https://scholar.dgist.ac.kr/handle/20.500.11750/277 2026-04-04T14:14:08Z 2026-04-04T14:14:08Z Kang, Mooseok Lee, Ae-Ree Jung, Hyeji Jang, Gyubin Kim, Byeongchan Yoon, Sung-Hyun Yu, Je-Wook Ko, Jaewon Um, Ji Won Chang, Iksoo https://scholar.dgist.ac.kr/handle/20.500.11750/59289 2026-02-04T04:40:14Z 2025-12-31T15:00:00Z

Title: Development of New IL-1R Antagonists with Improved Anti-inflammatory Efficacy Author(s): Kang, Mooseok; Lee, Ae-Ree; Jung, Hyeji; Jang, Gyubin; Kim, Byeongchan; Yoon, Sung-Hyun; Yu, Je-Wook; Ko, Jaewon; Um, Ji Won; Chang, Iksoo Abstract: Background: Anakinra, a recombinant human interleukin-1 receptor antagonist (hIL-1Ra), is a widely used anti-inflammatory biologic for conditions like rheumatoid arthritis and gout. However, its limited potency and dose-dependent side effects restrict broader therapeutic application, highlighting a need for more potent and stable IL-1R antagonists. Methods: To develop improved IL-1R antagonists, we rationally designed six hIL-1Ra variants using structure-guided mutagenesis. Molecular dynamics simulations and thermodynamic integration predicted enhanced binding stability, with an average binding free energy improvement of-7.8 +/- 0.9 kcal/mol compared to wild-type hIL-1Ra (hIL-1Ra WT). We assessed variant functions in microglia-derived HMC-3 cells by measuring IL-1 beta and IL-6 mRNA suppression and evaluated their ability to attenuate IL-1 beta-induced NMDAR hyperactivation in cultured cortical neurons using electrophysiological recordings. In vivo validation was performed using Nlrp3D301N knock-in mice, a model of chronic neuroinflammation. Results: All six hIL-1Ra variants demonstrated enhanced anti-inflammatory activity, suppressing IL-1 beta and IL-6 expression by 25-53% in HMC-3 cells. The E127Q variant exhibited the greatest efficacy. In primary cultured neurons, hIL-1Ra E127Q more effectively inhibited IL-1 beta-induced NMDAR-mediated postsynaptic responses at lower concentrations than hIL-1Ra WT. Furthermore, acute administration of hIL-1Ra E127Q, but not hIL-1Ra WT, reversed elevated NMDAR activity in the medial prefrontal cortex of Nlrp3D301N knock-in mice. Conclusion: This study successfully developed next-generation hIL-1Ra variants with superior receptor binding and anti-inflammatory activity. E127Q emerged as a promising therapeutic candidate, effectively attenuating inflammatory signaling and neuroinflammatory responses both in vitro and in vivo. These findings underscore the significant therapeutic potential of engineered IL-1R antagonists for treating inflammation-driven neurological and systemic disorders, paving the way for improved anti-inflammatory therapies.

2025-12-31T15:00:00Z Chang, Iksoo Chung, Taegon Kim, Sangyeol https://scholar.dgist.ac.kr/handle/20.500.11750/58294 2025-07-25T02:43:08Z 2024-12-31T15:00:00Z

Title: Wavenumber-dependent transmission of subthreshold waves on electrical synapses network model of Caenorhabditis elegans Author(s): Chang, Iksoo; Chung, Taegon; Kim, Sangyeol Abstract: Recent experimental studies showed that electrically coupled neural networks like in mammalian inferior olive nucleus generate synchronized rhythmic activity by the subthreshold sinusoidal-like oscillations of the membrane voltage. Understanding the basic mechanism and its implication of such phenomena in the nervous system bears fundamental importance and requires preemptively the connectome information of a given nervous system. Inspired by these necessities of developing a theoretical and computational model to this end and, however, in the absence of connectome information for the inferior olive nucleus, here we investigated interference phenomena of the subthreshold oscillations in the reference system Caenorhabditis elegans for which the structural anatomical connectome was completely known recently. We evaluated how strongly the sinusoidal wave was transmitted between arbitrary two cells in the model network. The region of cell-pairs that are good at transmitting waves changed according to the wavenumber of the wave, for which we named a wavenumber-dependent transmission map. Also, we unraveled that (1) the transmission of all cell-pairs disappeared beyond a threshold wavenumber, (2) long distance and regular patterned transmission existed in the body-wall muscles part of the model network, and (3) major hub cell-pairs of the transmission were identified for many wavenumber conditions. A theoretical and computational model presented in this study provided fundamental insight for understanding how the multi-path constructive/destructive interference of the subthreshold oscillations propagating on electrically coupled neural networks could generate wavenumber-dependent synchronized rhythmic activity. © 2024, Chang et al.

2024-12-31T15:00:00Z Park, Kyeongwon Chang, Iksoo Kim, Sangyeol https://scholar.dgist.ac.kr/handle/20.500.11750/57382 2025-07-25T02:42:39Z 2024-10-31T15:00:00Z

Title: Resting state of human brain measured by fMRI experiment is governed more dominantly by essential mode as a global signal rather than default mode network Author(s): Park, Kyeongwon; Chang, Iksoo; Kim, Sangyeol Abstract: Resting-state of the human brain has been described by a combination of various basis modes including the default mode network (DMN) identified by fMRI BOLD signals in human brains. Whether DMN is the most dominant representation of the resting-state has been under question. Here, we investigated the unexplored yet fundamental nature of the resting-state. In the absence of global signal regression for the analysis of brain-wide spatial activity pattern, the fMRI BOLD spatiotemporal signals during the rest were completely decomposed into time-invariant spatial-expression basis modes (SEBMs) and their time-evolution basis modes (TEBMs). Contrary to our conventional concept above, similarity clustering analysis of the SEBMs from 166 human brains revealed that the most dominant SEBM cluster is an asymmetric mode where the distribution of the sign of the components is skewed in one direction, for which we call essential mode (EM), whereas the second dominant SEBM cluster resembles the spatial pattern of DMN. Having removed the strong 1/f noise in the power spectrum of TEBMs, the genuine oscillatory behavior embedded in TEBMs of EM and DMN-like mode was uncovered around the low-frequency range below 0.2 Hz. © 2024

2024-10-31T15:00:00Z Chung, Taegon Chang, Iksoo Kim, Sangyeol https://scholar.dgist.ac.kr/handle/20.500.11750/57062 2025-10-20T06:40:11Z 2024-03-31T15:00:00Z

Title: Development of equation of motion deciphering locomotion including omega turns of Caenorhabditis elegans Author(s): Chung, Taegon; Chang, Iksoo; Kim, Sangyeol Abstract: Locomotion is a fundamental behavior of Caenorhabditis elegans (C. elegans). Previous works on kinetic simulations of animals helped researchers understand the physical mechanisms of locomotion and the muscle-controlling principles of neuronal circuits as an actuator part. It has yet to be understood how C. elegans utilizes the frictional forces caused by the tension of its muscles to perform sequenced locomotive behaviors. Here, we present a two-dimensional rigid body chain model for the locomotion of C. elegans by developing Newtonian equations of motion for each body segment of C. elegans. Having accounted for friction-coefficients of the surrounding environment, elastic constants of C. elegans, and its kymogram from experiments, our kinetic model (ElegansBot) reproduced various locomotion of C. elegans such as, but not limited to, forward-backward-(omega turn)-forward locomotion constituting escaping behavior and delta-turn navigation. Additionally, ElegansBot precisely quantified the forces acting on each body segment of C. elegans to allow investigation of the force distribution. This model will facilitate our understanding of the detailed mechanism of various locomotive behaviors at any given friction-coefficients of the surrounding environment. Furthermore, as the model ensures the performance of realistic behavior, it can be used to research actuator-controller interaction between muscles and neuronal circuits. © 2023, Chung et al.

2024-03-31T15:00:00Z