research
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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 33652 -
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 34618 -
Micropatch Made of DNA
Researchers reported the fabrication of microstructure arrays of DNA materials using topographic control. This method provides a platform for forming multiscale hierarchical orientations of soft and biomaterials using a process of simple shearing and controlled evaporation on a patterned substrate. This approach enables the potential of patterning applications using DNA or other anisotropic biomaterials.
DNA is one of the most abundant biomaterials found in all living organisms in nature. It has unique characteristics of fine feature size and liquid crystalline phase, enabling to create various kinds of microstructure DNA arrays. Based on these characteristics, DNA has been used as a building block for “origami” and textile art at the nanometer scale.
A KAIST research team led by Professors Dong Ki Yoon and Hyungsoo Kim fabricated a DNA-based micropatch using the “coffee ring effect” and its multi-angle control technology, which was published online in Nature Communications on June 7.
The research team used cheap DNA material extracted from salmon to realize the micropatch structure with well-aligned knit or ice cream cone shapes. When the DNA material in an aqueous solution is rubbed between two solid substrates while water is evaporating, DNA chains are unidirectionally aligned to make a thin film such as in LCD display devices. The DNA chains can make more complex microstructures such as knit or a texture with ice cream cone shapes when the same procedure is carried out in topographical patterns like microposts (Figure 1). This can be applied to make metamaterials by mixing with functionalized gold nanorods to show plasmonic color.
Plasmon resonance is a phenomenon in which electrons vibrate uniformly on the surface of a substrate made of metal, reacting only to light that matches a specific energy to enhance the clarity and expression of colors. For this, the most important factor is the orientation in which the gold nanorods align. That is, when the rods are aligned side by side in one direction, the optical and electrical characteristics are maximized. The research team focused on this point and made the DNA micropatch as a frame to orient the gold nanorods in a unique shape and fabricated a plasmonic color film (Figure 2).
Professor Yoon said this study is meaningful in that it deals with the evaporation phenomenon, which has not been studied much in the field of polymers and biopolymers in terms of basic science. He explained, “This will also help maximize the efficiency of polymeric materials that can be orientated in coating, 2D, and 3D printing applications. Furthermore, DNA that exists infinitely in nature can be expected to have industrial application value as a new material since it can easily form complexes with other materials as described in this study.”
(Figure 1. The DNA micropatch using topographic control. (a) The experimental scheme.
(b) Enlarged image of (e). (c-e) Different micropatches made of DNA using different shearing directions.)
(Figure 2. The knit-like structures made of DNA-gold nanorod complex. (a,b) Optical
and polarized optical microscopy images. (c-f) Plasmonic colors reflected from aligned DNA-gold nanorod complex depending on the sample rotation.)
2019.07.01 View 32744 -
Anti-drone Technology for Anti-Terrorism Applications
(from top right clockwise: Professor Yongdae Kim,
PhD Candidates Yujin Kwon, Juhwan Noh, Hocheol Shin, and Dohyun Kim)
KAIST researchers have developed anti-drone technology that can hijack other drones by spoofing its location using fake GPS signals. This technology can safely guide a drone to a desired location without any sudden change in direction in emergency situations, and thus respond effectively to dangerous drones such as those intending to carry out acts of terrorism.
Advancements in the drone industry have led to the wider use of drones in our daily lives in areas of reconnaissance, searching and rescuing, disaster prevention and response, and delivery services. At the same time, there has also been a growing concern about privacy, safety, and security issues regarding drones, especially those arising from intrusion into private property and secure facilities. Therefore, the anti-drone industry is rapidly expanding to detect and respond to this possible drone invasion.
The current anti-drone systems used in airports and other key locations utilize electronic jamming signals, high-power lasers, or nets to neutralize drones. For example, drones trespassing on airports are often countered with simple jamming signals that can prevent the drones from moving and changing position, but this may result in a prolonged delay in flight departures and arrivals at the airports. Drones used for terrorist attacks – armed with explosives or weapons – must also be neutralized a safe distance from the public and vital infrastructure to minimize any damage.
Due to this need for a new anti-drone technology to counter these threats, a KAIST research team led by Professor Yongdae Kim from the School of Electrical Engineering has developed technology that securely thwarts drones by tricking them with fake GPS signals.
Fake GPS signals have been used in previous studies to cause confusion inside the drone regarding its location, making the drone drift from its position or path. However, such attack tactics cannot be applied in GPS safety mode. GPS safety mode is an emergency mode that ensures drone safety when the signal is cut or location accuracy is low due to a fake GPS signals. This mode differs between models and manufacturers.
Professor Kim’s team analyzed the GPS safety mode of different drone models made from major drone manufacturers such as DJI and Parrot, made classification systems, and designed a drone abduction technique that covers almost all the types of drone GPS safety modes, and is universally applicable to any drone that uses GPS regardless of model or manufacturer. The research team applied their new technique to four different drones and have proven that the drones can be safely hijacked and guided to the direction of intentional abduction within a small margin of error.
Professor Kim said, “Conventional consumer drones equipped with GPS safety mode seem to be safe from fake GPS signals, however, most of these drones are able to be detoured since they detect GPS errors in a rudimentary manner.” He continued, “This technology can contribute particularly to reducing damage to airports and the airline industry caused by illegal drone flights.”
The research team is planning to commercialize the developed technology by applying it to existing anti-drone solutions through technology transfer.” This research, featured in the ACM Transactions on Privacy and Security (TOPS) on April 9, was supported by the Defense Acquisition Program Administration (DAPA) and the Agency for Defense Development (ADD).
Image 1.
Experimental environment in which a fake GPS signal was produced from a PC and injected into the drone signal using directional antennae
Publication:
Juhwan Noh, Yujin Kwon, Yunmok Son, Hocheol Shin, Dohyun Kim, Jaeyeong Choi, and Yongdae Kim. 2019. Tractor Beam: Safe-hijacking of Consumer Drones with Adaptive GPS Spoofing. ACM Transactions on Privacy and Security. New York, NY, USA, Vol. 22, No. 2, Article 12, 26 pages. https://doi.org/10.1145/3309735
Profile: Prof. Yongdae Kim, MS, PhD
yongdaek@kaist.ac.kr
https://www.syssec.kr/
Professor
School of Electrical Engineering
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Juhwan Noh, PhD Candidate
juhwan@kaist.ac.kr
PhD Candidate
System Security (SysSec) Lab
School of Electrical Engineering
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
(END)
2019.06.25 View 42399 -
Hydrogen-Natural Gas Hydrates Harvested by Natural Gas
A hydrogen-natural gas blend (HNGB) can be a game changer only if it can be stored safely and used as a sustainable clean energy resource. A recent study has suggested a new strategy for stably storing hydrogen, using natural gas as a stabilizer. The research proposed a practical gas phase modulator based synthesis of HNGB without generating chemical waste after dissociation for the immediate service.
The research team of Professor Jae Woo Lee from the Department of Chemical and Biomolecular Engineering in collaboration with the Gwangju Institute of Science and Technology (GIST) demonstrated that the natural gas modulator based synthesis leads to significantly reduced synthesis pressure simultaneously with the formation of hydrogen clusters in the confined nanoporous cages of clathrate hydrates. This approach minimizes the environmental impact and reduces operation costs since clathrate hydrates do not generate any chemical waste in both the synthesis and decomposition processes.
For the efficient storage and transportation of hydrogen, numerous materials have been investigated. Among others, clathrate hydrates offer distinct benefits. Clathrate hydrates are nanoporous inclusion compounds composed of a 3D network of polyhedral cages made of hydrogen-bonded ‘host’ water molecules and captured ‘guest’ gas or liquid molecules.
In this study, the research team used two gases, methane and ethane, which have lower equilibrium conditions compared to hydrogen as thermodynamic stabilizers. As a result, they succeeded in stably storing the hydrogen-natural gas compound in hydrates. According to the composition ratio of methane and ethane, structure I or II hydrates can be formed, both of which can stably store hydrogen-natural gas in low-pressure conditions.
The research team found that two hydrogen molecules are stored in small cages in tuned structure I hydrates, while up to three hydrogen molecules can be stored in both small and large cages in tuned structure II hydrates. Hydrates can store gas up to about 170-times its volume and the natural gas used as thermodynamic stabilizers in this study can also be used as an energy source.
The research team developed technology to produce hydrates from ice, produced hydrogen-natural gas hydrates by substitution, and successfully observed that the tuning phenomenon only occurs when hydrogen is involved in hydrate formation from the start for both structures of hydrates.
They expect that the findings can be applied to not only an energy-efficient gas storage material, but also a smart platform to utilize hydrogen natural gas blends, which can serve as a new alternative energy source with targeted hydrogen contents by designing synthetic pathways of mixed gas hydrates.
The research was published online in Energy Storage Materials on June 6, with the title ‘One-step formation of hydrogen clusters in clathrate hydrates stabilized via natural gas blending’.
Professor Lee said, “HNGB will utilize the existing natural gas infrastructure for transportation, so it is very likely that we can commercialize this hydrate system. We are investigating the kinetic performance through a follow-up strategy to increase the volume of gas storage.
This study was funded by the National Research Foundation of Korea and BK21 plus program.
(Figure1. Schematics showing the storage method for hydrogen in a natural gas hydrate using a substitution method and storage method directly from ice to a hydrogen-natural gas hydrate.)
(Figure 2. Artificially synthesized and dissociated hydrogen-natural gas hydrates. The Raman spectra of tuned sI and sII hydrate showing the hydrogen clusters in each cage.)
2019.06.21 View 39856 -
Efficiently Producing Fatty Acids and Biofuels from Glucose
Researchers have presented a new strategy for efficiently producing fatty acids and biofuels that can transform glucose and oleaginous microorganisms into microbial diesel fuel, with one-step direct fermentative production.
The newly developed strain, created by Distinguished Professor Sang Yup Lee and his team, showed the highest efficiency in producing fatty acids and biodiesels ever reported. It will be expected to serve as a new platform to sustainably produce a wide array of fatty acid-based products from glucose and other carbon substrates.
Fossil fuels, which have long been energy resources for our daily lives, are now facing serious challenges: depletion of their reserves and their role in global warming. The production of sustainable bio-based renewable energy has emerged as an essential alternative and many studies to replace fossil fuels are underway. One of the representative examples is biodiesel. Currently, it is mainly being produced through the transesterification of vegetable oils or animal fats.
The research team engineered oleaginous microorganisms, Rhodococcus opacus, to produce fatty acids and their derivatives that can be used as biodiesel from glucose, one of the most abundant and cheap sugars derived from non-edible biomass.
Professor Lee’s team has already engineered Escherichia coli to produce short-chain hydrocarbons, which can be used as gasoline (published in Nature as the cover paper in 2013). However, the production efficiency of the short-chain hydrocarbons using E. coli (0.58 g/L) fell short of the levels required for commercialization.
To overcome these issues, the team employed oil-accumulating Rhodococcus opacus as a host strain in this study. First, the team optimized the cultivation conditions of Rhodococcus opacus to maximize the accumulation of oil (triacylglycerol), which serves as a precursor for the biosynthesis of fatty acids and their derivatives. Then, they systematically analyzed the metabolism of the strain and redesigned it to enable higher levels of fatty acids and two kinds of fatty acid-derived biodiesels (fatty acid ethyl esters and long-chain hydrocarbons) to be produced.
They found that the resulting strains produced 50.2, 21.3, and 5.2 g/L of fatty acids, fatty acid ethyl esters, and long-chain hydrocarbons, respectively. These are all the highest concentrations ever reported by microbial fermentations. It is expected that these strains can contribute to the future industrialization of microbial-based biodiesel production.
“This technology creates fatty acids and biodiesel with high efficiency by utilizing lignocellulose, one of the most abundant resources on the Earth, without depending on fossil fuels and vegetable or animal oils. This will provide new opportunities for oil and petroleum industries, which have long relied on fossil fuels, to turn to sustainable and eco-friendly biotechnologies,” said Professor Lee.
This paper titled “Engineering of an oleaginous bacterium for the production of fatty acids and fuels” was published in Nature Chemical Biology on June 17.
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 (NRF) of Korea (NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557).
(Figure: Metabolic engineering for the production of free fatty acids (FFAs), fatty acid ethyl esters (FAEEs), and long-chain hydrocarbons (LCHCs) in Rhodococcus opacus PD630. Researchers have presented a new strategy for efficiently producing fatty acids and biofuels that can transform glucose and oleaginous microorganisms into microbial diesel fuel, with one-step direct fermentative production.)
# # #
Source:
Hye Mi Kim, Tong Un Chae, So Young Choi, Won Jun Kim and Sang Yup Lee. Engineering of an oleaginous bacterium for the production of fatty acids and fuels. Nature Chemical Biology ( https://www.nature.com/nchembio/ ) DOI: 10.1038/s41589-019-0295-5
Profile
Dr. Sang Yup Lee
leesy@kaist.ac.kr
Distinguished Professor at the Department of Chemical and Biomolecular Engineering
KAIST
2019.06.19 View 46494 -
Real-Time Analysis of MOF Adsorption Behavior
Researchers have developed a technology to analyze the adsorption behavior of molecules in each individual pore of a metal organic framework (MOF). This system has large specific surface areas, allowing for the real-time observation of the adsorption process of an MOF, a new material effective for sorting carbon dioxide, hydrogen, and methane.
Accurate measurements and assessments of gas adsorption isotherms are important for characterizing porous materials and developing their applications. The existing technology is only able to measure the amount of gas molecules adsorbed to the material, without directly observing the adsorption behavior.
The research team led by Professor Jeung Ku Kang from the Graduate School of Energy, Environment, Water and Sustainability (EEWS) prescribed a real time gas adsorption crystallography system by integrating an existing X-ray diffraction (XRD) measurement device that can provide structural information and a gas adsorption measurement device.
Specifically, the system allowed the observation of a mesoporous MOF that has multiple pores rather than a single pore structure. The research team categorized the adsorption behaviors of MOF molecules by pore type, followed by observations and measurements, resulting in the identification of a stepwise adsorption process that was previously not possible to analyze.
Further, the team systematically and quantitatively analyzed how the pore structure and the type of adsorption molecule affect the adsorption behavior to suggest what type of MOF structure is appropriate as a storage material for each type of adsorption behavior.
Professor Kang said, “We quantitatively analyzed each pore molecule in real time to identify the effects of chemical and structural properties of pores on adsorption behavior.” He continued, “By understanding the real-time adsorption behavior of molecules at the level of the pores that form the material, rather than the whole material, we will be able to apply this technology to develop a new high-capacity storage material.”
This research was published in Nature Chemistry online on May 13, 2019 under the title ‘Isotherms of Individual Pores by Gas Adsorption Crystallography’.
(Figure. Schematic illustration of molecules adsorbed on metal organic frameworks with different pores of various structures, where the In-situ X-ray crystallography has been developed to classify each pore structure and analyze the position of the molecule to determine the amount of molecules adsorbed to each pore.)
2019.06.18 View 38199 -
Novel Via-Hole-Less Multilevel Metal Interconnection Methods
Forming reliable multi-level metal interconnections is a key technology for integrating devices into organic integrated circuits (ICs). The conventional approach, called “via-hole,” locally removes the insulator and utilizes metal interconnects through the holes. Due to the high sensitivity of organic materials to chemical solvents, heat, and photo-radiation used in conventional “via-hole” methods, alternative printing methods or laser drilling methods have been developed. However, finding a reliable and practical metal interconnection for organic ICs is still challenging.
The research team of KAIST Professor Sung Gap Im and Postech Professor Kim Jae-Joon reported a new interconnection method that does not require via-hole formation, “via-hole-less metal interconnection,” in Nature Communications on June 3.
Metal electrodes in different layers can be isolated from each other by patterned dielectric layers, where they then can be interconnected to others in the open area where the dielectric layer is not present. See the images below. Vapor phase deposition and in-situ patterning of dielectric layer using iCVD (initiated chemical vapor deposition), used in the “via-hole-less” method, ensure a damage-free process for organic semiconductor materials and result in outstanding performance of the organic devices as multilevel metal interconnects are reliably formed. The team successfully demonstrated three-dimensional (3D) stacking of five organic transistors and integrated circuits using the proposed via-hole-less interconnect method. See the image below.
Vapor phase deposition and in-situ patterning of dielectric layer using iCVD (initiated chemical vapor deposition), used in the “via-hole-less” method, ensure a damage-free process for organic semiconductor materials and result in outstanding performance of the organic devices as multilevel metal interconnects are reliably formed. The team successfully demonstrated three-dimensional (3D) stacking of five organic transistors and integrated circuits using the proposed via-hole-less interconnect method. See the image below.
Professor Kim explained, “Our proposed via-hole-less interconnect method using a selectively patterned dielectric overcomes the limitations of the previous time-consuming, one-by-one via-hole formation process and provides reliable methods for creating metal interconnects in organic ICs. We expect the via-hole-less scheme to bring advances to organic IC technology.”
2019.06.18 View 42418 -
Play Games With No Latency
One of the most challenging issues for game players looks to be resolved soon with the introduction of a zero-latency gaming environment. A KAIST team developed a technology that helps game players maintain zero-latency performance. The new technology transforms the shapes of game design according to the amount of latency.
Latency in human-computer interactions is often caused by various factors related to the environment and performance of the devices, networks, and data processing. The term ‘lag’ is used to refer to any latency during gaming which impacts the user’s performance.
Professor Byungjoo Lee at the Graduate School of Culture Technology in collaboration with Aalto University in Finland presented a mathematical model for predicting players' behavior by understanding the effects of latency on players. This cognitive model is capable of predicting the success rate of a user when there is latency in a 'moving target selection' task which requires button input in a time constrained situation.
The model predicts the players’ task success rate when latency is added to the gaming environment. Using these predicted success rates, the design elements of the game are geometrically modified to help players maintain similar success rates as they would achieve in a zero-latency environment. In fact, this research succeeded in modifying the pillar heights of the Flappy Bird game, allowing the players to maintain their gaming performance regardless of the added latency.
Professor Lee said, "This technique is unique in the sense that it does not interfere with a player's gaming flow, unlike traditional methods which manipulate the game clock by the amount of latency. This study can be extended to various games such as reducing the size of obstacles in the latent computing environment.”
This research, in collaboration with Dr. Sunjun Kim from Aalto University and led by PhD candidate Injung Lee, was presented during the 2019 CHI Conference on Human Factors in Computing Systems last month in Glasgow in the UK.
This research was supported by the National Research Foundation of Korea (NRF) (2017R1C1B2002101, 2018R1A5A7025409), and the Aalto University Seed Funding Granted to the GamerLab respectively.
Figure 1. Overview of Geometric Compensation
Publication:
Injung Lee, Sunjun Kim, and Byungjoo Lee. 2019. Geometrically Compensating Effect of End-to-End Latency in Moving-Target Selection Games. In Proceedings of the 2019 CHI Conference on Human Factors in Computing Systems (CHI’19) . ACM, New York, NY, USA, Article 560, 12 pages. https://doi.org/10.1145/3290605.3300790
Video Material:
https://youtu.be/TTi7dipAKJs
Profile: Prof. Byungjoo Lee, MD, PhD
byungjoo.lee@kaist.ac.kr
http://kiml.org/
Assistant Professor
Graduate School of Culture Technology (CT)
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Injung Lee, PhD Candidate
edndn@kaist.ac.kr
PhD Candidate
Interactive Media Lab
Graduate School of Culture Technology (CT)
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr
Daejeon 34141, Korea
Profile: Postdoc. Sunjun Kim, MD, PhD
kuaa.net@gmail.com
Postdoctoral Researcher
User Interfaces Group
Aalto University
https://www.aalto.fi Espoo 02150, Finland
(END)
2019.06.11 View 44876 -
Early Genome Catastrophes Can Cause Non-Smoking Lung Cancer
Some teenagers harbor catastrophic changes to their genomes that can lead to lung cancer later on in life, even if they never smoke
(Professor Young Seok Ju at the Graduate School of Medical Science and Engineering)
Catastrophic rearrangements in the genome occurring as early as childhood and adolescence can lead to the development of lung cancer in later years in non-smokers. This finding, published in Cell, helps explain how some non-smoking-related lung cancers develop.
Researchers at KAIST, Seoul National University and their collaborators confirmed that gene fusions in non-smokers mostly occur early on, sometimes as early as childhood or adolescence, and on average about three decades before cancer is diagnosed. The study showed that these mutant lung cells, harboring oncogenic seeds, remain dormant for several decades until a number of further mutations accumulate sufficiently for progression into cancer. This is the first study to reveal the landscape of genome structural variations in lung adenocarcinoma.
Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is its most common type. Most lung adenocarcinomas are associated with chronic smoking, but about a fourth develop in non-smokers. Precisely what happens in non-smokers for this cancer to develop is not clearly understood.
Researchers analyzed the genomes of 138 lung adenocarcinoma patients, including smokers and non-smokers, with whole-genome sequencing technologies. They explored DNA damage that induced neoplastic transformation.
Lung adenocarcinomas that originated from chronic smoking, referred to as signature 4-high (S4-high) cancers in the study, showed several distinguishing features compared to smoking-unrelated cancers (S4-low).
People in the S4-high group were largely older, men and had more frequent mutations in a cancer-related gene called KRAS. Cancer genomes in the S4-high group were hypermutated with simple mutational classes, such as the substitution, insertion, or deletion of a single base, the building block of DNA.
But the story was very different in the S4-low group. Generally, mutational profiles in this group were much more silent than the S4-high group. However, all cancer-related gene fusions, which are abnormally activated from the merging of two originally separate genes, were exclusively observed in the S4-low group.
The patterns of genomic structural changes underlying gene fusions suggest that about three in four cases of gene fusions emerged from a single cellular crisis causing massive genomic fragmentation and subsequent imprecise repair in normal lung epithelium.
Most strikingly, these major genomic rearrangements, which led to the development of lung adenocarcinoma, are very likely to be acquired decades before cancer diagnosis. The researchers used genomic archaeology techniques to trace the timing of when the catastrophes took place.
Researchers started this study seven years ago when they discovered the expression of the KIF5B-RET gene fusion in lung adenocarcinoma for the first time. Professor Young-Seok Ju, co-lead author from the Graduate School of Medical Science and Engineering at KAIST says, “It is remarkable that oncogenesis can begin by a massive shattering of chromosomes early in life. Our study immediately raises a new question: What induces the mutational catastrophe in our normal lung epithelium.”
Professor Young Tae Kim, co-lead author from Seoul National University says, “We hope this work will help us get one step closer to precision medicine for lung cancer patients.”
The research team plans to further focus on the molecular mechanisms that stimulate complex rearrangements in the body, through screening the genomic structures of fusion genes in other cancer types.
This study was supported by the National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI), Suh Kyungbae Foundation, the College of Medicine Research Foundations at Seoul National University and others.
Figure.
(Smoking-unrelated oncogenesis of lung cancers by gene fusions)
Publication.
Jake June-Koo Lee, Seongyeol Park et al., Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma
Cell 177, June 13 2019, online publication ahead of print at May 30, 2019
https://doi.org/10.1016/j.cell.2019.05.013
Profile: Prof Young Seok Ju, MD, PhD
ysju@kaist.ac.kr
http://julab.kaist.ac.kr
Associate Professor
Graduate School of Medical Science and Engineering (GSMSE)
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 34141, Korea
Profile: Prof Young Tae Kim, MD, PhD
ytkim@snu.ac.kr
Professor
Seoul National University Cancer Research Institute
Department of Thoracic and Cardiovascular Surgery
Seoul National University Hospital Seoul 03080, Korea
2019.05.31 View 54870 -
5 Biomarkers for Overcoming Colorectal Cancer Drug Resistance Identified
< Professor Kwang-Hyun Cho's Team >
KAIST researchers have identified five biomarkers that will help them address resistance to cancer-targeting therapeutics. This new treatment strategy will bring us one step closer to precision medicine for patients who showed resistance.
Colorectal cancer is one of the most common types of cancer worldwide. The number of patients has surpassed 1 million, and its five-year survival rate significantly drops to about 20 percent when metastasized. In Korea, the surge of colorectal cancer has been the highest in the last 10 years due to increasing Westernized dietary patterns and obesity. It is expected that the number and mortality rates of colorectal cancer patients will increase sharply as the nation is rapidly facing an increase in its aging population.
Recently, anticancer agents targeting only specific molecules of colon cancer cells have been developed. Unlike conventional anticancer medications, these selectively treat only specific target factors, so they can significantly reduce some of the side-effects of anticancer therapy while enhancing drug efficacy.
Cetuximab is the most well-known FDA approved anticancer medication. It is a biomarker that predicts drug reactivity and utilizes the presence of the ‘KRAS’ gene mutation. Cetuximab is prescribed to patients who don’t carry the KRAS gene mutation.
However, even in patients without the KRAS gene mutation, the response rate of Cetuximab is only about fifty percent, and there is also resistance to drugs after targeted chemotherapy. Compared with conventional chemotherapy alone, the life expectancy only lasts five months on average.
In research featured in the FEBS Journal as the cover paper for the April 7 edition, the KAIST research team led by Professor Kwang-Hyun Cho at the Department of Bio and Brain Engineering presented five additional biomarkers that could increase Cetuximab responsiveness using systems biology approach that combines genomic data analysis, mathematical modeling, and cell experiments. The experimental inhibition of newly discovered biomarkers DUSP4, ETV5, GNB5, NT5E, and PHLDA1 in colorectal cancer cells has been shown to overcome Cetuximab resistance in KRAS-normal genes. The research team confirmed that when suppressing GNB5, one of the new biomarkers, it was shown to overcome resistance to Cetuximab regardless of having a mutation in the KRAS gene.
Professor Cho said, “There has not been an example of colorectal cancer treatment involving regulation of the GNB5 gene.” He continued, “Identifying the principle of drug resistance in cancer cells through systems biology and discovering new biomarkers that could be a new molecular target to overcome drug resistance suggest real potential to actualize precision medicine.”
This study was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT (2017R1A2A1A17069642 and 2015M3A9A7067220).
Image 1. The cover of FEBS Journal for April 2019
2019.05.27 View 57515 -
Engineered Microbial Production of Grape Flavoring
(Image 1: Engineered bacteria that produce grape flavoring.)
Researchers report a microbial method for producing an artificial grape flavor. Methyl anthranilate (MANT) is a common grape flavoring and odorant compound currently produced through a petroleum-based process that uses large volumes of toxic acid catalysts.
Professor Sang-Yup Lee’s team at the Department of Chemical and Biomolecular Engineering demonstrated production of MANT, a naturally occurring compound, via engineered bacteria. The authors engineered strains of Escherichia coli and Corynebacetrium glutamicum to produce MANT through a plant-based engineered metabolic pathway.
The authors tuned the bacterial metabolic pathway by optimizing the levels of AAMT1, the key enzyme in the process. To maximize production of MANT, the authors tested six strategies, including increasing the supply of a precursor compound and enhancing the availability of a co-substrate. The most productive strategy proved to be a two-phase extractive culture, in which MANT was extracted into a solvent. This strategy produced MANT on the scale of 4.47 to 5.74 grams per liter, a significant amount, considering that engineered microbes produce most natural products at a scale of milligrams or micrograms per liter.
According to the authors, the results suggest that MANT and other related molecules produced through industrial processes can be produced at scale by engineered microbes in a manner that would allow them to be marketed as natural one, instead of artificial one.
This study, featured at the Proceeding of the National Academy of Sciences of the USA on May 13, was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries from the Ministry of Science and ICT.
(Image 2. Overview of the strategies applied for the microbial production of grape flavoring.)
2019.05.15 View 52830