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Development of a Highly-Accurate Computational Model of Human Metabolism
A research team from KAIST developed a computational framework that enables the reconstruction of a comprehensive computational model of human metabolism, which allows for an accurate prediction of personal metabolic features (or phenotypes). Understanding personal metabolic phenotypes allows us to design effective therapeutic strategies for various chronic and infectious diseases. A human computational model called the genome-scale metabolic model (GEM) contains information on thousands of metabolic genes and their corresponding reactions and metabolites, and has played an important role in predicting metabolic phenotypes. Although several versions of human GEMs have been released, they had room for further development, especially as to incorporating biological information coming from a human genetics mechanism called “alternative splicing.” Alternative splicing is a genetic mechanism that allows a gene to give rise to multiple reactions, and is strongly associated with pathology. To tackle this problem, Jae Yong Ryu (a Ph.D. student), Dr. Hyun Uk Kim (Research Fellow), and Distinguished Professor Sang Yup Lee, all from the Department of Chemical and Biomolecular Engineering at KAIST, developed a computational framework that systematically generates metabolic reactions, and adds them to the human GEM. The resulting human GEM was demonstrated to accurately predict metabolic phenotypes under varied environmental conditions. The research results were published online in Proceedings of the National Academy of Sciences (PNAS) on October 24, 2017, under the title “Framework and resource for more than 11,000 gene-transcript-protein-reaction associations in human metabolism.” The research team first updated the biological contents of a previous version of the human GEM. The updated biological contents include metabolic genes and their corresponding metabolites and reactions. In particular, metabolic reactions catalyzed by already-known protein isoforms were additionally incorporated into the human GEM; protein isoforms are multiple variants of proteins generated from individual genes through the alternative splicing process. Each protein isoform is often responsible for the operation of a metabolic reaction. Although multiple protein isoforms generated from one gene can play different functions by having different sets of protein domains and/or subcellular localizations, such information was not properly considered in previous versions of human GEMs. Upon the initial update of the human GEM, named Recon 2M.1, the research team subsequently implemented a computational framework that systematically generates information on Gene-Transcript-Protein-Reaction Associations (GeTPRA) in order to identify protein isoforms that were previously not identified. This framework was developed in this study. As a result of the implementation of the framework for GeTPRA, more than 11,000 GeTPRA were automatically predicted, and thoroughly validated. Additional metabolic reactions were then added to Recon 2M.1 based on the predicted GeTPRA for the previously uncharacterized protein isoforms; Recon 2M.1 was renamed Recon 2M.2 from this upgrade. Finally, Recon 2M.2 was integrated with 446 sets of personal biological data (RNA-Seq data) in order to build patient-specific cancer models. These patient-specific cancer models were used to predict cancer metabolism activities and anticancer targets. The development of a new version of human GEMs along with the computational framework for GeTPRA is expected to boost studies in fundamental human genetics and medicine. Model files of the human GEMs Recon 2M.1 and 2M.2, a full list of the GeTPRA and the source code for the computational framework to predict the GeTPRA are all available as part of the publication of this study. Distinguished Professor Lee said, “The predicted GeTPRA from the computational framework is expected to serve as a guideline for future experiments on human genetics and biochemistry, whereas the resulting Recon 2M.2 can be used to predict drug targets for various human diseases.” This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557) from the Ministry of Science and ICT through the National Research Foundation (NRF) of Korea. (Figure 1:A scheme of Recon 2M.1 development and its use in reconstructing personal genome-scale metabolic models (GEMs). (A) A concept of alternative splicing of human genes and its use in Gene-Transcript-Protein-Reaction Associations (GeTPRA) of Recon 2M.1. (B) A procedure of systematic refinement of the Recon 2Q. Recon 2Q is one of the previously released human GEMs. Biochemically inconsistent reactions include unbalanced, artificial, blocked, and/or redundant reactions. Iterative manual curation was conducted while validating the Recon 2M.1. (C) Reconstruction of cancer patient-specific GEMs using Recon 2M.1 for further simulation studies. In this study, personal biological data (RNA-Seq data) were obtained from The Cancer Genome Atlas (TCGA; https://cancergenome.nih.gov/ ) across the ten cancer types. (Figure 2: Computational framework for the systematic generation of Gene-Transcript-Protein-Reaction Associations (GeTPRA; red box in the flowchart). Peptide sequences of metabolic genes defined in Recon 2M.1 were retrieved from a database called Ensembl. EC numbers and subcellular localizations of all the protein isoforms of metabolic genes in Recon 2M.1 were predicted using software programs EFICAz2.5 and Wolf PSort, respectively. Information on the newly predicted GeTPRA was systematically incorporated into the Recon 2M.1, thereby resulting in Recon 2M.2.)
Semiconductor Patterning of Seven Nanometers Technology Using a Camera Flash
A research team led by Professor Sang Ouk Kim in the Department of Materials Science and Engineering at KAIST has developed semiconductor manufacturing technology using a camera flash. This technology can manufacture ultra-fine patterns over a large area by irradiating a single flash with a seven-nanometer patterning technique for semiconductors. It can facilitate the manufacturing of highly efficient, integrated semiconductor devices in the future. Technology for the Artificial Intelligence (AI), the Internet of Things (IoTs), and big data, which are the major keys for the fourth Industrial Revolution, require high-capacity, high-performance semiconductor devices. It is necessary to develop lithography technology to produce such next-generation, highly integrated semiconductor devices. Although related industries have been using conventional photolithography for small patterns, this technique has limitations for forming a pattern of sub-10 nm patterns. Molecular assembly patterning technology using polymers has been in the spotlight as the next generation technology to replace photolithography because it is inexpensive to produce and can easily form sub-10 nm patterns. However, since it generally takes a long time for heat treatment at high-temperature or toxic solvent vapor treatment, mass production is difficult and thus its commercialization has been limited. The research team introduced a camera flash that instantly emits strong light to solve the issues of polymer molecular assembly patterning. Using a flash can possibly achieve a semiconductor patterning of seven nanometers within 15 milliseconds (1 millisecond = 1/1,000 second), which can generate a temperature of several hundred degrees Celsius in several tens of milliseconds. The team has demonstrated that applying this technology to polymer molecular assembly allows a single flash of light to form molecular assembly patterns. The team also identified its compatibility with polymer flexible substrates, which are impossible to process at high temperatures. Through these findings, the technology can be applied to the fabrication of next-generation, flexible semiconductors. The researchers said the camera flash photo-thermal process will be introduced into molecular assembly technology and this highly-efficiency technology can accelerate the realization of molecular assembly semiconductor technology. Professor Kim, who led the research, said, “Despite its potential, molecular assembly semiconductor technology has remained a big challenge in improving process efficiency.” “This technology will be a breakthrough for the practical use of molecular assembly-based semiconductors.” The paper was published in the international journal, Advanced Materials on August 21 with first authors, researcher Hyeong Min Jin and PhD candidate Dae Yong Park. The research, sponsored by the Ministry of Science and ICT, was co-led Professor by Keon Jae Lee in the Department of Materials Science and Engineering at KAIST, and Professor Kwang Ho Kim in the School of Materials Science and Engineering at Pusan National University. (1. Formation of semiconductor patterns using a camera flash) (Schematic diagram of molecular assembly pattern using a camera flash) (Self-assembled patterns)
Discovery of an Optimal Drug Combination: Overcoming Resistance to Targeted Drugs for Liver Cancer
A KAIST research team presented a novel method for improving medication treatment for liver cancer using Systems Biology, combining research from information technology and the life sciences. Professor Kwang-Hyun Cho in the Department of Bio and Brain Engineering at KAIST conducted the research in collaboration with Professor Jung-Hwan Yoon in the Department of Internal Medicine at Seoul National University Hospital. This research was published in Hepatology in September 2017 (available online from August 24, 2017). Liver cancer is the fifth and seventh most common cancer found in men and women throughout the world, which places it second in the cause of cancer deaths. In particular, Korea has 28.4 deaths from liver cancer per 100,000 persons, the highest death rate among OECD countries and twice that of Japan. Each year in Korea, 16,000 people get liver cancer on average, yet the five-year survival rate stands below 12%. According to the National Cancer Information Center, lung cancer (17,399) took the highest portion of cancer-related deaths, followed by liver cancer (11,311) based on last year data. Liver cancer is known to carry the highest social cost in comparison to other cancers and it causes the highest fatality in earlier age groups (40s-50s). In that sense, it is necessary to develop a new treatment that mitigates side effects yet elevates the survival rate. There are ways in which liver cancer can be cured, such as surgery, embolization, and medication treatments; however, the options become limited for curing progressive cancer, a stage in which surgical methods cannot be executed. Among anticancer medications, Sorafenib, a drug known for enhancing the survival rate of cancer patients, is a unique drug allowed for use as a targeted anticancer medication for progressive liver cancer patients. Its sales reached more than ten billion KRW annually in Korea, but its efficacy works on only about 20% of the treated patients. Also, acquired resistance to Sorafenib is emerging. Additionally, the action mechanism and resistance mechanism of Sorafenib is only vaguely identified.Although Sorafenib only extends the survival rate of terminal cancer patients less than three months on average, it is widely being used because drugs developed by global pharmaceutical companies failed to outperform its effectiveness. Professor Cho’s research team analyzed the expression changes of genes in cell lines in response to Sorafenib in order to identify the effect and the resistance mechanism of Sorafenib. As a result, the team discovered the resistance mechanism of Sorafenib using Systems Biology analysis. By combining computer simulations and biological experiments, it was revealed that protein disulfide isomerase (PDI) plays a crucial role in the resistance mechanism of Sorafenib and that its efficacy can be improved significantly by blocking PDI. The research team used mice in the experiment and discovered the synergic effect of PDI inhibition with Sorafenib for reducing liver cancer cells, known as hepatocellular carcinoma. Also, more PDIs are shown in tissue from patients who possess a resistance to Sorafenib. From these findings, the team could identify the possibility of its clinical applications. The team also confirmed these findings from clinical data through a retrospective cohort study. “Molecules that play an important role in cell lines are mostly put under complex regulation. For this reason, the existing biological research has a fundamental limitations for discovering its underlying principles,” Professor Cho said. “This research is a representative case of overcoming this limitation of traditional life science research by using a Systems Biology approach, combining IT and life science. It suggests the possibility of developing a new method that overcomes drug resistance with a network analysis of the targeted drug action mechanism of cancer.” The research was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT. (Figure 1. Simulation results from cellular experiments using hepatocellular carcinoma) (Figure 2. Network analysis and computer simulation by using the endoplasmic reticulum (ER) stress network) (Figure 3. ER stress network model)
Cooperative Tumor Cell Membrane-Targeted Phototherapy
A KAIST research team led by Professor Ji-Ho Park in the Bio and Brain Engineering Department at KAIST developed a technology for the effective treatment of cancer by delivering synthetic receptors throughout tumor tissue. The study, led by Ph.D. candidate Heegon Kim, was published online in Nature Communications on June 19. Cancer targeted therapy generally refers to therapy targeting specific molecules that are involved in the growth and generation of cancer. The targeted delivery of therapeutics using targeting agents such as antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumors have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. To solve this problem, the team constructed a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumor cell membrane-selective localization of synthetic receptors to amplify the subsequent targeting of therapeutics. Here, synthetic and biological nanocomponents refer to liposomes and extracellular vesicles, respectively. The synthetic receptors are first delivered selectively to tumor cell membranes in the perivascular region using liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the synthetic receptors are transferred to neighboring cells and further spread throughout the tumor tissues where the molecular targets are limited. Hitchhiking extracellular vesicles for delivery of synthetic receptors was possible since extracellular vesicles, such as exosomes, mediate intercellular communications by transferring various biological components such as lipids, cytosolic proteins, and RNA through a membrane fusion process. They also play a supportive role in promoting tumor progression in that tumor-derived extracellular vesicles deliver oncogenic signals to normal host cells. The team showed that this tumor cell membrane-targeted delivery of synthetic receptors led to a uniform distribution of synthetic receptors throughout a tumor and subsequently led to enhanced phototherapeutic efficacy of the targeted photosensitizer. Professor Park said, “The cooperative tumor targeting system is expected to be applied in treating various diseases that are hard to target.” The research was funded by the Basic Science Research Program through the National Research Foundation funded by the Ministry of Science, ICT & Future Planning, and the National R&D Program for Cancer Control funded by the Ministry for Health and Welfare. (Ph.D. candidates Hee Gon Kim (left) and Chanhee Oh) Figure 1. A schematic of a cooperative tumor targeting system via delivery of synthetic receptors. Figure 2. A confocal microscopic image of a tumor section after cooperative targeting by synthetic receptor delivery. Green and magenta represent vessels and therapeutic agents inside a tumor respectively.
Bio-based p-Xylene Oxidation into Terephthalic Acid by Engineered E.coli
KAIST researchers have established an efficient biocatalytic system to produce terephthalic acid (TPA) from p-xylene (pX). It will allow this industrially important bulk chemical to be made available in a more environmentally-friendly manner. The research team developed metabolically engineered Escherichia coli (E.coli) to biologically transform pX into TPA, a chemical necessary in the manufacturing of polyethylene terephthalate (PET). This biocatalysis system represents a greener and more efficient alternative to the traditional chemical methods for TPA production. This research, headed by Distinguished Professor Sang Yup Lee, was published in Nature Communications on May 31. The research team utilized a metabolic engineering and synthetic biology approach to develop a recombinant microorganism that can oxidize pX into TPA using microbial fermentation. TPA is a globally important chemical commodity for manufacturing PET. It can be applied to manufacture plastic bottles, clothing fibers, films, and many other products. Currently, TPA is produced from pX oxidation through an industrially well-known chemical process (with a typical TPA yield of over 95 mol%), which shows, however, such drawbacks as intensive energy requirements at high temperatures and pressure, usage of heavy metal catalysts, and the unavoidable byproduct formation of 4-carboxybenzaldehyde. The research team designed and constructed a synthetic metabolic pathway by incorporating the upper xylene degradation pathway of Pseudomonas putida F1 and the lower p-toluene sulfonate pathway of Comamonas testosteroni T-2, which successfully produced TPA from pX in small-scale cultures, with the formation of p-toluate (pTA) as the major byproduct. The team further optimized the pathway gene expression levels by using a synthetic biology toolkit, which gave the final engineered E. coli strain showing increased TPA production and the complete elimination of the byproduct. Using this best-performing strain, the team designed an elegant two-phase (aqueous/organic) fermentation system for TPA production on a larger scale, where pX was supplied in the organic phase. Through a number of optimization steps, the team ultimately achieved production of 13.3 g TPA from 8.8 g pX, which represented an extraordinary yield of 97 mol%. The team has developed a microbial biotechnology application which is reportedly the first successful example of the bio-based production of TPA from pX by the microbial fermentation of engineered E. coli. This bio-based TPA technology presents several advantages such as ambient reaction temperature and pressure, no use of heavy metals or other toxic chemicals, the removable of byproduct formation, and it is 100% environmentally compatible. Professor Lee said, “We presented promising biotechnology for producing large amounts of the commodity chemical TPA, which is used for PET manufacturing, through metabolically engineered gut bacterium. Our research is meaningful in that it demonstrates the feasibility of the biotechnological production of bulk chemicals, and if reproducible when up-scaled, it will represent a breakthrough in hydrocarbon bioconversions.” Ph.D. candidate Zi Wei Luo is the first author of this research (DOI:10.1038/ncomms15689).The research was supported by the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) of the Ministry of Science, ICT & Future Planning through the National Research Foundation of Korea. Figure: Biotransformation of pX into TPA by engineered E. coli. This schematic diagram shows the overall conceptualization of how metabolically engineered E. coli produced TPA from pX. The engineered E. coli was developed through reconstituting a synthetic metabolic pathway for pX conversion to TPA and optimized for increased TPA yield and byproduct elimination. Two-phase partitioning fermentation system was developed for demonstrating the feasibility of large-scale production of TPA from pX using the engineered E. coli strains, where pX was supplied in the organic phase and TPA was produced in the aqueous phase.
Observation of the Phase Transition of Liquid Crystal Defects
KAIST researchers observed the phase transition of topological defects formed by liquid crystal (LC) materials for the first time. The phase transition of topological defects, which was also the theme of the Nobel Prize for Physics in 2016, can be difficult to understand for a layperson but it needs to be studied to understand the mysteries of the universe or the underlying physics of skyrmions, which have intrinsic topological defects. If the galaxy is taken as an example in the universe, it is difficult to observe the topological defects because the system is too large to observe some changes over a limited period of time. In the case of defect structures formed by LC molecules, they are not only a suitable size to observe with an optical microscope, but also the time period in which the phase transition of a defect occurring can be directly observed over a few seconds, which can be extended to a few minutes. The defect structures formed by LC material have radial, circular, or spiral shapes centering on a singularity (defect core), like the singularity that was already introduced in the famous movie "Interstellar,” which is the center point of black hole. In general, LC materials are mainly used in liquid crystal displays (LCDs) and optical sensors because it is easy to control their specific orientation and they have fast response characteristics and huge anisotropic optical properties. It is advantageous in terms of the performance of LCDs that the defects of the LC materials are minimized. The research team led by Professor Dong Ki Yoon in the Graduate School of Nanoscience and Technology did not simply minimize such defects but actively tried to use the LC defects as building blocks to make micro- and nanostructures for the patterning applications. During these efforts, they found the way to directly study the phase transition of topological defects under in-situ conditions. Considering the LC material from the viewpoint of a device like a LCD, robustness is important. Therefore, the LC material is injected through the capillary phenomenon between a rigid two-glass plate and the orientation of the LCs can be followed by the surface anchoring condition of the glass substrate. However, in this conventional case, it is difficult to observe the phase transition of the LC defect due to this strong surface anchoring force induced by the solid substrate. In order to solve this problem, the research team designed a platform, in which the movement of the LC molecules was not restricted, by forming a thin film of LC material on water, which is like oil floating on water. For this, a droplet of LC material was dripped onto water and spread to form a thin film. The topological defects formed under this circumstance could show the thermal phase transition when the temperature was changed. In addition, this approach can trace back the morphology of the original defect structure from the sequential changes during the temperature changes, which can give hints to the study of the formation of topological defects in the cosmos or skyrmions. Prof. Yoon said, “The study of LC crystal defects itself has been extensively studied by physicists and mathematicians for about 100 years. However, this is the first time that we have observed the phase transition of LC defects directly.” He also added, "Korea is leading in the LCD industry, but our basic research on LCs is not at the world's research level." The first author of this study is Dr. Min-Jun Gimand supported by a grant from the National Research Foundation (NRF) and funded by the Korean Government (MSIP). The research result was published on May 30, 2017 in Nature Communications. Figure 1. The phase transition of the LC topological defect on cooling. Figure 2. Polarizing optical microscopy images of topological defects depending on the strength of the director field. (a,b,e) Convergent director field arrangements of LC molecules and corresponding schematic images; (c,d,f) Divergent director field arrangements of LC molecules and corresponding schematic images.
Extreme Materials for Fusion with Metal Cocktail
The research team under Professor Ryu Ho-jin of the Department of Nuclear and Quantum Engineering has developed a new material for facing fusion plasma environments using metal powder mixing technology. This technology is expected to extend the range of materials that can be designed for use in extreme environments such as in fusion power generators. The durability of the tokamak vessel, which holds high-temperature plasma, is very important to create fusion power reactors, which are expected to be a future energy source. Currently, high-melting-point metals, such as tungsten, are considered plasma-facing materials to protect the tokamak vessel. However, high-energy thermal shocks, plasma ions, and neutrons are fatal to the plasma-facing material during high temperature fusion plasma operation. Therefore, it is necessary to develop new high-performance materials. The ITER project, in which seven countries including the United States, the EU, and Korea participate jointly, is constructing a nuclear fusion experimental reactor in France with the goal of achieving the first plasma in 2025 and deuterium-tritium fusion operation in 2035. In Korea, the KSTAR tokamak at the National Fusion Research Institute has succeeded in maintaining high-performance plasma for 70 seconds. Researchers in Europe, the United States, and China, who are leading the research on fusion plasma-facing materials, are studying the improvement of physical properties by adding a small amount of metal elements to tungsten. However, Professor Ryu’s team reported that by mixing various metals’ powders, including tungsten, they have succeeded in producing a new material that has twice the hardness and strength of tungsten. The difference in the atomic sizes of the well-mixed elements in the alloy is very significant because it makes it difficult to deform the alloy. The team will continue its research to find alloying compositions that optimize mechanical properties as well as thermal conductivity, plasma interactions, neutron irradiation embrittlement, tritium absorption, and high-temperature oxidation properties. Professor Ryu said, "Fusion plasma-facing materials are exposed to extreme environments and no metal is capable of withstanding thermal shock, plasma, and neutron damage simultaneously. As a result of this research, attempts to develop complex metallic materials for nuclear fusion and nuclear power are expected to become more active around the world. " Ph.D. candidate Owais Ahmed Waseem is the first author of this project. The research is supported by the Ministry of Science, ICT and Future Planning, the Korea Research Foundation's Fusion Basic Research project, and the Engineering Research Center. The results were published in 'Scientific Report' on May 16. Figure 1. Tungsten-based high strengh alloy sample Figure 2. Fusion plasma facing material development by powder processing of refractory elements
Tactile Sensor for Robot Skin Advanced by KAIST Team
The joint research team of Professors Jung Kim and Inkyu Park from the Department of Mechanical Engineering developed a tactile sensor that can act as skin for robots using silicon and carbon materials. This technology produced a sensor that can absorb shock and distinguish various forms of touch, and it is hoped to be used as robot skin in the future. Skin serves an important role as the largest organ of the human body. As well as protecting major organs from external shock, skin also measures and distinguishes delicate tactile information and transfer it to the nervous system. Current robotic sensory technology allows robots to have visual and auditory systems at nearly similar levels to human capacity, but there are limitations in tactile sensors that can detect changes in the environment throughout the body. To apply skin with similar functions as humans to robots, it is essential to develop skin sensor technology with high flexibility and high shock absorption. Another limitation for developing robot skin was connecting numerous sensors all over the body using electric wiring. To overcome this problem, the research team combined silicon and carbon nanotubes (CNT) to produce a composite, which was then used in combination with a medical imaging technique called electrical impedance tomography (EIT). This led to technology that can distinguish various forms of force over a large area without electrical wiring. The sensing material can distinguish the location and the size of various forms by touch, and thus can be applied to robot skin that can absorb shock as well as serves as a 3D computer interface and tactile sensor. It can withstand strong force such as a hammer strike, and can be re-used even after partial damage to the sensor by filling and hardening the damaged region with composite. Further, the sensor can be made by filling a 3D shape frame with silicon-nanotube composite. Using this technology, new forms of computer interaces can be developed with both curbed and flat surfaces. This research was conducted through a collaboration between Professor Park, an expert in nanostructures and sensors, and Professor Kim, an expert in bio-robotics. Hence, the technology is likely to be applied in real products. Professor Kim said, “Flexible tactile sensors can not only be directly adhered to the body, but they also provides information on modified states in multiple dimensions”. He continued, “This technology will contribute to the soft robot industry in the areas of robot skin and the field of wearable medical appliances.” Professor Park said, “This technology implemented a next-generation user interface through the integration of functional nano-composite material and computer tomography.” This research was published in Scientific Reports, a sister journal of Nature, online on January 25. This research was conducted as joint research by first author Hyo-Sang Lee, as well as Donguk Kwon and Ji-seung Cho, and was funded by the Ministry of Science, ICT and Future Planning. (Fiigrue 1: Robotic hand responding to resistance via a connection with the developed tactile sensor) (Figure 2: Manufacturing process for pressure-resistant composite using silicon rubber and carbon nanotubes) (Figure 3: Computer interface using pressure-resistant composite)
An Improved Carbon Nanotube Semiconductor
Professor Yang-Kyu Choi and his research team of the School of Electrical Engineering at KAIST collaborated with Professor Sung-Jin Choi of Kookmin University to develop a large-scale carbon nanotube semiconductor by using a 3-D fin-gate structure with carbon nanotubes on its top. Dong Il Lee, a postdoctoral researcher at KAIST’s Electrical Engineering School, participated in this study as the first author. It was published in ACS Nano on November 10, 2016, and was entitled “Three-Dimensional Fin-Structured Semiconducting Carbon Nanotube Network Transistor.” A semiconductor made with carbon nanotubes operates faster than a silicon semiconductor and requires less energy, yielding higher performance. Most electronic equipment and devices, however, use silicon semiconductors because it is difficult to fabricate highly purified and densely packed semiconductors with carbon nanotubes (CNTs). To date, the performance of CNTs was limited due to their low density. Their purity was also low, so it was impossible to make products that had a constant yield on a large-surface wafer or substrate. These characteristics made the mass production of semiconducting CNTs difficult. To solve these difficulties, the research team used a 3-D fin-gate to vapor-deposit carbon nanotubes on its top. They developed a semiconductor that had a high current density with a width less than 50 nm. The three-dimensional fin structure was able to vapor-deposit 600 carbon nanotubes per micrometer. This structure could have 20 times more nanotubes than the two dimensional structure, which could only vapor-deposit thirty in the same 1 micrometer width. In addition, the research team used semi-conductive carbon nanotubes having a purity rating higher than 99.9% from a previous study to obtain a high yield semiconductor. The semiconductor from the research group has a high current density even with a width less than 50 μm. The new semiconductor is expected to be five times faster than a silicon-based semiconductor and will require five times less electricity during operation. Furthermore, the new semiconductor can be made by or will be compatible with the equipment for producing silicon-based semiconductors, so there will be no additional costs. Researcher Lee said, “As a next generation semiconductor, the carbon nanotube semiconductor will have better performance, and its effectiveness will be higher.” He also added, “Hopefully, the new semiconductor will replace the silicon-based semiconductors in ten years.” This study received support from the Center for Integrated Smart Sensors funded by the Ministry of Science, ICT & Future Planning of Korea as the Global Frontier Project, and from the CMOS (Complementary Metal-Oxide-Semiconductor) THz Technology Convergence Center of the Pioneer Research Center Program sponsored by the National Research Foundation of Korea. Picture 1: 3D Diagram of the Carbon Nanotube Electronic Device and Its Scanning Electron Microscope (SEM) Image Picture 2: 3D Transistor Device on an 8-inch Base and the SEM Image of Its Cross Section
Unveiling the Distinctive Features of Industrial Microorganism
KAIST researchers have sequenced the whole genome of Clostridium tyrobutyricum, which has a higher tolerance to toxic chemicals, such as 1-butanol, compared to other clostridial bacterial strains. Clostridium tyrobutyricum, a Gram-positive, anaerobic spore-forming bacterium, is considered a promising industrial host strain for the production of various chemicals including butyric acid which has many applications in different industries such as a precursor to biofuels. Despite such potential, C. tyrobutyricum has received little attention, mainly due to a limited understanding of its genotypic and metabolic characteristics at the genome level. A Korean research team headed by Distinguished Professor Sang Yup Lee of the Chemical and Biomolecular Engineering Department at the Korea Advanced Institute of Science and Technology (KAIST) deciphered the genome sequence of C. tyrobutyricum and its proteome profiles during the course of batch fermentation. As a result, the research team learned that the bacterium is not only capable of producing a large amount of butyric acid but also can tolerate toxic compounds such as 1-butanol. The research results were published in mBio on June 14, 2016. The team adopted a genoproteomic approach, combining genomics and proteomics, to investigate the metabolic features of C. tyrobutyricum. Unlike Clostridium acetobutylicum, the most widely used organism for 1-butanol production, C. tyrobutyricum has a novel butyrate-producing pathway and various mechanisms for energy conservation under anaerobic conditions. The expression of various metabolic genes, including those involved in butyrate formation, was analyzed using the “shotgun” proteome approach. To date, the bio-based production of 1-butanol, a next-generation biofuel, has relied on several clostridial hosts including C. acetobutylicum and C. beijerinckii. However, these organisms have a low tolerance against 1-butanol even though they are naturally capable of producing it. C. tyrobutyricum cannot produce 1-butanol itself, but has a higher 1-butanol-tolerance and rapid uptake of monosaccharides, compared to those two species. The team identified most of the genes involved in the central metabolism of C. tyrobutyricum from the whole-genome and shotgun proteome data, and this study will accelerate the bacterium’s engineering to produce useful chemicals including butyric acid and 1-butanol, replacing traditional bacterial hosts. Professor Lee said, “The unique metabolic features and energy conservation mechanisms of C. tyrobutyricum can be employed in the various microbial hosts we have previously developed to further improve their productivity and yield. Moreover, findings on C. tyrobutyricum revealed by this study will be the first step to directly engineer this bacterium.” Director Jin-Woo Kim at the Platform Technology Division of the Ministry of Science, ICT and Future Planning of Korea, who oversees the Technology Development Program to Solve Climate Change, said, “Over the years, Professor Lee’s team has researched the development of a bio-refinery system to produce natural and non-natural chemicals with the systems metabolic engineering of microorganisms. They were able to design strategies for the development of diverse industrial microbial strains to produce useful chemicals from inedible biomass-based carbon dioxide fixation. We believe the efficient production of butyric acid using a metabolic engineering approach will play an important role in the establishment of a bioprocess for chemical production.” The title of the research paper is “Deciphering Clostridium tyrobutyricum Metabolism Based on the Who-Genome Sequence and Proteome Analyses.” (DOI: 10.1128/mBio.00743-16) The lead authors are Joungmin Lee, a post-doctoral fellow in the BioProcess Research Center at KAIST, currently working in CJ CheilJedang Research Institute; Yu-Sin Jang, a research fellow in the BioProcess Research Center at KAIST, currently working at Gyeongsang National University as an assistant professor; and Mee-Jung Han, an assistant professor in the Environmental Engineering and Energy Department at Dongyang University. Jin Young Kim, a senior researcher at the Korea Basic Science Institute, also participated in the research. This research was supported by the Technology Development Program to Solve Climate Change’s research project entitled “Systems Metabolic Engineering for Biorefineries” from the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea (NRF-2012M1A2A2026556). Schematic Diagram of C. tyrobutyricum’s Genome Sequence and Its Proteome Profiles The picture below shows the complete genome sequence, global protein expression profiles, and the genome-based metabolic characteristics during batch fermentation of C. tyrobutyricum.
Establishment of System Metabolic Engineering Strategies
Although conventional petrochemical processes have generated chemicals and materials which have been useful to mankind, they have also triggered a variety of environmental problems including climate change and relied too much on nonrenewable natural resources. To ameliorate this, researchers have actively pursued the development of industrial microbial strains around the globe in order to overproduce industrially useful chemicals and materials from microbes using renewable biomass. This discipline is called metabolic engineering. Thanks to advances in genetic engineering and our knowledge of cellular metabolism, conventional metabolic engineering efforts have succeeded to a certain extent in developing microbial strains that overproduce bioproducts at an industrial level. However, many metabolic engineering projects launched in academic labs do not reach commercial markets due to a failure to fully integrate industrial bioprocesses. In response to this, Distinguished Professor Sang Yup Lee and Dr. Hyun Uk Kim, both from the Department of Chemical and Biomolecular Engineering at KAIST, have recently suggested ten general strategies of systems metabolic engineering to successfully develop industrial microbial strains. Systems metabolic engineering differs from conventional metabolic engineering by incorporating traditional metabolic engineering approaches along with tools of other fields, such as systems biology, synthetic biology, and molecular evolution. The ten strategies of systems metabolic engineering have been featured in Nature Biotechnology released online in October 2015, which is entitled "Systems strategies for developing industrial microbial strains." The strategies cover economic, state-of-the-art biological techniques and traditional bioprocess aspects. Specifically, they consist of: 1) project design including economic evaluation of a target bioproduct; 2) selection of host strains to be used for overproduction of a bioproduct; 3) metabolic pathway reconstruction for bioproducts that are not naturally produced in the selected host strains; 4) increasing tolerance of a host strain against the bioproduct; 5) removing negative regulatory circuits in the microbial host limiting overproduction of a bioproduct; 6) rerouting intracellular fluxes to optimize cofactor and precursor availability necessary for the bioproduct formation; 7) diagnosing and optimizing metabolic fluxes towards product formation; 8) diagnosis and optimization of microbial culture conditions including carbon sources; 9) system-wide gene manipulation to further increase the host strain's production performance using high-throughput genome-scale engineering and computational tools; and 10) scale-up fermentation of the developed strain and diagnosis for the reproducibility of the strain's production performance. These ten strategies were articulated with successful examples of the production of L-arginine using Corynebacterium glutamicum, 1,4-butanediol using Escherichia coli, and L-lysine and bio-nylon using C. glutamicum. Professor Sang Yup Lee said, "At the moment, the chance of commercializing microbial strains developed in academic labs is very low. The strategies of systems metabolic engineering outlined in this analysis can serve as guidelines when developing industrial microbial strains. We hope that these strategies contribute to improving opportunities to commercialize microbial strains developed in academic labs with drastically reduced costs and efforts, and that a large fraction of petroleum-based processes will be replaced with sustainable bioprocesses." Lee S. Y. & Kim, H. U. Systems Strategies for Developing Industrial Microbial Strains. Nature Biotechnology (2015). This work was supported by the Technology Development Program to Solve Climate Change on Systems Metabolic Engineering for Biorefineries (NRF-2012M1A2A2026556) and by the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) from the Ministry of Science, ICT and Future Planning (MSIP), Korea, and through the National Research Foundation (NRF) of Korea. This work was also supported by the Novo Nordisk Foundation. Picture: Concept of the Systems Metabolic Engineering Framework (a) Three major bioprocess stages (b) Considerations in systems metabolic engineering to optimize the whole bioprocess. List of considerations for the strain development and fermentation contribute to improving microbial strain's production performance (red), whereas those for the separation and purification help in reducing overall operation costs by facilitating the downstream process (blue). Some of the considerations can be repeated in the course of systems metabolic engineering.
KAIST Develops Subminiature, Power-Efficient Air Pollution Sensing Probe
Professor Inkyu Park and his research team from the Department of Mechanical Engineering at KAIST have developed a subminiature, power-efficient air-pollution sensing probe that can be applied to mobile devices. Their research findings were published online in the January 30th issue of Scientific Reports. As air pollution has increased, people have taken greater interest in health care. The developed technology could allow people to measure independently the air pollution level of their surrounding environments. Previous instruments used to measure air pollution levels were bulky and consumed a lot of power. They also often produced inaccurate results when measuring air pollution in which different toxic gases were mixed. These problems could not be resolved with existing semiconductor manufacturing process. Using local temperature field control technology, Professor Park’s team succeeded in integrating multiple heterogeneous nanomaterials and fitting them onto a small, low-power electronic chip. This microheating sensor can heat microscale regions through local hydrothermal synthesis. Because it requires a miniscale amount of nanomaterials to manufacture, the sensor is most suitable for mobile devices. Professor Park said, “Our research will contribute to the development of convergence technology in such field as air pollution sensing probes, biosensors, electronic devices, and displays.” The team's research was supported by the Ministry of Education and the Ministry of Science, ICT and Future Planning, Republic of Korea. Figure 1 – The Concept of Multiple Nanomaterial Device and Numerical Simulation Results of Precursor Solutions Figure 2 - Multiple Nanomaterial Manufactured in a Microscale Region
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