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Biology subjects

Truong, T. T.

Publications and source records attributed to Truong, T. T..

7 recordsLinked to original sources
bioRxiv2025

Amitraz Toxicity in Resistant Varroa Mites Can Be Increased by Inhibiting ABCB1 Transporters

As critical pollinators of agricultural crops, honey bees (Apis mellifera) play a vital role in food production. Therefore, it is imperative to investigate and develop new methods to control Varroa destructor, a devastating parasitic mite of honey bee colonies that weakens bees and spreads deadly diseases that lead to colony loss. Here, we adapted existing methods to investigate the role of ABCB1 transporters in mitigating the toxicity of amitraz, a widely used miticide approved for use in honey bee colonies, demonstrating that a pharmacological inhibitor can synergistically increase amitraz toxicity compared to the equivalent dose of amitraz alone. Evaluations performed on the mites used in one of the described experiments revealed a high proportion of the test subject mites (88.5%) possessed the amitraz resistant genotype, indicating that even in resistant mites, inhibiting ABCB1 transporters can increase amitraz efficacy. This promising finding may be useful in developing powerful synergists that can be used to increase the efficacy of new and existent miticides.

pharmacology and toxicology↗
bioRxiv2024

SARS-CoV-2 variants from long-term, persistently infected immunocompromised patients have altered syncytia formation, temperature-dependent replication, and serum neutralizing antibody escape

SARS-CoV-2 infection of immunocompromised individuals often leads to prolonged detection of viral RNA and infectious virus in nasal specimens, presumably due to the lack of induction of an appropriate adaptive immune response. Mutations identified in virus sequences obtained from persistently infected patients bear signatures of immune evasion and have some overlap with sequences present in variants of concern. We characterized virus isolates from two COVID-19 patients undergoing immunosuppressive cancer therapy, with all isolates obtained greater than 100 days after the initial COVID-19 diagnoses and compared to an isolate from the start of the infection. Isolates from an individual who never mounted an antibody response specific to SARS-CoV-2 despite the administration of convalescent plasma showed slight reductions in plaque size and some showed temperature-dependent replication attenuation on human nasal epithelial cell culture compared to the virus that initiated infection. An isolate from another patient - who did mount a SARS-CoV-2 IgM response - showed temperature dependent changes in plaque size as well as increased syncytia formation and escape from serum neutralizing antibody. Our results indicate that not all virus isolates from immunocompromised COVID-19 patients display clear signs of phenotypic change, but increased attention should be paid to monitoring virus evolution in this patient population.

microbiology↗
bioRxiv2022

Loss of EED in the oocyte causes initial fetal growth restriction followed by placental hyperplasia and offspring overgrowth

Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to placental hyperplasia in mammalian offspring generated by somatic cell nuclear transfer (SCNT). In this study, we show that offspring from mouse oocytes lacking the Polycomb protein Embryonic Ectoderm Development (EED) were initially growth restricted, characterised by low blastocyst cell counts and substantial mid-gestational developmental delay. This initial developmental delay was followed by striking late-gestational placental hyperplasia, fetal catch-up growth and extended gestational length that culminated in offspring overgrowth. This involved remodelling of the placenta, including expansion of fetal and maternal tissues and conspicuous expansion of the glycogen enriched cell population in the junctional zone that was associated with a delay in parturition. Despite this remodelling and offspring catchup growth, fetal/placental weight ratio and fetal blood glucose levels were low indicating low placental efficiency. Genome-wide analyses identified extensive transcriptional dysregulation in affected placentas, including a range of imprinted and non-imprinted genes and increased expression of the H3K27me3-imprinted gene Slc38a4, which regulates transport of essential amino acids in the placenta. Our data provide an explanation for apparently opposing observations of growth restriction and overgrowth of offspring derived from Eed-null oocytes and demonstrate that PRC2-dependent programming in the oocyte regulates fetal and placental growth and developmental outcomes.

developmental biology↗
bioRxiv2021

Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we have combined cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding by four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data revealed that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.

biochemistry↗
bioRxiv2021

Structural and Functional Diversity among Agonist-Bound States of the GLP-1 Receptor

Recent advances in G protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multi-dimensional signal propagation mediated by these receptors is, in part, dependent on their conformational mobility. However, the relationship between receptor function and static structures determined via crystallography or cryo-electron microscopy is not always clear. This study examines the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide-1 receptor (GLP-1R), an important clinical target. We employ variants of the peptides GLP-1 and exendin-4 to explore the interplay between helical propensity near the agonist N-terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an exendin-4 analogue, the GLP-1R and Gs protein revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.

pharmacology and toxicology↗
bioRxiv2020

Differential GLP-1R binding and activation by peptide and non-peptide agonists

Peptide drugs targeting class B1 GPCRs can treat multiple diseases, however there remains substantial interest in the development of orally delivered non-peptide drugs. Here we reveal unexpected overlap between signalling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist, PF 06882961, and GLP-1 that was not observed for another compound, OWL-833. Both compounds are currently in clinical trials for treatment of type 2 diabetes. High resolution cryo-EM structures reveal the binding sites for PF-06882961 and GLP-1 substantially overlap, whereas OWL-833 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not OWL-833, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

pharmacology and toxicology↗