research
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A New Therapeutic Drug for Alzheimer’s Disease without Inflammatory Side Effects
Although Aduhelm, a monoclonal antibody targeting amyloid beta (Aβ), recently became the first US FDA approved drug for Alzheimer’s disease (AD) based on its ability to decrease Aβ plaque burden in AD patients, its effect on cognitive improvement is still controversial. Moreover, about 40% of the patients treated with this antibody experienced serious side effects including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H) that are likely related to inflammatory responses in the brain when the Aβ antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages.
These inflammatory side effects can cause neuronal cell death and synapse elimination by activated microglia, and even have the potential to exacerbate cognitive impairment in AD patients. Thus, current Aβ antibody-based immunotherapy holds the inherent risk of doing more harm than good due to their inflammatory side effects.
To overcome these problems, a team of researchers at KAIST in South Korea has developed a novel fusion protein drug, αAβ-Gas6, which efficiently eliminates Aβ via an entirely different mechanism than Aβ antibody-based immunotherapy. In a mouse model of AD, αAβ-Gas6 not only removed Aβ with higher potency, but also circumvented the neurotoxic inflammatory side effects associated with conventional antibody treatments.
Their findings were published on August 4 in Nature Medicine.
Schematic of a chimeric Gas6 fusion protein. A single chain variable fragment (scFv) of
an Amyloid β (Aβ)-targeting monoclonal antibody is fused with a truncated receptor binding
domain of Gas6, a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL,
and MERTK) receptors, which are expressed by microglia and astrocytes.
“FcR activation by Aβ targeting antibodies induces microglia-mediated Aβ phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues,” said paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST.
“Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain,” Prof. Kim and Chung said. “Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Aβ plaques.”
The professors and their team demonstrated that the resulting αAβ-Gas6 induced Aβ engulfment by activating not only microglial but also astrocytic phagocytosis since TAM phagocytic receptors are highly expressed by these two major phagocytes in the brain. Importantly, αAβ-Gas6 promoted the robust uptake of Aβ without showing any signs of inflammation and neurotoxicity, which contrasts sharply with the treatment using an Aβ monoclonal antibody. Moreover, they showed that αAβ-Gas6 substantially reduced excessive synapse elimination by microglia, consequently leading to better behavioral rescues in AD model mice.
“By using a mouse model of cerebral amyloid angiopathy (CAA), a cerebrovascular disorder caused by the deposition of Aβ within the walls of the brain’s blood vessels, we also showed that the intrathecal administration of Gas6 fusion protein significantly eliminated cerebrovascular amyloids, along with a reduction of microhemorrhages. These data demonstrate that aAb-Gas6 is a potent therapeutic agent in eliminating Aβ without exacerbating CAA-related microhemorrhages.”
The resulting αAβ-Gas6 clears Aβ oligomers and fibrils without causing neurotoxicity (a-b, neurons: red, and fragmented axons: yellow) and proinflammatory responses (c, TNF release), which are conversely exacerbated by the treatment of an Aβ-targeting monoclonal antibody (Aducanumab).
Professors Kim and Chung noted, “We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses.”
The number and total area of Aβ plaques (Thioflavin-T, green) were significantly reduced in αAβ-Gas6-treated AD mouse brains compared to Aducanumab-treated ones (a, b). The cognitive functions of AD model mice were significantly rescued by αAβ-Gas6 treatment, whereas Aducanumab-treated AD mice showed partial rescue in these cognitive tests (c-e).
Professors Kim and Chung founded “Illimis Therapeutics” based on this strategy of designing chimeric Gas6 fusion proteins that would remove toxic aggregates from the nervous system. Through this company, they are planning to further develop various Gas6-fusion proteins not only for Ab but also for Tau to treat AD symptoms.
This work was supported by KAIST and the Korea Health Technology R&D Project that was administered by the Korea Health Industry Development Institute (KHIDI) and the Korea Dementia Research Center (KDRC) funded by the Ministry of Health & Welfare (MOHW) and the Ministry of Science and ICT (MSIT), and KAIST.
Other contributors include Hyuncheol Jung and Se Young Lee, Sungjoon Lim, Hyeong Ryeol Choi, Yeseong Choi, Minjin Kim, Segi Kim, the Department of Biological Sciences, and the Korea Advanced Institute of Science and Technology (KAIST).
To receive more up-to-date information on this new development, follow “Illimis Therapeutics” on twitter @Illimistx.
2022.08.05 View 9114 -
Metabolically Engineered Bacterium Produces Lutein
A research group at KAIST has engineered a bacterial strain capable of producing lutein. The research team applied systems metabolic engineering strategies, including substrate channeling and electron channeling, to enhance the production of lutein in an engineered Escherichia coli strain. The strategies will be also useful for the efficient production of other industrially important natural products used in the food, pharmaceutical, and cosmetic industries.
Figure: Systems metabolic engineering was employed to construct and optimize the metabolic pathways for lutein production, and substrate channeling and electron channeling strategies were additionally employed to increase the production of the lutein with high productivity.
Lutein is classified as a xanthophyll chemical that is abundant in egg yolk, fruits, and vegetables. It protects the eye from oxidative damage from radiation and reduces the risk of eye diseases including macular degeneration and cataracts. Commercialized products featuring lutein are derived from the extracts of the marigold flower, which is known to harbor abundant amounts of lutein. However, the drawback of lutein production from nature is that it takes a long time to grow and harvest marigold flowers. Furthermore, it requires additional physical and chemical-based extractions with a low yield, which makes it economically unfeasible in terms of productivity. The high cost and low yield of these bioprocesses has made it difficult to readily meet the demand for lutein.
These challenges inspired the metabolic engineers at KAIST, including researchers Dr. Seon Young Park, Ph.D. Candidate Hyunmin Eun, and Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering. The team’s study entitled “Metabolic engineering of Escherichia coli with electron channeling for the production of natural products” was published in Nature Catalysis on August 5, 2022.
This research details the ability to produce lutein from E. coli with a high yield using a cheap carbon source, glycerol, via systems metabolic engineering. The research group focused on solving the bottlenecks of the biosynthetic pathway for lutein production constructed within an individual cell. First, using systems metabolic engineering, which is an integrated technology to engineer the metabolism of a microorganism, lutein was produced when the lutein biosynthesis pathway was introduced, albeit in very small amounts.
To improve the productivity of lutein production, the bottleneck enzymes within the metabolic pathway were first identified. It turned out that metabolic reactions that involve a promiscuous enzyme, an enzyme that is involved in two or more metabolic reactions, and electron-requiring cytochrome P450 enzymes are the main bottleneck steps of the pathway inhibiting lutein biosynthesis.
To overcome these challenges, substrate channeling, a strategy to artificially recruit enzymes in physical proximity within the cell in order to increase the local concentrations of substrates that can be converted into products, was employed to channel more metabolic flux towards the target chemical while reducing the formation of unwanted byproducts.
Furthermore, electron channeling, a strategy similar to substrate channeling but differing in terms of increasing the local concentrations of electrons required for oxidoreduction reactions mediated by P450 and its reductase partners, was applied to further streamline the metabolic flux towards lutein biosynthesis, which led to the highest titer of lutein production achieved in a bacterial host ever reported. The same electron channeling strategy was successfully applied for the production of other natural products including nootkatone and apigenin in E. coli, showcasing the general applicability of the strategy in the research field.
“It is expected that this microbial cell factory-based production of lutein will be able to replace the current plant extraction-based process,” said Dr. Seon Young Park, the first author of the paper. She explained that another important point of the research is that integrated metabolic engineering strategies developed from this study can be generally applicable for the efficient production of other natural products useful as pharmaceuticals or nutraceuticals.
“As maintaining good health in an aging society is becoming increasingly important, we expect that the technology and strategies developed here will play pivotal roles in producing other valuable natural products of medical or nutritional importance,” explained Distinguished Professor Sang Yup Lee.
This work was supported by the Cooperative Research Program for Agriculture Science & Technology Development funded by the Rural Development Administration of Korea, with further support from the Development of Next-generation Biorefinery Platform Technologies for Leading Bio-based Chemicals Industry Project and by the Development of Platform Technologies of Microbial Cell Factories for the Next-generation Biorefineries Project of the National Research Foundation funded by the Ministry of Science and ICT of Korea.
2022.08.05 View 7392 -
KAIST Research Team Proves How a Neurotransmitter may be the Key in Controlling Alzheimer’s Toxicity
With nearly 50 million dementia patients worldwide, and Alzheimers’s disease is the most common neurodegenerative disease. Its main symptom is the impairment of general cognitive abilities, including the ability to speak or to remember. The importance of finding a cure is widely understood with increasingly aging population and the life expectancy being ever-extended. However, even the cause of the grim disease is yet to be given a clear definition.
A KAIST research team in the Department of Chemistry led by professor Mi Hee Lim took on a lead to discovered a new role for somatostatin, a protein-based neurotransmitter, in reducing the toxicity caused in the pathogenic mechanism taken towards development of Alzheimer’s disease. The study was published in the July issue of Nature Chemistry under the title, “Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β”.
According to the amyloid hypothesis, the abnormal deposition of Aβ proteins causes death of neuronal cells. While Aβ agglomerations make up most of the aged plaques through fibrosis, in recent studies, high concentrations of transitional metal were found in the plaques from Alzheimer’s patients.
This suggests a close interaction between metallic ions and Aβ, which accelerates the fibrosis of proteins. Copper in particular is a redox-activating transition metal that can produce large amounts of oxygen and cause serious oxidative stress on cell organelles. Aβ proteins and transition metals can closely interact with neurotransmitters at synapses, but the direct effects of such abnormalities on the structure and function of neurotransmitters are yet to be understood.
Figure 1. Functional shift of somatostatin (SST) by factors in the pathogenesis of Alzheimer's disease.
Figure 2. Somatostatin’s loss-of-function as neurotransmitter. a. Schematic diagram of SST auto-aggregation due to Alzheimer's pathological factors. b. SST’s aggregation by copper ions. c. Coordination-prediction structure and N-terminal folding of copper-SST. d. Inhibition of SST receptor binding specificity by metals.
In their research, Professor Lim’s team discovered that when somatostatin, the protein-based neurotransmitter, is met with copper, Aβ, and metal-Aβ complexes, self-aggregates and ceases to perform its innate function of transmitting neural signals, but begins to attenuate the toxicity and agglomeration of metal-Aβ complexes.
Figure 3. Gain-of-function of somatostatin (SST) in the dementia setting. a. Prediction of docking of SST and amyloid beta. b. SST making metal-amyloid beta aggregates into an amorphous form. c. Cytotoxic mitigation effect of SST. d. SST mitigating the interaction between amyloid beta protein with the cell membrane.
This research, by Dr. Jiyeon Han et al. from the KAIST Department of Chemistry, revealed the coordination structure between copper and somatostatin at a molecular level through which it suggested the agglomeration mechanism, and discovered the effects of somatostatin on Aβ agglomeration path depending on the presence or absence of metals. The team has further confirmed somatostatin’s receptor binding, interactions with cell membranes, and effects on cell toxicity for the first time to receive international attention.
Professor Mi Hee Lim said, “This research has great significance in having discovered a new role of neurotransmitters in the pathogenesis of Alzheimer’s disease.” “We expect this research to contribute to defining the pathogenic network of neurodegenerative diseases caused by aging, and to the development of future biomarkers and medicine,” she added.
This research was conducted jointly by Professor Seung-Hee Lee’s team of KAIST Department of Biological Sciences, Professor Kiyoung Park’s Team of KAIST Department of Chemistry, and Professor Yulong Li’s team of Peking University.
The research was funded by Basic Science Research Program of the National Research Foundation of Korea and KAIST.
For more information about the research team, visit the website: https://sites.google.com/site/miheelimlab/1-professor-mi-hee-lim.
2022.07.29 View 10489 -
A System for Stable Simultaneous Communication among Thousands of IoT Devices
A mmWave Backscatter System, developed by a team led by Professor Song Min Kim is exciting news for the IoT market as it will be able to provide fast and stable connectivity even for a massive network, which could finally allow IoT devices to reach their full potential.
A research team led by Professor Song Min Kim of the KAIST School of Electrical Engineering developed a system that can support concurrent communications for tens of millions of IoT devices using backscattering millimeter-level waves (mmWave).
With their mmWave backscatter method, the research team built a design enabling simultaneous signal demodulation in a complex environment for communication where tens of thousands of IoT devices are arranged indoors. The wide frequency range of mmWave exceeds 10GHz, which provides great scalability. In addition, backscattering reflects radiated signals instead of wirelessly creating its own, which allows operation at ultralow power. Therefore, the mmWave backscatter system offers internet connectivity on a mass scale to IoT devices at a low installation cost.
This research by Kangmin Bae et al. was presented at ACM MobiSys 2022. At this world-renowned conference for mobile systems, the research won the Best Paper Award under the title “OmniScatter: Sensitivity mmWave Backscattering Using Commodity FMCW Radar”. It is meaningful that members of the KAIST School of Electrical Engineering have won the Best Paper Award at ACM MobiSys for two consecutive years, as last year was the first time the award was presented to an institute from Asia.
IoT, as a core component of 5G/6G network, is showing exponential growth, and is expected to be part of a trillion devices by 2035. To support the connection of IoT devices on a mass scale, 5G and 6G each aim to support ten times and 100 times the network density of 4G, respectively. As a result, the importance of practical systems for large-scale communication has been raised.
The mmWave is a next-generation communication technology that can be incorporated in 5G/6G standards, as it utilizes carrier waves at frequencies between 30 to 300GHz. However, due to signal reduction at high frequencies and reflection loss, the current mmWave backscatter system enables communication in limited environments. In other words, it cannot operate in complex environments where various obstacles and reflectors are present. As a result, it is limited to the large-scale connection of IoT devices that require a relatively free arrangement.
The research team found the solution in the high coding gain of an FMCW radar. The team developed a signal processing method that can fundamentally separate backscatter signals from ambient noise while maintaining the coding gain of the radar. They achieved a receiver sensitivity of over 100 thousand times that of previously reported FMCW radars, which can support communication in practical environments. Additionally, given the radar’s property where the frequency of the demodulated signal changes depending on the physical location of the tag, the team designed a system that passively assigns them channels. This lets the ultralow-power backscatter communication system to take full advantage of the frequency range at 10 GHz or higher.
The developed system can use the radar of existing commercial products as gateway, making it easily compatible. In addition, since the backscatter system works at ultralow power levels of 10uW or below, it can operate for over 40 years with a single button cell and drastically reduce installation and maintenance costs.
The research team confirmed that mmWave backscatter devices arranged randomly in an office with various obstacles and reflectors could communicate effectively. The team then took things one step further and conducted a successful trace-driven evaluation where they simultaneously received information sent by 1,100 devices.
Their research presents connectivity that greatly exceeds network density required by next-generation communication like 5G and 6G. The system is expected to become a stepping stone for the hyper-connected future to come.
Professor Kim said, “mmWave backscatter is the technology we’ve dreamt of. The mass scalability and ultralow power at which it can operate IoT devices is unmatched by any existing technology”. He added, “We look forward to this system being actively utilized to enable the wide availability of IoT in the hyper-connected generation to come”.
To demonstrate the massive connectivity of the system, a trace-driven evaluation of 1,100 concurrent tag transmissions are made. Figure shows the demodulation result of each and every 1,100 tags as red triangles, where they successfully communicate without collision.
This work was supported by Samsung Research Funding & Incubation Center of Samsung Electronics and by the ITRC (Information Technology Research Center) support program supervised by the IITP (Institute of Information & Communications Technology Planning & Evaluation).
Profile: Song Min Kim, Ph.D.Professorsongmin@kaist.ac.krhttps://smile.kaist.ac.kr
SMILE Lab.School of Electrical Engineering
2022.07.28 View 7693 -
An AI-based, Indoor/Outdoor-Integrated (IOI) GPS System to Bring Seismic Waves in the Terrains of Positioning Technology
KAIST breaks new grounds in positioning technology with an AI-integrated GPS board that works both indoors and out
KAIST (President Kwang Hyung Lee) announced on the 8th that Professor Dong-Soo Han's research team (Intelligent Service Integration Lab) from the School of Computing has developed a GPS system that works both indoors and outdoors with quality precision regardless of the environment.
This Indoor/Outdoor-Integrated GPS System, or IOI GPS System, for short, uses the GPS signals outdoors and estimates locations indoors using signals from multiple sources like an inertial sensor, pressure sensors, geomagnetic sensors, and light sensors. To this end, the research team developed techniques to detect environmental changes such as entering a building, and methods to detect entrances, ground floors, stairs, elevators and levels of buildings by utilizing artificial intelligence techniques. Various landmark detecting techniques were also incorporated with pedestrian dead reckoning (PDR), a navigation tool for pedestrians, to devise the so-called “Sensor-Fusion Positioning Algorithm”.
To date, it was common to estimate locations based on wireless LAN signals or base station signals in a space where the GPS signal could not reach. However, the IOI GPS enables positioning even in buildings without signals nor indoor maps.
The algorithm developed by the research team can provide accurate floor information within a building where even big tech companies like Google and Apple's positioning services do not provide. Unlike other positioning methods that rely on visual data, geomagnetic positioning techniques, or wireless LAN, this system also has the advantage of not requiring any prior preparation. In other words, the foundation to enable the usage of a universal GPS system that works both indoors and outdoors anywhere in the world is now ready.
The research team also produced a circuit board for the purpose of operating the IOI GPS System, mounted with chips to receive and process GPS, Wi-Fi, and Bluetooth signals, along with an inertial sensor, a barometer, a magnetometer, and a light sensor. The sensor-fusion positioning algorithm the lab has developed is also incorporated in the board.
When the accuracy of the IOI GPS board was tested in the N1 building of KAIST’s main campus in Daejeon, it achieved an accuracy of about 95% in floor estimation and an accuracy of about 3 to 6 meters in distance estimation. As for the indoor/outdoor transition, the navigational mode change was completed in about 0.3 seconds. When it was combined with the PDR technique, the estimation accuracy improved further down to a scope of one meter.
The research team is now working on assembling a tag with a built-in positioning board and applying it to location-based docent services for visitors at museums, science centers, and art galleries. The IOI GPS tag can be used for the purpose of tracking children and/or the elderly, and it can also be used to locate people or rescue workers lost in disaster-ridden or hazardous sites. On a different note, the sensor-fusion positioning algorithm and positioning board for vehicles are also under development for the tracking of vehicles entering indoor areas like underground parking lots.
When the IOI GPS board for vehicles is manufactured, the research team will work to collaborate with car manufacturers and car rental companies, and will also develop a sensor-fusion positioning algorithm for smartphones. Telecommunication companies seeking to diversify their programs in the field of location-based services will also be interested in the use the IOI GPS.
Professor Dong-Soo Han of the School of Computing, who leads the research team, said, “This is the first time to develop an indoor/outdoor integrated GPS system that can pinpoint locations in a building where there is no wireless signal or an indoor map, and there are an infinite number of areas it can be applied to. When the integration with the Korea Augmentation Satellite System (KASS) and the Korean GPS (KPS) System that began this year, is finally completed, Korea can become the leader in the field of GPS both indoors and outdoors, and we also have plans to manufacture semi-conductor chips for the IOI GPS System to keep the tech-gap between Korea and the followers.”
He added, "The guidance services at science centers, museums, and art galleries that uses IOI GPS tags can provide a set of data that would be very helpful for analyzing the visitors’ viewing traces. It is an essential piece of information required when the time comes to decide when to organize the next exhibit. We will be working on having it applied to the National Science Museum, first.”
The projects to develop the IOI GPS system and the trace analysis system for science centers were supported through Science, Culture, Exhibits and Services Capability Enhancement Program of the Ministry of Science and ICT.
Profile: Dong-Soo Han, Ph.D.Professorddsshhan@kaist.ac.krhttp://isilab.kaist.ac.kr
Intelligent Service Integration Lab.School of Computing
http://kaist.ac.kr/en/
Korea Advanced Institute of Science and Technology (KAIST)Daejeon, Republic of Korea
2022.07.13 View 8234 -
Atomically-Smooth Gold Crystals Help to Compress Light for Nanophotonic Applications
Highly compressed mid-infrared optical waves in a thin dielectric crystal on monocrystalline gold substrate investigated for the first time using a high-resolution scattering-type scanning near-field optical microscope.
KAIST researchers and their collaborators at home and abroad have successfully demonstrated a new platform for guiding the compressed light waves in very thin van der Waals crystals. Their method to guide the mid-infrared light with minimal loss will provide a breakthrough for the practical applications of ultra-thin dielectric crystals in next-generation optoelectronic devices based on strong light-matter interactions at the nanoscale.
Phonon-polaritons are collective oscillations of ions in polar dielectrics coupled to electromagnetic waves of light, whose electromagnetic field is much more compressed compared to the light wavelength. Recently, it was demonstrated that the phonon-polaritons in thin van der Waals crystals can be compressed even further when the material is placed on top of a highly conductive metal. In such a configuration, charges in the polaritonic crystal are “reflected” in the metal, and their coupling with light results in a new type of polariton waves called the image phonon-polaritons. Highly compressed image modes provide strong light-matter interactions, but are very sensitive to the substrate roughness, which hinders their practical application.
Challenged by these limitations, four research groups combined their efforts to develop a unique experimental platform using advanced fabrication and measurement methods. Their findings were published in Science Advances on July 13.
A KAIST research team led by Professor Min Seok Jang from the School of Electrical Engineering used a highly sensitive scanning near-field optical microscope (SNOM) to directly measure the optical fields of the hyperbolic image phonon-polaritons (HIP) propagating in a 63 nm-thick slab of hexagonal boron nitride (h-BN) on a monocrystalline gold substrate, showing the mid-infrared light waves in dielectric crystal compressed by a hundred times.
Professor Jang and a research professor in his group, Sergey Menabde, successfully obtained direct images of HIP waves propagating for many wavelengths, and detected a signal from the ultra-compressed high-order HIP in a regular h-BN crystals for the first time. They showed that the phonon-polaritons in van der Waals crystals can be significantly more compressed without sacrificing their lifetime.
This became possible due to the atomically-smooth surfaces of the home-grown gold crystals used as a substrate for the h-BN. Practically zero surface scattering and extremely small ohmic loss in gold at mid-infrared frequencies provide a low-loss environment for the HIP propagation. The HIP mode probed by the researchers was 2.4 times more compressed and yet exhibited a similar lifetime compared to the phonon-polaritons with a low-loss dielectric substrate, resulting in a twice higher figure of merit in terms of the normalized propagation length.
The ultra-smooth monocrystalline gold flakes used in the experiment were chemically grown by the team of Professor N. Asger Mortensen from the Center for Nano Optics at the University of Southern Denmark.
Mid-infrared spectrum is particularly important for sensing applications since many important organic molecules have absorption lines in the mid-infrared. However, a large number of molecules is required by the conventional detection methods for successful operation, whereas the ultra-compressed phonon-polariton fields can provide strong light-matter interactions at the microscopic level, thus significantly improving the detection limit down to a single molecule. The long lifetime of the HIP on monocrystalline gold will further improve the detection performance.
Furthermore, the study conducted by Professor Jang and the team demonstrated the striking similarity between the HIP and the image graphene plasmons. Both image modes possess significantly more confined electromagnetic field, yet their lifetime remains unaffected by the shorter polariton wavelength. This observation provides a broader perspective on image polaritons in general, and highlights their superiority in terms of the nanolight waveguiding compared to the conventional low-dimensional polaritons in van der Waals crystals on a dielectric substrate.
Professor Jang said, “Our research demonstrated the advantages of image polaritons, and especially the image phonon-polaritons. These optical modes can be used in the future optoelectronic devices where both the low-loss propagation and the strong light-matter interaction are necessary. I hope that our results will pave the way for the realization of more efficient nanophotonic devices such as metasurfaces, optical switches, sensors, and other applications operating at infrared frequencies.”
This research was funded by the Samsung Research Funding & Incubation Center of Samsung Electronics and the National Research Foundation of Korea (NRF). The Korea Institute of Science and Technology, Ministry of Education, Culture, Sports, Science and Technology of Japan, and The Villum Foundation, Denmark, also supported the work.
Figure. Nano-tip is used for the ultra-high-resolution imaging of the image phonon-polaritons in hBN launched by the gold crystal edge.
Publication:
Menabde, S. G., et al. (2022) Near-field probing of image phonon-polaritons in hexagonal boron nitride on gold crystals. Science Advances 8, Article ID: eabn0627. Available online at https://science.org/doi/10.1126/sciadv.abn0627.
Profile:
Min Seok Jang, MS, PhD
Associate Professor
jang.minseok@kaist.ac.kr
http://janglab.org/
Min Seok Jang Research Group
School of Electrical Engineering
http://kaist.ac.kr/en/
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, Republic of Korea
2022.07.13 View 9326 -
PICASSO Technique Drives Biological Molecules into Technicolor
The new imaging approach brings current imaging colors from four to more than 15 for mapping overlapping proteins
Pablo Picasso’s surreal cubist artistic style shifted common features into unrecognizable scenes, but a new imaging approach bearing his namesake may elucidate the most complicated subject: the brain. Employing artificial intelligence to clarify spectral color blending of tiny molecules used to stain specific proteins and other items of research interest, the PICASSO technique, allows researchers to use more than 15 colors to image and parse our overlapping proteins.
The PICASSO developers, based in Korea, published their approach on May 5 in Nature Communications.
Fluorophores — the staining molecules — emit specific colors when excited by a light, but if more than four fluorophores are used, their emitted colors overlap and blend. Researchers previously developed techniques to correct this spectral overlap by precisely defining the matrix of mixed and unmixed images. This measurement depends on reference spectra, found by identifying clear images of only one fluorophore-stained specimen or of multiple, identically prepared specimens that only contain a single fluorophore each.
“Such reference spectra measurement could be complicated to perform in highly heterogeneous specimens, such as the brain, due to the highly varied emission spectra of fluorophores depending on the subregions from which the spectra were measured,” said co-corresponding author Young-Gyu Yoon, professor in the School of Electrical Engineering at KAIST. He explained that the subregions would each need their own spectra reference measurements, making for an inefficient, time-consuming process. “To address this problem, we developed an approach that does not require reference spectra measurements.”
The approach is the “Process of ultra-multiplexed Imaging of biomolecules viA the unmixing of the Signals of Spectrally Overlapping fluorophores,” also known as PICASSO. Ultra-multiplexed imaging refers to visualizing the numerous individual components of a unit. Like a cinema multiplex in which each theater plays a different movie, each protein in a cell has a different role. By staining with fluorophores, researchers can begin to understand those roles.
“We devised a strategy based on information theory; unmixing is performed by iteratively minimizing the mutual information between mixed images,” said co-corresponding author Jae-Byum Chang, professor in the Department of Materials Science and Engineering, KAIST. “This allows us to get away with the assumption that the spatial distribution of different proteins is mutually exclusive and enables accurate information unmixing.”
To demonstrate PICASSO’s capabilities, the researchers applied the technique to imaging a mouse brain. With a single round of staining, they performed 15-color multiplexed imaging of a mouse brain. Although small, mouse brains are still complex, multifaceted organs that can take significant resources to map. According to the researchers, PICASSO can improve the capabilities of other imaging techniques and allow for the use of even more fluorophore colors.
Using one such imaging technique in combination with PICASSO, the team achieved 45-color multiplexed imaging of the mouse brain in only three staining and imaging cycles, according to Yoon.
“PICASSO is a versatile tool for the multiplexed biomolecule imaging of cultured cells, tissue slices and clinical specimens,” Chang said. “We anticipate that PICASSO will be useful for a broad range of applications for which biomolecules’ spatial information is important. One such application the tool would be useful for is revealing the cellular heterogeneities of tumor microenvironments, especially the heterogeneous populations of immune cells, which are closely related to cancer prognoses and the efficacy of cancer therapies.”
The Samsung Research Funding & Incubation Center for Future Technology supported this work. Spectral imaging was performed at the Korea Basic Science Institute Western Seoul Center.
-PublicationJunyoung Seo, Yeonbo Sim, Jeewon Kim, Hyunwoo Kim, In Cho, Hoyeon Nam, Yong-Gyu Yoon, Jae-Byum Chang, “PICASSO allows ultra-multiplexed fluorescence imaging of spatiallyoverlapping proteins without reference spectra measurements,” May 5, Nature Communications (doi.org/10.1038/s41467-022-30168-z)
-ProfileProfessor Jae-Byum ChangDepartment of Materials Science and EngineeringCollege of EngineeringKAIST
Professor Young-Gyu YoonSchool of Electrical EngineeringCollege of EngineeringKAIST
2022.06.22 View 7269 -
New Polymer Mesophase Structure Discovered
Bilayer-folded lamellar mesophase induced by random polymer sequence
Polymers, large molecules made up of repeating smaller molecules called monomers, are found in nearly everything we use in our day-to-day lives. Polymers can be natural or created synthetically. Natural polymers, also called biopolymers, include DNA, proteins, and materials like silk, gelatin, and collagen. Synthetic polymers make up many different kinds of materials, including plastic, that are used in constructing everything from toys to industrial fiber cables to brake pads.
As polymers are formed through a process called polymerization, the monomers are connected through a chain. As the chain develops, the structure of the polymer determines its unique physical and chemical properties. Researchers are continually studying polymers, how they form, how they are structured, and how they develop these unique properties. By understanding this information, scientists can develop new uses for polymers and create new materials that can be used in a wide variety of industries.
In a paper published in Nature Communications on May 4, researchers describe a new structure found in an aqueous solution of an amphiphilic copolymer, called a bilayer-folded lamellar mesophase, that has been discovered through a random copolymer sequence.
“A new mesophase is an important discovery as it shows a new way for molecules to self-organize,” said Professor Myungeun Seo at the Department of Chemistry at KAIST. “We were particularly thrilled to identify this bilayer-folded lamellar phase because pure bilayer membranes are difficult to fold thermodynamically.”
Researchers think that this mesophase structure comes from the sequence of the monomers within the copolymer. The way the different monomers arrange themselves in the chain that makes up a copolymer is important and can have implications for what the copolymer can do. Many copolymers are random, which means that their structure relies on how the monomers interact with each other. In this case, the interaction between the hydrophobic monomers associates the copolymer chains to conceal the hydrophobic domain from water. As the structure gets more complex, researchers have found that a visible order develops so that monomers can be matched up with the right pair.
“While we tend to think random means disorder, here we showed that a periodic order can spontaneously arise from the random copolymer sequence based on their collective behavior,” said Professor Seo. “We believe this comes from the sequence matching problem: finding a perfectly complementary pair for a long sequence is nearly impossible.”
This is what creates the unique structure of this newly discovered mesophase. The copolymer spontaneously folds and creates a multilamellar structure that is separated by water. A multilamellar structure refers to plate-like folds and the folded layers stack on top of each other. The resulting mesophase is birefringent, meaning light refracts through it, it is similar to liquid crystalline, and viscoelastic, which means that it is both viscous and elastic at the same time.
Looking ahead, researchers hope to learn more about this new mesophase and figure out how to control the outcome. Once more is understood about the mesophase and how it is formed, it’s possible that new mesophases could be discovered as more sequences are researched. “One of the obvious questions for us is how to control the folding frequency and adjust the folded height, which we are currently working to address. Ultimately, we want to understand how different multinary sequences can associate with another to create order and apply the knowledge to develop new materials,” said Professor Seo. The National Research Foundation, the Ministry of Education, and the Ministry of Science and ICT of Korea funded this research.
-PublicationMinjoong Shin, Hayeon Kim, Geonhyeong Park, Jongmin Park, Hyungju Ahn, Dong Ki Yoon, Eunji Lee, Myungeun Seo, “Bilayer-folded lamellar mesophase induced by random polymersequence,” May 4, 2022, Nature Communications (https://doi.org/10.1038/s41467-022-30122-z)
-ProfileProfessor Myungeun SeoMacromolecular Materials Chemistry Lab (https://nanopsg.kaist.ac.kr/)Department of ChemistryCollege of Natural SciencesKAIST
2022.06.17 View 6494 -
Game Design Guide Book for Middle-Aged and Older Adult Players Helps Rewrite Gaming Culture
The online book ‘Game Design Guide for Adults in Their 50s and Older’ helps to increase accessibility for adult gamers
A KAIST multi-disciplinary research team published a game guide to respond to the new demands of senior gamers and expand the gaming market. The guide will be helpful for designing interfaces fit for senior groups as a way to minimize the cognitive burdens related to aging. It also helps readers understand older users’ cognitive abilities and socioemotional characteristics.
“This guide analyzed the game experience of players in their 50s and older and converted it into a game design element that can be easily referred to by game developers and designers,” explained Professor Young Im Do from the Graduate School of Culture Technology who led the research.
The gaming industry is paying attention to the emerging trend of ‘active aging’ and senior gamers. According to the National Purchase Diary Panel Inc., game play time increased significantly in the 45-64 age group compared to other age groups during the pandemic. Despite the growing number of senior gamers, it is still difficult for older novice players to start video games because most commercial games focus on younger players. For example, older players can feel frustrated if the game requires fast reflexes and accurate timing. Font sizes and objects that are too small as well as interfaces that are too complicated can be challenging for senior gamers.
The research team presents how to handle these difficulties in game design considering the visual-motor coordination of people in age groups ranging from their 20s to 80s. It also proposes various game elements such as audio-visual elements, cognitive and motor elements, game rules, stories and characters, social aspects, in-app purchases, and advertisements for senior groups. The guide also proposes a game service model and introduces examples of game prototypes that apply supportive technology.
For this guide, the researchers operated the “International Game Living Lab”, which is an open space for creating novel and innovative solutions by converging IT technology into daily life. In the lab, ordinary citizens, research institutes, companies, and local communities formed a cooperative network and actively participated in experiments, education, and discussions for finding solutions over three years.
Researchers in multi-disciplinary fields, including computer science, psychology, game design, and gerontechnology, covered various methodologies to understand the game experience of adults in their 50s and older. In order to profile players of this age group, three different approaches were performed: visual-motor coordination experiments, an EEG (Electroencephalogram) test, and a gameplay workshop. Then, they converted the results into practical knowledge that can be used in the gaming industry.
Professor Kyung Myun Lee from the School of Digital Humanities and Computational Social Sciences at KAIST, Professor Byungjoo Shin from Yonsei University, CEO Junyoung Shin of CareU, and CEO Minseok Doh of Heartverse participated in this online book which is available to the public at https://wikidocs.net/book/7356.
2022.06.10 View 4828 -
Now You Can See Floral Scents!
Optical interferometry visualizes how often lilies emit volatile organic compounds
Have you ever thought about when flowers emit their scents?
KAIST mechanical engineers and biological scientists directly visualized how often a lily releases a floral scent using a laser interferometry method. These measurement results can provide new insights for understanding and further exploring the biosynthesis and emission mechanisms of floral volatiles.
Why is it important to know this? It is well known that the fragrance of flowers affects their interactions with pollinators, microorganisms, and florivores. For instance, many flowering plants can tune their scent emission rates when pollinators are active for pollination. Petunias and the wild tobacco Nicotiana attenuata emit floral scents at night to attract night-active pollinators. Thus, visualizing scent emissions can help us understand the ecological evolution of plant-pollinator interactions.
Many groups have been trying to develop methods for scent analysis. Mass spectrometry has been one widely used method for investigating the fragrance of flowers. Although mass spectrometry reveals the quality and quantity of floral scents, it is impossible to directly measure the releasing frequency. A laser-based gas detection system and a smartphone-based detection system using chemo-responsive dyes have also been used to measure volatile organic compounds (VOCs) in real-time, but it is still hard to measure the time-dependent emission rate of floral scents.
However, the KAIST research team co-led by Professor Hyoungsoo Kim from the Department of Mechanical Engineering and Professor Sang-Gyu Kim from the Department of Biological Sciences measured a refractive index difference between the vapor of the VOCs of lilies and the air to measure the emission frequency. The floral scent vapor was detected and the refractive index of air was 1.0 while that of the major floral scent of a linalool lily was 1.46.
Professor Hyoungsoo Kim said, “We expect this technology to be further applicable to various industrial sectors such as developing it to detect hazardous substances in a space.” The research team also plans to identify the DNA mechanism that controls floral scent secretion.
The current work entitled “Real-time visualization of scent accumulation reveals the frequency of floral scent emissions” was published in ‘Frontiers in Plant Science’ on April 18, 2022. (https://doi.org/10.3389/fpls.2022.835305).
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2021R1A2C2007835), the Rural Development Administration (PJ016403), and the KAIST-funded Global Singularity Research PREP-Program.
-Publication:H. Kim, G. Lee, J. Song, and S.-G. Kim, "Real-time visualization of scent accumulation reveals the frequency of floral scent emissions," Frontiers in Plant Science 18, 835305 (2022) (https://doi.org/10.3389/fpls.2022.835305)
-Profile:Professor Hyoungsoo Kimhttp://fil.kaist.ac.kr
@MadeInH on TwitterDepartment of Mechanical EngineeringKAIST
Professor Sang-Gyu Kimhttps://sites.google.com/view/kimlab/home Department of Biological SciencesKAIST
2022.05.25 View 7018 -
Neuromorphic Memory Device Simulates Neurons and Synapses
Simultaneous emulation of neuronal and synaptic properties promotes the development of brain-like artificial intelligence
Researchers have reported a nano-sized neuromorphic memory device that emulates neurons and synapses simultaneously in a unit cell, another step toward completing the goal of neuromorphic computing designed to rigorously mimic the human brain with semiconductor devices.
Neuromorphic computing aims to realize artificial intelligence (AI) by mimicking the mechanisms of neurons and synapses that make up the human brain. Inspired by the cognitive functions of the human brain that current computers cannot provide, neuromorphic devices have been widely investigated. However, current Complementary Metal-Oxide Semiconductor (CMOS)-based neuromorphic circuits simply connect artificial neurons and synapses without synergistic interactions, and the concomitant implementation of neurons and synapses still remains a challenge. To address these issues, a research team led by Professor Keon Jae Lee from the Department of Materials Science and Engineering implemented the biological working mechanisms of humans by introducing the neuron-synapse interactions in a single memory cell, rather than the conventional approach of electrically connecting artificial neuronal and synaptic devices.
Similar to commercial graphics cards, the artificial synaptic devices previously studied often used to accelerate parallel computations, which shows clear differences from the operational mechanisms of the human brain. The research team implemented the synergistic interactions between neurons and synapses in the neuromorphic memory device, emulating the mechanisms of the biological neural network. In addition, the developed neuromorphic device can replace complex CMOS neuron circuits with a single device, providing high scalability and cost efficiency.
The human brain consists of a complex network of 100 billion neurons and 100 trillion synapses. The functions and structures of neurons and synapses can flexibly change according to the external stimuli, adapting to the surrounding environment. The research team developed a neuromorphic device in which short-term and long-term memories coexist using volatile and non-volatile memory devices that mimic the characteristics of neurons and synapses, respectively. A threshold switch device is used as volatile memory and phase-change memory is used as a non-volatile device. Two thin-film devices are integrated without intermediate electrodes, implementing the functional adaptability of neurons and synapses in the neuromorphic memory.
Professor Keon Jae Lee explained, "Neurons and synapses interact with each other to establish cognitive functions such as memory and learning, so simulating both is an essential element for brain-inspired artificial intelligence. The developed neuromorphic memory device also mimics the retraining effect that allows quick learning of the forgotten information by implementing a positive feedback effect between neurons and synapses.”
This result entitled “Simultaneous emulation of synaptic and intrinsic plasticity using a memristive synapse” was published in the May 19, 2022 issue of Nature Communications.
-Publication:Sang Hyun Sung, Tae Jin Kim, Hyera Shin, Tae Hong Im, and Keon Jae Lee (2022) “Simultaneous emulation of synaptic and intrinsic plasticity using a memristive synapse,” Nature Communications May 19, 2022 (DOI: 10.1038/s41467-022-30432-2)
-Profile:Professor Keon Jae Leehttp://fand.kaist.ac.kr
Department of Materials Science and EngineeringKAIST
2022.05.20 View 9938 -
Energy-Efficient AI Hardware Technology Via a Brain-Inspired Stashing System
Researchers demonstrate neuromodulation-inspired stashing system for the energy-efficient learning of a spiking neural network using a self-rectifying memristor array
Researchers have proposed a novel system inspired by the neuromodulation of the brain, referred to as a ‘stashing system,’ that requires less energy consumption. The research group led by Professor Kyung Min Kim from the Department of Materials Science and Engineering has developed a technology that can efficiently handle mathematical operations for artificial intelligence by imitating the continuous changes in the topology of the neural network according to the situation. The human brain changes its neural topology in real time, learning to store or recall memories as needed. The research group presented a new artificial intelligence learning method that directly implements these neural coordination circuit configurations.
Research on artificial intelligence is becoming very active, and the development of artificial intelligence-based electronic devices and product releases are accelerating, especially in the Fourth Industrial Revolution age. To implement artificial intelligence in electronic devices, customized hardware development should also be supported. However most electronic devices for artificial intelligence require high power consumption and highly integrated memory arrays for large-scale tasks. It has been challenging to solve these power consumption and integration limitations, and efforts have been made to find out how the human brain solves problems.
To prove the efficiency of the developed technology, the research group created artificial neural network hardware equipped with a self-rectifying synaptic array and algorithm called a ‘stashing system’ that was developed to conduct artificial intelligence learning. As a result, it was able to reduce energy by 37% within the stashing system without any accuracy degradation. This result proves that emulating the neuromodulation in humans is possible.
Professor Kim said, "In this study, we implemented the learning method of the human brain with only a simple circuit composition and through this we were able to reduce the energy needed by nearly 40 percent.”
This neuromodulation-inspired stashing system that mimics the brain’s neural activity is compatible with existing electronic devices and commercialized semiconductor hardware. It is expected to be used in the design of next-generation semiconductor chips for artificial intelligence.
This study was published in Advanced Functional Materials in March 2022 and supported by KAIST, the National Research Foundation of Korea, the National NanoFab Center, and SK Hynix.
-Publication:
Woon Hyung Cheong, Jae Bum Jeon†, Jae Hyun In, Geunyoung Kim, Hanchan Song, Janho An, Juseong Park, Young Seok Kim, Cheol Seong Hwang, and Kyung Min Kim (2022)
“Demonstration of Neuromodulation-inspired Stashing System for Energy-efficient Learning of Spiking Neural Network using a Self-Rectifying Memristor Array,” Advanced FunctionalMaterials March 31, 2022 (DOI: 10.1002/adfm.202200337)
-Profile:
Professor Kyung Min Kimhttp://semi.kaist.ac.kr https://scholar.google.com/citations?user=BGw8yDYAAAAJ&hl=ko
Department of Materials Science and EngineeringKAIST
2022.05.18 View 8520