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Unravelling Complex Brain Networks with Automated 3-D Neural Mapping
-Automated 3-D brain imaging data analysis technology offers more reliable and standardized analysis of the spatial organization of complex neural circuits.- KAIST researchers developed a new algorithm for brain imaging data analysis that enables the precise and quantitative mapping of complex neural circuits onto a standardized 3-D reference atlas. Brain imaging data analysis is indispensable in the studies of neuroscience. However, analysis of obtained brain imaging data has been heavily dependent on manual processing, which cannot guarantee the accuracy, consistency, and reliability of the results. Conventional brain imaging data analysis typically begins with finding a 2-D brain atlas image that is visually similar to the experimentally obtained brain image. Then, the region-of-interest (ROI) of the atlas image is matched manually with the obtained image, and the number of labeled neurons in the ROI is counted. Such a visual matching process between experimentally obtained brain images and 2-D brain atlas images has been one of the major sources of error in brain imaging data analysis, as the process is highly subjective, sample-specific, and susceptible to human error. Manual analysis processes for brain images are also laborious, and thus studying the complete 3-D neuronal organization on a whole-brain scale is a formidable task. To address these issues, a KAIST research team led by Professor Se-Bum Paik from the Department of Bio and Brain Engineering developed new brain imaging data analysis software named 'AMaSiNe (Automated 3-D Mapping of Single Neurons)', and introduced the algorithm in the May 26 issue of Cell Reports. AMaSiNe automatically detects the positions of single neurons from multiple brain images, and accurately maps all the data onto a common standard 3-D reference space. The algorithm allows the direct comparison of brain data from different animals by automatically matching similar features from the images, and computing the image similarity score. This feature-based quantitative image-to-image comparison technology improves the accuracy, consistency, and reliability of analysis results using only a small number of brain slice image samples, and helps standardize brain imaging data analyses. Unlike other existing brain imaging data analysis methods, AMaSiNe can also automatically find the alignment conditions from misaligned and distorted brain images, and draw an accurate ROI, without any cumbersome manual validation process. AMaSiNe has been further proved to produce consistent results with brain slice images stained utilizing various methods including DAPI, Nissl, and autofluorescence. The two co-lead authors of this study, Jun Ho Song and Woochul Choi, exploited these benefits of AMaSiNe to investigate the topographic organization of neurons that project to the primary visual area (VISp) in various ROIs, such as the dorsal lateral geniculate nucleus (LGd), which could hardly be addressed without proper calibration and standardization of the brain slice image samples. In collaboration with Professor Seung-Hee Lee's group of the Department of Biological Science, the researchers successfully observed the 3-D topographic neural projections to the VISp from LGd, and also demonstrated that these projections could not be observed when the slicing angle was not properly corrected by AMaSiNe. The results suggest that the precise correction of a slicing angle is essential for the investigation of complex and important brain structures. AMaSiNe is widely applicable in the studies of various brain regions and other experimental conditions. For example, in the research team’s previous study jointly conducted with Professor Yang Dan’s group at UC Berkeley, the algorithm enabled the accurate analysis of the neuronal subsets in the substantia nigra and their projections to the whole brain. Their findings were published in Science on January 24. AMaSiNe is of great interest to many neuroscientists in Korea and abroad, and is being actively used by a number of other research groups at KAIST, MIT, Harvard, Caltech, and UC San Diego. Professor Paik said, “Our new algorithm allows the spatial organization of complex neural circuits to be found in a standardized 3-D reference atlas on a whole-brain scale. This will bring brain imaging data analysis to a new level.” He continued, “More in-depth insights for understanding the function of brain circuits can be achieved by facilitating more reliable and standardized analysis of the spatial organization of neural circuits in various regions of the brain.” This work was supported by KAIST and the National Research Foundation of Korea (NRF). Figure and Image Credit: Professor Se-Bum Paik, KAIST Figure and Image Usage Restrictions: News organizations may use or redistribute these figures and images, with proper attribution, as part of news coverage of this paper only. Publication: Song, J. H., et al. (2020). Precise Mapping of Single Neurons by Calibrated 3D Reconstruction of Brain Slices Reveals Topographic Projection in Mouse Visual Cortex. Cell Reports. Volume 31, 107682. Available online at https://doi.org/10.1016/j.celrep.2020.107682 Profile: Se-Bum Paik Assistant Professor sbpaik@kaist.ac.kr http://vs.kaist.ac.kr/ VSNN Laboratory Department of Bio and Brain Engineering Program of Brain and Cognitive Engineering http://kaist.ac.kr Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea (END)
2020.06.08
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Universal Virus Detection Platform to Expedite Viral Diagnosis
Reactive polymer-based tester pre-screens dsRNAs of a wide range of viruses without their genome sequences The prompt, precise, and massive detection of a virus is the key to combat infectious diseases such as Covid-19. A new viral diagnostic strategy using reactive polymer-grafted, double-stranded RNAs will serve as a pre-screening tester for a wide range of viruses with enhanced sensitivity. Currently, the most widely using viral detection methodology is polymerase chain reaction (PCR) diagnosis, which amplifies and detects a piece of the viral genome. Prior knowledge of the relevant primer nucleic acids of the virus is quintessential for this test. The detection platform developed by KAIST researchers identifies viral activities without amplifying specific nucleic acid targets. The research team, co-led by Professor Sheng Li and Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering, constructed a universal virus detection platform by utilizing the distinct features of the PPFPA-grafted surface and double-stranded RNAs. The key principle of this platform is utilizing the distinct feature of reactive polymer-grafted surfaces, which serve as a versatile platform for the immobilization of functional molecules. These activated surfaces can be used in a wide range of applications including separation, delivery, and detection. As long double-stranded RNAs are common byproducts of viral transcription and replication, these PPFPA-grafted surfaces can detect the presence of different kinds of viruses without prior knowledge of their genomic sequences. “We employed the PPFPA-grafted silicon surface to develop a universal virus detection platform by immobilizing antibodies that recognize double-stranded RNAs,” said Professor Kim. To increase detection sensitivity, the research team devised two-step detection process analogues to sandwich enzyme-linked immunosorbent assay where the bound double-stranded RNAs are then visualized using fluorophore-tagged antibodies that also recognize the RNAs’ double-stranded secondary structure. By utilizing the developed platform, long double-stranded RNAs can be detected and visualized from an RNA mixture as well as from total cell lysates, which contain a mixture of various abundant contaminants such as DNAs and proteins. The research team successfully detected elevated levels of hepatitis C and A viruses with this tool. “This new technology allows us to take on virus detection from a new perspective. By targeting a common biomarker, viral double-stranded RNAs, we can develop a pre-screening platform that can quickly differentiate infected populations from non-infected ones,” said Professor Li. “This detection platform provides new perspectives for diagnosing infectious diseases. This will provide fast and accurate diagnoses for an infected population and prevent the influx of massive outbreaks,” said Professor Kim. This work is featured in Biomacromolecules. This work was supported by the Agency for Defense Development (Grant UD170039ID), the Ministry of Science and ICT (NRF-2017R1D1A1B03034660, NRF-2019R1C1C1006672), and the KAIST Future Systems Healthcare Project from the Ministry of Science and ICT (KAISTHEALTHCARE42). Profile:-Professor Yoosik KimDepartment of Chemical and Biomolecular Engineeringhttps://qcbio.kaist.ac.kr KAIST-Professor Sheng LiDepartment of Chemical and Biomolecular Engineeringhttps://bcpolymer.kaist.ac.kr KAIST Publication:Ku et al., 2020. Reactive Polymer Targeting dsRNA as Universal Virus Detection Platform with Enhanced Sensitivity. Biomacromolecules (https://doi.org/10.1021/acs.biomac.0c00379).
2020.06.01
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Professor Sue-Hyun Lee Listed Among WEF 2020 Young Scientists
Professor Sue-Hyun Lee from the Department of Bio and Brain Engineering joined the World Economic Forum (WEF)’s Young Scientists Community on May 26. The class of 2020 comprises 25 leading researchers from 14 countries across the world who are at the forefront of scientific problem-solving and social change. Professor Lee was the only Korean on this year’s roster. The WEF created the Young Scientists Community in 2008 to engage leaders from the public and private sectors with science and the role it plays in society. The WEF selects rising-star academics, 40 and under, from various fields every year, and helps them become stronger ambassadors for science, especially in tackling pressing global challenges including cybersecurity, climate change, poverty, and pandemics. Professor Lee is researching how memories are encoded, recalled, and updated, and how emotional processes affect human memory, in order to ultimately direct the development of therapeutic methods to treat mental disorders. She has made significant contributions to resolving ongoing debates over the maintenance and changes of memory traces in the brain. In recognition of her research excellence, leadership, and commitment to serving society, the President and the Dean of the College of Engineering at KAIST nominated Professor Lee to the WEF’s Class of 2020 Young Scientists Selection Committee. The Committee also acknowledged Professor Lee’s achievements and potential for expanding the boundaries of knowledge and practical applications of science, and accepted her into the Community. During her three-year membership in the Community, Professor Lee will be committed to participating in WEF-initiated activities and events related to promising therapeutic interventions for mental disorders and future directions of artificial intelligence. Seven of this year’s WEF Young Scientists are from Asia, including Professor Lee, while eight are based in Europe. Six study in the Americas, two work in South Africa, and the remaining two in the Middle East. Fourteen, more than half, of the newly announced 25 Young Scientists are women. (END)
2020.05.26
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The 10th KINC Fusion Research Awardees
The KAIST Institute for NanoCentury (KINC) recognized three distinguished researchers whose convergence studies made significant impacts. The KINC presented the 10th KINC Fusion Research Awards during a ceremony that took place at KAIST’s main campus in Daejeon on May 19. This year’s ‘best’ convergence research award went to a joint research group led by Professor Hee Tak Kim from the Department of Chemical and Biomolecular Engineering and Professor Sang Ouk Kim from the Department of Materials Science and Engineering. Their research, featured in the December 27 issue of Advanced Materials as a front cover article last year, introduced the world’s first high-energy efficiency, membraneless, flowless, zinc-bromine battery. This study, in which research professor Gyoung Hwa Jeong, postdoctoral researcher Yearin Byun, and PhD candidate Ju-Hyuck Lee took part as co-lead authors, is deemed as an example of a best practice in convergence research in which two groups’ respective expertise in the fields of carbon materials and electrochemical analysis created a synergistic effect. Professor Bumjoon Kim from the Department of Chemical and Biomolecular Engineering was also recognized for having published the most interdisciplinary research papers on polymer electronics and nanomaterials at home and abroad. Professor Hee-Tae Jung, the Director of KINC and the host of the KINC Fusion Research Awards, said, “The KINC is happy to announce the 10th awardees in nano-fusion research this year. Since convergence is crucial for making revolutionary changes, the importance of convergence studies should be recognized. Our institute will spare no effort to create a research environment suitable for convergence studies, which will be crucial for making a significant difference.” The KINC was established in June 2006 under the KAIST Institute with the mission of facilitating convergence studies by tearing down boarders among departments and carrying out interdisciplinary joint research. Currently, the institute is comprised of approximately 90 professors from 13 departments. It aims to become a hub of university institutes for nano-fusion research. (END)
2020.05.19
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Researchers Present a Microbial Strain Capable of Massive Succinic Acid Production
A research team led by Distinguished Professor Sang Yup Lee reported the production of a microbial strain capable of the massive production of succinic acid with the highest production efficiency to date. This strategy of integrating systems metabolic engineering with enzyme engineering will be useful for the production of industrially competitive bio-based chemicals. Their strategy was described in Nature Communications on April 23. The bio-based production of industrial chemicals from renewable non-food biomass has become increasingly important as a sustainable substitute for conventional petroleum-based production processes relying on fossil resources. Here, systems metabolic engineering, which is the key component for biorefinery technology, is utilized to effectively engineer the complex metabolic pathways of microorganisms to enable the efficient production of industrial chemicals. Succinic acid, a four-carbon dicarboxylic acid, is one of the most promising platform chemicals serving as a precursor for industrially important chemicals. Among microorganisms producing succinic acid, Mannheimia succiniciproducens has been proven to be one of the best strains for succinic acid production. The research team has developed a bio-based succinic acid production technology using the M. succiniciproducens strain isolated from the rumen of Korean cow for over 20 years and succeeded in developing a strain capable of producing succinic acid with the highest production efficiency. They carried out systems metabolic engineering to optimize the succinic acid production pathway of the M. succiniciproducens strain by determining the crystal structure of key enzymes important for succinic acid production and performing protein engineering to develop enzymes with better catalytic performance. As a result, 134 g per liter of succinic acid was produced from the fermentation of an engineered strain using glucose, glycerol, and carbon dioxide. They were able to achieve 21 g per liter per hour of succinic acid production, which is one of the key factors determining the economic feasibility of the overall production process. This is the world’s best succinic acid production efficiency reported to date. Previous production methods averaged 1~3 g per liter per hour. Distinguished professor Sang Yup Lee explained that his team’s work will significantly contribute to transforming the current petrochemical-based industry into an eco-friendly bio-based one. “Our research on the highly efficient bio-based production of succinic acid from renewable non-food resources and carbon dioxide has provided a basis for reducing our strong dependence on fossil resources, which is the main cause of the environmental crisis,” Professor Lee said. This work was supported by the Technology Development Program to Solve Climate Changes via Systems Metabolic Engineering for Biorefineries and the C1 Gas Refinery Program from the Ministry of Science and ICT through the National Research Foundation of Korea.
2020.05.06
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A Study Finds Neuropeptide Somatostatin Enhances Visual Processing
Researchers have confirmed that neuropeptide somatostatin can improve cognitive function in the brain. A research group of Professor Seung-Hee Lee from the Department of Biological Sciences at KAIST found that the application of neuropeptide somatostatin improves visual processing and cognitive behaviors by reducing excitatory inputs to parvalbumin-positive interneurons in the cortex. This study, reported at Science Advances on April 22nd (EST), sheds a new light on the therapeutics of neurodegenerative diseases. According to a recent study in Korea, one in ten seniors over 65 is experiencing dementia-related symptoms in their daily lives such like memory loss, cognitive decline, and motion function disorders. Professor Lee believes that somatostatin treatment can be directly applied to the recovery of cognitive functions in Alzheimer’s disease patients. Professor Lee started this study noting the fact that the level of somatostatin expression was dramatically decreased in the cerebral cortex and cerebrospinal fluid of Alzheimer’s disease patients Somatostatin-expressing neurons in the cortex are known to exert the dendritic inhibition of pyramidal neurons via GABAergic transmission. Previous studies focused on their inhibitory effects on cortical circuits, but somatostatin-expressing neurons can co-release somatostatin upon activation. Despite the abundant expression of somatostatin and its receptors in the cerebral cortex, it was not known if somatostatin could modulate cognitive processing in the cortex. The research team demonstrated that the somatostatin treatment into the cerebral cortex could enhance visual processing and cognitive behaviors in mice. The research team combined behaviors, in vivo and in vitro electrophysiology, and electron microscopy techniques to reveal how the activation of somatostatin receptors in vivo enhanced the ability of visual recognition in animals. Interestingly, somatostatin release can reduce excitatory synaptic transmission to another subtype of GABAergic interneurons, parvalbumin (PV)-expressing neurons. As somatostatin is a stable and safe neuropeptide expressed naturally in the mammalian brain, it was safe to be injected into the cortex and cerebrospinal fluid, showing a potential application to drug development for curing cognitive disorders in humans. Professor Lee said, “Our research confirmed the key role of the neuropeptide SST in modulating cortical function and enhancing cognitive ability in the mammalian brain. I hope new drugs can be developed based on the function of somatostatin to treat cognitive disabilities in many patients suffering from neurological disorders.” This study was supported by the National Research Foundation of Korea. Publication: Song, Y. H et al. (2020) ‘Somatostatin enhances visual processing and perception by suppressing excitatory inputs to parvalbumin-positive interneurons in V1’, Science Advances, 6(17). Available online at https://doi.org/10.1126/sciadv.aaz0517 Profile: Seung-Hee Lee Associate Professor shlee1@kaist.ac.kr https://sites.google.com/site/leelab2013/ Sensory Processing Lab (SPL) Department of Biological Sciences (BIO) Korea Advanced Institute of Science and Technology (KAIST) Profile: You-Hyang Song Researcher (Ph.D.) dbgidtm17@kaist.ac.kr SPL, KAIST BIO Profile: Yang-Sun Hwang Researcher (M.S.) hys940129@kaist.ac.kr SPL, KAIST BIO (END)
2020.04.23
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Ultrathin but Fully Packaged High-Resolution Camera
- Biologically inspired ultrathin arrayed camera captures super-resolution images. - The unique structures of biological vision systems in nature inspired scientists to design ultracompact imaging systems. A research group led by Professor Ki-Hun Jeong have made an ultracompact camera that captures high-contrast and high-resolution images. Fully packaged with micro-optical elements such as inverted micro-lenses, multilayered pinhole arrays, and gap spacers on the image sensor, the camera boasts a total track length of 740 μm and a field of view of 73°. Inspired by the eye structures of the paper wasp species Xenos peckii, the research team completely suppressed optical noise between micro-lenses while reducing camera thickness. The camera has successfully demonstrated high-contrast clear array images acquired from tiny micro lenses. To further enhance the image quality of the captured image, the team combined the arrayed images into one image through super-resolution imaging. An insect’s compound eye has superior visual characteristics, such as a wide viewing angle, high motion sensitivity, and a large depth of field while maintaining a small volume of visual structure with a small focal length. Among them, the eyes of Xenos peckii and an endoparasite found on paper wasps have hundreds of photoreceptors in a single lens unlike conventional compound eyes. In particular, the eye structures of an adult Xenos peckii exhibit hundreds of photoreceptors on an individual eyelet and offer engineering inspiration for ultrathin cameras or imaging applications because they have higher visual acuity than other compound eyes. For instance, Xenos peckii’s eye-inspired cameras provide a 50 times higher spatial resolution than those based on arthropod eyes. In addition, the effective image resolution of the Xenos peckii’s eye can be further improved using the image overlaps between neighboring eyelets. This unique structure offers higher visual resolution than other insect eyes. The team achieved high-contrast and super-resolution imaging through a novel arrayed design of micro-optical elements comprising multilayered aperture arrays and inverted micro-lens arrays directly stacked over an image sensor. This optical component was integrated with a complementary metal oxide semiconductor image sensor. This is first demonstration of super-resolution imaging which acquires a single integrated image with high contrast and high resolving power reconstructed from high-contrast array images. It is expected that this ultrathin arrayed camera can be applied for further developing mobile devices, advanced surveillance vehicles, and endoscopes. Professor Jeong said, “This research has led to technological advances in imaging technology. We will continue to strive to make significant impacts on multidisciplinary research projects in the fields of microtechnology and nanotechnology, seeking inspiration from natural photonic structures.” This work was featured in Light Science & Applications last month and was supported by the National Research Foundation (NRF) of and the Ministry of Health and Welfare (MOHW) of Korea. Image credit: Professor Ki-Hun Jeong, KAIST Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of news coverage of this paper only. Publication: Kisoo Kim, Kyung-Won Jang, Jae-Kwan Ryu, and Ki-Hun Jeong. (2020) “Biologically inspired ultrathin arrayed camera for high-contrast and high-resolution imaging”. Light Science & Applications. Volume 9. Article 28. Available online at https://doi.org/10.1038/s41377-020-0261-8 Profile: Ki-Hun Jeong Professor kjeong@kaist.ac.kr http://biophotonics.kaist.ac.kr/ Department of Bio and Brain Engineering KAIST Profile: Kisoo Kim Ph.D. Candidate kisoo.kim1@kaist.ac.kr http://biophotonics.kaist.ac.kr/ Department of Bio and Brain Engineering KAIST (END)
2020.03.23
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A Single Biological Factor Predicts Distinct Cortical Organizations across Mammalian Species
-A KAIST team’s mathematical sampling model shows that retino-cortical mapping is a prime determinant in the topography of cortical organization.- Researchers have explained how visual cortexes develop uniquely across the brains of different mammalian species. A KAIST research team led by Professor Se-Bum Paik from the Department of Bio and Brain Engineering has identified a single biological factor, the retino-cortical mapping ratio, that predicts distinct cortical organizations across mammalian species. This new finding has resolved a long-standing puzzle in understanding visual neuroscience regarding the origin of functional architectures in the visual cortex. The study published in Cell Reports on March 10 demonstrates that the evolutionary variation of biological parameters may induce the development of distinct functional circuits in the visual cortex, even without species-specific developmental mechanisms. In the primary visual cortex (V1) of mammals, neural tuning to visual stimulus orientation is organized into one of two distinct topographic patterns across species. While primates have columnar orientation maps, a salt-and-pepper type organization is observed in rodents. For decades, this sharp contrast between cortical organizations has spawned fundamental questions about the origin of functional architectures in the V1. However, it remained unknown whether these patterns reflect disparate developmental mechanisms across mammalian taxa, or simply originate from variations in biological parameters under a universal development process. To identify a determinant predicting distinct cortical organizations, Professor Paik and his researchers Jaeson Jang and Min Song examined the exact condition that generates columnar and salt-and-pepper organizations, respectively. Next, they applied a mathematical model to investigate how the topographic information of the underlying retinal mosaics pattern could be differently mapped onto a cortical space, depending on the mapping condition. The research team proved that the retino-cortical feedforwarding mapping ratio appeared to be correlated to the cortical organization of each species. In the model simulations, the team found that distinct cortical circuitries can arise from different V1 areas and retinal ganglion cell (RGC) mosaic sizes. The team’s mathematical sampling model shows that retino-cortical mapping is a prime determinant in the topography of cortical organization, and this prediction was confirmed by neural parameter analysis of the data from eight phylogenetically distinct mammalian species. Furthermore, the researchers proved that the Nyquist sampling theorem explains this parametric division of cortical organization with high accuracy. They showed that a mathematical model predicts that the organization of cortical orientation tuning makes a sharp transition around the Nyquist sampling frequency, explaining why cortical organizations can be observed in either columnar or salt-and-pepper organizations, but not in intermediates between these two stages. Professor Paik said, “Our findings make a significant impact for understanding the origin of functional architectures in the visual cortex of the brain, and will provide a broad conceptual advancement as well as advanced insights into the mechanism underlying neural development in evolutionarily divergent species.” He continued, “We believe that our findings will be of great interest to scientists working in a wide range of fields such as neuroscience, vision science, and developmental biology.” This work was supported by the National Research Foundation of Korea (NRF). Image credit: Professor Se-Bum Paik, KAIST Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of news coverage of this paper only. Publication: Jaeson Jang, Min Song, and Se-Bum Paik. (2020). Retino-cortical mapping ratio predicts columnar and salt-and-pepper organization in mammalian visual cortex. Cell Reports. Volume 30. Issue 10. pp. 3270-3279. Available online at https://doi.org/10.1016/j.celrep.2020.02.038 Profile: Se-Bum Paik Assistant Professor sbpaik@kaist.ac.kr http://vs.kaist.ac.kr/ VSNN Laboratory Department of Bio and Brain Engineering Program of Brain and Cognitive Engineering http://kaist.ac.kr Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea Profile: Jaeson Jang Ph.D. Candidate jaesonjang@kaist.ac.kr Department of Bio and Brain Engineering, KAIST Profile: Min Song Ph.D. Candidate night@kaist.ac.kr Program of Brain and Cognitive Engineering, KAIST (END)
2020.03.11
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Professor Jong Chul Ye Appointed as Distinguished Lecturer of IEEE EMBS
Professor Jong Chul Ye from the Department of Bio and Brain Engineering was appointed as a distinguished lecturer by the International Association of Electrical and Electronic Engineers (IEEE) Engineering in Medicine and Biology Society (EMBS). Professor Ye was invited to deliver a lecture on his leading research on artificial intelligence (AI) technology in medical video restoration. He will serve a term of two years beginning in 2020. IEEE EMBS's distinguished lecturer program is designed to educate researchers around the world on the latest trends and technology in biomedical engineering. Sponsored by IEEE, its members can attend lectures on the distinguished professor's research subject. Professor Ye said, "We are at a time where the importance of AI in medical imaging is increasing.” He added, “I am proud to be appointed as a distinguished lecturer of the IEEE EMBS in recognition of my contributions to this field.” (END)
2020.02.27
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What Fuels a “Domino Effect” in Cancer Drug Resistance?
KAIST researchers have identified mechanisms that relay prior acquired resistance to the first-line chemotherapy to the second-line targeted therapy, fueling a “domino effect” in cancer drug resistance. Their study featured in the February 7 edition of Science Advances suggests a new strategy for improving the second-line setting of cancer treatment for patients who showed resistance to anti-cancer drugs. Resistance to cancer drugs is often managed in the clinic by chemotherapy and targeted therapy. Unlike chemotherapy that works by repressing fast-proliferating cells, targeted therapy blocks a single oncogenic pathway to halt tumor growth. In many cases, targeted therapy is engaged as a maintenance therapy or employed in the second-line after front-line chemotherapy. A team of researchers led by Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering and the KAIST Institute for Health Science and Technology (KIHST) has discovered an unexpected resistance signature that occurs between chemotherapy and targeted therapy. The team further identified a set of integrated mechanisms that promotes this kind of sequential therapy resistance. “There have been multiple clinical accounts reflecting that targeted therapies tend to be least successful in patients who have exhausted all standard treatments,” said the first author of the paper Mark Borris D. Aldonza. He continued, “These accounts ignited our hypothesis that failed responses to some chemotherapies might speed up the evolution of resistance to other drugs, particularly those with specific targets.” Aldonza and his colleagues extracted large amounts of drug-resistance information from the open-source database the Genomics of Drug Sensitivity in Cancer (GDSC), which contains thousands of drug response data entries from various human cancer cell lines. Their big data analysis revealed that cancer cell lines resistant to chemotherapies classified as anti-mitotic drugs (AMDs), toxins that inhibit overacting cell division, are also resistant to a class of targeted therapies called epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). In all of the cancer types analyzed, more than 84 percent of those resistant to AMDs, representatively ‘paclitaxel’, were also resistant to at least nine EGFR-TKIs. In lung, pancreatic, and breast cancers where paclitaxel is often used as a first-line, standard-of-care regimen, greater than 92 percent showed resistance to EGFR-TKIs. Professor Kim said, “It is surprising to see that such collateral resistance can occur specifically between two chemically different classes of drugs.” To figure out how failed responses to paclitaxel leads to resistance to EGFR-TKIs, the team validated co-resistance signatures that they found in the database by generating and analyzing a subset of slow-doubling, paclitaxel-resistant cancer models called ‘persisters’. The results demonstrated that paclitaxel-resistant cancers remodel their stress response by first becoming more stem cell-like, evolving the ability to self-renew to adapt to more stressful conditions like drug exposures. More surprisingly, when the researchers characterized the metabolic state of the cells, EGFR-TKI persisters derived from paclitaxel-resistant cancer cells showed high dependencies to energy-producing processes such as glycolysis and glutaminolysis. “We found that, without an energy stimulus like glucose, these cells transform to becoming more senescent, a characteristic of cells that have arrested cell division. However, this senescence is controlled by stem cell factors, which the paclitaxel-resistant cancers use to escape from this arrested state given a favorable condition to re-grow,” said Aldonza. Professor Kim explained, “Before this research, there was no reason to expect that acquiring the cancer stem cell phenotype that dramatically leads to a cascade of changes in cellular states affecting metabolism and cell death is linked with drug-specific sequential resistance between two classes of therapies.” He added, “The expansion of our work to other working models of drug resistance in a much more clinically-relevant setting, perhaps in clinical trials, will take on increasing importance, as sequential treatment strategies will continue to be adapted to various forms of anti-cancer therapy regimens.” This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF-2016R1C1B2009886), and the KAIST Future Systems Healthcare Project (KAISTHEALTHCARE42) funded by the Korean Ministry of Science and ICT (MSIT). Undergraduate student Aldonza participated in this research project and presented the findings as the lead author as part of the Undergraduate Research Participation (URP) Program at KAIST. < Figure 1. Schematic overview of the study. > < Figure 2. Big data analysis revealing co-resistance signatures between classes of anti-cancer drugs. > Publication: Aldonza et al. (2020) Prior acquired resistance to paclitaxel relays diverse EGFR-targeted therapy persistence mechanisms. Science Advances, Vol. 6, No. 6, eaav7416. Available online at http://dx.doi.org/10.1126/sciadv.aav7416 Profile: Prof. Yoosik Kim, MA, PhD ysyoosik@kaist.ac.kr https://qcbio.kaist.ac.kr/ Assistant Professor Bio Network Analysis Laboratory Department of Chemical and Biomolecular Engineering Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon, Republic of Korea Profile: Mark Borris D. Aldonza borris@kaist.ac.kr Undergraduate Student Department of Biological Sciences Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon, Republic of Korea (END)
2020.02.10
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Cancer cell reversion may offer a new approach to colorectal cancer treatment
A novel approach to reverse the progression of healthy cells to malignant ones may offer a more effective way to eradicate colorectal cancer cells with far fewer side effects, according to a team of researchers based in South Korea. Colorectal cancer, or cancer of the colon, is the third most common cancer in men and the second most common in women worldwide. South Korea has the second highest incident rate of colorectal cancer in the world, topped only by Hungary, according to the World Cancer Research Fund. Their results were published as a featured cover article on January 2 in Molecular Cancer Research, a journal of the American Association for Cancer Research. Led by Kwang-Hyun Cho, a professor and associate vice president of research at KAIST , the researchers used a computational framework to analyze healthy colon cells and colorectal cancer cells. They found that some master regulator proteins involved in cellular replication helped healthy colon cells mature, or differentiate into their specific cell type, and remain healthy. One particular protein, called SETDB1, suppressed the helpful proteins, forcing new cells to remain in a state of immaturity with the potential to become cancerous. “This suggests that differentiated cells have an inherent resistance mechanism against malignant transformation and indicates that cellular reprogramming is indispensable for malignancy,” said Cho. “We speculated that malignant properties might be eradicated if the tissue-specific gene expression is reinstated — if we repress SETDB1 and allow the colon cells to mature and differentiate as they would normally.” Image credit: Kwang-Hyun Cho, KAIST Image restriction: News organizations may use or redistribute this image, with proper attribution, as part of news coverage of this paper only. Using human-derived cells, Cho and his team targeted the tissue-specific gene expression programs identified in their computational analysis. These are the blueprints for the proteins that eventually help immature cells differentiate into tissue-specific cell types, such as colon cells. When a person has a genetic mutation, or has exposure to certain environmental factors, this process can go awry, leading to an overexpression of unhelpful proteins, such as SEDTB1. The researchers specifically reduced the amount of SEDTB1 in these tissue-specific gene expression programs, which allowed the cells to mature and fully differentiate into colon cells. “Our experiment also shows that SETDB1 depletion combined with cytotoxic drugs might be potentially beneficial to anticancer treatment,” Cho said. Cytotoxic drugs are often used for cancer treatment because the type of medicine contains chemicals that are toxic to cancer cells which can prevent them from replicating or growing. He noted that this combination could be more effective in treating cancer by transforming the cancer cell state into a less malignant or resistant state. He eventually pursues a cancer reversion therapy alone instead of conventional cytotoxic drug therapy since the cancer reversion therapy can provide a much less painful experience for patients with cancer who often have severe side effects from treatments intended to kill off cancerous cells, such as chemotherapy. The researchers plan to continue studying how to return cancer cells to healthier states, with the ultimate goal of translating their work to therapeutic treatment for patients with colorectal cancer. “I think our study of cancer reversion would eventually change the current medical practice of treating cancer toward the direction of keeping the patient’s quality of life while minimizing the side effects of current anti-cancer therapies,” Cho said. ### This work was funded by KAIST and the National Research Foundation of Korea grants funded by the Korean government, the Ministry of Science and Information and Communication Technology. Other authors include Soobeom Lee, Chae Young Hwang and Dongsan Kim, all of whom are affiliated with the Laboratory for Systems Biology and Bio-Inspired Engineering in the Department of Bio and Brain Engineering at KAIST; Chansu Lee and Sung Noh Hong, both with the Department of Medicine, and Seok-Hyung Kim of the Department of Pathology in the Samsung Medical Center at the Sungkyunkwan University School of Medicine. -Profile Professor Kwang-Hyun Cho ckh@kaist.ac.kr http://sbie.kaist.ac.kr/ Department of Bio and Brain Engineering KAIST https://www.kaist.ac.kr
2020.01.31
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New Insights into How the Human Brain Solves Complex Decision-Making Problems
A new study on meta reinforcement learning algorithms helps us understand how the human brain learns to adapt to complexity and uncertainty when learning and making decisions. A research team, led by Professor Sang Wan Lee at KAIST jointly with John O’Doherty at Caltech, succeeded in discovering both a computational and neural mechanism for human meta reinforcement learning, opening up the possibility of porting key elements of human intelligence into artificial intelligence algorithms. This study provides a glimpse into how it might ultimately use computational models to reverse engineer human reinforcement learning. This work was published on Dec 16, 2019 in the journal Nature Communications. The title of the paper is “Task complexity interacts with state-space uncertainty in the arbitration between model-based and model-free learning.” Human reinforcement learning is an inherently complex and dynamic process, involving goal setting, strategy choice, action selection, strategy modification, cognitive resource allocation etc. This a very challenging problem for humans to solve owing to the rapidly changing and multifaced environment in which humans have to operate. To make matters worse, humans often need to often rapidly make important decisions even before getting the opportunity to collect a lot of information, unlike the case when using deep learning methods to model learning and decision-making in artificial intelligence applications. In order to solve this problem, the research team used a technique called 'reinforcement learning theory-based experiment design' to optimize the three variables of the two-stage Markov decision task - goal, task complexity, and task uncertainty. This experimental design technique allowed the team not only to control confounding factors, but also to create a situation similar to that which occurs in actual human problem solving. Secondly, the team used a technique called ‘model-based neuroimaging analysis.’ Based on the acquired behavior and fMRI data, more than 100 different types of meta reinforcement learning algorithms were pitted against each other to find a computational model that can explain both behavioral and neural data. Thirdly, for the sake of a more rigorous verification, the team applied an analytical method called ‘parameter recovery analysis,’ which involves high-precision behavioral profiling of both human subjects and computational models. In this way, the team was able to accurately identify a computational model of meta reinforcement learning, ensuring not only that the model’s apparent behavior is similar to that of humans, but also that the model solves the problem in the same way as humans do. The team found that people tended to increase planning-based reinforcement learning (called model-based control), in response to increasing task complexity. However, they resorted to a simpler, more resource efficient strategy called model-free control, when both uncertainty and task complexity were high. This suggests that both the task uncertainty and the task complexity interact during the meta control of reinforcement learning. Computational fMRI analyses revealed that task complexity interacts with neural representations of the reliability of the learning strategies in the inferior prefrontal cortex. These findings significantly advance understanding of the nature of the computations being implemented in the inferior prefrontal cortex during meta reinforcement learning as well as providing insight into the more general question of how the brain resolves uncertainty and complexity in a dynamically changing environment. Identifying the key computational variables that drive prefrontal meta reinforcement learning, can also inform understanding of how this process might be vulnerable to break down in certain psychiatric disorders such as depression and OCD. Furthermore, gaining a computational understanding of how this process can sometimes lead to increased model-free control, can provide insights into how under some situations task performance might break down under conditions of high cognitive load. Professor Lee said, “This study will be of enormous interest to researchers in both the artificial intelligence and human/computer interaction fields since this holds significant potential for applying core insights gleaned into how human intelligence works with AI algorithms.” This work was funded by the National Institute on Drug Abuse, the National Research Foundation of Korea, the Ministry of Science and ICT, Samsung Research Funding Center of Samsung Electronics. Figure 1 (modified from the figures of the original paper doi:10.1038/s41467-019-13632-1). Computations implemented in the inferior prefrontal cortex during meta reinforcement learning. (A) Computational model of human prefrontal meta reinforcement learning (left) and the brain areas whose neural activity patterns are explained by the latent variables of the model. (B) Examples of behavioral profiles. Shown on the left is choice bias for different goal types and on the right is choice optimality for task complexity and uncertainty. (C) Parameter recoverability analysis. Compared are the effect of task uncertainty (left) and task complexity (right) on choice optimality. -Profile Professor Sang Wan Lee sangwan@kaist.ac.kr Department of Bio and Brain Engineering Director, KAIST Center for Neuroscience-inspired AI KAIST Institute for Artificial Intelligence (http://aibrain.kaist.ac.kr) KAIST Institute for Health, Science, and Technology KAIST (https://www.kaist.ac.kr)
2020.01.31
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