Biology subjects

Barclay, E.

Publications and source records attributed to Barclay, E..

3 recordsLinked to original sources

bioRxiv2025

G-quadruplexes represent promising new targets to overcome multidrug-resistant fungal infections

The growing emergence of antifungal resistance has prompted the identification of novel antifungal targets. G-quadruplexes (G4s), four-stranded secondary structures that form in DNA and RNA, have arisen as a drug target to treat bacterial, viral, and parasitic infections. Here, we provide the first demonstration that G4s form in fungi and represent a promising new target for antifungal development. We found that PhenDC3 and pyridostatin (PDS), ligands that bind to and stabilise G4s, potently inhibited the metabolism of fungal pathogens in different ways. These pathogens included the pan azole-resistant Aspergillus fumigatus isolate TR34/L98H and Candida auris. Notably, PhenDC3 could synergise with amphotericin B, was protective in an in vivo model of fungal infection, and was well-tolerated by human cells. However, continuous exposure to PhenDC3 resulted in some cross-resistance to current antifungals and this needs to be explored further. PhenDC3 could also increase the number of RNA G4s in live A. fumigatus. Further, we demonstrated the structural flexibility of DNA sequences found in cyp51A and cyp51B, with these sequences capable of forming duplexes, hairpins, G4s and i-motifs. Finally, PhenDC3, but not PDS, caused duplex DNA structures in cyp51A to transition into antiparallel G4 structures potentially associated with PhenDC3s increased antifungal potency. Taken together, G4s represent an exciting antifungal target, but a more detailed understanding of their biological roles is essential.

microbiology↗

bioRxiv2024

Genomic and Genetic Insights into Mendel's Pea Genes

Pea, Pisum sativum, is an excellent model system through which Gregor Mendel established the foundational principles of inheritance. Surprisingly, till today, the molecular nature of the genetic differences underlying the seven pairs of contrasting traits that Mendel studied in detail remains partially understood. Here, we present a genomic and phenotypic variation map, coupled with haplotype-phenotype association analyses across a wide range of traits in a global Pisum diversity panel. We focus on a genomics-enabled genetic dissection of each of the seven traits Mendel studied, revealing many previously undescribed alleles for the four characterized genes, R, Le, I and A, and elucidating the gene identities and mutations for the remaining three uncharacterized traits. Notably, we identify: (1) a ca. 100kb deletion upstream of the Chlorophyll synthase (ChlG) gene, which generates aberrant transcripts and confers the yellow pod phenotype of gp mutants; (2) an in-frame premature stop codon mutation in a Dodeca-CLE41/44 signalling peptide which explains the parchmentless mutant phenotype corresponding to p; and (3) a 5bp in-frame deletion in a CIK-like receptor kinase gene corresponding to the fasciated stem phenotype fa, which Mendel described in terms of flower position, and we postulate the existence of a Modifier of fa (Mfa) locus that masks this meristem defect. Mendel noted the pleiotropy of the a mutation, including inhibition of axil ring anthocyanin pigmentation, a trait we found to be controlled by allelic variants of the gene D within an R2R3-MYB gene cluster. Furthermore, we characterize and validate natural variation of a quantitative genetic locus governing both pod width and seed weight, characters that Mendel deemed were not sufficiently demarcated for his analyses. This study establishes a cornerstone for fundamental research, education in biology and genetics, and pea breeding practices.

genetics↗

bioRxiv2023

Genetic control of cell layer interactions in plants via tissue mechanics

Plant development depends on coordination of growth between different cell layers. Coordination may be mediated by molecular signalling or mechanical connectivity between cells, but evidence for genetic control via direct mechanics has been lacking. We show that a brassinosteroid-deficient dwarf mutant of the aquatic plant Utricularia gibba has twisted internal tissue, likely caused by a mechanical constraint from a slow-growing epidermis creating tissue stresses. This conclusion is supported by showing that inhibition of brassinosteroid action in an Arabidopsis mutant compromised for cell adhesion, enhances epidermal crack formation, an indicator of increased tissue tension. Thus, genes driving brassinosteroid synthesis can promote growth of internal tissue by reducing mechanical epidermal constraint, showing that tissue mechanics plays a key role in coordinating growth between cell layers. One-Sentence SummaryInternal twists in a mutant carnivorous plant reveal how genes control growth via tissue mechanics.

plant biology↗