Biology subjects

Tsui, T.

Publications and source records attributed to Tsui, T..

5 recordsLinked to original sources

bioRxiv2025

Environment shapes the association between the skin microbiome and infection dynamics of the Dermocystid pathogen Amphibiothecum in Palmate newts (Lissotriton helveticus).

Infectious diseases are a leading cause of biodiversity declines, but the factors shaping the prevalence and intensity of wildlife disease outbreaks remain unresolved. Host-associated microbes are likely a key component of host resistance to infection, but a hosts ability to recruit such protective microbes may be restricted by the availability of microbes present in their immediate environment. Here we investigate the associations between the abiotic environment, skin microbiome, and infection with the Dermocystid pathogen Amphibiothecum meredithae in Palmate newts (Lissotriton helveticus) on the Isle of Rum, Scotland. We found more acidic ponds to be associated with higher skin microbiome diversity and lower pathogen prevalence. Predicted functional analysis of microbiota composition identified bacterially-mediated pathways linked to host immunity upregulated in skin microbiotas associated with more acidic ponds and lower infection prevalence. This study highlights the potential importance of the environment in modulating host- microbiome-pathogen relationships and patterns of infection in the wild.

ecology↗

bioRxiv2025

DEER of Singly Labelled Proteins to Evaluate Supramolecular Packing of Amyloid Fibrils

1The formation of protein amyloid fibrils in the brain is a hallmark of various neurodegenerative diseases, including Alzheimer diseases and Parkinson diseases. Amyloid fibrils are highly ordered aggregates in which proteins folded in two-dimensional layers stack along one axis to form elongated linear assemblies. The specific conformations adopted by the proteins within each layer of the amyloid correlates with the pathology. Furthermore, their spreading and templating competency relies on strict in register packing of the folded proteins along the fibril growing axis. There is a need for tools to characterize not only the protein fold across the fibril cross section but also the spatial ordering of the proteins stacked along the amyloid fibril axis. We present an approach based on double electron electron resonance spectroscopy (DEER) using singly labelled tau protein assembled in amyloid fibrils that can deliver an apparent dimensionality of the supramolecular organization of tau fibrils. The parameters of the DEER background function can be used to assess the amyloid core location and packing order, and track time-resolved formation of aggregation intermediates. Showcasing the method on tau, we demonstrate that heparin-induced tau fibrils are mispacked while seeded aggregation can template amyloid fibrils with a higher packing order. This study benchmarks a new method that will provide critical structural insights into amyloid assemblies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/687719v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@8c42c9org.highwire.dtl.DTLVardef@74b0f8org.highwire.dtl.DTLVardef@10e8095org.highwire.dtl.DTLVardef@11bc727_HPS_FORMAT_FIGEXP M_FIG DEER-derived dimensionality parameter differentiates between spin-labelled tau protein in solution, in perfectly aligned fibril or in imperfectly aligned fibril (fibril structure edited from PDB 6qjh). C_FIG

biophysics↗

bioRxiv2024

A bacterial cell wall repair and modification system to resist host antibacterial factors

Pathogenic bacteria have acquired the ability to resist antibacterial defense mechanisms of the host. Streptococci are common in animal microbiota and include opportunistic pathogens like Group A Streptococcus (GAS) and Streptococcus pneumoniae (pneumococcus). While the conserved streptococcal S protein has been identified as a key factor in GAS virulence, its exact function is unclear. Here, we show that the pneumococcal S protein is crucial for resisting against host-derived antimicrobials by coordinating cell wall modification and repair. Specifically, we show that S proteins are septally localized through their transmembrane domain and contain an extracellular peptidoglycan (PG) binding LysM domain which is required for its function. Protein-protein and genetic interaction studies demonstrate that the pneumococcal S protein directly interacts with a PG synthase, class A penicillin binding protein PBP1a, and the PG deacetylase PgdA. Single-molecule experiments reveal that the fraction of circumferentially moving PBP1a molecules is reduced in the absence of S protein. Consistent with an impaired PBP1a function, streptococci lacking S protein exhibit increased susceptibility to cell wall targeting antibiotics and altered cell morphologies. PG analysis showed reduced N-deacetylation of glycans in the S. pneumoniae S protein mutant, indicating reduced PgdA activity. We show that pneumococci lacking the S protein cannot persist transient penicillin treatment, are more susceptible to the human antimicrobial peptide LL-37 and to lysozyme, and show decreased virulence in zebrafish and mice. Our data support a model in which S proteins regulate PBP1a activity and play a key role in coordinating PG repair and modification. This cell wall sentinel control system provides defense against host-derived and environmental antimicrobial attack.

microbiology↗

bioRxiv2023

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the "WIN" site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small molecule WIN site inhibitors, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anti-cancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anti-cancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

cancer biology↗

bioRxiv2020

A computational framework to explore cellular response mechanisms from multi-omics datasets

Recent technological advances have made it feasible to collect multi-condition transcriptome and proteome time-courses of cellular response to perturbation. The increasing size and complexity of these datasets impedes mechanism of action discovery due to challenges in data management, analysis, visualization, and interpretation. Here, we introduce MAGINE, a software framework to explore complex time-course multi-omics datasets and build mechanistic hypotheses of dynamic cellular response. MAGINE combines data management, enrichment, and network analysis and visualization within an interactive, Jupyter notebook-based environment to enable human-in-the-loop inquiry of complex datasets. We demonstrate how measurements from HL-60 cellular response to bendamustine treatment can be used to build a mechanistic, multi-resolution description of cellular commitment to fate. We present a systems-level description of signal execution from cellular DNA-damage response, to cell cycle arrest, and eventual commitment to apoptosis, mediated by over 2000 biochemical species. We further show that MAGINE can reveal unexpected, non-canonical effects of bendamustine treatment, including disruption of cellular pathways relevant to HIV infection response. MAGINE is available from https://github.com/lolab-vu/magine.

systems biology↗