Biology subjects

Choi, J. W.

Publications and source records attributed to Choi, J. W..

10 recordsLinked to original sources

bioRxiv2026

Repeated experience drives multiscale engram reorganization to shape memory strength and precision

How memories are shaped by repeated experiences remains unclear. Reorganization of memory engram could underlie memory transformation. Here, by combining c-Fos-based engram cell tagging with optogenetics, spine imaging, and reactivation analyses in the dentate gyrus (DG) and medial prefrontal cortex (mPFC), we discovered a distinct system-wide engram reorganization following repeated learning; that is, a reshuffling of engram cells in the DG, as well as the rapid maturation of mPFC engram cells, forming a dual engram distributed within the hippocampal-mPFC network. These mPFC engram cells were crucial for relearning-dependent enhancement of memory precision. In addition, we found that reactivation of DG engram cells during retraining is critical for engram reorganization-dependent memory strengthening. These findings establish a causal link between engram reorganization and memory transformation by relearning.

neuroscience↗

bioRxiv2025

Periventricular Diffusivity Reflects APOE4-modulated Amyloid Accumulation and Cognitive Impairment in Alzheimers Continuum

BackgroundAltered glymphatic-related fluid dynamics are increasingly recognized as a key feature of Alzheimers disease (AD). We generalized an established diffusion imaging technique to estimate periventricular diffusivity (PVeD), hypothesizing that fast diffusion signals in the periventricular region can reflect amyloid-beta (A{beta}) deposition across the Alzheimers continuum. MethodsParticipants from two multi-site cohorts (n = 440 and 414), comprising cognitively unimpaired individuals, those with mild cognitive impairment, and patients with AD, were included. We tested and validated the association of PVeD with A{beta} burden and core AD characteristics. ResultsLower PVeD was extensively associated with greater A{beta} burden, neurodegeneration, cognitive impairment, and clinical severity. Importantly, the relationship between PVeD and A{beta} burden was significantly modulated by APOE4 status, with APOE4 carriers showing a stronger negative association. Baseline PVeD also predicted longitudinal cognitive decline. DiscussionThese findings suggest that periventricular fast diffusion signals can reflect APOE4-modulated A{beta} burden and cognitive decline in AD. Research-in-ContextO_ST_ABSSystematic reviewC_ST_ABSA comprehensive PubMed literature search indicates that fluid movement related to glymphatic activity assessed by diffusion tensor image analysis along the perivascular space (DTI-ALPS) is associated with amyloid-beta deposition in Alzheimers disease (AD). However, recent evidence underscores certain limitations of DTI-ALPS, suggesting that it may not fully capture the diffusion processes involved in amyloid clearance. Moreover, no previous studies have investigated the role of APOE4 in modulating the relationship between glymphatic-related fast diffusion signals and amyloid-beta deposition. InterpretationThe transverse diffusion process along the perivenous space in the periventricular region appears to reflect glymphatic-related dysfunction manifested by amyloid-beta deposition. Reduced periventricular diffusivity is associated with greater amyloid burden across the AD continuum. This association is notably enhanced in APOE4 carriers, who exhibit higher amyloid accumulation for a given reduction in the periventricular diffusivity. Besides, periventricular diffusivity is related to other pathological markers of AD, including clinical symptom severity and neurodegeneration, and may also predict subsequent cognitive decline. Future directionsAlthough diffusion-based neuroimaging metrics hold promise as surrogate imaging biomarkers for glymphatic-related activity, they do not comprehensively capture the complex fluid dynamics such as convective bulk flow within the glymphatic system. By leveraging multimodal neuroimaging techniques and advanced analytic approaches, future research can refine these metrics into more sensitive, non-invasive tools capable of evaluating fluid dynamics related to glymphatic dysfunction in AD.

neuroscience↗

bioRxiv2024

Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer

This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICI). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (AUC) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

bioinformatics↗

bioRxiv2022

Bi-phasic regulation of AIMP2 and its splice variant in PARP-1- dependent neurodegeneration

Parthanatos is a significant molecular cause of Parkinsons disease, in which AIMP2 aberrantly activates PARP-1 through a physical interaction. Interestingly, AIMP2 has an antagonistic splice variant, named DX2, which compromises AIMP2-induced apoptosis via p53 or inflammatory pathway. Here we suggested that DX2 binds to PARP-1 with a higher affinity than AIMP2, deactivating it and improving synaptic physiology. To deliver DX2 into deep brain areas, miR142 target sequence-embedded adeno-associated virus was designed to avoid unexpected expression in hematopoietic cells. RNAseq analysis revealed that DX2 selectively suppressed cell death-associated pathways, such as p53 and neuroinflammation. Upon a single intracranial injection, both behaviour and motility were mitigated in three animal models of Parkinsonism, induced by MPTP, rotenone, or 6-OHDA. Efficacy was observed in therapeutic model as well as preventive ones. Thus, AIMP2 and DX2 are suggested to act as an ON/OFF switch for PARP-1. In particular, as cell survival properties of DX2 was exerted only when AIMP2 is accumulated abnormally, without its own additional tumorigenicity, DX2 could be a unique therapeutic tool for treating patients with Parkinsons disease.

molecular biology↗

bioRxiv2021

Testing in vitro toxicity of nanoparticles in 3D cell culture with various extracellular matrix scaffold

Nanomaterials are used in a variety of fields and toxicity assessment is paramount for their development and application. Although most toxicity assessments have been performed in 2D (2-Dimensional) cell culture, the inability to adequately replicate the in vivo environment and toxicity is a limitation. To overcome the limitation, a 3D (3-Dimensional) cell culture method has been developed to make an environment closer to an in vivo system. In this study, 20 nm SiO2 nanoparticles were dispersed in serum-containing (SC) and serum-free (SF) media to compare 2D cell culture and 3D cell culture toxicity. The cells were subjected to a 3D cell culture method in which HepG2, a human-derived liver cancer cell line, was mixed on a scaffold. We found that nanoparticles induced toxicity in 2D cell culture, but toxicity was not observed in 3D cell culture similar to in vivo environment. However, differences in toxicity were observed between the three types of scaffolds in the absence of serum as the number of cells decreased.

pharmacology and toxicology↗

bioRxiv2020

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson's disease

Background and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinsons disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD. Experimental ApproachWe designed and synthesized -aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates. Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the -aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates. Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD. Representative Schematic O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY What is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor. MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis. What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD. KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates. What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinsons disease. Reversible MAO-B inhibitors could be more effective for treatment of Parkinsons disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.

pharmacology and toxicology↗

bioRxiv2020

Movement-related changes in pallidocortical synchrony differentiate action execution and observation in humans

Suppression of local and network alpha (8-12 Hz) and beta (12-35 Hz) oscillations in the human basal ganglia-thalamocortical (BGTC) circuit is a prominent feature of movement. Local alpha/beta power, cross-region beta phase coupling, and phase-amplitude coupling (PAC) have all been shown to be suppressed during movement in multiple nodes of the BGTC. However, the specificity of these various movement-related changes to actual movement execution remains poorly understood. To differentiate signals that are specifically related to movement execution, we compared changes in globus pallidus internus (GPi) and motor cortical local oscillatory activity and coupling (cross-region phase coupling and local PAC) during movement execution and movement observation in 12 patients with Parkinson disease undergoing deep brain stimulator implantation. We hypothesized that network coupling is more directly related to movement execution than local power changes, given the putative role of pathological network coupling in movement disorders such as Parkinson disease. We observed suppression of alpha/beta power during action observation and execution in the globus pallidus and motor cortex during both action execution and action observation. In contrast, pallidocortical coherence and GPi and motor cortical alpha/beta-gamma PAC were significantly suppressed only during action execution. Our results demonstrate a functional dissociation within the BG-cortical network during action execution and observation in which suppression of BG-cortical functional connectivity and local phase amplitude coupling are features specifically of overt movement, suggesting a particularly important role in motor execution. This has implications for identification and use of intracranial signals for closed loop brain stimulation therapies.

neuroscience↗

bioRxiv2020

Third-generation dual-source computed tomography of the abdomen: comparison of radiation dose and image quality of 80kVp and 80/150kVp with tin filter

ObjectiveTo compare the radiation dose, objective and subjective image quality, and diagnostic performances of 80 kVp and 80/150 kVp with tin filter (80/Sn150 kVp) computed tomography (CT) in oncology patients. MethodsOne hundred forty-five consecutive oncology patients who underwent third-generation dual-source dual-energy CT of the abdomen for evaluation of malignant visceral, peritoneal, extraperitoneal, and bone tumor were retrospectively recruited. Two radiologists independently reviewed each observation in 80 kVp CT and 80/Sn150 kVp CT. Modified line-density profile of the tumor and contrast-to-noise ratio (CNR) were measured. Diagnostic confidence, lesion conspicuity, and subjective image quality were calculated and compared between image sets. ResultsModified line-density profile analysis revealed higher attenuation differences between the tumor and the normal tissue in 80 kVp CT than in 80/Sn150 kVp CT (127 vs. 107, P = 0.05). The 80 kVp CT showed increased CNR in the liver (8.0 vs. 7.6) and the aorta (18.9 vs. 16.3) than the 80/Sn150 kVp CT. The 80 kVp CT yielded higher enhancement of organs (4.9 {+/-} 0.2 vs. 4.7 {+/-} 0.4, P < 0.001) and lesion conspicuity (4.9 {+/-} 0.3 vs. 4.8 {+/-} 0.5, P = 0.035) than the 80/Sn150 kVp CT; overall image quality and confidence index were comparable. The effective dose reduced by 45.2% with 80 kVp CT (2.3 mSv {+/-} 0.9) compared to 80/Sn150 kVp CT (4.1 mSv {+/-} 1.5). ConclusionsThe 80 kVp CT performed similar or better than 80/Sn150 kVp CT for abdominal tumor evaluation with 45.2% radiation dose reduction in oncology patients.

cancer biology↗

bioRxiv2019

SpCas9 activity prediction by DeepCas9, a deep learning-based model with unparalleled generalization performance

We evaluated SpCas9 activities at 12,832 target sequences using a high-throughput approach based on a human cell library containing sgRNA-encoding and target sequence pairs. Deep learning-based training on this large data set of SpCas9-induced indel frequencies led to the development of a SpCas9-activity predicting model named DeepSpCas9. When tested against independently generated data sets (our own and those published by other groups), DeepSpCas9 showed unprecedentedly high generalization performance. DeepSpCas9 is available at http://deepcrispr.info/DeepCas9.

genetics↗

bioRxiv2018

Phenotypic landscape of schizophrenia-associated genes defines candidates and their shared functions

Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologues of 132 human schizophrenia-associated genes and created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus or tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.

genetics↗