Biology subjects

Prosser, R.

Publications and source records attributed to Prosser, R..

4 recordsLinked to original sources

bioRxiv2026

A structure-guided pipeline yields peptide inhibitors that disarm fungal peptidase-driven virulence and resistance

Fungal infections are a major global health challenge, with current antifungal therapies limited by toxicity, cost, and resistance. For Cryptococcus neoformans, key virulence factors that initiate and sustain infection are regulated by fungal peptidases to produce a polysaccharide capsule, promote immune evasion, and support antifungal resistance. These peptidases represent promising targets for antivirulent therapeutic strategies. Here, we developed a computational pipeline to predict and design peptide- and protein-based inhibitors against cryptococcal peptidases. Specifically, we targeted three virulence-associated peptidases: Rim13 (cysteine), May1 (aspartic), and CnMpr1 (metallo). Cysteine peptidase inhibition decreased capsule/cell size ratios without impeding fungal growth and reduced fungal survival within macrophages. Similarly, aspartic peptidase inhibition enhanced fungal clearance within alveolar macrophages and disrupted biofilm formation with additive effects towards fluconazole susceptibility in resistant strains. Additionally, metallopeptidase inhibition through catalytic zinc chelation and blocked substrate binding led to enhanced enzymatic inhibition and reduced in vitro blood-brain barrier crossing. Moreover, an in vivo larval model assessing inhibitor efficacy produced additive effects with fluconazole and lacked host cell cytotoxicity and fungicidal properties, reinforcing anti-virulence mechanisms and therapeutic potential while limiting the evolution of resistance. Further, global proteome profiling of inhibitor treated cells defined a mechanism of cell wall disruption, impeding fungal virulence. Taken together, the designed peptidase inhibitors exhibited potent antifungal activity without harming mammalian cells, establishing a predictive framework for rational scaffold design of next-generation antifungals that disarm the pathogen enabling immune-mediated clearance.

microbiology↗

bioRxiv2025

Low nucleus to cytoplasmic ratio compromises cytokinesis, genome stability and development in haploid embryonic cells

Mammalian species exist as diploid organisms, with only gametes existing as stable, nonproliferating haploids. Haploid mammalian pluripotent stem cells, in all derived species to date - mouse, human and rat - undergo spontaneous diploidization. Here, we investigated the mechanisms affecting the stability of the haploid state using the mouse and human embryo, as well as a human embryonic stem cells. We demonstrate that diploidization occurs early in preimplantation development and is often unproductive, with haploid embryos exhibiting decreased developmental potential. Haploid embryos show increased chromosome segregation errors at the first mitosis, failure to align chromosomes on the metaphase plate in the second mitosis. Delayed mitotic progression and failure to form a central spindle and a midbody are followed by cytokinesis failure, diploidization, increased DNA damage marked by {gamma}H2AX and RPA32 foci, and low developmental potential. By increasing the nucleo-cytoplasmic ratio in diploids, or reducing this ratio in haploids, these phenotypes can be induced in diploids or reduced in haploids. Changing ploidy alone from haploid to diploid without also adjusting nucleo-cytoplasmic ratio does not improve mitotic phenotypes and developmental outcomes. Thus, the most upstream driver responsible for the instability of the haploid state is a stage- specific ratio of nucleus to cell size.

cell biology↗

bioRxiv2023

Urban-use pesticides in stormwater ponds and their accumulation in biofilms

Stormwater ponds frequently receive urban runoff, increasing the likelihood of pesticide contamination. Biofilms growing in surface waters of these ponds are known to accumulate a range of aquatic contaminants, paradoxically providing both water purification services and potentially posing a threat to urban wildlife. Thus, sampling biofilms in stormwater ponds may be a critical and biologically relevant tool for characterizing pesticide contamination and toxicity in urban environments. Here, we aimed to investigate pesticide occurrences at 21 stormwater ponds in Brampton, ON, one of Canadas fastest growing municipalities, and quantify their accumulation in biofilm. Over nine weeks, we collected time-integrated composite water and biofilm samples for analysis of [~]500 current-use and legacy pesticides. Thirty-two pesticide compounds were detected across both matrices, with 2,4-D, MCPA, MCPP, azoxystrobin, bentazon, triclopyr, and diuron having near-ubiquitous occurrences. Several compounds not typically monitored in pesticide suites (e.g., melamine and nicotine) were also detected, but only in biofilms. Overall, 56% of analytes detected in biofilms were not found in water samples, indicating traditional pesticide monitoring practices fail to capture all exposure routes, as even when pesticides are below detection levels in water, organisms may still be exposed via dietary pathways. Calculated bioconcentration factors ranged from 4.2 - 1275 and were not predicted by standard pesticide physicochemical properties. Monitoring biofilms provides a sensitive and comprehensive supplement to water sampling for pesticide quantification in urban areas, and identifying pesticide occurrences in stormwater could improve source-tracking efforts in the future. Further research is needed to understand the mechanisms driving pesticide accumulation, to investigate toxicity risks associated with pesticide-contaminated biofilm, and to evaluate whether pesticide accumulation in stormwater pond biofilms represents a route through which contaminants are mobilized into the surrounding terrestrial and downstream aquatic environments.

ecology↗

bioRxiv2020

Degradation of boscalid, pyraclostrobin, fenbuconazole, and glyphosate residues by an advanced oxidative process utilizing ultraviolet light and hydrogen peroxide

Recently an advanced oxidative process (AOP) combining H2O2 and UV-C light was observed to be effective at controlling Listeria monocytogens (Murray et al., 2018) and Escherichia coli O157:H7 and degrading chlorpyrifos residues on the surface of apples (Ho et al., 2020). Little is known about the application of AOP for the degradation of other pesticide residues. This study examined degradation of boscalid, pyraclostrobin, fenbuconazole and glyphosate by 3% (w/v) H2O2, UV-C (254 nm) irradiation and their combination on apple skin and glass. The extent of degradation was not significantly different between the AOP and optimal individual treatment. However, treatment susceptibility was different with glyphosate most effectively degraded by H2O2 exposure (up to 98% on apple, 3% (w/v) H2O2 at 30{square}C for 15 min) while boscalid, pyraclostrobin and fenbuconazole were more effectively degraded by UV-C (up to 88%, 100% and 70% degradation after ~11,000 mJ/cm2). Suggestions for possible causes of degradation are proposed.

plant biology↗