Biology subjects

Choi, J. S.

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

At least 19 recordsLinked to original sources

bioRxiv2026

Blood-brain barrier-traversing multivalent TGFβ trap for anti-cancer immunomodulation of gliomas

Clinical studies have revealed that glioblastoma (GBM) is refractory to immunotherapy, such as immune checkpoint inhibitors (ICIs), due to the immunosuppressive tumor microenvironment (TME) primarily intensified by intratumoral upregulation of transforming growth factor-{beta} (TGF{beta}). Primary GBM tumor bulks are surgically removed in clinic, but invasive tumor cells infiltrated into surrounding normal brain tissue cannot be eradicated by systemic therapy due to the integral blood-brain barrier (BBB), leading to near-inevitable tumor recurrence. To address these translational challenges, we have engineered a TGF{beta}-inhibiting protein nanocage comprising human heavy-chain ferritin protein and TGF{beta} receptor II ectodomain that enables BBB penetration and multivalent TGF{beta} entrapment, respectively. We demonstrate that the nanocage platform, denoted T{beta}R2-HFt, following systemic administration, traverses the BBB, and extensively modulates immunosuppressive TME, both stromal and immune components, thereby potentiating the therapeutic efficacy of a clinically used ICI in multiple mouse glioma models. Notably, a majority of the glioma-bearing animals that received surgical tumor resection, followed by treatment with T{beta}R2-HFt and the ICI, survived the tumor and resisted tumor rechallenge, providing a potential means to control GBM in a durable manner.

bioengineering↗

bioRxiv2026

Inhibition of Gasdermin D by Disulfiram Attenuates Cardiac Inflammation and Fibrosis following Ischaemia Reperfusion Injury

IntroductionInadequately controlled inflammation is a key driver of adverse cardiac remodelling after acute myocardial infarction (AMI). Central to this process is activation of the NLRP3 inflammasome-gasdermin D (GSDMD) pathway, which promotes pyroptosis and the release of the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}), a mediator strongly associated with infarct severity and poor clinical outcomes. This study investigates whether repurposing the FDA-approved therapeutic Disulfiram, recently shown to inhibit GSDMD pore formation, could reduce inflammation and thus improve cardiac injury after AMI. Methods and ResultsCardiac ischemia-reperfusion (I/R) injury was induced in C57BL/6 mice by 60-minute ligation of the left coronary artery followed by reperfusion. Disulfiram (25 or 50 mg/kg) was administered at reperfusion and daily thereafter. Cardiac function was assessed by echocardiography, while fibrosis and inflammation were evaluated by histology, RT-PCR, immunohistochemistry and immunoblotting. Leukocyte populations in blood, spleen, bone marrow and heart were analysed by flow cytometry. In vitro, mouse bone marrow-derived macrophages (BMDMs) and PMA-differentiated THP-1 cells were treated with Disulfiram. Cytokine secretion, inflammatory gene expression and changes in cell viability (propidium iodide (PI) staining and lactate dehydrogenase (LDH) release) were measured. Disulfiram (50 mg/kg) significantly improved cardiac function 7 days post-I/R. This was accompanied by a significant reduction in cardiac fibrosis and inflammation, as reflected by a lower abundance of inflammatory cells in circulation and cardiac tissue. In LPS- and ATP/Nigericin-stimulated BMDMs and THP-1 cells, Disulfiram dose-dependently (0.1-50 {micro}M) reduced IL-1{beta} and IL-6 secretion and attenuated membrane permeability and cell lysis. ConclusionsThis study demonstrates that Disulfiram improves cardiac function post-AMI by ameliorating inflammation and fibrosis, which was associated with reductions in cytokine release from inflammatory cells in vitro. Therefore, targeting GSDMD by "repurposing" the FDA-approved drug, Disulfiram, may represent a novel way to provide cardio-protection post-AMI. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/710794v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@7fd82eorg.highwire.dtl.DTLVardef@149de52org.highwire.dtl.DTLVardef@a2fe0eorg.highwire.dtl.DTLVardef@d56b4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Molecular pathology of acute spinal cord injury in middle-aged mice

The median age of sustaining a spinal cord injury has steadily increased from 29 to 43 over the last several decades. Although more pre-clinical studies in aged rodents are being done to address this shift in demographics, there have not been comprehensive transcriptomic studies investigating SCI pathobiology in middle-aged mice. To address this gap in knowledge, we compared behavioral, histopathological, and transcriptional outcomes in young (2-4 months-old) and middle-aged (10-12 months-old) mice. In contrast to previous studies, open field tests showed no differences in locomotor recovery between the young and middle-aged mice over a one-month period. The injury site also demonstrated similar histopathology in terms of lesion size, and numbers of macrophages and fibroblasts. Acutely after injury, proliferation of macrophages, fibroblasts, and astrocytes were also similar between the two age groups. In addition, spatial transcriptomics showed similar transcriptionally defined regions around the injury site at 3 days post injury. However, single cell RNA-sequencing of the cells at the injury site and surrounding spared tissue showed differences in select cell subpopulations. Taken together, our results indicate that although young and middle-aged mice display similar locomotor recovery and histopathology after SCI, changes in cell subpopulations may underly a decline in repair mechanisms that are manifested after this age.

neuroscience↗

bioRxiv2024

Modulatory Effects of M3 Muscarinic Acetylcholine Receptor on Inflammatory Profiles of Human Memory T Helper Cells

Memory T helper (Th) cells, generated after immunogenic challenge, are crucial in directing the adaptive immune response. Muscarinic ACh receptor (mAChR) subtypes expressed by immune cells can be stimulated with acetylcholine or muscarinic-selective drug oxotremorine-M. Cholinergic signaling can influence immune cells, but it is not known how cholinergic stimuli regulate memory Th cells. This study focused on the role of mAChRs, specifically the M3 muscarinic ACh receptor (M3R), in the cytokine profile and NF-{kappa}B p65 activity of primary human memory Th cells. Memory Th cells (CD3+CD4+CD45RA-CD45RO+) were isolated from healthy participants peripheral blood. Cell culture was performed with anti-CD3/anti-CD28/anti-CD2 reagent, oxotremorine-M (M1R-M5R agonist), atropine (M1R-M5R antagonist), and J104129 (M3R-selective antagonist). MR1-MR5 genes CHRM1-CHRM5 were measured with RT-qPCR. Protein expression of M3R and phosphorylated NF-{kappa}B p65 were quantified by Western blot. The secretion of IFN-{gamma}, IL-17A, and IL-4 was assessed by ELISA and intracellular cytokine staining flow cytometry. CHRM3, encoding M3R, was knocked out using CRISPR-Cas9 gene targeting. Memory Th cells expressed all five mAChR subtypes. Oxotremorine-M increased IFN-{gamma} and IL-17A while reducing IL-4 in an atropine-sensitive manner. Stimulation of mAChRs in cells with CHRM3-knockout or M3R blockade prevented increases in IFN-{gamma} and IL-17A but continued to inhibit IL-4. mAChR stimulation enhanced NF-{kappa}B p65 activity without affecting cell proliferation, viability, or M3R expression. This investigation demonstrates that muscarinic signaling increases the pro-inflammatory profile of memory Th cells, including NF-{kappa}B p65, IFN-{gamma}, and IL-17A, with a reduction in IL-4. Focusing on M3R blockers could modulate adaptive immune responses and alleviate immune-related conditions.

immunology↗

bioRxiv2024

Investigating Sensitivity, Specificity and Accuracy of Variant Calling Pipelines for Analyzing SARS-CoV-2 Data

The rapidly increasing popularity of Next Generation Sequencing and analysis methods in clinical and research settings necessitates an understanding of ideal combinations in identifying genomic variants. Especially with the importance of detecting accurate variants for the development of targeted SARS-CoV-2 vaccines. This research compares the results of two Mapping Algorithms , BWA-MEM and Bowtie2, and two Variant Calling Algorithms , LoFreq and FreeBayes, and their combinatory Variant Calling Pipelines on the analyses of Next Generation Sequencing (NGS) data of five SARS-CoV-2 samples collected from patients in the USA, India, Italy, and Malawi and sourced for this research from the publicly available NCBI SRA database. Our analysis of mapping algorithms found that BWA-MEM likely has higher sensitivity and specificity than Bowtie2 for mapping reads, and their specificity and sensitivity vary with read length. Furthermore, the accuracy of variant calling algorithms increases with the number of reads, while higher read length possibly leads to divergence in accuracy and sensitivity. Overall, FreeBayes was found to likely be more sensitive to detecting variants when used with Bowtie2 rather than BWA-MEM for analyzing SARS-CoV-2 data.

bioinformatics↗

bioRxiv2023

Whole-genome sequences reveal zygotic composition in chimeric twins

The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified on mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin families to precisely understand their zygotic compositions, using millions of genomic variants as barcodes of zygotic origins. Peripheral blood showed asymmetrical contributions from two sister zygotes, where one of the zygotes was the major clone in both twins. Single-cell RNA sequencing of peripheral blood tissues further showed differential contributions from the two sister zygotes across blood cell types. In contrast, buccal tissues were pure in genetic composition, suggesting that in utero cellular exchanges were confined to the blood tissues. Our study illustrates the cellular history of twinning during human development, which is critical for managing the health of chimeric individuals in the era of genomic medicine.

genomics↗

bioRxiv2023

Onsager's relations and Ecology

There are two complementary approaches to thermodynamics, one is an empirical, phenomenological representation of macroscopic states and the second is a model-based, statistical-mechanical representation of microscopic states. If only a few energy transformation steps are involved, macroscopic quantities such as energy and entropy can be estimated without ambiguity, and often the associated microscopic states are well characterised. Both approaches have been used to develop and guide many key early ecological ideas. However, most ecosystems are characterized by uncountably many transformations that operate on a wide range of space and time scales. This renders the bounds of such systems ambiguous making both the macroscopic and microscopic approaches a challenge. As such, the implementation of both approaches remain areas ripe for further investigation. In particular, the Onsager reciprocal relations permit simplification of expectations that are yet to be fully understood in an ecological context. Here we begin to take a few first steps in trying to understand the far-reaching ramifications of these thermodynamic relations.

ecology↗

bioRxiv2023

Herbicidal Quassinoids Isolated from Ailanthus altissima Leaves

Bioassay-guided fractionation of the methanolic extract of Ailanthus altissima leaves led to the isolation of one new quassinoid, named 6--tigloyloxyailanthone (3), and three known quassinoids, ailanthone (1), 13, 18-dehydroglaucarubinone (2), and 6--tigloyloxychaparrinone (4) by a series of chromatographic methods. The structures of the isolates were established by one-dimensional (1D) and 2D-nuclear magnetic resonance (NMR) analysis along with high-resolution time-of-flight mass spectrometry (HRTOFMS) and chemical methods. In addition, herbicidal activity against five grassy weeds and five broad-leaf weeds was evaluated.

biochemistry↗

bioRxiv2023

A multi-stage, delay differential model of snow crab population dynamics in the Scotian Shelf of Atlantic Canada

Snow crab (Chionoecetes opilio) are cold-water stenotherms in the northern hemisphere. As they are long-lived and have a complex life history, developing an operational model of population dynamics has been a challenge, especially in the context of an ever increasing and varied human footprint upon nature. Here we review past efforts at understanding the population dynamics of snow crab in an environmentally and spatiotemporally heterogeneous area, the Scotian Shelf of the northwest Atlantic of Canada. We address these difficulties with a moderately complex multi-stage, delay differential model and parameterize it leveraging Bayesian techniques. Operational solutions were stable and reasonable and permitted inference upon the intra-annual dynamics of snow crab. Further, a concept of a Fisheries footprint, akin to instantaneous fishing mortality rate, can be elucidated that directly addresses the conceptual impact of a fishery upon a non-stationary population. The approach is promising. The model suggests additional processes need to be accounted. We hypothesize that seasonal, interannual movement and spatiotemporally structured predation are key processes that require further attention. However, as computational costs are significant, these additional processes will need to be parameterized carefully.

ecology↗

bioRxiv2023

Subdural CMOS optical probe (SCOPe) for bidirectional neural interfacing

Optical neurotechnologies use light to interface with neurons and can monitor and manipulate neural activity with high spatial-temporal precision over large cortical extents. While there has been significant progress in miniaturizing microscope for head-mounted configurations, these existing devices are still very bulky and could never be fully implanted. Any viable translation of these technologies to human use will require a much more noninvasive, fully implantable form factor. Here, we leverage advances in microelectronics and heterogeneous optoelectronic packaging to develop a transformative, ultrathin, miniaturized device for bidirectional optical stimulation and recording: the subdural CMOS Optical Probe (SCOPe). By being thin enough to lie entirely within the subdural space of the primate brain, SCOPe defines a path for the eventual human translation of a new generation of brain-machine interfaces based on light.

neuroscience↗

bioRxiv2023

Single-Nucleus RNA Sequencing of Developing and Mature Superior Colliculus Identifies Neuronal Diversity and Candidate Mediators of Circuit Assembly

The superior colliculus (SC) is a sensorimotor structure in the midbrain that integrates input from multiple sensory modalities to initiate motor commands. It undergoes well-characterized steps of circuit assembly during development, rendering the mouse SC a popular model to study establishment and refinement of neural connectivity. Here we performed single nucleus RNA-sequencing analysis of the mouse SC isolated at various developmental time points. Our study provides a transcriptomic landscape of the cell types that comprise the SC across murine development with particular emphasis on neuronal heterogeneity. We used these data to identify Pax7 as a marker for an anatomically homogeneous population of GABAergic neurons. Lastly, we report a repertoire of genes differentially expressed across the different postnatal ages, many of which are known to regulate axon guidance and synapse formation. Our data provide a valuable resource for interrogating the mechanisms of circuit development, and identifying markers for manipulating specific SC neuronal populations and circuits.

neuroscience↗

bioRxiv2022

Temperature and depth dependence of the spatial distribution of snow crab

The cascading effects of rapid climate change is a reality with which all biota are challenged. In this context, we examine the spatiotemporal probability of occurrence of snow crab as a means to express viable habitat. This is attempted for three demographic components, morphometrically mature males and females and immature adolescent crab in the Scotian Shelf region of the northwest Atlantic, Canada. We use a robust approach, known as Conditional AutoRegressive models, to define viable habitat. Further, we focus upon viable habitat, conditioned on the marginal influence of temperature and depth as they are known to be important constraints on snow crab. We observe some niche partitioning in terms of depth and temperature. We also note declines in viable habitat marginal to depth and temperature since 2010 for all demographic groups. This population representing the southern-most distribution of snow crab in the northwest Atlantic are vulnerable to degradation of viable habitat attributable to rapid climate change. One-Sentence SummaryRapid climate change and a decadal scale change in the viable habitat of snow crab of the Scotian Shelf ecosystem.

ecology↗

bioRxiv2022

Reconstructing the decline of Atlantic Cod with the help of environmental variability in the Scotia Shelf of Canada

Ignoring environmental variability can lead to imprecise and inaccurate estimates of abundance and their spatial distribution of organisms. Fully embracing environmental variability can improve precision and accuracy of estimates of abundance and distribution, especially when they can often be measured with lower costs. Using the example of Atlantic cod in the Scotian Shelf of the northwest Atlantic Ocean, we demonstrate the improved clarity of their historical population trends when such informative features are included. Further, the use of Bayesian spatiotemporal Conditional auto-regressive models substantially improves our ability to understand the role of ecosystem variability upon cod, even when samples are incomplete or missing. Finally, by decomposing biomass into number, weight and a Hurdle process to estimate habitat conditions, we can extract much more information on what has occurred in the past and make reasoned inference on processes. One-Sentence SummaryDeconstructing and reconstructing cod with environmental variability

ecology↗

bioRxiv2022

Atlantic cod as an indicator of rapid climate change

Atlantic cod (Gadus morhua) in the northwest Atlantic has become the textbook example of overfishing. However, this narrative has blinded us from the larger environmental context of this decline. Cod prefer cold and shallow habitats, environments that are also the most susceptible to rapid climate change. Cod habitat deterioration was evident well before their numerical decline, and as such, cod was a harbinger of rapid climate change. Recovery requires their habitat quality to first improve and stabilize. Calls for a cull of seals, the consensus actor causing the lack of recovery of cod, may therefore be unwise. Recovery will only occur once the variability associated with rapid climate change subsides and habitat quality improves. The timeline for this is of course unknown. One-Sentence SummaryWas the decline of cod a harbinger of rapid climate change in the northwest Atlantic?

ecology↗

bioRxiv2022

A Systematic Evaluation of the Computational Tools for Ligand-receptor-based Cell-Cell Interaction Inference

Cell-cell interactions (CCIs) are essential for multicellular organisms to coordinate biological processes and functions. Many molecules and signaling processes can mediate CCIs. One classical type of CCI mediator is the interaction between secreted ligands and cell surface receptors, i.e., ligand-receptor (LR) interaction. With the recent development of single-cell technologies, a large amount of single-cell RNA Sequencing (scRNA-Seq) data has become widely available. This data availability motivated the single-cell-resolution study of CCIs, particularly LR-based CCIs. Dozens of computational methods and tools have been developed to predict CCIs by identifying LR-based CCIs. Many of these tools have been theoretically reviewed. However, there is little study on current LR-based CCI prediction tools regarding their performance and running results on public scRNA-Seq datasets. In this work, to fill this gap, we tested and compared nine of the most recent computational tools for LR-based CCI prediction. We used fifteen mouse scRNA-Seq samples that correspond to nearly 100K single cells under different experimental conditions for testing and comparison. Besides briefing the methodology used in these nine tools, we summarized the similarities and differences of these tools in terms of both LR prediction and CCI inference between cell types. We provided insight into using these tools to make meaningful discoveries in understanding cell communications.

bioinformatics↗

bioRxiv2021

Epigenetic MRI: Noninvasive Imaging of DNA Methylation in the Brain

Both neuronal and genetic mechanisms regulate brain function. While there are excellent methods to study neuronal activity in vivo, there are no nondestructive methods to measure global gene expression in living brains. Here we present a method, epigenetic magnetic resonance imaging (eMRI), that overcomes this limitation via direct imaging of DNA methylation, a major gene expression regulator. eMRI exploits the methionine metabolic pathways for DNA methylation to label genomic DNA through 13C-enriched diets. A novel 13C magnetic resonance spectroscopic imaging method then maps the spatial distribution of labeled DNA. We validated eMRI using pigs, whose brains have stronger similarity to humans in volume and anatomy than rodents, and confirmed efficient 13C labeling of brain DNA. We also discovered strong regional differences in global DNA methylation. Just as MRI measurements of regional neuronal activity have had a transformational effect on neuroscience, we expect that the eMRI signal as a surrogate for regional gene expression will enable many new investigations into the roles of gene expression in human brain function, behavior, and disease.

bioengineering↗

bioRxiv2020

Single cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord

The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor-ligand pairs to identify signaling pathways that potentially drive specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury, but also other traumatic disorders of the CNS.

neuroscience↗

bioRxiv2019

Functional Maturation of Human iPSC-based Cardiac Microphysiological Systems with Tunable Electroconductive Decellularized Extracellular Matrices

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer tremendous potential for use in engineering human tissues for regenerative therapy and drug screening. However, differentiated cardiomyocytes are phenotypically immature, reducing assay reliability when translating in vitro results to clinical studies and precluding hiPSC-derived cardiac tissues from therapeutic use in vivo. To address this, we have developed hybrid hydrogels comprised of decellularized porcine myocardial extracellular matrix (dECM) and reduced graphene oxide (rGO) to provide a more instructive microenvironment for proper cellular and tissue development. A tissue-specific protein profile was preserved post-decellularization, and through the modulation of rGO content and degree of reduction, the mechanical and electrical properties of the hydrogels could be tuned. Engineered heart tissues (EHTs) generated using dECM-rGO hydrogel scaffolds and hiPSC-derived cardiomyocytes exhibited significantly increased twitch forces at 14 days of culture and had increased the expression of genes that regulate contractile function. Similar improvements in various aspects of electrophysiological function, such as calcium-handling, action potential duration, and conduction velocity, were also induced by the hybrid biomaterial. We also demonstrate that dECM-rGO hydrogels can be used as a bioink to print cardiac tissues in a high-throughput manner, and these tissues were utilized to assess the proarrhythmic potential of cisapride. Action potential prolongation and beat interval irregularities was observed in dECM-rGO tissues at clinical doses of cisapride, indicating that the enhanced maturation of these tissues corresponded well with a capability to produce physiologically relevant drug responses.

bioengineering↗