research
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Anti-Cancer Therapy Delivering Drug to an Entire Tumor Developed
KAIST’s Department of Bio and Brain Engineering Professor Ji-Ho Park and his team successfully developed a new highly efficacious anti-cancer nanotechnology by delivering anti-cancer drugs uniformly to an entire tumor. Their research results were published in Nano Letters online on March 31, 2015.
To treat inoperable tumors, anti-cancer medicine is commonly used. However, efficient drug delivery to tumor cells is often difficult, treating an entire tumor with drugs even more so.
Using the existing drug delivery systems, including nanotechnology, a drug can be delivered only to tumor cells near blood vessels, leaving cells at the heart of a tumor intact. Since most drugs are injected into the bloodstream, tumor recurrence post medication is frequent.
Therefore, the team used liposomes that can fuse to the cell membrane and enter the cell. Once inside liposomes the drug can travel into the bloodstream, enter tumor cells near blood vessels, where they are loaded to exosomes, which are naturally occurring nanoparticles in the body. Since exosomes can travel between cells, the drug can be delivered efficiently into inner cells of the tumor.
Exosomes, which are secreted by cells that exist in the tumor microenvironment, is known to have an important role in tumor progression and metastasis since they transfer biological materials between cells. The research team started the investigation recognizing the possibility of delivering the anti-cancer drug to the entire tumor using exosomes.
The team injected the light-sensitive anti-cancer drug using their new delivery technique into experimental mice. The researchers applied light to the tumor site to activate the anti-cancer treatment and analyzed a tissue sample. They observed the effects of the anti-cancer drug in the entire tumor tissue.
The team’s results establish a ground-breaking foothold in drug delivery technology development that can be tailored to specific diseases by understanding its microenvironment. The work paves the way to more effective drug delivery systems for many chronic diseases, including cancer tumors that were difficult to treat due to the inability to penetrate deep into the tissue.
The team is currently conducting experiments with other anti-cancer drugs, which are being developed by pharmaceutical companies, using their tumor-penetrating drug delivery nanotechnology, to identify its effects on malignant tumors.
Professor Park said, “This research is the first to apply biological nanoparticles, exosomes that are continuously secreted and can transfer materials to neighboring cells, to deliver drugs directly to the heart of tumor.”
Picture: Incorporation of hydrophilic and hydrophobic compounds into membrane vesicles by engineering the parental cells via synthetic liposomes.
2015.04.07 View 11962 -
Novel Photolithographic Technology Enabling 3D Control over Functional Shapes of Microstructures
Professor Shin-Hyun Kim and his research team in the Department of Chemical and Biomolecular Engineering at KAIST have developed a novel photolithographic technology enabling control over the functional shapes of micropatterns using oxygen diffusion.
The research was published online in the March 13th issue of Nature Communications and was selected as a featured image for the journal.
Photolithography is a standard optical process for transferring micropatterns on to a substrate by exposing specific regions of the photoresist layer to ultraviolet (UV) light. It is used widely throughout industries that require micropatterns, especially in the semiconductor manufacturing industry.
Conventional photolithography relied on photomasks which protected certain regions of the substrate from the input UV light. Areas covered by the photomasks remain intact with the base layer while the areas exposed to the UV light are washed away, thus creating a micropattern. This technology was limited to a two-dimensional, disc-shaped design as the boundaries between the exposed and roofed regions are always in a parallel arrangement with the direction of the light.
Professor Kim’s research team discovered that: 1) the areas exposed to UV light lowered the concentration of oxygen and thus resulted in oxygen diffusion; and 2) manipulation of the diffusion speed and direction allowed control of the growth, shape and size of the polymers. Based on these findings, the team developed a new photolithographic technology that enabled the production of micropatterns with three-dimensional structures in various shapes and sizes.
Oxygen was considered an inhibitor during photopolymerization. Photoresist under UV light creates radicals which initialize a chemical reaction. These radicals are eliminated with the presence of oxygen and thus prevents the reaction. This suggests that the photoresist must be exposed to UV light for an extended time to completely remove oxygen for a chemical reaction to begin.
The research team, however, exploited the presence of oxygen. While the region affected by the UV light lowered oxygen concentration, the concentration in the untouched region remained unchanged. This difference in the concentrations caused a diffusion of oxygen to the region under UV light.
When the speed of the oxygen flow is slow, the diffusion occurs in parallel with the direction of the UV light. When fast, the diffusion process develops horizontally, outward from the area affected by the UV light. Professor Kim and his team proved this phenomenon both empirically and theoretically. Furthermore, by injecting an external oxygen source, the team was able to manipulate diffusion strength and direction, and thus control the shape and size of the polymer. The use of the polymerization inhibitors enabled and facilitated the fabrication of complex, three-dimensional micropatterns.
Professor Kim said, “While 3D printing is considered an innovative manufacturing technology, it cannot be used for mass-production of microscopic products. The new photolithographic technology will have a broad impact on both the academia and industry especially because existing, conventional photolithographic equipment can be used for the development of more complex micropatterns.” His newest technology will enhance the manufacturing process of three-dimensional polymers which were considered difficult to be commercialized.
The research was also dedicated to the late Professor Seung-Man Yang of the Department of Chemical and Biomolecular Engineering at KAIST. He was considered one of the greatest scholars in Korea in the field of hydrodynamics and colloids.
Picture 1: Featured Image of Nature Communications, March 2015
Picture 2: Polymers with various shapes and sizes produced with the new photolithographic technology developed by Professor Kim
2015.04.06 View 10540 -
Polymers with Highly Improved Light-transformation Efficiency
A joint Korean research team, led by Professor Bum-Joon Kim of the Department of Chemical and Biomolecular Engineering at KAIST and Professor Young-Woo Han of the Department of Nanofusion Engineering at Pusan National University, has developed a new type of electrically-conductive polymer for solar batteries with an improved light-transformation efficiency of up to 5%. The team considers it a viable replacement for existing plastic batteries for solar power which is viewed as the energy source of the future.
Polymer solar cells have greater structural stability and heat resistance compared to fullerene organic solar cells. However, they have lower light-transformation efficiency—below 4%—compared to 10% of the latter. The low efficiency is due to the failure of blending among the polymers that compose the active layer of the cell. This phenomenon deters the formation and movement of electrons and thus lowers light-transformation efficiency.
By manipulating the structure and concentration of conductive polymers, the team was able to effectively increase the polymer blending and increase light-transformation efficiency. The team was able to maximize the efficiency up to 6% which is the highest reported ratio.
Professor Kim said, “This research demonstrates that conductive polymer plastics can be used widely for solar cells and batteries for mobile devices.”
The research findings were published in the February 18th issue of the Journal of the American Chemical Society (JACS).
Picture: Flexible Solar Cell Polymer Developed by the Research Team
2015.04.05 View 10951 -
Mystery in Membrane Traffic How NSF Disassembles Single SNAR Complex Solved
KAIST researchers discovered that the protein N-ethylmaleimide-sensitive factor (NSF) unravels a single SNARE complex using one round ATP turnover by tearing the complex with a single burst, contradicting a previous theory that it unwinds in a processive manner.
In 2013, James E. Rothman, Randy W. Schekman, and Thomas C. Südhof won the Nobel Prize in Physiology or Medicine for their discoveries of molecular machineries for vesicle trafficking, a major transport system in cells for maintaining cellular processes. Vesicle traffic acts as a kind of “home-delivery service” in cells. Vesicles package and deliver materials such as proteins and hormones from one cell organelle to another. Then it releases its contents by fusing with the target organelle’s membrane. One example of vesicle traffic is in neuronal communications, where neurotransmitters are released from a neuron. Some of the key proteins for vesicle traffic discovered by the Nobel Prize winners were N-ethylmaleimide-sensitive factor (NSF), alpha-soluble NSF attachment protein (α-SNAP), and soluble SNAP receptors (SNAREs).
SNARE proteins are known as the minimal machinery for membrane fusion. To induce membrane fusion, the proteins combine to form a SNARE complex in a four helical bundle, and NSF and α-SNAP disassemble the SNARE complex for reuse. In particular, NSF can bind an energy source molecule, adenosine triphosphate (ATP), and the ATP-bound NSF develops internal tension via cleavage of ATP. This process is used to exert great force on SNARE complexes, eventually pulling them apart. However, although about 30 years have passed since the Nobel Prize winners’ discovery, how NSF/α-SNAP disassembled the SNARE complex remained a mystery to scientists due to a lack in methodology.
In a recent issue of Science, published on March 27, 2015, a research team, led by Tae-Young Yoon of the Department of Physics at the Korea Advanced Institute of Science and Technology (KAIST) and Reinhard Jahn of the Department of Neurobiology of the Max-Planck-Institute for Biophysical Chemistry, reports that NSF/α-SNAP disassemble a single SNARE complex using various single-molecule biophysical methods that allow them to monitor and manipulate individual protein complexes.
“We have learned that NSF releases energy in a burst within 20 milliseconds to “tear” the SNARE complex apart in a one-step global unfolding reaction, which is immediately followed by the release of SNARE proteins,” said Yoon.
Previously, it was believed that NSF disassembled a SNARE complex by unwinding it in a processive manner. Also, largely unexplained was how many cycles of ATP hydrolysis were required and how these cycles were connected to the disassembly of the SNARE complex.
Yoon added, “From our research, we found that NSF requires hydrolysis of ATPs that were already bound before it attached to the SNAREs—which means that only one round of an ATP turnover is sufficient for SNARE complex disassembly. Moreover, this is possible because NSF pulls a SNARE complex apart by building up the energy from individual ATPs and releasing it at once, yielding a “spring-loaded” mechanism.”
NSF is a member of the ATPases associated with various cellular activities family (AAA+ ATPase), which is essential for many cellular functions such as DNA replication and protein degradation, membrane fusion, microtubule severing, peroxisome biogenesis, signal transduction, and the regulation of gene expression. This research has added valuable new insights and hints for studying AAA+ ATPase proteins, which are crucial for various living beings.
The title of the research paper is “Spring-loaded unraveling of a single SNARE complex by NSF in one round of ATP turnover.” (DOI: 10.1126/science.aaa5267)
Youtube Link: https://www.youtube.com/watch?v=FqTSYHtyHWE&feature=youtu.be
Picture 1. Working model of how NSF/α-SNAP disassemble a single SNARE complex
Picture 2. After neurotransmitter release, NSF disassembles a single SNARE complex using a single round of ATP turnover in a single burst reaction.
2015.03.28 View 10794 -
Mutations Occurring Only in Brain Responsible for Intractable Epilepsy Identified
KAIST researchers have discovered that brain somatic mutations in MTOR gene induce intractable epilepsy and suggest a precision medicine to treat epileptic seizures.
Epilepsy is a brain disorder which afflicts more than 50 million people worldwide. Many epilepsy patients can control their symptoms through medication, but about 30% suffer from intractable epilepsy and are unable to manage the disease with drugs. Intractable epilepsy causes multiple seizures, permanent mental, physical, and developmental disabilities, and even death. Therefore, surgical removal of the affected area from the brain has been practiced as a treatment for patients with medically refractory seizures, but this too fails to provide a complete solution because only 60% of the patients who undergo surgery are rendered free of seizures.
A Korean research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering at the Korea Advanced Institute of Science and Technology (KAIST) and Professor Dong-Seok Kim of Epilepsy Research Center at Yonsei University College of Medicine has recently identified brain somatic mutations in the gene of mechanistic target of rapamycin (MTOR) as the cause of focal cortical dysplasia type II (FCDII), one of the most important and common inducers to intractable epilepsy, particularly in children. They propose a targeted therapy to lessen epileptic seizures by suppressing the activation of mTOR kinase, a signaling protein in the brain. Their research results were published online in Nature Medicine on March 23, 2015.
FCDII contributes to the abnormal developments of the cerebral cortex, ranging from cortical disruption to severe forms of cortical dyslamination, balloon cells, and dysplastic neurons. The research team studied 77 FCDII patients with intractable epilepsy who had received a surgery to remove the affected regions from the brain. The researchers used various deep sequencing technologies to conduct comparative DNA analysis of the samples obtained from the patients’ brain and blood, or saliva. They reported that about 16% of the studied patients had somatic mutations in their brain. Such mutations, however, did not take place in their blood or saliva DNA.
Professor Jeong Ho Lee of KAIST said, “This is an important finding. Unlike our previous belief that genetic mutations causing intractable epilepsy exist anywhere in the human body including blood, specific gene mutations incurred only in the brain can lead to intractable epilepsy. From our animal models, we could see how a small fraction of mutations carrying neurons in the brain could affect its entire function.”
The research team recapitulated the pathogenesis of intractable epilepsy by inducing the focal cortical expression of mutated mTOR in the mouse brain via electroporation method and observed as the mouse develop epileptic symptoms. They then treated these mice with the drug called “rapamycin” to inhibit the activity of mTOR protein and observed that it suppressed the development of epileptic seizures with cytomegalic neurons.
“Our study offers the first evidence that brain-somatic activating mutations in MTOR cause FCDII and identifies mTOR as a treatment target for intractable epilepsy,” said co-author Dr. Dong-Seok Kim, a neurosurgeon at Yonsei Medical Center with the country’s largest surgical experiences in treating patients with this condition.
The research paper is titled “Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy.” (Digital Object Identifier #: 10.1038/nm.3824)
Picture 1: A schematic image to show how to detect brain specific mutation using next-generation sequencing technology with blood-brain paired sample. Simple comparison of non-overlapping mutations between affected and unaffected tissues is able to detect brain specific mutations.
Picture 2: A schematic image to show how to generate focal cortical dysplasia mouse model. This mouse model open the new window of drug screening for seizure patients.
Picture 3: Targeted medicine can rescue the focal cortical dysplasia symptoms including cytomegalic neuron & intractable epilepsy.
2015.03.25 View 14172 -
KAIST Develops a Credit-Card-Thick Flexible Lithium Ion Battery
Since the battery can be charged wirelessly, useful applications are expected including medical patches and smart cards.
Professor Jang Wook Choi at KAIST’s Graduate School of Energy, Environment, Water, and Sustainability (EEWS) and Dr. Jae Yong Song at the Korea Research Institute of Standards and Science jointly led research to invent a flexible lithium ion battery that is thinner than a credit card and can be charged wirelessly.
Their research findings were published online in Nano Letters on March 6, 2015. Lithium ion batteries are widely used today in various electronics including mobile devices and electronic cars. Researchers said that their work could help accelerate the development of flexible and wearable electronics.
Conventional lithium ion batteries are manufactured based on a layering technology, stacking up anodes, separating films, and cathodes like a sandwich, which makes it difficult to reduce their thickness. In addition, friction arises between layers, making the batteries impossible to bend. The coating films of electrodes easily come off, which contributes to the batteries’ poor performance.
The research team abandoned the existing production technology. Instead, they removed the separating films, layered the cathodes and anodes collinearly on a plane, and created a partition between electrodes to eliminate potential problems, such as short circuits and voltage dips, commonly present in lithium ion batteries.
After more than five thousand consecutive flexing experiments, the research team confirmed the possibility of a more flexible electrode structure while maintaining the battery performance comparable to the level of current lithium ion batteries.
Flexible batteries can be applied to integrated smart cards, cosmetic and medical patches, and skin adhesive sensors that can control a computer with voice commands or gesture as seen in the movie “Iron Man.”
Moreover, the team has successfully developed wireless-charging technology using electromagnetic induction and solar batteries.
They are currently developing a mass production process to combine this planar battery technology and printing, to ultimately create a new paradigm to print semiconductors and batteries using 3D printers.
Professor Choi said, “This new technology will contribute to diversifying patch functions as it is applicable to power various adhesive medical patches.”
Picture 1: Medical patch (left) and flexible secondary battery (right)
Picture 2: Diagram of flexible battery
Picture 3: Smart card embedding flexible battery
2015.03.24 View 12387 -
KAIST Introduces New UI for K-Glass 2
A newly developed user interface, the “i-Mouse,” in the K-Glass 2 tracks the user’s gaze and connects the device to the Internet through blinking eyes such as winks. This low-power interface provides smart glasses with an excellent user experience, with a long-lasting battery and augmented reality.
Smart glasses are wearable computers that will likely lead to the growth of the Internet of Things. Currently available smart glasses, however, reveal a set of problems for commercialization, such as short battery life and low energy efficiency. In addition, glasses that use voice commands have raised the issue of privacy concerns.
A research team led by Professor Hoi-Jun Yoo of the Electrical Engineering Department at the Korea Advanced Institute of Science and Technology (KAIST) has recently developed an upgraded model of the K-Glass (http://www.eurekalert.org/pub_releases/2014-02/tkai-kdl021714.php) called “K-Glass 2.”
K-Glass 2 detects users’ eye movements to point the cursor to recognize computer icons or objects in the Internet, and uses winks for commands. The researchers call this interface the “i-Mouse,” which removes the need to use hands or voice to control a mouse or touchpad. Like its predecessor, K-Glass 2 also employs augmented reality, displaying in real time the relevant, complementary information in the form of text, 3D graphics, images, and audio over the target objects selected by users.
The research results were presented, and K-Glass 2’s successful operation was demonstrated on-site to the 2015 Institute of Electrical and Electronics Engineers (IEEE) International Solid-State Circuits Conference (ISSCC) held on February 23-25, 2015 in San Francisco. The title of the paper was “A 2.71nJ/Pixel 3D-Stacked Gaze-Activated Object Recognition System for Low-power Mobile HMD Applications” (http://ieeexplore.ieee.org/Xplore/home.jsp).
The i-Mouse is a new user interface for smart glasses in which the gaze-image sensor (GIS) and object recognition processor (ORP) are stacked vertically to form a small chip. When three infrared LEDs (light-emitting diodes) built into the K-Glass 2 are projected into the user’s eyes, GIS recognizes their focal point and estimates the possible locations of the gaze as the user glances over the display screen. Then the electro-oculography sensor embedded on the nose pads reads the user’s eyelid movements, for example, winks, to click the selection. It is worth noting that the ORP is wired to perform only within the selected region of interest (ROI) by users. This results in a significant saving of battery life. Compared to the previous ORP chips, this chip uses 3.4 times less power, consuming on average 75 milliwatts (mW), thereby helping K-Glass 2 to run for almost 24 hours on a single charge.
Professor Yoo said, “The smart glass industry will surely grow as we see the Internet of Things becomes commonplace in the future. In order to expedite the commercial use of smart glasses, improving the user interface (UI) and the user experience (UX) are just as important as the development of compact-size, low-power wearable platforms with high energy efficiency. We have demonstrated such advancement through our K-Glass 2. Using the i-Mouse, K-Glass 2 can provide complicated augmented reality with low power through eye clicking.”
Professor Yoo and his doctoral student, Injoon Hong, conducted this research under the sponsorship of the Brain-mimicking Artificial Intelligence Many-core Processor project by the Ministry of Science, ICT and Future Planning in the Republic of Korea.
Youtube Link:
https://www.youtube.com/watchv=JaYtYK9E7p0&list=PLXmuftxI6pTW2jdIf69teY7QDXdI3Ougr
Picture 1: K-Glass 2
K-Glass 2 can detect eye movements and click computer icons via users’ winking.
Picture 2: Object Recognition Processor Chip
This picture shows a gaze-activated object-recognition system.
Picture 3: Augmented Reality Integrated into K-Glass 2
Users receive additional visual information overlaid on the objects they select.
2015.03.13 View 16430 -
KAIST Develops Ultrathin Polymer Insulators Key to Low-Power Soft Electronics
Using an initiated chemical vapor deposition technique, the research team created an ultrathin polymeric insulating layer essential in realizing transistors with flexibility and low power consumption. This advance is expected to accelerate the commercialization of wearable and soft electronics.
A group of researchers at the Korea Advanced Institute of Science and Technology (KAIST) developed a high-performance ultrathin polymeric insulator for field-effect transistors (FETs). The researchers used vaporized monomers to form polymeric films grown conformally on various surfaces including plastics to produce a versatile insulator that meets a wide range of requirements for next-generation electronic devices. Their research results were published online in Nature Materials on March 9th, 2015.
FETs are an essential component for any modern electronic device used in our daily life from cell phones and computers, to flat-panel displays. Along with three electrodes (gate, source, and drain), FETs consist of an insulating layer and a semiconductor channel layer. The insulator in FETs plays an important role in controlling the conductance of the semiconductor channel and thus current flow within the translators. For reliable and low-power operation of FETs, electrically robust, ultrathin insulators are essential. Conventionally, such insulators are made of inorganic materials (e.g., oxides and nitrides) built on a hard surface such as silicon or glass due to their excellent insulating performance and reliability.
However, these insulators were difficult to implement into soft electronics due to their rigidity and high process temperature. In recent years, many researchers have studied polymers as promising insulating materials that are compatible with soft unconventional substrates and emerging semiconductor materials. The traditional technique employed in developing a polymer insulator, however, had the limitations of low surface coverage at ultra-low thickness, hindering FETs adopting polymeric insulators from operating at low voltage.
A KAIST research team led by Professor Sung Gap Im of the Chemical and Biomolecular Engineering Department and Professor Seunghyup Yoo and Professor Byung Jin Cho of the Electrical Engineering Department developed an insulating layer of organic polymers, “pV3D3,” that can be greatly scaled down, without losing its ideal insulating properties, to a thickness of less than 10 nanometers (nm) using the all-dry vapor-phase technique called the “initiated chemical vapor deposition (iCVD).”
The iCVD process allows gaseous monomers and initiators to react with each other in a low vacuum condition, and as a result, conformal polymeric films with excellent insulating properties are deposited on a substrate. Unlike the traditional technique, the surface-growing character of iCVD can overcome the problems associated with surface tension and produce highly uniform and pure ultrathin polymeric films over a large area with virtually no surface or substrate limitations. Furthermore, most iCVD polymers are created at room temperature, which lessens the strain exerted upon and damage done to the substrates.
With the pV3D3 insulator, the research team built low-power, high-performance FETs based on various semiconductor materials such as organics, graphene, and oxides, demonstrating the pV3D3 insulator’s wide range of material compatibility. They also manufactured a stick-on, removable electronic component using conventional packaging tape as a substrate. In collaboration with Professor Yong-Young Noh from Dongguk University in Korea, the team successfully developed a transistor array on a large-scale flexible substrate with the pV3D3 insulator.
Professor Im said, “The down-scalability and wide range of compatibility observed with iCVD-grown pV3D3 are unprecedented for polymeric insulators. Our iCVD pV3D3 polymeric films showed an insulating performance comparable to that of inorganic insulating layers, even when their thickness were scaled down to sub-10 nm. We expect our development will greatly benefit flexible or soft electronics, which will play a key role in the success of emerging electronic devices such as wearable computers.”
The title of the research paper is “Synthesis of ultrathin polymer insulating layers by initiated chemical vapor deposition for low-power soft electronics” (Digital Object Identifier (DOI) number is 10.1038/nmat4237).
Picture 1: A schematic image to show how the initiated chemical vapor deposition (iCVD) technique produces pV3D3 polymeric films: (i) introduction of vaporized monomers and initiators, (ii) activation of initiators to thermally dissociate into radicals, (iii) adsorption of monomers and initiator radicals onto a substrate, and (iv) transformation of free-radical polymerization into pV3D3 thin films.
Picture 2: This is a transistor array fabricated on a large scale, highly flexible substrate with pV3D3 polymeric films.
Picture 3: This photograph shows an electronic component fabricated on a conventional packaging tape, which is attachable or detachable, with pV3D3 polymeric films embedded.
2015.03.10 View 13369 -
System Approach Using Metabolite Structural Similarity Toward TOM Suggested
A Korean research team at KAIST suggests that a system approach using metabolite structural similarity helps to elucidate the mechanisms of action of traditional oriental medicine.
Traditional oriental medicine (TOM) has been practiced in Asian countries for centuries, and is gaining increasing popularity around the world. Despite its efficacy in various symptoms, TOM has been practiced without precise knowledge of its mechanisms of action. Use of TOM largely comes from empirical knowledge practiced over a long period of time. The fact that some of the compounds found in TOM have led to successful modern drugs such as artemisinin for malaria and taxol (Paclitaxel) for cancer has spurred modernization of TOM.
A research team led by Sang-Yup Lee at KAIST has focused on structural similarities between compounds in TOM and human metabolites to help explain TOM’s mechanisms of action. This systems approach using structural similarities assumes that compounds which are structurally similar to metabolites could affect relevant metabolic pathways and reactions by biosynthesizing structurally similar metabolites.
Structural similarity analysis has helped to identify mechanisms of action of TOM. This is described in a recent study entitled “A systems approach to traditional oriental medicine,” published online in Nature Biotechnology on March 6, 2015. In this study, the research team conducted structural comparisons of all the structurally known compounds in TOM and human metabolites on a large-scale. As a control, structures of all available approved drugs were also compared against human metabolites. This structural analysis provides two important results. First, the identification of metabolites structurally similar to TOM compounds helped to narrow down the candidate target pathways and reactions for the effects from TOM compounds. Second, it suggested that a greater fraction of all the structurally known TOM compounds appeared to be more similar to human metabolites than the approved drugs. This second finding indicates that TOM has a great potential to interact with diverse metabolic pathways with strong efficacy. This finding, in fact, shows that TOM compounds might be advantageous for the multitargeting required to cure complex diseases. “Once we have narrowed down candidate target pathways and reactions using this structural similarity approach, additional in silico tools will be necessary to characterize the mechanisms of action of many TOM compounds at a molecular level,” said Hyun Uk Kim, a research professor at KAIST.
TOM’s multicomponent, multitarget approach wherein multiple components show synergistic effects to treat symptoms is highly distinctive. The researchers investigated previously observed effects recorded since 2000 of a set of TOM compounds with known mechanisms of action. TOM compounds’ synergistic combinations largely consist of a major compound providing the intended efficacy to the target site and supporting compounds which maximize the efficacy of the major compound. In fact, such combination designs appear to mirror the Kun-Shin-Choa-Sa design principle of TOM.
That principle, Kun-Shin-Choa-Sa (君臣佐使 or Jun-Chen-Zuo-Shi in Chinese) literally means “king-minister-assistant-ambassador.” In ancient East Asian medicine, treating human diseases and taking good care of the human body are analogous to the politics of governing a nation. Just as good governance requires that a king be supported by ministers, assistants and/or ambassadors, treating diseases or good care of the body required the combined use of herbal medicines designed based on the concept of Kun-Shin-Choa-Sa. Here, the Kun (king or the major component) indicates the major medicine (or herb) conveying the major drug efficacy, and is supported by three different types of medicines: the Shin (minister or the complementary component) for enhancing and/or complementing the efficacy of the Kun, Choa (assistant or the neutralizing component) for reducing any side effects caused by the Kun and reducing the minor symptoms accompanying major symptom, and Sa (ambassador or the delivery/retaining component) which facilitated the delivery of the Kun to the target site, and retaining the Kun for prolonged availability in the cells.
The synergistic combinations of TOM compounds reported in the literature showed four different types of synergisms: complementary action (similar to Kun-Shin), neutralizing action (similar to Kun-Choa), facilitating action or pharmacokinetic potentiation (both similar to Kun-Choa or Kun-Sa). Additional structural analyses for these compounds with synergism show that they appeared to affect metabolism of amino acids, co-factors and vitamins as major targets.
Professor Sang Yup Lee remarks, “This study lays a foundation for the integration of traditional oriental medicine with modern drug discovery and development. The systems approach taken in this analysis will be used to elucidate mechanisms of action of unknown TOM compounds which will then be subjected to rigorous validation through clinical and in silico experiments.”
Sources: Kim, H.U. et al. “A systems approach to traditional oriental medicine.” Nature Biotechnology. 33: 264-268 (2015).
This work was supported by the Bio-Synergy Research Project (2012M3A9C4048759) of the Ministry of Science, ICT and Future Planning through the National Research Foundation. This work was also supported by the Novo Nordisk Foundation.
The picture below presents the structural similarity analysis of comparing compounds in traditional oriental medicine and those in all available approved drugs against the structures of human metabolites.
2015.03.09 View 10512 -
The Real Time Observation of the Birth of a Molecule
From right to left: Dr. Kyung-Hwan Kim, Professor Hyotcherl Lhee, and Jong-Gu Kim, a Ph.D. candidate
Professor Hyotcherl Lhee of the Department of Chemistry at KAIST and Japanese research teams jointly published their research results showing that they have succeeded in the direct observation of how atoms form a molecule in the online issue of Nature on February 19, 2015.
The researchers used water in which gold atoms ([Au(CN) 2- ]) are dissolved and fired X-ray pulses over the specimen in femtosecond timescales to study chemical reactions taking place among the gold atoms. They were able to examine in real time the instant process of how gold atoms bond together to become a molecule, to a trimer or tetramer state.
This direct viewing of the formation of a gold trimer complex ([Au(CN) 2- ] 3 ) will provide an opportunity to understand complex chemical and biological systems.
For details, please see the following press release that was distributed by the High Energy Accelerator Research Organization, KEK, in Japan:
Direct Observation of Bond Formations
February 18, 2015
A collaboration between researchers from KEK, the Institute for Basic Science (IBS), the Korea Advanced Institute of Science and Technology (KAIST), RIKEN, and the Japan Synchrotron Radiation Research Institute (JASRI) used the SACLA X-ray free electron laser (XFEL) facility for a real time visualization of the birth of a molecular that occurs via photoinduced formation of a chemical bonds. This achievement was published in the online version of the scientific journal “Nature” (published on 19 February 2015).
Direct “observation” of the bond making, through a chemical reaction, has been longstanding dream for chemists. However, the distance between atoms is very small, at about 100 picometer, and the bonding is completed very quickly, taking less than one picosecond (ps). Hence, previously, one could only imagine the bond formation between atoms while looking at the chemical reaction progressing in the test-tube.
In this study, the research group focused on the process of photoinduced bond formation between gold (Au) ions dissolved in water. In the ground state (S 0 state in Fig. 1) Au ions that are weakly bound to each other by an electron affinity and aligned in a bent geometry. Upon a photoexcitation, the S 0 state rapidly converts into an excited (S 1 state in Fig. 1) state where Au-Au covalent bonds are formed among Au ions aligned in a linear geometry. Subsequently, the S 1 state transforms to a triplet state (T 1 state in Fig. 1) in 1.6 ps while accompanying further contraction of Au-Au bonds by 0.1 Å. Later, the T 1 state of the trimer converts to a tetramer (tetramer state in Fig. 1) on nanosecond time scale. Finally, the Au ions returned to their original loosely interacting bent structure.
In this research, the direct observation of a very fast chemical reaction, induced by the photo-excitation, was succeeded (Fig. 2, 3). Therefore, this method is expected to be a fundamental technology for understanding the light energy conversion reaction. The research group is actively working to apply this method to the development of viable renewable energy resources, such as a photocatalysts for artificial photosynthesis using sunlight.
This research was supported by the X-ray Free Electron Laser Priority Strategy Program of the MEXT, PRESTO of the JST, and the the Innovative Areas "Artificial Photosynthesis (AnApple)" grant from the Japan Society for the Promotion of Science (JSPS).
Publication: Nature , 518 (19 February 2015)
Title: Direct observation of bond formation in solution with femtosecond X-ray scattering
Authors: K. H. Kim 1 , J. G. Kim 1 , S. Nozawa 1 , T. Sato 1 , K. Y. Oang, T. W. Kim, H. Ki, J. Jo, S. Park, C. Song, T. Sato, K. Ogawa, T. Togashi, K. Tono, M. Yabashi, T. Ishikawa, J. Kim, R. Ryoo, J. Kim, H. Ihee, S. Adachi. ※ 1: These authors contributed equally to the work.
DOI: 10.1038/nature14163
Figure 1. Structure of a gold cyano trimer complex (Au(CN) 2 - ) 3 .
Figure 2. Observed changes in the molecular structure of the gold complex
Figure 3. Schematic view of the research of photo-chemical reactions by the molecular movie
2015.02.27 View 12428 -
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
2015.02.27 View 10655 -
News Article: Flexible, High-performance Nonvolatile Memory Developed with SONOS Technology
Professor Yang-Kyu Choi of KAIST’s Department of Electrical Engineering and his team presented a research paper entitled “Flexible High-performance Nonvolatile Memory by Transferring GAA Silicon Nanowire SONOS onto a Plastic Substrate” at the conference of the International Electron Devices Meeting that took place on December 15-17, 2014 in San Francisco.
The Electronic Engineering Journal (http://www.eejournal.com/) recently posted an article on the paper:
Electronic Engineering Journal, February 2, 2015
“A Flat-Earth Memory”
Another Way to Make the Brittle Flexible
http://www.techfocusmedia.net/archives/articles/20150202-flexiblegaa/?printView=true
2015.02.03 View 7661