Biology subjects

Park, H. H.

Publications and source records attributed to Park, H. H..

5 recordsLinked to original sources

bioRxiv2026

An expanded realm of anti-CRISPR-associated proteins and regulatory mechanisms

Many bacteriophages encode anti-CRISPR (Acr) proteins that inhibit the CRISPR-Cas immune systems. Rapid acr gene expression upon phage entry enables CRISPR-Cas neutralisation, but can impact phage fitness if unregulated. Therefore, Acr production is often controlled by distinct families of co-encoded anti-CRISPR-associated (Aca) proteins, which are usually helix-turn-helix (HTH) regulators that bind DNA within acr-aca operon promoters. Previously, we demonstrated that the Aca2 family additionally represses Acr production translationally by binding structured RNA motifs within the 5' untranslated regions (UTRs) of the acr-aca mRNA. Here, through systematic bioinformatic analyses, we provide evidence of structured RNA motifs in the 5' UTRs of operons encoding members of other Aca families, and that Aca1 also specifically binds its cognate RNA motif. Additionally, many Aca proteins are predicted to regulate not only their own but also adjacent operons with potential anti-defence genes. Indeed, we show that Aca14, newly identified in this study, represses two predicted anti-defence operons. Aca14 is a ribbon-helix-helix domain protein, revealing regulatory diversity beyond the canonical HTH Aca family members. Collectively, our findings expand the understanding of acr regulation in mobile genetic elements and reveal novel mechanisms by which phages fine-tune anti-defence gene expression. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/740549v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@23e8edorg.highwire.dtl.DTLVardef@19146a8org.highwire.dtl.DTLVardef@b5e553org.highwire.dtl.DTLVardef@1e2ddbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

Mechanical environment afforded by engineered polymer hydrogel critically regulates survival of neural stem cells transplanted in the injured spinal cord via Piezo1-mediated mechanotransduction

Neural stem cell (NSC) transplantation is a promising therapeutic approach for spinal cord repair, but poor graft survival remains a critical challenge. Here, we demonstrate that the mechanical properties of the transplantation microenvironment play a crucial role in NSC survival in the injured spinal cord. While our previously engineered imidazole-poly(organophosphazene) (I-5) hydrogel effectively prevented cavity formation by promoting extracellular matrix remodeling, NSCs transplanted with 10% hydrogel exhibited poor survival. Remarkably, increasing the hydrogel concentration to 16%, which created a 5-fold stiffer matrix, significantly enhanced NSC graft survival and synaptic integration. Using in vitro models with controlled substrate stiffness, we found that NSCs on stiffer substrates displayed enhanced adhesion, complex morphology, and increased viability. Importantly, we identified the mechanosensitive ion channel Piezo1 as the key molecular mediator of these stiffness-dependent behaviors. CRISPR/Cas9-mediated Piezo1 gene editing in NSCs significantly reduced graft survival in vivo when transplanted with 16% hydrogel, confirming that Piezo1-mediated mechanotransduction is essential for NSC survival in the injured spinal cord. Our findings reveal a previously unrecognized mechanism governing graft survival in the injured spinal cord and suggest that optimizing the mechanical properties of biomaterial scaffolds or targeting Piezo1-dependent mechanotransduction could substantially improve outcomes of cell-based therapies for neurological disorders.

neuroscience↗

bioRxiv2024

Bridging in vitro and in vivo insights: A PKPD model for effective phage therapy against multidrug-resistant Pseudomonas aeruginosa

Bacteriophage therapy provides a promising solution for multidrug-resistant Pseudomonas aeruginosa. However, optimizing phage combinations and dosages remains challenging. Here, we developed and validated a pharmacokinetic-pharmacodynamic (PKPD) model integrating in vitro and in vivo efficacy data using three phage strains (MP-A, PP-A, and PP-B), administered both alone and in combination. In vitro phage resistance was substantially delayed by combining phages that exhibit collateral sensitivity. However, multiple phage resistance eventually emerged. In vivo, growth of phage-resistant mutants was minimal. Our model suggests that this outcome was due to an initial phage-induced reduction in bacterial load, followed by immune clearance of the phage-resistant bacteria. Simulations indicated that higher phage exposure at the site of infection caused a faster decline in bacterial levels below the immune clearance threshold and prevented excessive immune activation. Overall, this study offers crucial guidance for treatment strategies and highlights the importance of mathematical modeling in advancing phage therapy.

microbiology↗

bioRxiv2024

Detrimental Influence of Arginase-1 in Infiltrating Macrophages on Post-Stroke Functional Recovery and Inflammatory Milieu

Post-stroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is conventionally understood as a marker for anti-inflammatory macrophages, associated with the resolution of inflammation and promotion of tissue repair in various pathological conditions. However, its specific role in post-stroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on post-stroke recovery and inflammatory milieu. We observed a time-dependent increase in Arg1 expression, peaking at 7 days after photothrombotic stroke in mice. Cellular mapping analysis revealed that Arg1 was predominantly expressed in LysM-positive infiltrating macrophages. Using a conditional knockout (cKO) mouse model, we examined the role of Arg1 expressed in infiltrating macrophages. Contrary to its presumed beneficial effects, Arg1 cKO in LysM-positive macrophages significantly improved skilled forelimb motor function recovery after stroke. Mechanistically, Arg1 cKO attenuated fibrotic scar formation, enhanced peri-infarct remyelination, and increased synaptic density while reducing microglial synaptic elimination in the peri-infarct cortex. Gene expression analysis of FACS-sorted microglia revealed decreased TGF-{beta} signaling and pro-inflammatory cytokine activity in peri-infarct microglia from Arg1 cKO animals. In vitro co-culture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocytosis, providing evidence for macrophage-microglia interaction. These findings provide new insights into Arg1 function in CNS injury and highlight an interaction between infiltrating macrophages and resident microglia in shaping the post-stroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential therapeutic target for modulating post-stroke inflammation and improving functional recovery.

neuroscience↗

bioRxiv2021

Oncomodulin derived from regeneration-associated macrophages in dorsal root ganglia promotes axon regeneration in the spinal cord

Preconditioning nerve injury drives pro-regenerative perineuronal macrophage activation in dorsal root ganglia (DRG). The present study reports that oncomodulin (ONCM) is produced from the regeneration-associated macrophages (RAMs) and strongly influences regeneration of DRG sensory axons. Preconditioning injury upregulated ONCM in DRG macrophages in a CCR2 dependent manner. ONCM in macrophages was necessary to produce RAMs in the in vitro model of neuron-macrophage interaction and played an essential role in for preconditioning or CCL2-induced neurite outgrowth. ONCM potently increased neurite outgrowth in cultured DRG neurons by activating a distinct gene set, particularly neuropeptide-related genes. Increasing extracellularly secreted ONCM in DRGs sufficiently enhanced capacity of neurite outgrowth. To achieve sustained ONCM activity in vivo, recombinant ONCM was encapsulated by a reducible epsilon-poly(L-lysine)-nanogel (REPL-NG) system based on electrostatic interaction. Localized injection of REPL-NG/ONCM complex into DRGs achieved a remarkable long-range axonal regeneration beyond spinal cord lesion, surpassing the extent of the preconditioning effects.

neuroscience↗