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Simple Molecular Reagents to Treat Alzheimer’s Disease
- Researchers report minimalistic principles for designing small molecules with multiple reactivities against dementia. - Sometimes the most complex problems actually have very simple solutions. A group of South Korean researchers reported an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents against neurodegenerative disorders. The team developed redox-active aromatic molecular reagents with a simple structural composition that can simultaneously target and modulate various pathogenic factors in complex neurodegenerative disorders such as Alzheimer’s disease. Alzheimer’s disease is one of the most prevalent neurodegenerative disorders, affecting one in ten people over the age of 65. Early-onset dementia also increasingly affects younger people. A number of pathogenic elements such as reactive oxygen species, amyloid-beta, and metal ions have been suggested as potential causes of Alzheimer’s disease. Each element itself can lead to Alzheimer’s disease, but interactions between them may also aggravate the patient’s condition or interfere with the appropriate clinical care. For example, when interacting with amyloid-beta, metal ions foster the aggregation and accumulation of amyloid-beta peptides that can induce oxidative stress and toxicity in the brain and lead to neurodegeneration. Because these pathogenic factors of Alzheimer’s disease are intertwined, developing therapeutic agents that are capable of simultaneously regulating metal ion dyshomeostasis, amyloid-beta agglutination, and oxidative stress responses remains a key to halting the progression of the disease. A research team led by Professor Mi Hee Lim from the Department of Chemistry at KAIST demonstrated the feasibility of structure-mechanism-based molecular design for controlling a molecule’s chemical reactivity toward the various pathological factors of Alzheimer’s disease by tuning the redox properties of the molecule. This study, featured as the ‘ACS Editors’ Choice’ in the May 6th issue of the Journal of the American Chemical Society (JACS), was conducted in conjunction with KAIST Professor Mu-Hyun Baik’s group and Professor Joo-Young Lee’s group at the Asan Medical Center. Professor Lim and her collaborators rationally designed and generated 10 compact aromatic molecules presenting a range of redox potentials by adjusting the electronic distribution of the phenyl, phenylene, or pyridyl moiety to impart redox-dependent reactivities against the multiple pathogenic factors in Alzheimer’s disease. During the team’s biochemical and biophysical studies, these designed molecular reagents displayed redox-dependent reactivities against numerous desirable targets that are associated with Alzheimer’s disease such as free radicals, metal-free amyloid-beta, and metal-bound amyloid-beta. Further mechanistic results revealed that the redox properties of these designed molecular reagents were essential for their function. The team demonstrated that these reagents engaged in oxidative reactions with metal-free and metal-bound amyloid-beta and led to chemical modifications. The products of such oxidative transformations were observed to form covalent adducts with amyloid-beta and alter its aggregation. Moreover, the administration of the most promising candidate molecule significantly attenuated the amyloid pathology in the brains of Alzheimer’s disease transgenic mice and improved their cognitive defects. Professor Lim said, “This strategy is straightforward, time-saving, and cost-effective, and its effect is significant. We are excited to help enable the advancement of new therapeutic agents for neurodegenerative disorders, which can improve the lives of so many patients.” This work was supported by the National Research Foundation (NRF) of Korea, the Institute for Basic Science (IBS), and the Asan Institute for Life Sciences. Image credit: Professor Mi Hee Lim, KAIST Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of the news coverage of this paper only. Publication: Kim, M. et al. (2020) ‘Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.’ Journal of the American Chemical Society (JACS), Volume 142, Issue 18, pp.8183-8193. Available online at https://doi.org/10.1021/jacs.9b13100 Profile: Mi Hee Lim Professor email@example.com http://sites.google.com/site/miheelimlab Lim Laboratory Department of Chemistry KAIST Profile: Mu-Hyun Baik Professor firstname.lastname@example.org https://baik-laboratory.com/ Baik Laboratory Department of Chemistry KAIST Profile: Joo-Yong Lee Professor email@example.com Asan Institute for Life Sciences Asan Medical Center (END)
A Global Campaign of ‘Facts before Rumors’ on COVID-19 Launched
- A KAIST data scientist group responds to facts and rumors on COVID-19 for global awareness of the pandemic. - Like the novel coronavirus, rumors have no borders. The world is fighting to contain the pandemic, but we also have to deal with the appalling spread of an infodemic that is as contagious as the virus. This infodemic, a pandemic of false information, is bringing chaos and extreme fear to the general public. Professor Meeyoung Cha’s group at the School of Computing started a global campaign called ‘Facts before Rumors,’ to prevent the spread of false information from crossing borders. She explained, “We saw many rumors that had already been fact-checked long before in China and South Korea now begin to circulate in other countries, sometimes leading to detrimental results. We launched an official campaign, Facts before Rumors, to deliver COVID-19-related facts to countries where the number of cases is now increasing.” She released the first set of facts on March 26 via her Twitter account @nekozzang. Professor Cha, a data scientist who has focused on detecting global fake news, is now part of the COVID-19 AI Task Force at the Global Strategy Institute at KAIST. She is also leading the Data Science Group at the Institute for Basic Science (IBS) as Chief Investigator. Her research group worked in collaboration with the College of Nursing at Ewha Woman’s University to identify 15 claims about COVID-19 that circulated on social networks (SNS) and among the general public. The team fact-checked these claims based on information from the WHO and CDCs of Korea and the US. The research group is now working on translating the list of claims into Portuguese, Spanish, Persian, Chinese, Amharic, Hindi, and Vietnamese. Delivering facts before rumors, the team says, will help contain the disease and prevent any harm caused by misinformation. The pandemic, which spread in China and South Korea before arriving in Europe and the US, is now moving into South America, Africa, and Southeast Asia. “We would like to play a part in preventing the further spread of the disease with the provision of only scientifically vetted, truthful facts,” said the team. For this campaign, Professor Cha’s team investigated more than 200 rumored claims on COVID-19 in China during the early days of the pandemic. These claims spread in different levels: while some were only relevant locally or in larger regions of China, others propagated in Asia and are now spreading to countries that are currently most affected by the disease. For example, the false claim which publicized that ‘Fireworks can help tame the virus in the air’ only spread in China. Other claims such as ‘Eating garlic helps people overcome the disease’ or ‘Gargling with salt water prevents the contraction of the disease,’ spread around the world even after being proved groundless. The team noted, however, that the times at which these claims propagate are different from one country to another. “This opens up an opportunity to debunk rumors in some countries, even before they start to emerge,” said Professor Cha. Kun-Woo Kim, a master’s candidate in the Department of Industrial Design who joined this campaign and designed the Facts before Rumors chart also expressed his hope that this campaign will help reduce the number of victims. He added, “I am very grateful to our scientists who quickly responded to the Fact Check in these challenging times.”
COVID-19 Map Shows How the Global Pandemic Moves
- A School of Computing team facilitated the data from COVID-19 to show the global spread of the virus. - The COVID-19 map made by KAIST data scientists shows where and how the virus is spreading from China, reportedly the epicenter of the disease. Professor Meeyoung Cha from the School of Computing and her group facilitated data based on the number of confirmed cases from January 22 to March 22 to analyze the trends of this global epidemic. The statistics include the number of confirmed cases, recoveries, and deaths across major continents based on the number of confirmed case data during that period. The moving dot on the map strikingly shows how the confirmed cases are moving across the globe. According to their statistics, the centroid of the disease starts from near Wuhan in China and moved to Korea, then through the European region via Italy and Iran. The data is collected by a graduate student from the School of Computing, Geng Sun, who started the process during the time he was quarantined since coming back from his home in China. An undergraduate colleague of Geng's, Gabriel Camilo Lima who made the map, is now working remotely from his home in Brazil since all undergraduate students were required to move out of the dormitory last week. The university closed all undergraduate housing and advised the undergraduate students to go back home in a preventive measure to stop the virus from spreading across the campus. Gabriel said he calculated the centroid of all confirmed cases up to a given day. He explained, “I weighed each coordinate by the number of cases in that region and country and calculated an approximate center of gravity.” “The Earth is round, so the shortest path from Asia to Europe is often through Russia. In early March, the center of gravity of new cases was moving from Asia to Europe. Therefore, the centroid is moving to the west and goes through Russia, even though Russia has not reported many cases,” he added. Professor Cha, who is also responsible for the Data Science Group at the Institute for Basic Science (IBS) as the Chief Investigator, said their group will continue to update the map using public data at https://ds.ibs.re.kr/index.php/covid-19/. (END)
Newly Identified Meningeal Lymphatic Vessels Answers the Key Questions on Brain Clearance
(Figure: Schematic images of location and features of meningeal lymphatic vessels and their changes associated with ageing.) Just see what happens when your neighborhood’s waste disposal system is out of service. Not only do the piles of trash stink but they can indeed hinder the area’s normal functioning. That is also the case when the brain’s waste management is on the blink. The buildup of toxic proteins in the brain causes a massive damage to the nerves, leading to cognitive dysfunction and increased probability of developing neurodegenerative disorders such as Alzheimer's disease. Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain’s cleansing mechanism. Medical scientists led by Professor Gou Young Koh at the Graduate School of Medical Science and Engineering have reported the basal side of the skull as the major route, so called “hotspot” for CSF drainage. They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain’s major drainage system, specifically basal mLVs are impaired with aging. Their findings have been reported in the journal Nature on July 24. Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question — where is the main exit for the CSF? Though mLVs in the upper part of the skull (dorsal meningeal lymphatic vessels) were reported as the brain’s clearance pathways in 2014, no substantial drainage mechanism was observed in that section. “As a hidden exit for CSF, we looked into the mLVs trapped within complex structures at the base of the skull,” says Dr. Ji Hoon Ahn, the first author of this study. The researchers used several techniques to characterize the basal mLVs in detail. They used a genetically engineered lymphatic-reporter mouse model to visualize mLVs under a fluorescence microscope. By performing a careful examination of the mice skull, they found distinctive features of basal mLVs that make them suitable for CSF uptake and drainage. Just like typical functional lymphatic vessels, basal mLVs are found to have abundant lymphatic vessel branches with finger-like protrusions. Additionally, valves inside the basal mLVs allow the flow to go in one direction. In particular, they found that the basal mLVs are closely located to the CSF. Dr. Hyunsoo Cho, the first author of this study explains, “All up, it seemed a solid case that basal mLVs are the brain’s main clearance pathways. The researchers verified such specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs. Jun-Hee Kim, the first author of this study notes, “We literally saw that the brain clearance mechanism utilizing basal outflow route to exit the skull. It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. The corresponding author of this study, Dr. Koh says, “By characterizing the precise route for fluids leaving the brain, this study improves our understanding on how waste is cleared from the brain. Our findings also provide further insights into the role of impaired CSF clearance in the development of age-related neurodegenerative diseases.” Many current therapies for Alzheimer’s disease target abnormally accumulated proteins, such as beta-amyloid. By mapping out a precise route for the brain’s waste clearance system, this study may be able to help find ways to improve the brain’s cleansing function. Such breakthrough might become quite a sensational strategy for eliminating the buildup of aging-related toxic proteins. “It definitely warrants more extensive investigation of mLVs in patients with age-related neurodegenerative disease such as Alzheimer’s disease prior to clinical investigation,” adds Professor Koh.
The 1st Korea Toray Science and Technology Awardee, Prof. Sukbok Chang
(Distinguished Professor Sukbok Chang from the Department of Chemistry) The Korea Toray Science Foundation (KTSF) awarded the first Korea Toray Science Technology Award in basic science to Distinguished Professor Sukbok Chang from the Department of Chemistry on September 19. KTSF was established in January 2018, and its award goes to researchers who have significantly contributed to the development of chemistry and materials research with funds to support research projects. Distinguished Professor Chang has devoted himself in organocatalysis research; in particular, his work on catalysts for effective lactam formation, which was an intricate problem, received great attention. The award ceremony will take place in The Federation of Korean Industries Hall on October 31. KTFS board members, judges, and the CEO of Toray Industries Akihiro Nikkaku will attend the ceremony. Also, Dr. Ryoji Noyori, the Nobel Laureate in Chemistry, will give a talk on the role of chemistry and creative challenges as a researcher.
Total Synthesis of Flueggenine C via an Accelerated Intermolecular Rauhut-Currier Reaction
The first total synthesis of dimeric securinega alkaloid (-)-flueggenine C was completed via an accelerated intermolecular Rauhut–Currier (RC) reaction. The research team led by Professor Sunkyu Han in the Department of Chemistry succeeded in synthesizing the natural product by reinventing the conventional RC reaction. The total synthesis of natural products refers to the process of synthesizing secondary metabolites isolated from living organisms in the laboratory through a series of chemical reactions. Each stage of chemical reaction needs to be successful to produce the final target molecule, and thus the process requires high levels of patience and creativity. For that reason, the researchers working on natural products total synthesis are often called “molecular artists”. Despite numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas, whose monomeric units are connected by a putative enzymatic RC reaction, has not been reported to date. The team used a Rauhut-Currier (RC) reaction, a carboncarbon bond forming a reaction between two Michael acceptors first reported by Rauhut and Currier in 1963, to successfully synthesize a dimeric natural product, flueggenine C. This new work featured the first application of an intermolecular RC reaction in total synthesis. The conventional intermolecular RC reaction was driven non-selectively by a toxic nucleophilic catalyst at a high temperature of over 150°C and a highly concentrated reaction mixture, and thus has never been applied to natural products total synthesis. To overcome this long-standing problem, the research team placed a nucleophilic moiety at the γ-position of the enone derivative. As a result, the RC reaction could be induced by the simple addition of a base at ambient temperature and dilute solution, without the need of a nucleophilic catalyst. Using this newly discovered reactivity, the team successfully synthesized the natural product (-)-flueggenine C from commercially available amino acid derivative in 12 steps. Professor Han said, “Our key finding regarding the remarkably improved reactivity and selectivity of the intermolecular RC reaction will serve as a significant stepping stone in allowing this reaction to be considered a practical and reliable chemical tool with broad applicability in natural products, pharmaceuticals, and materials syntheses. ” This research was led by Ph.D. candidate Sangbin Jeon and was published in The Journal of the American Chemical Society (JACS) on May 10. This research was funded by KAIST start-up funds, HRHR (High-Risk High-Return), RED&B (Research, Education, Development & Business) projects, the National Research Foundation of Korea, and the Institute for Basic Science. (Figure 1: Representative dimeric/oligomeric securinega alkaloids) (Figure 2: Our reinvented Rauhut-Currier reaction) (Figure 3: Total Synthesis of (-)-flueggenine C)
EEWS Graduate School Team Receives the S-Oil Best Paper Award
Professor Hyungjun Kim and Dr. He-Young Shin from the EEWS (Energy, Environment, Water and Sustainability) Graduate School at KAIST received the Best Paper Award in Chemistry from S-Oil, a Korean petroleum and refinery company, on November 29, 2016. Established in 2011, the S-Oil Best Paper Awards are bestowed annually upon ten young scientists in the fields of five basic sciences: mathematics, physics, chemistry, biology, and earth science. The scientists are selected at the recommendation of the Korean Academy of Science and Technology and the Association of Korean Universities. The awards grant a total of USD 230,000 for research funding. Dr. Shin, the lead author of the awarded research paper, said, “My research interest has been catalyst studies based on theoretical chemistry. I am pleased to accept this award that will support my studies, and will continue to research catalyst design that can predict parameters and integrate them into catalytic systems.” Professor Hyungjun Kim (left) and Dr. He-Young Shin (right)
2016 KAIST EEWS Workshop
The Energy, Environment, Water and Sustainability (EEWS) Graduate School of KAIST hosted a workshop entitled “Progress and Perspectives of Energy Science and Technology” on October 20, 2016. The workshop took place at the Fusion Hall of the KAIST Institute on campus. About 400 experts in energy science and engineering participated in the event. Eight globally recognized scientists introduced the latest research trends in nanomaterials, energy theory, catalysts, and photocatalysts and led discussions on the current status and prospects of EEWS. Professors Yi Cui of Stanford University, an expert in nanomaterials, and William A. Goddard of California Institute of Technology presented their research experiments on materials design and recent results on the direction of theory under the topics of energy and environment. Dr. Miquel Salmeron, a former head of the Material Science Division of Lawrence Berkeley National Laboratory, and Professor Yuichi Ikuhara of Tokyo University introduced their analysis of catalysts and energy matters at an atomic scale. Professor Sukbok Chang of the Chemistry Department at KAIST, a deputy editor of ACS Catalysis and the head of the Center for Catalytic Hydrocarbon Functionalizations at the Institute of Basic Science, and Professor Yang-Kook Sun of Energy Engineering at Hanyang University, who is also a deputy editor of ACS Energy Letters, presented their latest research results on new catalytic reaction development and energy storage. The workshop consisted of three sections which addressed the design of energy and environment materials; analysis of energy and catalytic materials; and energy conversion and catalysts. The EEWS Graduate School was established in 2008 with the sponsorship of the Korean government’s World Class University (WCU) project to support science education in Korea. Professor J. Fraser Stoddart, the winner of the 2016 Nobel Prize in Chemistry, was previously worked at the KAIST EEWS Graduate School as a WCU visiting professor for two years, from 2011 to 2013. Professor Ali Coskun, who was a postdoctoral researcher in the laboratory of Professor Stoddart, now teaches and conducts research as a full-time professor at the graduate school. Dean Yousung Jung of the EEWS Graduate School said: “This workshop has provided us with a meaningful opportunity to engage in discussions on energy science and technology with world-class scholars from all around the world. It is also a good venue for our graduate school to share with them what we have been doing in research and education.”
Efficient Methane C-H Bond Activated by KAIST and UPenn Teams
Professor Mu-Hyun Baik of the Chemistry Department at KAIST and his team collaborated with an international team to discover a novel chemical reaction, carbon-hydrogen borylation using methane, and their research results were published in the March 25th issue of Science. For details, please refer to the following press release from the Institute for Basic Sciences (IBS) in Korea and the University of Pennsylvania in the United States. Efficient Methane C-H Bond Activation Achieved for the First Time The Institute for Basic Science, March 24, 2016 Penn Chemists Lay Groundwork for Countless New, Cleaner Uses of Methane University of Pennsylvania, March 24, 2016
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
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