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Accurate Detection of Low-Level Somatic Mutation in Intractable Epilepsy
KAIST medical scientists have developed an advanced method for perfectly detecting low-level somatic mutation in patients with intractable epilepsy. Their study showed that deep sequencing replicates of major focal epilepsy genes accurately and efficiently identified low-level somatic mutations in intractable epilepsy.
According to the study, their diagnostic method could increase the accuracy up to 100%, unlike the conventional sequencing analysis, which stands at about 30% accuracy. This work was published in Acta Neuropathologica.
Epilepsy is a neurological disorder common in children. Approximately one third of child patients are diagnosed with intractable epilepsy despite adequate anti-epileptic medication treatment.
Somatic mutations in mTOR pathway genes, SLC35A2, and BRAF are the major genetic causes of intractable epilepsies. A clinical trial to target Focal Cortical Dysplasia type II (FCDII), the mTOR inhibitor is underway at Severance Hospital, their collaborator in Seoul, Korea. However, it is difficult to detect such somatic mutations causing intractable epilepsy because their mutational burden is less than 5%, which is similar to the level of sequencing artifacts. In the clinical field, this has remained a standing challenge for the genetic diagnosis of somatic mutations in intractable epilepsy.
Professor Jeong Ho Lee’s team at the Graduate School of Medical Science and Engineering analyzed paired brain and peripheral tissues from 232 intractable epilepsy patients with various brain pathologies at Severance Hospital using deep sequencing and extracted the major focal epilepsy genes.
They narrowed down target genes to eight major focal epilepsy genes, eliminating almost all of the false positive calls using deep targeted sequencing. As a result, the advanced method robustly increased the accuracy and enabled them to detect low-level somatic mutations in unmatched Formalin Fixed Paraffin Embedded (FFPE) brain samples, the most clinically relevant samples.
Professor Lee conducted this study in collaboration with Professor Dong Suk Kim and Hoon-Chul Kang at Severance Hospital of Yonsei University. He said, “This advanced method of genetic analysis will improve overall patient care by providing more comprehensive genetic counseling and informing decisions on alternative treatments.”
Professor Lee has investigated low-level somatic mutations arising in the brain for a decade. He is developing innovative diagnostics and therapeutics for untreatable brain disorders including intractable epilepsy and glioblastoma at a tech-startup called SoVarGen. “All of the technologies we used during the research were transferred to the company. This research gave us very good momentum to reach the next phase of our startup,” he remarked.
The work was supported by grants from the Suh Kyungbae Foundation, a National Research Foundation of Korea grant funded by the Ministry of Science and ICT, the Korean Health Technology R&D Project from the Ministry of Health & Welfare, and the Netherlands Organization for Health Research and Development.
(Figure: Landscape of somatic and germline mutations identified in intractable epilepsy patients. a Signaling pathways for all of the mutated genes identified in this study. Bold: somatic mutation, Regular: germline mutation. b The distribution of variant allelic frequencies (VAFs) of identified somatic mutations. c The detecting rate and types of identified mutations according to histopathology. Yellow: somatic mutations, green: two-hit mutations, grey: germline mutations.)
2019.08.14 View 27006 -
Enhanced Natural Gas Storage to Help Reduce Global Warming
< Professor Atilhan (left) and Professor Yavuz (right) >
Researchers have designed plastic-based materials that can store natural gas more effectively. These new materials can not only make large-scale, cost-effective, and safe natural gas storage possible, but further hold a strong promise for combating global warming.
Natural gas (predominantly methane) is a clean energy alternative. It is stored by compression, liquefaction, or adsorption. Among these, adsorbed natural gas (ANG) storage is a more efficient, cheaper, and safer alternative to conventional compressed natural gas (CNG) and liquefied natural gas (LNG) storage approaches that have drawbacks such as low storage efficiency, high costs, and safety concerns. However, developing adsorptive materials that can more fully exploit the advantages of ANG storage has remained a challenging task.
A KAIST research team led by Professor Cafer T. Yavuz from the Graduate School of Energy, Environment, Water, and Sustainability (EEWS), in collaboration with Professor Mert Atilhan’s group from Texas A&M University, synthesized 29 unique porous polymeric structures with inherent flexibility, and tested their methane gas uptake capacity at high pressures. These porous polymers had varying synthetic complexities, porosities, and morphologies, and the researchers subjected each porous polymer to pure methane gas under various conditions to study the ANG performances.
Of these 29 distinct chemical structures, COP-150 was particularly noteworthy as it achieved a high deliverable gravimetric methane working capacity when cycled between 5 and 100 bar at 273 K, which is 98% of the total uptake capacity. This result surpassed the target set by the United States Department of Energy (US DOE).
COP-150 is the first ever structure to fulfil both the gravimetric and volumetric requirements of the US DOE for successful vehicular use, and the total cost to produce the COP-150 adsorbent was only 1 USD per kilogram.
COP-150 can be produced using freely available and easily accessible plastic materials, and moreover, its synthesis takes place at room temperature, open to the air, and no previous purification of the chemicals is required. The pressure-triggered flexible structure of COP-150 is also advantageous in terms of the total working capacity of deliverable methane for real applications.
The research team believed that the increased pressure flexes the network structure of COP-150 showing “swelling” behavior, and suggested that the flexibility provides rapid desorption and thermal management, while the hydrophobicity and the nature of the covalently bonded framework allow these promising materials to tolerate harsh conditions.
This swelling mechanism of expansion-contraction solves two other major issues, the team noted. Firstly, when using adsorbents based on such a mechanism, unsafe pressure spikes that may occur due to temperature swings can be eliminated. In addition, contamination can also be minimized, since the adsorbent remains contracted when no gas is stored.
Professor Yavuz said, “We envision a whole host of new designs and mechanisms to be developed based on our concept. Since natural gas is a much cleaner fuel than coal and petroleum, new developments in this realm will help switching to the use of less polluting fuels.”
Professor Atilhan agreed the most important impact of their research is on the environment. “Using natural gas more than coal and petroleum will significantly reduce greenhouse gas emissions. We believe, one day, we might see vehicles equipped with our materials that are run by a cleaner natural gas fuel,” he added.
This study, reported in Nature Energy on July 8, was supported by National Research Foundation of Korea (NRF) grants ( NRF-2016R1A2B4011027, NRF-2017M3A7B4042140, and NRF-2017M3A7B4042235).
< Suggested chemical structure of COP-150 >
< Initial ingredients (left) and final product (right) of COP-150 synthesis >
< Comparison of highest reported volumetric working capacities >
(END)
2019.08.09 View 25614 -
Manipulating Brain Cells by Smartphone
Researchers have developed a soft neural implant that can be wirelessly controlled using a smartphone. It is the first wireless neural device capable of indefinitely delivering multiple drugs and multiple colour lights, which neuroscientists believe can speed up efforts to uncover brain diseases such as Parkinson’s, Alzheimer’s, addiction, depression, and pain.
A team under Professor Jae-Woong Jeong from the School of Electrical Engineering at KAIST and his collaborators have invented a device that can control neural circuits using a tiny brain implant controlled by a smartphone. The device, using Lego-like replaceable drug cartridges and powerful, low-energy Bluetooth, can target specific neurons of interest using drugs and light for prolonged periods. This study was published in Nature Biomedical Engineering.
“This novel device is the fruit of advanced electronics design and powerful micro and nanoscale engineering,” explained Professor Jeong. “We are interested in further developing this technology to make a brain implant for clinical applications.”
This technology significantly overshadows the conventional methods used by neuroscientists, which usually involve rigid metal tubes and optical fibers to deliver drugs and light. Apart from limiting the subject’s movement due to bulky equipment, their relatively rigid structure causes lesions in soft brain tissue over time, therefore making them not suitable for long-term implantation. Although some efforts have been made to partly mitigate adverse tissue response by incorporating soft probes and wireless platforms, the previous solutions were limited by their inability to deliver drugs for long periods of time as well as their bulky and complex control setups.
To achieve chronic wireless drug delivery, scientists had to solve the critical challenge of the exhaustion and evaporation of drugs. To combat this, the researchers invented a neural device with a replaceable drug cartridge, which could allow neuroscientists to study the same brain circuits for several months without worrying about running out of drugs.
These ‘plug-n-play’ drug cartridges were assembled into a brain implant for mice with a soft and ultrathin probe (with the thickness of a human hair), which consisted of microfluidic channels and tiny LEDs (smaller than a grain of salt), for unlimited drug doses and light delivery.
Controlled with an elegant and simple user interface on a smartphone, neuroscientists can easily trigger any specific combination or precise sequencing of light and drug delivery in any implanted target animal without the need to be physically inside the laboratory. Using these wireless neural devices, researchers can also easily setup fully automated animal studies where the behaviour of one animal could affect other animals by triggering light and/or drug delivery.
“The wireless neural device enables chronic chemical and optical neuromodulation that has never been achieved before,” said lead author Raza Qazi, a researcher with KAIST and the University of Colorado Boulder.
This work was supported by grants from the National Research Foundation of Korea, US National Institute of Health, National Institute on Drug Abuse, and Mallinckrodt Professorship.
(A neural implant with replaceable drug cartridges and Bluetooth low-energy can target specific neurons .)
(Micro LED controlling using smartphone application)
2019.08.07 View 30366 -
Synthesizing Single-Crystalline Hexagonal Graphene Quantum Dots
(Figure: Uniformly ordered single-crystalline graphene quantum dots of various sizes synthesized through solution chemistry.)
A KAIST team has designed a novel strategy for synthesizing single-crystalline graphene quantum dots, which emit stable blue light. The research team confirmed that a display made of their synthesized graphene quantum dots successfully emitted blue light with stable electric pressure, reportedly resolving the long-standing challenges of blue light emission in manufactured displays. The study, led by Professor O Ok Park in the Department of Chemical and Biological Engineering, was featured online in Nano Letters on July 5.
Graphene has gained increased attention as a next-generation material for its heat and electrical conductivity as well as its transparency. However, single and multi-layered graphene have characteristics of a conductor so that it is difficult to apply into semiconductor. Only when downsized to the nanoscale, semiconductor’s distinct feature of bandgap will be exhibited to emit the light in the graphene. This illuminating featuring of dot is referred to as a graphene quantum dot.
Conventionally, single-crystalline graphene has been fabricated by chemical vapor deposition (CVD) on copper or nickel thin films, or by peeling graphite physically and chemically. However, graphene made via chemical vapor deposition is mainly used for large-surface transparent electrodes. Meanwhile, graphene made by chemical and physical peeling carries uneven size defects.
The research team explained that their graphene quantum dots exhibited a very stable single-phase reaction when they mixed amine and acetic acid with an aqueous solution of glucose. Then, they synthesized single-crystalline graphene quantum dots from the self-assembly of the reaction intermediate. In the course of fabrication, the team developed a new separation method at a low-temperature precipitation, which led to successfully creating a homogeneous nucleation of graphene quantum dots via a single-phase reaction.
Professor Park and his colleagues have developed solution phase synthesis technology that allows for the creation of the desired crystal size for single nanocrystals down to 100 nano meters. It is reportedly the first synthesis of the homogeneous nucleation of graphene through a single-phase reaction.
Professor Park said, "This solution method will significantly contribute to the grafting of graphene in various fields. The application of this new graphene will expand the scope of its applications such as for flexible displays and varistors.”
This research was a joint project with a team from Korea University under Professor Sang Hyuk Im from the Department of Chemical and Biological Engineering, and was supported by the National Research Foundation of Korea, the Nano-Material Technology Development Program from the Electronics and Telecommunications Research Institute (ETRI), KAIST EEWS, and the BK21+ project from the Korean government.
2019.08.02 View 31127 -
Newly Identified Meningeal Lymphatic Vessels Answers the Key Questions on Brain Clearance
(Figure: Schematic images of location and features of meningeal lymphatic vessels and their changes associated with ageing.)
Just see what happens when your neighborhood’s waste disposal system is out of service. Not only do the piles of trash stink but they can indeed hinder the area’s normal functioning. That is also the case when the brain’s waste management is on the blink.
The buildup of toxic proteins in the brain causes a massive damage to the nerves, leading to cognitive dysfunction and increased probability of developing neurodegenerative disorders such as Alzheimer's disease. Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain’s cleansing mechanism.
Medical scientists led by Professor Gou Young Koh at the Graduate School of Medical Science and Engineering have reported the basal side of the skull as the major route, so called “hotspot” for CSF drainage.
They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain’s major drainage system, specifically basal mLVs are impaired with aging. Their findings have been reported in the journal Nature on July 24.
Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question — where is the main exit for the CSF? Though mLVs in the upper part of the skull (dorsal meningeal lymphatic vessels) were reported as the brain’s clearance pathways in 2014, no substantial drainage mechanism was observed in that section.
“As a hidden exit for CSF, we looked into the mLVs trapped within complex structures at the base of the skull,” says Dr. Ji Hoon Ahn, the first author of this study. The researchers used several techniques to characterize the basal mLVs in detail. They used a genetically engineered lymphatic-reporter mouse model to visualize mLVs under a fluorescence microscope. By performing a careful examination of the mice skull, they found distinctive features of basal mLVs that make them suitable for CSF uptake and drainage. Just like typical functional lymphatic vessels, basal mLVs are found to have abundant lymphatic vessel branches with finger-like protrusions. Additionally, valves inside the basal mLVs allow the flow to go in one direction. In particular, they found that the basal mLVs are closely located to the CSF. Dr. Hyunsoo Cho, the first author of this study explains, “All up, it seemed a solid case that basal mLVs are the brain’s main clearance pathways.
The researchers verified such specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs. Jun-Hee Kim, the first author of this study notes, “We literally saw that the brain clearance mechanism utilizing basal outflow route to exit the skull.
It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. The corresponding author of this study, Dr. Koh says, “By characterizing the precise route for fluids leaving the brain, this study improves our understanding on how waste is cleared from the brain. Our findings also provide further insights into the role of impaired CSF clearance in the development of age-related neurodegenerative diseases.”
Many current therapies for Alzheimer’s disease target abnormally accumulated proteins, such as beta-amyloid. By mapping out a precise route for the brain’s waste clearance system, this study may be able to help find ways to improve the brain’s cleansing function. Such breakthrough might become quite a sensational strategy for eliminating the buildup of aging-related toxic proteins. “It definitely warrants more extensive investigation of mLVs in patients with age-related neurodegenerative disease such as Alzheimer’s disease prior to clinical investigation,” adds Professor Koh.
2019.07.25 View 31115 -
Flexible User Interface Distribution for Ubiquitous Multi-Device Interaction
< Research Group of Professor Insik Shin (center) >
KAIST researchers have developed mobile software platform technology that allows a mobile application (app) to be executed simultaneously and more dynamically on multiple smart devices. Its high flexibility and broad applicability can help accelerate a shift from the current single-device paradigm to a multiple one, which enables users to utilize mobile apps in ways previously unthinkable.
Recent trends in mobile and IoT technologies in this era of 5G high-speed wireless communication have been hallmarked by the emergence of new display hardware and smart devices such as dual screens, foldable screens, smart watches, smart TVs, and smart cars. However, the current mobile app ecosystem is still confined to the conventional single-device paradigm in which users can employ only one screen on one device at a time. Due to this limitation, the real potential of multi-device environments has not been fully explored.
A KAIST research team led by Professor Insik Shin from the School of Computing, in collaboration with Professor Steve Ko’s group from the State University of New York at Buffalo, has developed mobile software platform technology named FLUID that can flexibly distribute the user interfaces (UIs) of an app to a number of other devices in real time without needing any modifications. The proposed technology provides single-device virtualization, and ensures that the interactions between the distributed UI elements across multiple devices remain intact.
This flexible multimodal interaction can be realized in diverse ubiquitous user experiences (UX), such as using live video steaming and chatting apps including YouTube, LiveMe, and AfreecaTV. FLUID can ensure that the video is not obscured by the chat window by distributing and displaying them separately on different devices respectively, which lets users enjoy the chat function while watching the video at the same time.
In addition, the UI for the destination input on a navigation app can be migrated into the passenger’s device with the help of FLUID, so that the destination can be easily and safely entered by the passenger while the driver is at the wheel.
FLUID can also support 5G multi-view apps – the latest service that allows sports or games to be viewed from various angles on a single device. With FLUID, the user can watch the event simultaneously from different viewpoints on multiple devices without switching between viewpoints on a single screen.
PhD candidate Sangeun Oh, who is the first author, and his team implemented the prototype of FLUID on the leading open-source mobile operating system, Android, and confirmed that it can successfully deliver the new UX to 20 existing legacy apps.
“This new technology can be applied to next-generation products from South Korean companies such as LG’s dual screen phone and Samsung’s foldable phone and is expected to embolden their competitiveness by giving them a head-start in the global market.” said Professor Shin.
This study will be presented at the 25th Annual International Conference on Mobile Computing and Networking (ACM MobiCom 2019) October 21 through 25 in Los Cabos, Mexico. The research was supported by the National Science Foundation (NSF) (CNS-1350883 (CAREER) and CNS-1618531).
Figure 1. Live video streaming and chatting app scenario
Figure 2. Navigation app scenario
Figure 3. 5G multi-view app scenario
Publication: Sangeun Oh, Ahyeon Kim, Sunjae Lee, Kilho Lee, Dae R. Jeong, Steven Y. Ko, and Insik Shin. 2019. FLUID: Flexible User Interface Distribution for Ubiquitous Multi-device Interaction. To be published in Proceedings of the 25th Annual International Conference on Mobile Computing and Networking (ACM MobiCom 2019). ACM, New York, NY, USA. Article Number and DOI Name TBD.
Video Material:
https://youtu.be/lGO4GwH4enA
Profile: Prof. Insik Shin, MS, PhD
ishin@kaist.ac.kr
https://cps.kaist.ac.kr/~ishin
Professor
Cyber-Physical Systems (CPS) Lab
School of Computing
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Sangeun Oh, PhD Candidate
ohsang1213@kaist.ac.kr
https://cps.kaist.ac.kr/
PhD Candidate
Cyber-Physical Systems (CPS) Lab
School of Computing
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Prof. Steve Ko, PhD
stevko@buffalo.edu
https://nsr.cse.buffalo.edu/?page_id=272
Associate Professor
Networked Systems Research Group
Department of Computer Science and Engineering
State University of New York at Buffalo
http://www.buffalo.edu/ Buffalo 14260, USA
(END)
2019.07.20 View 37674 -
Deciphering Brain Somatic Mutations Associated with Alzheimer's Disease
Researchers have found a potential link between non-inherited somatic mutations in the brain and the progression of Alzheimer’s disease
Researchers have identified somatic mutations in the brain that could contribute to the development of Alzheimer’s disease (AD). Their findings were published in the journal Nature Communications last week.
Decades worth of research has identified inherited mutations that lead to early-onset familial AD. Inherited mutations, however, are behind at most half the cases of late onset sporadic AD, in which there is no family history of the disease. But the genetic factors causing the other half of these sporadic cases have been unclear.
Professor Jeong Ho Lee at the Graduate School of Medical Science and Engineering and colleagues analysed the DNA present in post-mortem hippocampal formations and in blood samples from people aged 70 to 96 with AD and age-matched controls. They specifically looked for non-inherited somatic mutations in their brains using high-depth whole exome sequencing.
The team developed a bioinformatics pipeline that enabled them to detect low-level brain somatic single nucleotide variations (SNVs) – mutations that involve the substitution of a single nucleotide with another nucleotide. Brain somatic SNVs have been reported on and accumulate throughout our lives and can sometimes be associated with a range of neurological diseases.
The number of somatic SNVs did not differ between individuals with AD and non-demented controls. Interestingly, somatic SNVs in AD brains arise about 4.8 times more slowly than in blood. When the team performed gene-set enrichment tests, 26.9 percent of the AD brain samples had pathogenic brain somatic SNVs known to be linked to hyperphosphorylation of tau proteins, which is one of major hallmarks of AD.
Then, they pinpointed a pathogenic SNV in the PIN1 gene, a cis/trans isomerase that balances phosphorylation in tau proteins, found in one AD patient’s brain. They found the mutation was 4.9 time more abundant in AT8-positive – a marker for hyper-phosphorylated tau proteins– neurons in the entorhinal cortex than the bulk hippocampal tissue. Furthermore, in a series of functional assays, they observed the mutation causing a loss of function in PIN1 and such haploinsufficiency increased the phosphorylation and aggregation of tau proteins.
“Our study provides new insights into the molecular genetic factors behind Alzheimer’s disease and other neurodegenerative diseases potentially linked to somatic mutations in the brain,” said Professor Lee.
The team is planning to expand their study to a larger cohort in order to establish stronger links between these brain somatic mutations and the pathogenesis of Alzheimer’s disease.
(Figure 1. Bioinformatic pipeline for detecting low-level brain somatic mutations in AD and non-AD.)
(Figure 2. Pathogenic brain somatic mutations associated with tau phosphorylation are significantly enriched in AD brains.)
(Figure 3. A pathogenic brain somatic mutation in PIN1 (c. 477 C>T) is a loss-of-function and related functional assays show its haploinsufficiency increases phosphorylation and aggregation of tau.)
2019.07.19 View 34222 -
President Shin Shares Innovation Strategy at Moscow
President Sung-Chul Shin shared the recipe for success for rapid national development through university education during the Island 10-22 Conference held at the Skolov Institute of Science and Technology in Moscow on July 16.
President Shin stressed how urgent it is for higher education to rapidly embrace the new global economic environment brought about by the Fourth Industrial Revolution in his keynote address entitled ‘Roles and Responsibilities of Universities for Rapid National Development’.
The Island 10-22 Conference is a summit co-organized by the National University of Science and Technology MISIS and University of the National Technological Initiative 2035 and supported by the Ministry of Science and Higher Education of the Russian Federation. More than 30 world-renowned experts, presidents of leading technological universities including President Peretz Lavie from the Israel Institute of Technology Technion, President Scott Pulsipher from Western Governors University and specialists in big data participated in the conference as speakers and discussed a diverse spectrum of ideas for making innovations and digital transformations in universities. More than 1,600 participants joined the conference.
During his keynote speech, President Shin explained how Korea has achieved such rapid economic growth over the past half century. He cited the Korean government’s vision and innovation policies as factors leading to Korea’s phenomenal success. KAIST, one of the results of the Korean government’s innovation policy, led the nation to advanced technological breakthroughs in industries such as semiconductors. Such visionary policies and investments in science, technology, and education eventually made the Korea of today possible.
President Shin said that KAIST distinguished itself through its new vision of C3 that fosters intellectual creativity, caring for others, and a challenging mind . Under Vision 2031, a blueprint for becoming a leading global university, President Shin said the KAIST continues to strive for innovations in convergent education,research and entreprenurship.
2019.07.18 View 5361 -
Mathematical Modeling Makes a Breakthrough for a New CRSD Medication
PhD Candidate Dae Wook Kim (Left) and Professor Jae Kyoung Kim (Right)
- Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy -
Mathematicians’ new modeling has identified major sources of interspecies and inter-individual variations in the clinical efficacy of a clock-modulating drug: photosensitivity and PER2 level. This enabled precision medicine for circadian disruption.
A KAIST mathematics research team led by Professor Jae Kyoung Kim, in collaboration with Pfizer, applied a combination of mathematical modeling and simulation tools for circadian rhythms sleep disorders (CRSDs) to analyze the animal data generated by Pfizer. This study was reported in Molecular Systems Biology as the cover article on July 8.
Pharmaceutical companies have conducted extensive studies on animals to determine the candidacy of this new medication. However, the results of animal testing do not always translate to the same effects in human trials. Furthermore, even between humans, efficacy differs across individuals depending on an individual’s genetic and environmental factors, which require different treatment strategies.
To overcome these obstacles, KAIST mathematicians and their collaborators developed adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions.
A circadian rhythm is a 24-hour cycle in the physiological processes of living creatures, including humans. A biological clock in the hypothalamic suprachiasmatic nucleus in the human brain sets the time for various human behaviors such as sleep.
A disruption of the endogenous timekeeping system caused by changes in one’s life pattern leads to advanced or delayed sleep-wake cycle phase and a desynchronization between sleep-wake rhythms, resulting in CRSDs. To restore the normal timing of sleep, timing of the circadian clock could be adjusted pharmacologically.
Pfizer identified PF-670462, which can adjust the timing of circadian clock by inhibiting the core clock kinase of the circadian clock (CK1d/e). However, the efficacy of PF-670462 significantly differs between nocturnal mice and diurnal monkeys, whose sleeping times are opposite.
The research team discovered the source of such interspecies variations in drug response by performing thousands of virtual experiments using a mathematical model, which describes biochemical interactions among clock molecules and PF-670462. The result suggests that the effect of PF-670462 is reduced by light exposure in diurnal primates more than in nocturnal mice. This indicates that the strong counteracting effect of light must be considered in order to effectively regulate the circadian clock of diurnal humans using PF-670462.
Furthermore, the team also found the source of inter-patients variations in drug efficacy using virtual patients whose circadian clocks were disrupted due to various mutations. The degree of perturbation in the endogenous level of the core clock molecule PER2 affects the efficacy.
This explains why the clinical outcomes of clock-modulating drugs are highly variable and certain subtypes are unresponsive to treatment. Furthermore, this points out the limitations of current treatment strategies tailored to only the patient’s sleep and wake time but not to the molecular cause of sleep disorders.
PhD candidate Dae Wook Kim, who is the first author, said that this motivates the team to develop an adaptive chronotherapy, which identifies a personalized optimal dosing time of day by tracking the sleep-wake up time of patients via a wearable device and allows for a precision medicine approach for CRSDs.
Professor Jae Kyoung Kim said, "As a mathematician, I am excited to help enable the advancement of a new drug candidate, which can improve the lives of so many patients. I hope this result promotes more collaborations in this translational research.”
This research was supported by a Pfizer grant to KAIST (G01160179), the Human Frontiers Science Program Organization (RGY0063/2017), and a National Research Foundation (NRF) of Korea Grant (NRF-2016 RICIB 3008468 and NRF-2017-Fostering Core Leaders of the Future Basic Science Program/ Global Ph.D. Fellowship Program).
Figure 1. Interspecies and Inter-patients Variations in PF-670462 Efficacy
Figure 2. Journal Cover Page
Publication:
Dae Wook Kim, Cheng Chang, Xian Chen, Angela C Doran, Francois Gaudreault, Travis Wager, George J DeMarco, and Jae Kyoung Kim. 2019. Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Molecular Systems Biology. EMBO Press, Heidelberg, Germany, Vol. 15, Issue No. 7, Article, 16 pages. https://doi.org/10.15252/msb.20198838
Profile: Prof. Jae Kyoung Kim, PhD
jaekkim@kaist.ac.kr
http://mathsci.kaist.ac.kr/~jaekkim
Associate Professor
Department of Mathematical Sciences
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Dae Wook Kim, PhD Candidate
0308kdo@kaist.ac.kr
http://mathsci.kaist.ac.kr/~jaekkim
PhD Candidate
Department of Mathematical Sciences
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Dr. Cheng Chang, PhD
cheng.chang@pfizer.com
Associate Director of Clinical Pharmacology
Clinical Pharmacology, Global Product Development
Pfizer
https://www.pfizer.com/ Groton 06340, USA
(END)
2019.07.09 View 33593 -
Two Alumni Win the Korea Best Scientist and Technologist Awards
Vice Chairman Ki-Nam Kim (Left) and Distinguished Professor Sukbok Chang (Right)
<ⓒ Photo by MSIT and KOFST>
Distinguished KAIST Professor Sukbok Chang from the Department of Chemistry and Vice Chairman Ki-Nam Kim of Samsung Electronics were selected as the winners of the “2019 Korea Best Scientist and Technologist Awards” by the Ministry of Science and ICT (MSIT) and the Korean Federation of Science and Technology Societies (KOFST). The awards, which were first handed out in 2003, are the highest honor bestowed to the two most outstanding scientists in Korea every year, and this year’s awardees are of greater significance as they are both KAIST alumni.
Professor Chang was recognized for his pioneering achievements and lifetime contributions to the development of carbon-hydrogen activation strategies, especially for carbon-carbon, carbon-nitrogen, and carbon-oxygen formations. His research group has also been actively involved in the development of highly selective catalytic systems allowing the controlled defunctionalization of bio-derived platform substrates under mild conditions, and opening a new avenue for the utilization of biomass-derived platform chemicals. The results of his study have been introduced worldwide through many prestigious journals including Science, Nature Chemistry, and Nature Catalysis, making him one of the world's top 1% researchers by the number of references made to his papers by his peers over four consecutive years from 2015 to 2018.
Vice Chairman Kim, who received his M.E. degree from KAIST’s School of Electrical Engineering in 1983, has been credited with playing a leading role in the development of system semiconductors.
The awards were conferred on July 4 at the opening ceremony of the 2019 Korea Science and Technology Annual Meeting.
(END)
2019.07.09 View 9782 -
Deep Learning-Powered 'DeepEC' Helps Accurately Understand Enzyme Functions
(Figure: Overall scheme of DeepEC)
A deep learning-powered computational framework, ‘DeepEC,’ will allow the high-quality and high-throughput prediction of enzyme commission numbers, which is essential for the accurate understanding of enzyme functions.
A team of Dr. Jae Yong Ryu, Professor Hyun Uk Kim, and Distinguished Professor Sang Yup Lee at KAIST reported the computational framework powered by deep learning that predicts enzyme commission (EC) numbers with high precision in a high-throughput manner.
DeepEC takes a protein sequence as an input and accurately predicts EC numbers as an output. Enzymes are proteins that catalyze biochemical reactions and EC numbers consisting of four level numbers (i.e., a.b.c.d) indicate biochemical reactions. Thus, the identification of EC numbers is critical for accurately understanding enzyme functions and metabolism.
EC numbers are usually given to a protein sequence encoding an enzyme during a genome annotation procedure. Because of the importance of EC numbers, several EC number prediction tools have been developed, but they have room for further improvement with respect to computation time, precision, coverage, and the total size of the files needed for the EC number prediction.
DeepEC uses three convolutional neural networks (CNNs) as a major engine for the prediction of EC numbers, and also implements homology analysis for EC numbers if the three CNNs do not produce reliable EC numbers for a given protein sequence. DeepEC was developed by using a gold standard dataset covering 1,388,606 protein sequences and 4,669 EC numbers.
In particular, benchmarking studies of DeepEC and five other representative EC number prediction tools showed that DeepEC made the most precise and fastest predictions for EC numbers. DeepEC also required the smallest disk space for implementation, which makes it an ideal third-party software component.
Furthermore, DeepEC was the most sensitive in detecting enzymatic function loss as a result of mutations in domains/binding site residue of protein sequences; in this comparative analysis, all the domains or binding site residue were substituted with L-alanine residue in order to remove the protein function, which is known as the L-alanine scanning method.
This study was published online in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on June 20, 2019, entitled “Deep learning enables high-quality and high-throughput prediction of enzyme commission numbers.”
“DeepEC can be used as an independent tool and also as a third-party software component in combination with other computational platforms that examine metabolic reactions. DeepEC is freely available online,” said Professor Kim.
Distinguished Professor Lee said, “With DeepEC, it has become possible to process ever-increasing volumes of protein sequence data more efficiently and more accurately.”
This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries from the Ministry of Science and ICT through the National Research Foundation of Korea. This work was also funded by the Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Korean government, the Ministry of Science and ICT.
Profile:
-Professor Hyun Uk Kim (ehukim@kaist.ac.kr)
https://sites.google.com/view/ehukim
Department of Chemical and Biomolecular Engineering
-Distinguished Professor Sang Yup Lee (leesy@kaist.ac.kr)
Department of Chemical and Biomolecular Engineering
http://mbel.kaist.ac.kr
2019.07.09 View 34542 -
KAIST-KU Joint Research Center Opens
The Joint Research Center partnering KAIST and Khalifa University has been completed and the opening of the KAIST center was held on July 5, 2019, following the opening at Khalifa in April.
The joint research center will explore the most impactful technologies that will change people’s lives in the face of the new industrial environment brought about by the Fourth Industrial Revolution. The breakthroughs include smart transportation and smart healthcare such as wireless electric vehicles, unmanned vehicles, and wearable healthcare devices. The two institutions signed an MOU on the Joint Research Agreement on the Technology Development for the Fourth Industrial Revolution in 2018.
This is the second phase of collaboration following the partnership agreement that was signed in 2010 between the two institutions, which aimed to provide the best science and technology education as well as develop nuclear energy in the UAE.
The Khalifa University delegation, headed by Executive Vice President Arif Sultan Al Hammadi and Senior Vice President of Research and Development Steven Griffiths, flew in to attend the ceremony at KAIST. President Sung-Chul Shin, Vice President for Research Hyun Wook Park, Vice President for Planning and Budget Su-chan Chae, Associate Vice President of the International Office Man-Sung Yim joined and Co-Directors of the Joint Research Center Daniel Choi from Khalifa and Jong-Hyun Kim from KAIST also participated in the opening ceremony.
2019.07.06 View 6425