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Revolutionary 'scLENS' Unveiled to Decode Complex Single-Cell Genomic Data
Unlocking biological information from complex single-cell genomic data has just become easier and more precise, thanks to the innovative 'scLENS' tool developed by the Biomedical Mathematics Group within the IBS Center for Mathematical and Computational Sciences led by Chief Investigator Jae Kyoung Kim, who is also a professor at KAIST. This new finding represents a significant leap forward in the field of single-cell transcriptomics. Single-cell genomic analysis is an advanced technique that measures gene expression at the individual cell level, revealing cellular changes and interactions that are not observable with traditional genomic analysis methods. When applied to cancer tissues, this analysis can delineate the composition of diverse cell types within a tumor, providing insights into how cancer progresses and identifying key genes involved during each stage of progression. Despite the immense potential of single-cell genomic analysis, handling the vast amount of data that it generates has always been challenging. The amount of data covers the expression of tens of thousands of genes across hundreds to thousands of individual cells. This not only results in large datasets but also introduces noise-related distortions, which arise in part due to current measurement limitations. < Figure 1. Overview of scLENS (single-cell Low-dimensional embedding using the effective Noise Subtract) > (Left) Current dimensionality reduction methods for scRNA-seq data involve conventional data preprocessing steps, such as log normalization, followed by manual selection of signals from the scaled data. However, this study reveals that the high levels of sparsity and variability in scRNA-seq data can lead to signal distortion during the data preprocessing, compromising the accuracy of downstream analyses. (Right) To address this issue, the researchers integrated L2 normalization into the conventional preprocessing pipeline, effectively mitigating signal distortion. Moreover, they developed a novel signal detection algorithm that eliminates the need for user intervention by leveraging random matrix theory-based noise filtering and signal robustness testing. By incorporating these techniques, scLENS enables accurate and automated analysis of scRNA-seq data, overcoming the limitations of existing dimensionality reduction methods. Corresponding author Jae Kyoung Kim highlighted, “There has been a remarkable advancement in experimental technologies for analyzing single-cell transcriptomes over the past decade. However, due to limitations in data analysis methods, there has been a struggle to fully utilize valuable data obtained through extensive cost and time." Researchers have developed numerous analysis methods over the years to discern biological signals from this noise. However, the accuracy of these methods has been less than satisfactory. A critical issue is that determining signal and noise thresholds often depends on subjective decisions from the users. The newly developed scLENS tool harnesses Random Matrix Theory and Signal robustness test to automatically differentiate signals from noise without relying on subjective user input. First author Hyun Kim stated, "Previously, users had to arbitrarily decide the threshold for signal and noise, which compromised the reproducibility of analysis results and introduced subjectivity. scLENS eliminates this problem by automatically detecting signals using only the inherent structure of the data." During the development of scLENS, researchers identified the fundamental reasons for inaccuracies in existing analysis methods. They found that commonly used data preprocessing methods distort both biological signals and noise. The new preprocessing approach that scLENS offers is free from such distortions. By resolving issues related to noise threshold determined by subjective user choice and signal distortion in conventional data preprocessing, scLENS significantly outperforms existing methods in accuracy. Additionally, scLENS automates the laborious process of signal dimension selection, allowing researchers to extract biological signals conveniently and automatically. CI Kim added, "scLENS solves major issues in single-cell transcriptome data analysis, substantially improving the accuracy and efficiency throughout the analysis process. This is a prime example of how fundamental mathematical theories can drive innovation in life sciences research, allowing researchers to more quickly and accurately answer biological questions and uncover secrets of life that were previously hidden." This research was published in the international journal 'Nature Communications' on April 27. Terminology * Single-cell RNA sequencing (scRNA-seq): A technique used to measure gene expression levels in individual cells, providing insights into cell heterogeneity and rare cell types. * Dimensionality reduction: A method to reduce the number of features or variables in a dataset while preserving the most important information, making data analysis more manageable and interpretable. * Random matrix theory: A mathematical framework used to model and analyze the properties of large, random matrices, which can be applied to filter out noise in high-dimensional data. * Signal robustness test: Among the signals, this test selects signals that are robust to the slight perturbation in data because real biological signals should be invariant for such slight modification in the data.
2024.05.09
View 2223
A KAIST Research Team Observes the Processes of Memory and Cognition in Real Time
The human brain contains approximately 86 billion neurons and 600 trillion synapses that exchange signals between the neurons to help us control the various functions of the brain including cognition, emotion, and memory. Interestingly, the number of synapses decrease with age or as a result of diseases like Alzheimer’s, and research on synapses thus attracts a lot of attention. However, limitations have existed in observing the dynamics of synapse structures in real time. On January 9, a joint research team led by Professor Won Do Heo from the KAIST Department of Biological Sciences, Professor Hyung-Bae Kwon from Johns Hopkins School of Medicine, and Professor Sangkyu Lee from the Institute for Basic Science (IBS) revealed that they have developed the world’s first technique to allow a real-time observation of synapse formation, extinction, and alterations. Professor Heo’s team conjugated dimerization-dependent fluorescent proteins (ddFP) to synapses in order to observe the process in which synapses create connections between neurons in real time. The team named this technique SynapShot, by combining the words ‘synapse’ and snapshot’, and successfully tracked and observed the live formation and extinction processes of synapses as well as their dynamic changes. < Figure 1. To observe dynamically changing synapses, dimerization-dependent fluorescent protein (ddFP) was expressed to observe flourescent signals upon synapse formation as ddFP enables fluorescence detection through reversible binding to pre- and postsynaptic terminals. > Through a joint research project, the teams led by Professor Heo and Professor Sangkyu Lee at IBS together designed a SynapShot with green and red fluorescence, and were able to easily distinguish the synapse connecting two different neurons. Additionally, by combining an optogenetic technique that can control the function of a molecule using light, the team was able to observe the changes in the synapses while simultaneously inducing certain functions of the neurons using light. Through more joint research with the team led by Professor Hyung-Bae Kwon at the Johns Hopkins School of Medicine, Professor Heo’s team induced several situations on live mice, including visual discrimination training, exercise, and anaesthesia, and used SynapShot to observe the changes in the synapses during each situation in real time. The observations revealed that each synapse could change fairly quickly and dynamically. This was the first-ever case in which the changes in synapses were observed in a live mammal. < Figure 2. Microscopic photos observed through changes of the flourescence of the synapse sensor (SynapShot) by cultivating the neurons of an experimental rat and expressing the SynapShot. The changes in the synapse that is created when the pre- and post-synaptic terminals come into contact and the synapse that disappears after a certain period of time are measured by the fluorescence of the SynapShot. > Professor Heo said, “Our group developed SynapShot through a collaboration with domestic and international research teams, and have opened up the possibility for first-hand live observations of the quick and dynamic changes of synapses, which was previously difficult to do. We expect this technique to revolutionize research methodology in the neurological field, and play an important role in brightening the future of brain science.” This research, conducted by co-first authors Seungkyu Son (Ph.D. candidate), Jinsu Lee (Ph.D. candidate) and Dr. Kanghoon Jung from Johns Hopkins, was published in the online edition of Nature Methods on January 8 under the title “Real-time visualization of structural dynamics of synapses in live cells in vivo”, and will be printed in the February volume. < Figure 3. Simultaneous use of green-SynapShot and red-SynapShot to distinguish and observe synapses with one post-terminal and different pre-terminals. > < Figure 4. Dimer-dependent fluorescent protein (ddFP) exists as a green fluorescent protein as well as a red fluorescent protein, and can be applied together with blue light-activated optogenetic technology. After activating Tropomyosin receptor kinase B (TrkB) by blue light using optogenetic technology, the strengthening of synaptic connections through signals of brain-derived neurotrophic factor is observed using red-SynapShot. > < Figure 5. Micrographs showing real-time changing synapses in the visual cortex of mice trained through visual training using in vivo imaging techniques such as two-photon microscopy as well as at the cellular level. > This research was supported by Mid-Sized Research Funds and the Singularity Project from KAIST, and by IBS.
2024.01.18
View 3275
KAIST researchers find sleep delays more prevalent in countries of particular culture than others
Sleep has a huge impact on health, well-being and productivity, but how long and how well people sleep these days has not been accurately reported. Previous research on how much and how well we sleep has mostly relied on self-reports or was confined within the data from the unnatural environments of the sleep laboratories. So, the questions remained: Is the amount and quality of sleep purely a personal choice? Could they be independent from social factors such as culture and geography? < From left to right, Sungkyu Park of Kangwon National University, South Korea; Assem Zhunis of KAIST and IBS, South Korea; Marios Constantinides of Nokia Bell Labs, UK; Luca Maria Aiello of the IT University of Copenhagen, Denmark; Daniele Quercia of Nokia Bell Labs and King's College London, UK; and Meeyoung Cha of IBS and KAIST, South Korea > A new study led by researchers at Korea Advanced Institute of Science and Technology (KAIST) and Nokia Bell Labs in the United Kingdom investigated the cultural and individual factors that influence sleep. In contrast to previous studies that relied on surveys or controlled experiments at labs, the team used commercially available smartwatches for extensive data collection, analyzing 52 million logs collected over a four-year period from 30,082 individuals in 11 countries. These people wore Nokia smartwatches, which allowed the team to investigate country-specific sleep patterns based on the digital logs from the devices. < Figure comparing survey and smartwatch logs on average sleep-time, wake-time, and sleep durations. Digital logs consistently recorded delayed hours of wake- and sleep-time, resulting in shorter sleep durations. > Digital logs collected from the smartwatches revealed discrepancies in wake-up times and sleep-times, sometimes by tens of minutes to an hour, from the data previously collected from self-report assessments. The average sleep-time overall was calculated to be around midnight, and the average wake-up time was 7:42 AM. The team discovered, however, that individuals' sleep is heavily linked to their geographical location and cultural factors. While wake-up times were similar, sleep-time varied by country. Individuals in higher GDP countries had more records of delayed bedtime. Those in collectivist culture, compared to individualist culture, also showed more records of delayed bedtime. Among the studied countries, Japan had the shortest total sleep duration, averaging a duration of under 7 hours, while Finland had the longest, averaging 8 hours. Researchers calculated essential sleep metrics used in clinical studies, such as sleep efficiency, sleep duration, and overslept hours on weekends, to analyze the extensive sleep patterns. Using Principal Component Analysis (PCA), they further condensed these metrics into two major sleep dimensions representing sleep quality and quantity. A cross-country comparison revealed that societal factors account for 55% of the variation in sleep quality and 63% of the variation in sleep quantity. Countries with a higher individualism index (IDV), which placed greater emphasis on individual achievements and relationships, had significantly longer sleep durations, which could be attributed to such societies having a norm of going to bed early. Spain and Japan, on the other hand, had the bedtime scheduled at the latest hours despite having the highest collectivism scores (low IDV). The study also discovered a moderate relationship between a higher uncertainty avoidance index (UAI), which measures implementation of general laws and regulation in daily lives of regular citizens, and better sleep quality. Researchers also investigated how physical activity can affect sleep quantity and quality to see if individuals can counterbalance cultural influences through personal interventions. They discovered that increasing daily activity can improve sleep quality in terms of shortened time needed in falling asleep and waking up. Individuals who exercise more, however, did not sleep longer. The effect of exercise differed by country, with more pronounced effects observed in some countries, such as the United States and Finland. Interestingly, in Japan, no obvious effect of exercise could be observed. These findings suggest that the relationship between daily activity and sleep may differ by country and that different exercise regimens may be more effective in different cultures. This research published on the Scientific Reports by the international journal, Nature, sheds light on the influence of social factors on sleep. (Paper Title "Social dimensions impact individual sleep quantity and quality" Article number: 9681) One of the co-authors, Daniele Quercia, commented: “Excessive work schedules, long working hours, and late bedtime in high-income countries and social engagement due to high collectivism may cause bedtimes to be delayed.” Commenting on the research, the first author Shaun Sungkyu Park said, "While it is intriguing to see that a society can play a role in determining the quantity and quality of an individual's sleep with large-scale data, the significance of this study is that it quantitatively shows that even within the same culture (country), individual efforts such as daily exercise can have a positive impact on sleep quantity and quality." "Sleep not only has a great impact on one’s well-being but it is also known to be associated with health issues such as obesity and dementia," said the lead author, Meeyoung Cha. "In order to ensure adequate sleep and improve sleep quality in an aging society, not only individual efforts but also a social support must be provided to work together," she said. The research team will contribute to the development of the high-tech sleep industry by making a code that easily calculates the sleep indicators developed in this study available free of charge, as well as providing the benchmark data for various types of sleep research to follow.
2023.07.07
View 4311
Researchers finds a way to reduce the overheating of semiconductor devices
The demand to shrink the size of semiconductors coupled with the problem of the heat generated at the hot spots of the devices not being effectively dispersed has negatively affected the reliability and durability of modern devices. Existing thermal management technologies have not been up to the task. Thus, the discovery of a new way of dispersing heat by using surface waves generated on the thin metal films over the substrate is an important breakthrough. KAIST (President Kwang Hyung Lee) announced that Professor Bong Jae Lee's research team in the Department of Mechanical Engineering succeeded in measuring a newly observed transference of heat induced by 'surface plasmon polariton' (SPP) in a thin metal film deposited on a substrate for the first time in the world. ☞ Surface plasmon polariton (SPP) refers to a surface wave formed on the surface of a metal as a result of strong interaction between the electromagnetic field at the interface between the dielectric and the metal and the free electrons on the metal surface and similar collectively vibrating particles. The research team utilized surface plasmon polaritons (SPP), which are surface waves generated at the metal-dielectric interface, to improve thermal diffusion in nanoscale thin metal films. Since this new heat transfer mode occurs when a thin film of metal is deposited on a substrate, it is highly usable in the device manufacturing process and has the advantage of being able to be manufactured over a large area. The research team showed that the thermal conductivity increased by about 25% due to surface waves generated over a 100-nm-thick titanium (Ti) film with a radius of about 3 cm. KAIST Professor Bong Jae Lee, who led the research, said, "The significance of this research is that a new heat transfer mode using surface waves over a thin metal film deposited on a substrate with low processing difficulty was identified for the first time in the world. It can be applied as a nanoscale heat spreader to efficiently dissipate heat near the hot spots for easily overheatable semiconductor devices.” The result has great implications for the development of high-performance semiconductor devices in the future in that it can be applied to rapidly dissipate heat on a nanoscale thin film. In particular, this new heat transfer mode identified by the research team is expected to solve the fundamental problem of thermal management in semiconductor devices as it enables even more effective heat transfer at nanoscale thickness while the thermal conductivity of the thin film usually decreases due to the boundary scattering effect. This study was published online on April 26 in 'Physical Review Letters' and was selected as an Editors' Suggestion. The research was carried out with support from the Basic Research Laboratory Support Program of the National Research Foundation of Korea. < Figure. Schematic diagram of the principle of measuring the thermal conductivity of thin Titanium (TI) films and the thermal conductivity of surface plasmon polariton measured on the Ti film >
2023.06.01
View 4206
Afternoon chemotherapy proved to deliver more desirable results for female lymphoma patients
Chemotherapy is a commonly used regimen for cancer treatment, but it is also a double-edged sword. While the drugs are highly effective at killing cancer cells, they are also notorious for killing healthy cells in the body. As such, minimizing the drug’s damage to the patient’s body is necessary for improving the prognosis of chemotherapy. Recently, “chrono-chemotherapy” have been gaining interest in the research community. As the name suggests, the aim is timing the delivery of the drugs when the body is least vulnerable to their harmful effects and while the cancer cells are at their most vulnerable. < Figure 1. Chrono-chemotherapy considering circadian rhythm > Chrono-chemotherapy exploits the fact that human physiological processes, including cell proliferation and differentiation, are regulated by an endogenous timer called the circadian clock. However, this has not been widely exploited in real-world clinical settings because, as of now, there is no systematic method for finding the optimal chemotherapy delivery time. This problem was tackled by an interdisciplinary team of researchers from South Korea. They were led by principal investigators Jae Kyoung Kim (a mathematician from the Biomedical Mathematics Group, Institute for Basic Science) and Youngil Koh (an oncologist at Seoul National University Hospital). The researchers studied a group of patients suffering from diffuse large B-cell lymphoma (DLBCL). Terminology * Diffuse large B-cell lymphoma (DLBCL): Lymphoma is a type of blood cancer caused by the malignant transformation of lymphoid tissue cells. Lymphoma is divided into Hodgkin's lymphoma and non-Hodgkin's lymphoma (malignant lymphoma), and diffuse large B-cell lymphoma accounts for about 30 to 40% of non-Hodgkin's lymphoma. The research team noticed that DLBCL patients at Seoul National University Hospital received chemotherapy on two different schedules, with some patients receiving morning treatment (8:30 a.m.) and others taking the drugs in the afternoon (2:30 p.m.). All patients received the same cancer treatment (R-CHOP), which is a combination of targeted therapy and chemotherapy, four to six times in the morning or afternoon at intervals of about three weeks. They analyzed 210 patients to investigate whether there was any difference between morning and afternoon treatments. It was found that female patients who received the afternoon treatment had a 12.5 times reduced mortality rate (25% to 2%), while the cancer recurrence after 60 months decreased by 2.8 times (37% to 13%). In addition, chemotherapy side effects such as neutropenia were more common in female patients who received the morning treatment. Surprisingly, there was no differences found in treatment efficiency depending on the treatment schedule in the cases of male patients. To understand the cause of the gender differences, the research team analyzed upto 14,000 blood samples from the Seoul National University Hospital Health Examination Center. It was found that in females, white blood cell counts tended to decrease in the morning and increase in the afternoon. This indicates that the bone marrow proliferation rate was higher in the morning than in the afternoon because there is a upto 12 hour delay between bone marrow proliferation and blood cell production. This means that if a female patient receives chemotherapy in the morning when bone marrow is actively producing blood cells, the possibility of adverse side effects becomes greater. These results are consistent with the findings from recent randomized clinical trials that showed female colorectal cancer patients treated with irinotecan in the morning suffered from higher drug toxicities. One confounding variable was the drug dose. Since the morning female patients suffered from greater adverse side effects, oftentimes the dose had to be reduced for these patients. On average, the drug dose was reduced by upto 10% compared to the dose intensity given to female patients receiving the afternoon treatment. Unlike the female patients, it was found that male patients did not show a significant difference in white blood cell count and bone marrow cell proliferation activity throughout the day, which explains why the timing of the treatment had no impact. Professor Youngil Koh said, “We plan to verify the conclusions of this study again with a large-scale follow-up study that completely controls for the confounding variables, and to confirm whether chrono-chemotherapy has similar effects on other cancers.” CI Jae Kyoung Kim said, “Because the time of the internal circadian clock can vary greatly depending on the individual's sleep-wake patterns, we are currently developing a technology to estimate a patient’s circadian clock from their sleep pattern. We hope that this can be used to develop an individualized anti-cancer chronotherapy schedule.” < Figure 2. Chemotherapy in the afternoon can improve treatment outcomes. > The daily fluctuation of proliferative activity of bone marrow is larger in females than in males, and it becomes higher in the morning (left). Thus, chemotherapy in the morning strongly inhibits proliferative activity in female lymphoma patients, resulting in a higher incidence of adverse events such as neutropenia and infections. This forced the clinicians to reduce the dose intensity (center). Consequently, female patients undergoing the morning treatment showed a lower survival probability than those undergoing the afternoon treatment (right). Specifically, only ~13% of female patients treated in the afternoon had a worse outcome and ~2% of them died while ~37% of female patients treated in the morning had a worse outcome and ~25% of them died. Male patients did not show any difference in treatment outcomes depending on the chemotherapy delivery time.
2023.01.27
View 4516
Scientists re-writes FDA-recommended equation to improve estimation of drug-drug interaction
Drugs absorbed into the body are metabolized and thus removed by enzymes from several organs like the liver. How fast a drug is cleared out of the system can be affected by other drugs that are taken together because added substance can increase the amount of enzyme secretion in the body. This dramatically decreases the concentration of a drug, reducing its efficacy, often leading to the failure of having any effect at all. Therefore, accurately predicting the clearance rate in the presence of drug-drug interaction* is critical in the process of drug prescription and development of a new drug in order to ensure its efficacy and/or to avoid unwanted side-effects. *Drug-drug interaction: In terms of metabolism, drug-drug interaction is a phenomenon in which one drug changes the metabolism of another drug to promote or inhibit its excretion from the body when two or more drugs are taken together. As a result, it increases the toxicity of medicines or causes loss of efficacy. Since it is practically impossible to evaluate all interactions between new drug candidates and all marketed drugs during the development process, the FDA recommends indirect evaluation of drug interactions using a formula suggested in their guidance, first published in 1997, revised in January of 2020, in order to evaluate drug interactions and minimize side effects of having to use more than one type of drugs at once. The formula relies on the 110-year-old Michaelis-Menten (MM) model, which has a fundamental limit of making a very broad and groundless assumption on the part of the presence of the enzymes that metabolizes the drug. While MM equation has been one of the most widely known equations in biochemistry used in more than 220,000 published papers, the MM equation is accurate only when the concentration of the enzyme that metabolizes the drug is almost non-existent, causing the accuracy of the equation highly unsatisfactory – only 38 percent of the predictions had less than two-fold errors. “To make up for the gap, researcher resorted to plugging in scientifically unjustified constants into the equation,” Professor Jung-woo Chae of Chungnam National University College of Pharmacy said. “This is comparable to having to have the epicyclic orbits introduced to explain the motion of the planets back in the days in order to explain the now-defunct Ptolemaic theory, because it was 'THE' theory back then.” < (From left) Ph.D. student Yun Min Song (KAIST, co-first authors), Professor Sang Kyum Kim (Chungnam National University, co-corresponding author), Jae Kyoung Kim, CI (KAIST, co-corresponding author), Professor Jung-woo Chae (Chungnam National University, co-corresponding author), Ph.D. students Quyen Thi Tran and Ngoc-Anh Thi Vu (Chungnam National University, co-first authors) > A joint research team composed of mathematicians from the Biomedical Mathematics Group within the Institute for Basic Science (IBS) and the Korea Advanced Institute of Science and Technology (KAIST) and pharmacological scientists from the Chungnam National University reported that they identified the major causes of the FDA-recommended equation’s inaccuracies and presented a solution. When estimating the gut bioavailability (Fg), which is the key parameter of the equation, the fraction absorbed from the gut lumen (Fa) is usually assumed to be 1. However, many experiments have shown that Fa is less than 1, obviously since it can’t be expected that all of the orally taken drugs to be completely absorbed by the intestines. To solve this problem, the research team used an “estimated Fa” value based on factors such as the drug’s transit time, intestine radius, and permeability values and used it to re-calculate Fg. Also, taking a different approach from the MM equation, the team used an alternative model they derived in a previous study back in 2020, which can more accurately predict the drug metabolism rate regardless of the enzyme concentration. Combining these changes, the modified equation with re-calculated Fg had a dramatically increased accuracy of the resulting estimate. The existing FDA formula predicted drug interactions within a 2-fold margin of error at the rate of 38%, whereas the accuracy rate of the revised formula reached 80%. “Such drastic improvement in drug-drug interaction prediction accuracy is expected to make great contribution to increasing the success rate of new drug development and drug efficacy in clinical trials. As the results of this study were published in one of the top clinical pharmacology journal, it is expected that the FDA guidance will be revised according to the results of this study.” said Professor Sang Kyum Kim from Chungnam National University College of Pharmacy. Furthermore, this study highlights the importance of collaborative research between research groups in vastly different disciplines, in a field that is as dynamic as drug interactions. “Thanks to the collaborative research between mathematics and pharmacy, we were able to recify the formula that we have accepted to be the right answer for so long to finally grasp on the leads toward healthier life for mankind.,” said Professor Jae Kyung Kim. He continued, “I hope seeing a ‘K-formula’ entered into the US FDA guidance one day.” The results of this study were published in the online edition of Clinical Pharmacology and Therapeutics (IF 7.051), an authoritative journal in the field of clinical pharmacology, on December 15, 2022 (Korean time). Thesis Title: Beyond the Michaelis-Menten: Accurate Prediction of Drug Interactions through Cytochrome P450 3A4 Induction (doi: 10.1002/cpt.2824) < Figure 1. The formula proposed by the FDA guidance for predicting drug-drug interactions (top) and the formula newly derived by the researchers (bottom). AUCR (the ratio of substrate area under the plasma concentration-time curve) represents the rate of change in drug concentration due to drug interactions. The research team more than doubled the accuracy of drug interaction prediction compared to the existing formula. > < Figure 2. Existing FDA formulas tend to underestimate the extent of drug-drug interactions (gray dots) than the actual measured values. On the other hand, the newly derived equation (red dot) has a prediction rate that is within the error range of 2 times (0.5 to 2 times) of the measured value, and is more than twice as high as the existing equation. The solid line in the figure represents the predicted value that matches the measured value. The dotted line represents the predicted value with an error of 0.5 to 2 times. > For further information or to request media assistance, please contact Jae Kyoung Kim at Biomedical Mathematics Group, Institute for Basic Science (IBS) (jaekkim@ibs.re.kr) or William I. Suh at the IBS Communications Team (willisuh@ibs.re.kr). - About the Institute for Basic Science (IBS) IBS was founded in 2011 by the government of the Republic of Korea with the sole purpose of driving forward the development of basic science in South Korea. IBS has 4 research institutes and 33 research centers as of January 2023. There are eleven physics, three mathematics, five chemistry, nine life science, two earth science, and three interdisciplinary research centers.
2023.01.18
View 9118
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 8379
Thermal Superconductor Lab Becomes the 7th Cross-Generation Collaborative Lab
The Thermal Superconductor Lab led by Senior Professor Sung Jin Kim from the Department of Mechanical Engineering will team up with Junior Professor Youngsuk Nam to develop next-generation superconductors. The two professor team was selected as the 7th Cross-Generation Collaborative Lab last week and will sustain the academic legacy of Professor Kim’s three decades of research on superconductors. The team will continue to develop thin, next-generation superconductors that carry super thermal conductivity using phase transition control technology and thin film packaging. Thin-filmed, next-generation superconductors can be used in various high-temperature flexible electronic devices. The superconductors built inside of the semiconductor device packages will also be used for managing the low-powered but high-performance temperatures of semiconductor and electronic equipment. Professor Kim said, “I am very pleased that my research, know-how, and knowledge from over 30 years of work will continue through the Cross-Generation Collaborative Lab system with Professor Nam. We will spare no effort to advance superconductor technology and play a part in KAIST leading global technology fields.” Junior Professor Nam also stressed that the team is excited to continue its research on crucial technology for managing the temperatures of semiconductors and other electronic equipment. KAIST started this innovative research system in 2018, and in 2021 it established the steering committee to select new labs based on: originality, differentiation, and excellence; academic, social, economic impact; the urgency of cross-generation research; the senior professor’s academic excellence and international reputation; and the senior professor’s research vision. Selected labs receive 500 million KRW in research funding over five years.
2022.01.27
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AI Weather Forecasting Research Center Opens
The Kim Jaechul Graduate School of AI in collaboration with the National Institute of Meteorological Sciences (NIMS) under the National Meteorological Administration launched the AI Weather Forecasting Research Center last month. The KAIST AI Weather Forecasting Research Center headed by Professor Seyoung Yoon was established with funding from from the AlphaWeather Development Research Project of the National Institute of Meteorological Sciences. KAIST was finally selected asas the project facilitator. AlphaWeather is an AI system that utilizes and analyzes approximately approximately 150,000 ,000 pieces of weather information per hour to help weather forecasters produce accurate weather forecasts. The research center is composed of three research teams with the following goals: (a) developdevelop AI technology for precipitation nowcasting, (b) developdevelop AI technology for accelerating physical process-based numerical models, and (c) develop dAI technology for supporting weather forecasters. The teams consist of 15 staff member members from NIMS and 61 researchers from the Kim Jaechul Graduate School of AI at KAIST. The research center is developing an AI algorithm for precipitation nowcasting (with up to six hours of lead time), which uses satellite images, radar reflectivity, and data collected from weather stations. It is also developing an AI algorithm for correcting biases in the prediction results from multiple numerical models. Finally, it is Finally, it is developing AI technology that supports weather forecasters by standardizing and automating repetitive manual processes. After verification, the the results obtained will be used by by the Korean National Weather Service as a next-generation forecasting/special-reporting system intelligence engine from 2026.
2022.01.10
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3D Visualization and Quantification of Bioplastic PHA in a Living Bacterial Cell
3D holographic microscopy leads to in-depth analysis of bacterial cells accumulating the bacterial bioplastic, polyhydroxyalkanoate (PHA) A research team at KAIST has observed how bioplastic granule is being accumulated in living bacteria cells through 3D holographic microscopy. Their 3D imaging and quantitative analysis of the bioplastic ‘polyhydroxyalkanoate’ (PHA) via optical diffraction tomography provides insights into biosynthesizing sustainable substitutes for petroleum-based plastics. The bio-degradable polyester polyhydroxyalkanoate (PHA) is being touted as an eco-friendly bioplastic to replace existing synthetic plastics. While carrying similar properties to general-purpose plastics such as polyethylene and polypropylene, PHA can be used in various industrial applications such as container packaging and disposable products. PHA is synthesized by numerous bacteria as an energy and carbon storage material under unbalanced growth conditions in the presence of excess carbon sources. PHA exists in the form of insoluble granules in the cytoplasm. Previous studies on investigating in vivo PHA granules have been performed by using fluorescence microscopy, transmission electron microscopy (TEM), and electron cryotomography. These techniques have generally relied on the statistical analysis of multiple 2D snapshots of fixed cells or the short-time monitoring of the cells. For the TEM analysis, cells need to be fixed and sectioned, and thus the investigation of living cells was not possible. Fluorescence-based techniques require fluorescence labeling or dye staining. Thus, indirect imaging with the use of reporter proteins cannot show the native state of PHAs or cells, and invasive exogenous dyes can affect the physiology and viability of the cells. Therefore, it was difficult to fully understand the formation of PHA granules in cells due to the technical limitations, and thus several mechanism models based on the observations have been only proposed. The team of metabolic engineering researchers led by Distinguished Professor Sang Yup Lee and Physics Professor YongKeun Park, who established the startup Tomocube with his 3D holographic microscopy, reported the results of 3D quantitative label-free analysis of PHA granules in individual live bacterial cells by measuring the refractive index distributions using optical diffraction tomography. The formation and growth of PHA granules in the cells of Cupriavidus necator, the most-studied native PHA (specifically, poly(3-hydroxybutyrate), also known as PHB) producer, and recombinant Escherichia coli harboring C. necator PHB biosynthesis pathway were comparatively examined. From the reconstructed 3D refractive index distribution of the cells, the team succeeded in the 3D visualization and quantitative analysis of cells and intracellular PHA granules at a single-cell level. In particular, the team newly presented the concept of “in vivo PHA granule density.” Through the statistical analysis of hundreds of single cells accumulating PHA granules, the distinctive differences of density and localization of PHA granules in the two micro-organisms were found. Furthermore, the team identified the key protein that plays a major role in making the difference that enabled the characteristics of PHA granules in the recombinant E. coli to become similar to those of C. necator. The research team also presented 3D time-lapse movies showing the actual processes of PHA granule formation combined with cell growth and division. Movies showing the living cells synthesizing and accumulating PHA granules in their native state had never been reported before. Professor Lee said, “This study provides insights into the morphological and physical characteristics of in vivo PHA as well as the unique mechanisms of PHA granule formation that undergo the phase transition from soluble monomers into the insoluble polymer, followed by granule formation. Through this study, a deeper understanding of PHA granule formation within the bacterial cells is now possible, which has great significance in that a convergence study of biology and physics was achieved. This study will help develop various bioplastics production processes in the future.” This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (Grants NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557) and the Bio & Medical Technology Development Program (Grant No. 2021M3A9I4022740) from the Ministry of Science and ICT (MSIT) through the National Research Foundation (NRF) of Korea to S.Y.L. This work was also supported by the KAIST Cross-Generation Collaborative Laboratory project. -PublicationSo Young Choi, Jeonghun Oh, JaeHwang Jung, YongKeun Park, and Sang Yup Lee. Three-dimensional label-free visualization and quantification of polyhydroxyalkanoates in individualbacterial cell in its native state. PNAS(https://doi.org./10.1073/pnas.2103956118) -ProfileDistinguished Professor Sang Yup LeeMetabolic Engineering and Synthetic Biologyhttp://mbel.kaist.ac.kr/ Department of Chemical and Biomolecular Engineering KAIST Endowed Chair Professor YongKeun ParkBiomedical Optics Laboratoryhttps://bmokaist.wordpress.com/ Department of PhysicsKAIST
2021.07.28
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Professor Heung-Sun Sim the MSIT Scientist of July
Professor Heung-Sun Sim from the Department of Physics was selected as the Scientist of July by the Ministry of Science and ICT. Professor Sim was recognized for his research of the Kondo effect, which opened a novel way to engineer spin screening and entanglement by directly observing a quantum phenomenon known as a Kondo screening cloud. His research revealed that the cloud can mediate interactions between distant spins confined in quantum dots, which is a necessary protocol for semiconductor spin-based quantum information processing. This phenomenon is essentially a cloud that masks magnetic impurities in a material. It was known to exist but its spatial extension had never been observed, creating controversy over whether such an extension actually existed. The research was reported in Nature in March 2020. With this award, Professor Sim received 10 million KRW in prize money.
2021.07.12
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Scientists Observe the Elusive Kondo Screening Cloud
Scientists ended a 50-year quest by directly observing a quantum phenomenon An international research group of Professor Heung-Sun Sim has ended a 50-year quest by directly observing a quantum phenomenon known as a Kondo screening cloud. This research, published in Nature on March 11, opens a novel way to engineer spin screening and entanglement. According to the research, the cloud can mediate interactions between distant spins confined in quantum dots, which is a necessary protocol for semiconductor spin-based quantum information processing. This spin-spin interaction mediated by the Kondo cloud is unique since both its strength and sign (two spins favor either parallel or anti-parallel configuration) are electrically tunable, while conventional schemes cannot reverse the sign. This phenomenon, which is important for many physical phenomena such as dilute magnetic impurities and spin glasses, is essentially a cloud that masks magnetic impurities in a material. It was known to exist but its spatial extension had never been observed, creating controversy over whether such an extension actually existed. Magnetism arises from a property of electrons known as spin, meaning that they have angular momentum aligned in one of either two directions, conventionally known as up and down. However, due to a phenomenon known as the Kondo effect, the spins of conduction electrons—the electrons that flow freely in a material—become entangled with a localized magnetic impurity, and effectively screen it. The strength of this spin coupling, calibrated as a temperature, is known as the Kondo temperature. The size of the cloud is another important parameter for a material containing multiple magnetic impurities because the spins in the cloud couple with one another and mediate the coupling between magnetic impurities when the clouds overlap. This happens in various materials such as Kondo lattices, spin glasses, and high temperature superconductors. Although the Kondo effect for a single magnetic impurity is now a text-book subject in many-body physics, detection of its key object, the Kondo cloud and its length, has remained elusive despite many attempts during the past five decades. Experiments using nuclear magnetic resonance or scanning tunneling microscopy, two common methods for understanding the structure of matter, have either shown no signature of the cloud, or demonstrated a signature only at a very short distance, less than 1 nanometer, so much shorter than the predicted cloud size, which was in the micron range. In the present study, the authors observed a Kondo screening cloud formed by an impurity defined as a localized electron spin in a quantum dot—a type of “artificial atom”—coupled to quasi-one-dimensional conduction electrons, and then used an interferometer to measure changes in the Kondo temperature, allowing them to investigate the presence of a cloud at the interferometer end. Essentially, they slightly perturbed the conduction electrons at a location away from the quantum dot using an electrostatic gate. The wave of conducting electrons scattered by this perturbation returned back to the quantum dot and interfered with itself. This is similar to how a wave on a water surface being scattered by a wall forms a stripe pattern. The Kondo cloud is a quantum mechanical object which acts to preserve the wave nature of electrons inside the cloud. Even though there is no direct electrostatic influence of the perturbation on the quantum dot, this interference modifies the Kondo signature measured by electron conductance through the quantum dot if the perturbation is present inside the cloud. In the study, the researchers found that the length as well as the shape of the cloud is universally scaled by the inverse of the Kondo temperature, and that the cloud’s size and shape were in good agreement with theoretical calculations. Professor Sim at the Department of Physics proposed the method for detecting the Kondo cloud in the co-research with the RIKEN Center for Emergent Matter Science, the City University of Hong Kong, the University of Tokyo, and Ruhr University Bochum in Germany. Professor Sim said, “The observed spin cloud is a micrometer-size object that has quantum mechanical wave nature and entanglement. This is why the spin cloud has not been observed despite a long search. It is remarkable in a fundamental and technical point of view that such a large quantum object can now be created, controlled, and detected. Dr. Michihisa Yamamoto of the RIKEN Center for Emergent Matter Science also said, “It is very satisfying to have been able to obtain real space image of the Kondo cloud, as it is a real breakthrough for understanding various systems containing multiple magnetic impurities. The size of the Kondo cloud in semiconductors was found to be much larger than the typical size of semiconductor devices.” Publication: Borzenets et al. (2020) Observation of the Kondo screening cloud. Nature, 579. pp.210-213. Available online at https://doi.org/10.1038/s41586-020-2058-6 Profile: Heung-Sun Sim, PhD Professor hssim@kaist.ac.kr https://qet.kaist.ac.kr/ Quantum Electron Correlation & Transport Theory Group (QECT Lab) https://qc.kaist.ac.kr/index.php/group1/ Center for Quantum Coherence In COndensed Matter Department of Physics https://www.kaist.ac.kr Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea
2020.03.13
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