Biology subjects

Gage, A.

Publications and source records attributed to Gage, A..

3 recordsLinked to original sources

bioRxiv2025

Bioinformatics-Driven Identification and Prioritization of PTSD Targets Based on Published Multi-omic Data

Efforts in recent years to uncover neurobiological mechanisms underlying post-traumatic stress disorder (PTSD) have yielded an expanding candidate pool of targets from genomic and transcriptomic data. However, not all candidates are disease-causing, related to pathological mechanisms, clinically relevant, nor druggable by conventional means. An effective method to systematically identify and prioritize high-confidence, high-impact targets in the central nervous system (CNS) is required to de-risk resource-intensive experimental validation of disease mechanisms and accelerate the development of novel treatments. Here, we describe methods and implementation of a novel 3-phased, biologically rationalized, and quantitative prioritization strategy to identify and rank PTSD-associated targets based on confidence of association to PTSD and estimated CNS-relevant pathogenicity. Phase 1 was designed to identify and advance targets confidently associated with PTSD through their expression in CNS tissues. Putative targets derived from 29 transcriptomic and genomic analyses of PTSD were evaluated for: 1. Replication in independent cohorts, 2. Observation of differential expression in PTSD CNS tissues, and 3. Demonstration of consistent direction of effect. This strategy resulted in 177 targets that passed criteria for advancement. Phase 1-selected targets were enriched for PTSD relevant traits including irritability, emotional symptoms, and insomnia (FDR <0.05). Phase 2 advanced targets with additional evidence of association to pathological CNS phenotypes. DisGeNET gene-disease association scores were applied to each Phase 1-selected target to assign a confidence score indicating that a target was associated with CNS-relevant pathology using criteria for moderate or strong evidence of CNS disease association. Phase 2 advanced 55 of the 177 (31.1%) targets. The Phase 2 target pool was enriched for CNS phenotypic abnormalities (FDR<0.05). Finally, Phase 3 enabled target prioritization by annotating targets with a composite pathogenicity score. Components of the pathogenicity score included metrics derived from drug trial databases, predicted loss-of-function intolerance, and connectivity within a protein-protein interaction network defined by PTSD-associated targets. The resulting 55 targets were ultimately prioritized by the sum of Phase 2 and Phase 3 scores, where top-ranked targets had strong evidence to support both association with PTSD in brain and high pathogenicity estimates in a CNS-relevant context. Biologically, top-ranked targets implicate transmitter systems (GABA, histamine, and estrogen), structural regulation of neurites, and protein homeostasis. Future work will be required to experimentally validate the utility of the high priority PTSD targets we identified as well as to demonstrate the general applicability of this methodology. Ultimately, we anticipate that the three phased approach will enable efficient de-risking of PTSD and other poorly understood CNS disorders.

neuroscience↗

bioRxiv2024

Glyphosate Effects on Growth and Biofilm Formation in Bee Gut Symbionts and Diverse Associated Bacteria

Biofilm formation is a common adaptation enabling bacteria to thrive in various environments and to withstand external pressures. In the context of host-microbe interactions, biofilms play vital roles in establishing microbiomes associated with animals and plants and are used by opportunistic microbes to facilitate proliferation within hosts. Investigating biofilm dynamics, composition, and responses to environmental stressors is crucial for understanding microbial community assembly and biofilm regulation in health and disease. In this study, we explore the independent gut colonization and in vitro biofilm formation abilities of core members of the honey bee (Apis mellifera) gut microbiota. Additionally, we assess the impact of glyphosate, a widely used herbicide with antimicrobial properties, and a glyphosate-based formulation on growth and biofilm formation in bee gut symbionts as well as in other biofilm-forming bacteria associated with diverse animals and plants. Our results demonstrate that several strains of core bee gut bacterial species can independently colonize the bee gut, which probably depends on their ability to form biofilms. Furthermore, glyphosate exposure has varying effects on bacterial growth and biofilm formation. These findings imply specific impacts of environmental stressors on microbial biofilms with both ecological and host health-related implications. Importance Biofilms are essential for microbial communities to establish and thrive in diverse environments. In the honey bee gut, the core microbiota member Snodgrassella alvi forms biofilms, potentially aiding the establishment of other members and promoting interactions with the host. In this study, we show that specific strains of other core members, including Bifidobacterium, Bombilactobacillus, Gilliamella, and Lactobacillus, also form biofilms. We then examine the impact of glyphosate, a widely used herbicide that disrupts the bee microbiota, on their growth and biofilm formation. Our findings demonstrate diverse effects of glyphosate on biofilm formation, ranging from inhibition to enhancement, reflecting observations in other beneficial or pathogenic bacteria associated with animals and plants. Thus, glyphosate exposure may influence bacterial growth and biofilm formation, potentially shaping microbial establishment on host surfaces and impacting health outcomes.

microbiology↗

bioRxiv2022

Cooperative host-microbe metabolism of a plant toxin in bees

During pollination, bees are exposed to a myriad of xenobiotics, including plant metabolites, which may exert a wide range of effects on their health. Although bees encode enzymes that help in the metabolism of xenobiotics, they still have reduced detoxification gene diversity when compared to other insects, and may rely on other components of their physiology, such as the microbiota, to degrade potentially toxic molecules. In this study, we show that amygdalin, a cyanogenic glycoside found in honey bee-pollinated almond trees, can be metabolized by both bees and members of the gut microbiota. In microbiota-deprived bees, amygdalin is degraded into prunasin, leading to prunasin accumulation in the midgut and hindgut. In microbiota-colonized bees, on the other hand, amygdalin is degraded even further, and prunasin does not accumulate in the gut, suggesting that the microbiota contribute to the full degradation of amygdalin into hydrogen cyanide. In vitro experiments demonstrated that amygdalin degradation by bee gut bacteria is strain-specific and not characteristic of a particular genus or species. We found strains of Bifidobacterium, Bombilactobacillus and Gilliamella that can degrade amygdalin, and the degradation mechanism appears to vary since only some strains produce prunasin as an intermediate. Finally, we investigated the basis of degradation in Bifidobacterium wkB204, a strain that fully degrades amygdalin. We found overexpression and secretion of several carbohydrate-degrading enzymes, including one in glycoside hydrolase family 3 (GH3). We expressed this GH3 in Escherichia coli and detected prunasin as a byproduct when cell lysates were cultured with amygdalin, supporting its contribution to amygdalin degradation. These findings demonstrate that both host and microbiota can act together to metabolize dietary plant metabolites. How amygdalin degradation into hydrogen cyanide affects bee health remains to be elucidated.

ecology↗