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Mystery Solved with Math: Cytoplasmic Traffic Jam Disrupts Sleep-Wake Cycles
KAIST mathematicians and their collaborators at Florida State University have identified the principle of how aging and diseases like dementia and obesity cause sleep disorders. A combination of mathematical modelling and experiments demonstrated that the cytoplasmic congestion caused by aging, dementia, and/or obesity disrupts the circadian rhythms in the human body and leads to irregular sleep-wake cycles. This finding suggests new treatment strategies for addressing unstable sleep-wake cycles. Human bodies adjust sleep schedules in accordance with the ‘circadian rhythms’, which are regulated by our time keeping system, the ‘circadian clock’. This clock tells our body when to rest by generating the 24-hour rhythms of a protein called PERIOD (PER) (See Figure 1). The amount of the PER protein increases for half of the day and then decreases for the remaining half. The principle is that the PER protein accumulating in the cytoplasm for several hours enters the cell nucleus all at once, hindering the transcription of PER genes and thereby reducing the amount of PER. However, it has remained a mystery how thousands of PER molecules can simultaneously enter into the nucleus in a complex cell environment where a variety of materials co-exist and can interfere with the motion of PER. This would be like finding a way for thousands of employees from all over New York City to enter an office building at the same time every day. A group of researchers led by Professor Jae Kyoung Kim from the KAIST Department of Mathematical Sciences solved the mystery by developing a spatiotemporal and probabilistic model that describes the motion of PER molecules in a cell environment. This study was conducted in collaboration with Professor Choogon Lee’s group from Florida State University, where the experiments were carried out, and the results were published in the Proceedings of the National Academy of Sciences (PNAS) last month. The joint research team’s spatial stochastic model (See Figure 2) described the motion of PER molecules in cells and demonstrated that the PER molecule should be sufficiently condensed around the cell nucleus to be phosphorylated simultaneously and enter the nucleus together (See Figure 3 Left). Thanks to this phosphorylation synchronization switch, thousands of PER molecules can enter the nucleus at the same time every day and maintain stable circadian rhythms. However, when aging and/or diseases including dementia and obesity cause the cytoplasm to become congested with increased cytoplasmic obstacles such as protein aggregates and fat vacuoles, it hinders the timely condensation of PER molecules around the cell nucleus (See Figure 3 Right). As a result, the phosphorylation synchronization switch does not work and PER proteins enter into the nucleus at irregular times, making the circadian rhythms and sleep-wake cycles unstable, the study revealed. Professor Kim said, “As a mathematician, I am excited to help enable the advancement of new treatment strategies that can improve the lives of so many patients who suffer from irregular sleep-wake cycles. Taking these findings as an opportunity, I hope to see more active interchanges of ideas and collaboration between mathematical and biological sciences.” This work was supported by the National Institutes of Health and the National Science Foundation in the US, and the International Human Frontiers Science Program Organization and the National Research Foundation of Korea. Publication: Beesley, S. and Kim, D. W, et al. (2020) Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis. Proceedings of the National Academy of Sciences (PNAS), Vol. 117, No. 45, 28402-28411. Available online at https://doi.org/10.1073/pnas.2003524117 Profile: Jae Kyoung Kim, Ph.D. Associate Professor firstname.lastname@example.org http://mathsci.kaist.ac.kr/~jaekkim @umichkim on Twitter Department of Mathematical Sciences Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea Profile: Choogon Lee, Ph.D. Associate Professor email@example.com https://med.fsu.edu/biosci/lee-lab Department of Biomedical Sciences Florida State University Florida, USA (END)
KAIST Professor Finds Paradox in Human Behaviors on Road
-Strange as it might seem, closing roads can cut delays A new route opened to ease traffic jam, but commuting time has not been reduced.Conversely, motorists reached their destinations in shorter times after a big street was closed. These paradoxical phenomena are the result of human selfishness, according to recent findings of a research team led by a KAIST physics professor. Prof. Ha-Woong Jeong, 40, at the Department of Physics, conducted a joint research with a team from Santa Fe Institute of the U.S. to analyze the behaviors of drivers in Boston, New York and London. Their study found that when individual drivers, fed with traffic information via various kinds of media, try to choose the quickest route, it can cause delays for others and even worsen congestion. Prof. Jeong and his group"s study will be published in the Sept. 18 edition of the authoritative Physical Review Letters. The London-based Economist magazine introduced Prof. Jeong"s finding in its latest edition. Prof. Jeong, a pioneer in the study of "complex system," has published more than 70 research papers in the world"s leading science journals, including Nature, PNAS and Physical Review Letters. "Initially, my study was to reduce annoyance from traffic jam during rush hours," Prof. Jeong said. "Ultimately, it is purposed to eliminate inefficiency located in various corners of social activities, with the help of the network science." The Economist article read (in part): "...when individual drivers each try to choose the quickest route it can cause delays for others and even increase hold-ups in the entire road network. "The physicists give a simplified example of how this can happen: trying to reach a destination either by using a short but narrow bridge or a longer but wide motorway. In their hypothetical case, the combined travel time of all the drivers is minimized if half use the bridge and half the motorway. But that is not what happens. Some drivers will switch to the bridge to shorten their commute, but as the traffic builds up there the motorway starts to look like a better bet, so some switch back. Eventually the traffic flow on the two routes settles into what game theory calls a Nash equilibrium, named after John Nash, the mathematician who described it. This is the point where no individual driver could arrive any faster by switching routes. "The researchers looked at how this equilibrium could arise if travelling across Boston from Harvard Square to Boston Common. They analysed 246 different links in the road network that could be used for the journey and calculated traffic flows at different volumes to produce what they call a “price of anarchy” (POA). This is the ratio of the total cost of the Nash equilibrium to the total cost of an optimal traffic flow directed by an omniscient traffic controller. In Boston they found that at high traffic levels drivers face a POA which results in journey times 30% longer than if motorists were co-ordinated into an optimal traffic flow. Much the same thing was found in London (a POA of up to 24% for journeys between Borough and Farringdon Underground stations) and New York (a POA of up to 28% from Washington Market Park to Queens Midtown Tunnel). "Modifying the road network could reduce delays. And contrary to popular belief, a simple way to do that might be to close certain roads. This is known as Braess’s paradox, after another mathematician, Dietrich Braess, who found that adding extra capacity to a network can sometimes reduce its overall efficiency. "In Boston the group looked to see if the paradox could be created by closing any of the 246 links. In 240 cases their analysis showed that a closure increased traffic problems. But closing any one of the remaining six streets reduced the POA of the new Nash equilibrium. Much the same thing was found in London and New York. More work needs to be done to understand these effects, say the researchers. But even so, planners should note that there is now evidence that even a well intentioned new road may make traffic jams worse."
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