he moved into seasonal time-keeping in mammals with a focus on the role of the pineal gland and its hormone melatonin in photoperiodic regulation of reproduction and metabolism. In 1984 he was appointed to a junior lectureship, receiving tenure in 1988 and a readership in neuroscience in 1998. In this time he developed a research programme into the cellular actions of melatonin in the brain, and the neurochemistry of the central circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus.
In relation to this work, Rogulja explores how sensory information guides the circadian clock to drive specific behaviors at certain times of day. Lastly, Rogulja collaborates extensively with the Crickmore Lab, lead by Michael Crickmore at Harvard, to explore motivated states that drive behavior in animal models, with a specific focus on how sexual behavior is calibrated by internal states. In 2016, Rogulja gave a TEDX Talk in Boston describing the importance of basic science research to understand fundamental mechanisms governing sleep and how our increased exposure to light and dysregulated sleep-wake schedules due to globalization and travel affect our biology. One facet of Rogulja's lab explores the neural mechanisms governing mating behavior in drosophila.
Communication of these units is required to match their release of clock proteins which begin a transcription cascade of many other proteins that produce functional responses in tissues. The cyclic pattern of these responses is due to the feedback of the clock proteins and consequent changes to this transcription cascade. Reduced Lim-1 expression leads to inadequate levels of proteins such as Vasoactive Intestinal Polypeptide (VIP) that work to produce the neuron coordination required for a regulated circadian rhythm. The lack of such coupling factors causes the circadian clock to not function properly because the units within the SCN cannot match their release of clock proteins, and therefore their transcriptional cascades of proteins that cause changes in arousal do not align.
Based on this Cab:luc fusion technology, Kay set up luciferase imaging assays for large scale forward genetics screening and identified the first short period mutant of TOC1 gene. TOC1 was proved to be a core clock gene in Arabidopsis and was cloned by Kay lab after a long period of time Kay also revealed the biochemical function of TOC1 and found that TOC1 and LHY/CCA1 reciprocally regulate each other, and further studied the mechanism of this regulation. Kay identified ELF3, GI, Lux, CHE and PRRs as core clock genes and studied their role in the circadian regulation loop. He also profiled clock controlled genes (ccg) in Arabidopsis with several technologies and identified key pathways temporally controlled by circadian clock.
Although light pulses do not entrain, full photoperiod LD cycles can still drive cycling in the ventral-lateral neurons in the Drosophila brain. These data along with other results suggest that CRY is the cell-autonomous photoreceptor for body clocks in Drosophila and may play a role in nonparametric entrainment (entrainment by short discrete light pulses). However, the lateral neurons receive light information through both the blue light CRY pathway and the rhodopsin pathway. Therefore, CRY is involved in light perception and is an input to the circadian clock, however it is not the only input for light information, as a sustained rhythm has been shown in the absence of the CRY pathway, in which it is believed that the rhodopsin pathway is providing some light input.
This indicated that some blind humans can entrain to light through non-visual photoreceptors (2007). Czeisler found that intrinsically photosensitive retinal ganglion cells (ipRGCs) influence both the circadian clock and visual perception, indicating that ipRGCs contribute to “visual” light perception even in the absence of rod and cone photoreceptors. Significantly, this challenged the misconception that rod and cone photoreceptors were the sole receptors for photo-entrainment in humans. In 2002, Czeisler published a study that defended the long-held notion that mammals do not have extra-occular photoreceptors. The findings of his study definitively refute those of the famous 1998 Science publication, “Extraocular Circadian Phototransduction in Humans,” which found that bright light behind the knees can help regulated human circadian photoentrainment.
In mutant breeds of mice that lacked only rods, only cones, or both rods and cones, all breeds of mice still entrained to changing light stimuli in the environment, but with a limited response, suggesting that rods and cones are not necessary for circadian photoentrainment and that the mammalian eye must have another photopigment required for the regulation of the circadian clock. Melanopsin-knockout mice display reduced photoentrainment. In comparison to wild-type mice that expressed melanopsin normally, deficits in light-induced phase shifts in locomotion activity were noted in melanopsin- null mice (Opn4 -/-). These melanopsin-deficient mice did not completely lose their circadian rhythms, as they were still able to entrain to changing environmental stimuli, albeit more slowly than normal.
Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in Alzheimer's disease, type 2 diabetes mellitus (T2DM), some forms of cancer, and bipolar disorder. It has now been shown that lithium, which is used as a treatment for bipolar disorder, acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition stabilizes mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect. Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock.
In 2008, Truman went on to discover that eclosion rhythms, which are mediated by the circadian release of the neurohormone EH, can be masked. In chronobiology, masking refers to the apparent coupling of an observable biological rhythm with an external environmental time cue, without affecting the underlying circadian clock that mediates the observed rhythm. Truman and colleagues observed increased eclosion in adult Drosophila flies immediately following a lights-on signal, which lead to their subsequent discovery that light triggers rapid eclosion in Drosophila on the condition that there was prior EH release. This occurs through the convergence of parallel neurosecretory pathways, both of which are activated by EH. These two EH activated pathways oppose each other; one is an excitatory behavioral pathway and one is inhibitory.
Given that CREB has been shown to regulate c-fos transcription in PC12 pheochromocytoma cells, Takahashi and Greenberg were able to conclude that phosphorylation of CREB in the SCN may play an important role in mammalian photic entrainment. After the in vitro research on the pineal gland culture system used to understand circadian oscillations, the limitations of the cell culture system were evident and Takahashi switched methods to begin using forward genetics and positional cloning—tools which required no advanced knowledge of the underlying mechanism—to understand the genetic and molecular bases of circadian rhythms. Using mutated mouse strains, Takahashi and his colleagues isolated strains with abnormal period length and discovered the clock gene in 1994. They cloned the mammalian circadian clock gene in 1997.
Using mutagenesis screens (forward genetics) found both the clock mutant mouse and the tau mutant hamster. Takahashi's lab has continued use of this method in order to lead to discoveries of the role of the circadian clock in vision, learning, memory, stress, and addiction, among other behavioral properties. In 2007, Takahashi and his colleagues at Northwestern ran a forward mutagenesis screen in mice looking for variations in circadian oscillations and subsequently identified a mutant which they named overtime (Ovtm). Using positional cloning, genetic complementation, and in-situ hybridization Takahashi and colleagues discovered that Ovtm was a point mutation that caused a loss of function in FBXL3 – an F-box protein – and was expressed throughout the brain and in the SCN.
One postsynaptic target of ipRGCs is the suprachiasmatic nucleus (SCN) of the hypothalamus, which serves as the circadian clock in an organism. ipRGCs release both pituitary adenylyl cyclase-activating protein (PACAP) and glutamate onto the SCN via a monosynaptic connection called the retinohypothalamic tract (RHT). Glutamate has an excitatory effect on SCN neurons, and PACAP appears to enhance the effects of glutamate in the hypothalamus. Other post synaptic targets of ipRGCs include: the intergenticulate leaflet (IGL), a cluster of neurons located in the thalamus, which play a role in circadian entrainment; the olivary pretectal nucleus (OPN), a cluster of neurons in the midbrain that controls the pupillary light reflex; the ventrolateral preoptic nucleus (VLPO), located in the hypothalamus and is a control center for sleep; the amygdala.
From 1998–2000, Huberman worked in the laboratory of Irving Zucker and with Marc Breedlove, at University of California, Berkeley, as part of a team that defined how early androgen exposure impacts development, and he performed the first experiments defining the structure of binocular visual pathways that set the circadian clock in the hypothalamus. From 2000-2004, working as a Ph.D. student in the laboratory of Barbara Chapman at the Center for Neuroscience at the University of California, Davis, he discovered that neural activity and axon guidance molecules work in concert to ensure proper wiring of binocular maps in the brain. Huberman was a Helen Hay Whitney Postdoctoral Fellow researcher in the laboratory of Ben A. Barres from 2005-2010.
A sleep diary with nighttime in the middle and the weekend in the middle, to notice trends like gradually shifting nighttime Non-24-hour sleep–wake disorder is diagnosed when the patient fails to follow (entrain to) a 24-hour light-dark cycle and clock times. As such, the entrainment status (defined as whether the hypothalamic circadian clock is synchronized to a 24-hour day) physiologically defines this disorder and can thus be used as the sole outcome measure. This is similar to elevated blood pressure characterizing essential hypertension. In contrast to other circadian rhythm sleep disorders (CRSD), a diagnosis of non-24-hour sleep-wake disorder requires the documentation of progressive shifting of the sleep-wake times over at least 14 days using sleep diaries and/or actigraphy.
ERRα regulates genes involved in mitochondrial biogenesis, gluconeogenesis, oxidative phosphorylation, and fatty acid metabolism, and brown adipose tissue thermogenesis. It was recently identified as an important regulator of the mammalian circadian clock, and its output pathways at both transcriptional and physiological levels regulated the expression of transcription factors involved in metabolic homeostasis. It has been demonstrated that ERRα is required for the maintenance of diurnal cholesterol, glucose, insulin, bile acid, and trygliceride levels as well as locomotor rhythms in mice. ERRα is related to mitochondrial function but studies involving ERRα knockout mice suggested that this receptor, while dispensable for basal cellular function, is definitely necessary to provide the levels of energy necessary to respond to physiological and pathological insults in diverse tissues, the lack of that nuclear receptor leading to impaired fat metabolism and absorption.
In vertebrates, the master circadian clock is contained within the suprachiasmatic nucleus (SCN), a bilateral nerve cluster of about 20,000 neurons. The SCN itself is located in the hypothalamus, a small region of the brain situated directly above the optic chiasm, where it receives input from specialized photosensitive ganglion cells in the retina via the retinohypothalamic tract. The SCN maintains control across the body by synchronizing "slave oscillators", which exhibit their own near-24-hour rhythms and control circadian phenomena in local tissue. Through intercellular signalling mechanisms such as vasoactive intestinal peptide, the SCN signals other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and melatonin; these hormones enter the circulatory system, and induce clock-driven effects throughout the organism.
No significant similarity was found among the kai genes and any other previously reported genes in eukaryotes, but there are potential homologs in the genomic sequences of other bacteria (both eubacteria and archaea). At first, the cyanobacterial clockwork appeared to be a transcription and translation feedback loop in which clock proteins autoregulate the activity of their own promoters by a process that was similar in concept to the circadian clock loops of eukaryotes.> Subsequently, however, several lines of evidence indicated that transcription and translation was not necessary for circadian rhythms of Kai proteins, the most spectacular being that the three purified Kai proteins can reconstitute a temperature- compensated circadian oscillation in a test tube. The rhythm that is measurable in vitro is the phosphorylation status of the clock protein KaiC.
In work published not long before Feldman arrived at CalTech, Malcolm L. Sargent, Winslow R. Briggs and Dow O. Woodward at Stanford University reported that overt expression of the developmental rhythm in conidiation was enhanced in a strain of Neurospora called Timex. (This strain contained a mutation in the locus band (bd), later shown to encode a mildly hyperactive allele of ras-1 so strains are now known as ras-1[bd]. Because rhythms in strains that include ras-1[bd] are easier to detect, ras-1[bd] is often incorporated into strains used for studies of circadian biology in Neurospora.). Outputs of the Neurospora circadian clock include carotenoid synthesis as well as the asexual spore formation seen on race tubes, and recent evidence suggests that thousands of genes are under circadian control.
Hekkens W, Th JM, Jerkhof GA and Rhietveld WJ, Pergamon Press, Oxford and New York, pp. 149–161, 1988 Parametric entrainment is entrainment that does not result from an instant change in phase, as governed by a Phase Response Curve, as in the case of masking signals. The term Aschoff used for this phenomenon is “arousal” due to non-photic zeitgebers. Data from experimental assays show a relationship between masking effects and phase, leading to a “demasking” effect whereby animals arrhythmic in constant conditions have free-running periods in high frequency light-dark cycles. Aschoff concluded that the oscillator or circadian clock “integrates” over the intensity of light to which it has been exposed, and then responds with a change in the period of activity, as seen in greenfinches, chaffinches, hamsters, and siskins.
Since the SCN is responsible for mediating the production of melatonin by the pineal gland, it creates a feedback loop that regulates the production of melatonin according to the master circadian clock. As was discussed previously, the MT1 receptor is largely thought of as the major player in sleep-promotion and the MT2 receptor is most strongly linked to phase shifting activity. Both major subtypes of the melatonin receptor are expressed in relatively large amounts in the SCN which allow it to both regulate sleep-wake cycles and induce phase shifting in response to natural light-dark cycles. This functional diversity of melatonin receptors helps give the SCN the ability to not only keep near 24-hour time and entrain to an exactly 24-hour period, but also regulate, among other factors, wakefulness and activity throughout this cycle.
Multiple labs identified the PRR genes as parts of the circadian clock in the 1990s. In 2000, Akinori Matsushika, Seiya Makino, Masaya Kojima, and Takeshi Mizuno were the first to understand PRR genes as pseudo-response repressor genes rather than as response regulator (ARR) genes. The factor that distinguishes PRR from ARR genes is the lack of a phospho-accepting aspartate site that characterizes ARR proteins. Though their research that discovered PRR genes was primarily hailed during the early 2000s as informing the scientific community about the function of TOC1 (named APRR1 by the Mizuno lab), an additional pseudo-response regulator in the Arabidopsis thaliana biological clock, the information about PRR genes that Matsushika and his team found deepened scientific understanding of circadian clocks in plants and led other researchers to hypothesize about the purpose of the PRR genes.
The photoreceptors involved in the synchronisation of the circadian clock to the external light-dark cycle are located in the brain and can be stimulated by light reaching them directly though the skull, as revealed by experiments in which blind sparrows, which normally can still synchronise to the light- dark cycle, failed to do so once India ink was injected as a screen under the skin on top of their skulls. Similarly, even when blind, house sparrows continue to be photoperiodic, i.e. show reproductive development when the days are long, but not when the days are short. This response is stronger when the feathers on top of the head are plucked, and is eliminated when India ink is injected under the skin at the top of the head, showing that the photoreceptors involved in the photoperiodic response to day length are located inside the brain.
Brown developed statistical methods to characterize the properties of the human circadian system (biological clock) from core temperature data recorded under the constant routine and free-running and forced desynchrony protocols. Through the early part of his career, Brown collaborated with circadian researchers to apply his methods to answer fundamental research questions in circadian physiology. Brown’s statistical methods were critical for: estimating accurately the period and internal time on human circadian clocks from continuous core temperature measurement; showing that bright lights could be used to shift the phase of the human circadian clock; properly timed administration of light and dark periods could be used to realign the internal clocks of shift workers with external time; and that, contrary to beliefs at the time, the period of the human biological clock, like that of other animals, was closer to 24 hours rather than 25 hours.
Elements of the circadian clock may be connected with predisposition to bipolar mood disorder. GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of amyloid-β (Aβ) deposits and the formation of neurofibrillary tangles. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the hyperphosphorylation of tau proteins, which leads to the tangles. Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing. In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote apoptosis in some cases, it has also been reported to be a key factor in tumorigenesis in some cancers. Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.
Dr. Chen is known for his pioneering work on defining genomic and epigenetic changes in plant hybrids and polyploids with an emphasis on associating gene expression variation with phenotypic traits using Arabidopsis, cotton, and corn as experimental systems. He and his colleagues have discovered that epigenetic mechanisms drive genome-wide nonadditive expression of the genes in different regulatory pathways, including circadian clock genes that promote growth vigor, transcription factor genes that control fiber cell development, and genes and small RNAs that mediate seed size. Chen has led an international effort to sequence the tetraploid genome of Upland cotton that accounts for 90% of the cotton produced worldwide, providing a unique resource for cotton improvement using breeding and biotechnology. His research findings have significant implications, not only for advancing the field of genetics and epigenetics, but also for successful applications of biotechnology to safely and effectively manipulate gene expression associated with growth vigor in plants and crops that produce food, feed, and biomaterials.
TOC1 binds to the G-box and EE-motif promoter regions of genes involved in both the morning and evening transcription- translation feedback loops that drive the plant circadian clock; these genes include PRR7 and 9, CCA1, and LHY in the morning feedback loop and GI and ELF4 in the evening loop. Discrete induction of TOC1 gene expression results in reduced CCA1 and PRR9 expression, indicating that TOC1 plays a repressive rather than stimulatory role in regulating circadian gene expression. Repression of morning loop genes lhy and cca1 was predicted by computational modeling and was the piece of evidence needed to re-define toc1's role in the plant clock as part of a triple negative-component repressilator model rather than a positive/negative-element system of the sort seen in mammals. The binding pattern of TOC1's CCT domain exhibits circadian oscillations, with maximum binding to G-box and EE motifs—promoter regions that bind transcription factors—occurring at CT15 in the plant's early subjective night.
UK Team Leader: Professor Tony James, University of Bath Japan Team Leader: Professor Seiji Shinkai, Kyushu University Circadian regulation of photosynthesis: discovering mechanisms that connect the circadian clock with photosynthesis in chloroplasts in order to understand how circadian and environmental signals optimise photosynthesis and plant productivity. Institutions: University of Bristol, University of Edinburgh, Chiba University and Tokyo Institute of Technology. UK Team Leader: Dr Antony Dodd, University of Bristol Japan Team Leader: Dr Mitsumasa Hanaoka, Chiba University Exploration of active functionality in abundant oxide materials utilising unique nanostructure: discovering novel properties in traditional materials and addressing the limited availability of technologically important elements through curiosity-driven research. Institutions: University College London and Tokyo Institute of Technology UK Team Leader: Professor Alexander Shluger, University College London Japan Team Leader: Professor Hideo Hosono, Tokyo Institute of Technology Extension of terrestrial radiocarbon age calibration curve using annually laminated sediment core from Lake Suigetsu, Japan – establishing a reliable calibration for radiocarbon dates thus considerably improving the accuracy of the age determination.
A thermographic image of an ectothermic snake wrapping around the hand of an endothermic human Information about the direct neuronal regulation of metabolic processes and circadian rhythm-controlled behaviors is not well known among either endothermic or ectothermic vertebrates, although extensive research has been done on the SCN in model animals such as the mammalian mouse and ectothermic reptiles, in particular, lizards. The SCN is known to be involved not only in photoreception through innervation from the retinohypothalamic tract but also in thermoregulation of vertebrates capable of homeothermy, as well as regulating locomotion and other behavioral outputs of the circadian clock within ectothermic vertebrates. The behavioral differences between both classes of vertebrates, when compared to the respective structures and properties of the SCN and various other nuclei proximate to the hypothalamus, provide insight into how these behaviors are the consequence of differing circadian regulation. Ultimately, many neuroethological studies must be done to completely ascertain the direct and indirect roles of the SCN on circadian- regulated behaviors of vertebrates.
In general, external temperature does not influence endothermic animal behavior or circadian rhythm because of the ability of these animals to keep their internal body temperature constant through homeostatic thermoregulation; however, peripheral oscillators (see Circadian rhythm) in mammals are sensitive to temperature pulses and will experience resetting of the circadian clock phase and associated genetic expression, suggesting how peripheral circadian oscillators may be separate entities from one another despite having a master oscillator within the SCN. Furthermore, when individual neurons of the SCN from a mouse were treated with heat pulses, a similar resetting of oscillators was observed, but when an intact SCN was treated with the same heat pulse treatment the SCN was resistant to temperature change by exhibiting an unaltered circadian oscillating phase. In ectothermic animals, particularly the ruin lizard Podacris sicula, temperature has been shown to affect the circadian oscillators within the SCN. This reflects a potential evolutionary relationship among endothermic and ectothermic vertebrates, in how ectotherms rely on environmental temperature to affect their circadian rhythms and behavior and endotherms have an evolved SCN to essentially ignore external temperature and use photoreception as a means for entraining the circadian oscillators within their SCN.
The general focus of the Green Lab is to understand the molecular mechanism of the mammalian circadian clock and how it mediates rhythmicity within the physiology, biochemistry, and behavior of an organism. Her lab currently has three main projects: identifying targets and mechanisms of expression regulation of the Nocturnin gene; identifying the mechanism of metabolic control of Nocturnin knockout lean mice; and defining structural components of the repressor protein Cryptochrome and how regulation of the nuclear entry of the protein contributes to circadian period length. Green has formal training in cell biology, biochemistry, and molecular biology, which has given her a broad skill set to further expand her areas of study such as genomics, proteomics, structural biology, and metabolic studies over the course of her career. Aside from her scientific focuses, she also contributes to the greater science community. At the June 23–28, 2019 Gordon Research Conference, “Clocks in Model Organisms: Circadian Networks, Physiology and Health,” she is organizing the “GRC Power Hour,” a panel designed to promote diversity and inclusion for women and minorities in the STEM field as well as encourage the professional growth of all members from all communities by providing a space for discussion and mentorship.

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