Biology subjects

Shin, D. S.

Publications and source records attributed to Shin, D. S..

6 recordsLinked to original sources

bioRxiv2024

Synergistic Cytotoxicity of Permethrin and N,N-Diethyl-Meta-Toluamide on Sinonasal Epithelial Cells

BackgroundN,N-Diethyl-Meta-Toluamide (DEET) and permethrin are pesticides commonly used in combination due to their synergistic insecticidal and repellent properties. This study investigates whether simultaneous exposure to these compounds elicits synergistic cytotoxicity in sinonasal epithelial cells (SNECs). Material and MethodsEthmoid sinus mucosal specimens were procured from eight patients during endoscopic sinus surgery. SNECs were expanded on culture plates and exposed to various concentrations of DEET and permethrin (0-5m), individually and concurrently, for up to 156 hours. Experiments were replicated in triplicates and cell viability was recorded every 2 hours using IncuCyte real-time cell imaging system. Synergy score was calculated on the basis of Loewe additivity synergy finder model. ResultsDEET and permethrin exhibited synergistic cytotoxicity across all eight tissues, albeit with variations in onset and magnitude. Peak synergy was observed at 144h for tissue 1 (SLoewe 4.2, 95% CI 1.8-7.3; [permethrin concentration, DEET concentration] [2.5M, 1.25M]), 48h for tissue 2 (19.9, 16.5-23.6; [1.25, 0.625]), 144h for tissue 3 (15.2, 3.9-30.4; [0.625, 1.25]), 144h for tissue 4 (6.4, -3.6 to 18.0; [0.625, 0.625]), 48h for tissue 5 (10.1, 8.9-12.5; [0.625, 1.25]), 96h for tissue 6 (24.7, 12.2-36.3; [0.625, 0.625]), 48h for tissue 7 (47.7, 29.6-62.2; [0.625, 1.25]), and 96h for 8 (47.4, 26.8-67.0; [0.625, 0.625]). ConclusionThe concurrent exposure of DEET and permethrin can lead to synergistic cytotoxicity in sinonasal epithelia. Further research is warranted in preclinical animal models to explore whether this synergy accelerates the pathogenesis of chronic rhinosinusitis.

pharmacology and toxicology↗

bioRxiv2024

CAG repeat-selective compounds reduce abundance of expanded CAG RNAs in patient cell and murine models of SCAs

Spinocerebellar ataxias (SCAs) are a genetically heterogenous group of devastating neurodegenerative conditions for which clinical care currently focuses on managing symptoms. Across these diseases there is an unmet need for therapies that address underlying disease mechanisms. We utilised the shared CAG repeat expansion mutation causative for a large subgroup of SCAs, to develop a novel disease-gene independent and mechanism agnostic small molecule screening approach to identify compounds with therapeutic potential across multiple SCAs. Using this approach, we identified the FDA approved microtubule inhibitor Colchicine and a novel CAG-repeat binding compound that reduce expression of disease associated transcripts across SCA1, 3 and 7 patient derived fibroblast lines and the Atxn1154Q/2Q SCA1 mouse model in a repeat selective manner. Furthermore, our lead candidate rescues dysregulated alternative splicing in Atxn1154Q/2Q mice. This work provides the first example of small molecules capable of targeting the underlying mechanism of disease across multiple CAG SCAs.

molecular biology↗

bioRxiv2024

The SUbventral-Gland master Regulator (SUGR) of nematode virulence

All pathogens must tailor their gene expression to their environment. Therefore, targeting host:parasite biology that regulates these changes in gene expression could open up routes to pathogen control. Here, we show that in the plant-parasitic nematode Heterodera schachtii, host signals (termed effectostimulins) within plant roots activate the master regulator sugr1. SUGR1, then, directly binds effector promoters, and orchestrates their production. Effector production, in turn, facilitates host entry, releasing more effectostimulins. These data show that gene expression during the very earliest stages of parasitism is defined by a feed forward loop for host entry. Importantly, we demonstrate that blocking SUGR1 blocks parasitism, underlining the SUGR1 signalling cascade as a valuable target for crop protection. Given that nematodes also parasitise humans and other animals, the potential impact is broad: disrupting effector production could, in principle, be applied to any pathogen that secrets effectors. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/576598v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@cebedaorg.highwire.dtl.DTLVardef@153fe87org.highwire.dtl.DTLVardef@16b6957org.highwire.dtl.DTLVardef@d0e920_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2024

The origin, deployment, and evolution of a plant-parasitic nematode effectorome

Plant-parasitic nematodes constrain global food security. During parasitism, they secrete effectors into the host plant from two types of pharyngeal gland cells. These effectors elicit profound changes in host biology to suppress immunity and establish a unique feeding organ from which the nematode draws nutrition. Despite the importance of effectors in nematode parasitism, there has been no comprehensive identification and characterisation of the effector repertoire of any plant-parasitic nematode. To address this, we advance techniques for gland cell isolation and transcriptional analysis to define a stringent annotation of putative effectors for the cyst nematode Heterodera schachtii at three key life-stages. We define 659 effector gene loci: 293 "known" high-confidence homologs of plant-parasitic nematode effectors, and 366 "novel" effectors with high gland cell expression. In doing so we define a comprehensive "effectorome" of a plant-parasitic nematode. Using this effector definition, we provide the first systems-level understanding of the origin, deployment and evolution of a plant-parasitic nematode effectorome. The robust identification of the comprehensive effector repertoire of a plant-parasitic nematode will underpin our understanding of nematode pathology, and hence, inform strategies for crop protection.

plant biology↗

bioRxiv2023

Lung injury induces a polarized immune response by self antigen-specific Foxp3+ regulatory T cells

Self antigen-specific T cells are prevalent in the mature adaptive immune system, but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may provide these T cells with an opportunity to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self antigen under highly stimulatory conditions, we used peptide:MHCII tetramers to track the behavior of endogenous CD4+ T cells with specificity to a lung-expressed self antigen in mouse models of immune-mediated lung injury. Acute injury resulted in the exclusive expansion of regulatory T cells (Tregs) that was dependent on self antigen recognition and IL-2. Conversely, conventional T cells of the same self antigen specificity remained unresponsive, even following Treg ablation. Thus, the self antigen-specific T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.

immunology↗

bioRxiv2022

Mesenchymal stromal cell encapsulation in uniform chitosan beads using microchannel emulsification

Mesenchymal stromal/stem cells hold potential in repairing damaged tissue through paracrine effects. Their delivery though injectable biodegradable microbeads can improve cell retention and survival at the infusion site. A stirred emulsion process was previously implemented to immobilize these cells in injectable chitosan microbeads for cell therapy applications, but this process leads to broad bead size distribution (coefficient of variation > 40 %). Polydisperse beads may negatively affect the viability of the entrapped cells through oxygen limitations, damage to larger beads during injection, and reduced control over the cell payload and treatment reproducibility. The objective of this work was to modify a microchannel emulsification system initially designed for alginate-based encapsulation to immobilize mesenchymal stromal/stem cells in monodisperse chitosan microbeads. The main factors (e.g., microchannel geometry, chitosan solution viscosity, interfacial tension and flow rate) affecting droplet generation and diameter were investigated. The adapted process enabled the production of monodisperse chitosan microbeads with controlled sizes ranging from 600 {micro}m - 1500 {micro}m in diameter at a coefficient of variation less than 10 %. In a single pass through a 21 G syringe needle (ID: 513 {micro}m), the fraction of ruptured beads was significantly reduced for microchannel-generated vs stirred emulsion-generated beads with matching volume-weighed bead diameter (D[4,3]). The viability of the immobilized cells immediately after the process was 95 % {+/-} 2 % and no significant difference in cell survival and growth factor secretion was observed between microchannel and stirred emulsion-generated beads over 3 days of culture. Future directions include channel multiplexing to increase throughput for clinical applications. Although the device was developed for cell encapsulation, this process could be implemented for encapsulation of other biomolecules, bioactive or living cell agents for applications in the food and drug industry.

bioengineering↗