Biology subjects

Liu, S. Y.

Publications and source records attributed to Liu, S. Y..

6 recordsLinked to original sources

bioRxiv2025

Engineering magnetically guided bacteriophages for precision antimicrobial therapy and targeted biofilm eradication

Viruses, including bacteriophages, rely on passive diffusion to reach their hosts, limiting the efficacy of virus-based therapies and leading to off-target accumulation with systemic effects. Here, we present a strategy to confer controllable motility to bacteriophages by incorporating iron nanoparticles (FeNPs) into their head structures while preserving infectivity. Cryo-electron microscopy (Cryo-EM) and transmission electron microscopy-energy dispersive spectroscopy (TEM-EDS) confirmed the FeNP presence in the phages head. FeNP-tagged phages can be magnetically enriched and isolated from bacterial prey cultures, eliminating the need for ultracentrifugation. Under magnetic guidance, these engineered phages exhibit rapid and directed movement through complex microenvironments, including mazes and polymer barriers, enabling precise bacterial targeting and biofilm eradication in a microfluidic system. In an in vivo wound infection model, magnetically guided phages successfully navigated from the peritoneum to the biofilms on the wound, thus selectively eliminating biofilms while minimizing systemic exposure to other organs. Hence, our approach confers viral mobility, thus enhancing the precision and efficacy of bacteriophage-based biotechnological and therapeutic applications.

microbiology↗

bioRxiv2024

Potent antitumor activity of a designed interleukin-21 mimic

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report a de novo IL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and in ex vivo human melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity. 21h10 generates significantly prolonged STAT signaling in vivo compared with native IL-21, and has considerably stronger anti-tumor activity. Toxicities associated with systemic administration of 21h10 could be mitigated by TNF blockade without compromising antitumor efficacy. In the tumor microenvironment, 21h10 induced highly cytotoxic antitumor T cells from clonotypes with a range of affinities for endogenous tumor antigens, robustly expanding low-affinity cytotoxic T cells and driving high expression of interferon- (IFN-) and granzyme B compared to native IL-21, while increasing the frequency of IFN-+ Th1 cells and reducing that of Foxp3+ Tregs. As 21h10 has full human/mouse cross-reactivity, high stability and potency, and potentiates low-affinity antitumor responses, it has considerable translational potential.

biochemistry↗

bioRxiv2024

SMAC mimetics induce human macrophages to phagocytose live cancer cells

Macrophages engulf apoptotic bodies and cellular debris as part of homeostasis, but they can also phagocytose live cells such as aged red blood cells. Pharmacologic reprogramming with the SMAC mimetic LCL161 in combination with T cell-derived cytokines can induce macrophages to phagocytose live cancer cells in mouse models. Here we extend these findings to encompass a wide range of monovalent and bivalent SMAC mimetic compounds, demonstrating that live cell phagocytosis is a class effect of these agents. We demonstrate robust phagocytosis of live pancreatic and breast cancer cells by primary human macrophages across a range of healthy donors. Unlike mouse macrophages where combination of SMAC mimetics with lymphotoxin enhanced phagocytosis, human macrophages were more efficiently polarized to phagocytose live cells by the combination of SMAC mimetics and IFN{psi}. We profiled phagocytic macrophages by transcriptional and proteomic methodologies, uncovering a positive feedback loop of autocrine TNF production.

immunology↗

bioRxiv2023

Dual-species proteomics and targeted intervention of animal-pathogen interactions

Complexity in host-pathogen interactions drives the need to develop sensitive and accurate biochemical techniques to elucidate host and pathogen protein expressions. Current proteomics techniques reveal information from the point of view of either the host or pathogen, but do not provide data on the corresponding partner. While dual-species transcriptomics is increasingly used to study RNA expression in host and pathogen, it remains challenging to simultaneously study host-pathogen proteomes that reflect the direct competition between host and pathogen. Using Caenorhabditis elegans-Pseudomonas aeruginosa infection model as proof-of-concept, we established a forward+reverse SILAC proteomics approach to simultaneously label and quantify newly-expressed proteins of host and pathogen without physical isolation. We observed iron competition between pathogen iron scavenger and host iron uptake protein, where P. aeruginosa upregulated pyoverdine synthesis protein (PvdA) and secreted pyoverdine, and C. elegans expressed ferritin (FTN-2) respectively. Using Galangin as a novel PvdA inhibitor identified by structure-based virtual-screening, targeted intervention of iron competition eliminated P. aeruginosa infection, and enabled animal survival. Our work provides insights into the mechanisms dictating host-pathogen interactions and offers novel strategies for anti-infective therapy.

biochemistry↗

bioRxiv2022

Identification and characterization of a dlx2b cis-regulatory element both sufficient and necessary for correct transcription during zebrafish tooth development

Despite growing recognition of the importance of cis-regulatory elements in vertebrate development, the mechanisms by which enhancers control gene expression during organogenesis remain incompletely understood. To address this gap, we investigated the regulation of the transcription factor dlx2b during zebrafish larval tooth formation. Using CRISPR/Cas9-mediated genome editing, we generated a GFP knock-in line that recapitulates dlx2b expression in developing tooth germs. Through targeted manipulation of enhancer sequences, we identified a minimal tooth enhancer (MTE), which is sufficient to drive most of the endogenous dlx2b tooth germ expression pattern in vivo. Functional dissection of the MTE revealed that four evolutionarily conserved transcription factor binding sites are essential for enhancer activity. Mutating these sites within a transgenic reporter abolishes enhancer-driven expression, while deletion of the same sequences at the endogenous dlx2b locus causes a dramatic shift in the genes expression pattern. These findings suggest that loss of MTE function permits alternative cis-regulatory elements to gain control of the promoter, highlighting the dynamic nature of enhancer-promoter interactions during development. Together, these results uncover fundamental principles of enhancer function during vertebrate organogenesis and demonstrate the power of empirical dissection in decoding cis-regulatory architecture. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/477116v3_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@5a5909org.highwire.dtl.DTLVardef@18b79bforg.highwire.dtl.DTLVardef@1e61eaeorg.highwire.dtl.DTLVardef@e845f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2020

Effectively control of viral disease outbreak in shrimp culture system by selective predation

Due to the limited understanding of the characteristics of predator-pathogen-prey interactions, few attempts to use selective predation for controlling diseases in prey populations have been successful. The global pandemic of white spot syndrome (WSS), caused by white spot syndrome virus (WSSV), causes devastating economic losses in farmed shrimp production. Currently, there is no effective control for WSS. Here, we determined the transmission dynamics of WSSV and the feeding ability and selectivity of fish on healthy, infected and dead shrimp by experiments and mathematical modeling. Accordingly, we developed a novel and convenient shrimp cultural ecosystem, which that effectively prevented WSS outbreaks, by introducing aquaculture fish species. This provides a scheme for developing control strategies for viral diseases with high transmission rate.

ecology↗