Biology subjects

Foley, A.

Publications and source records attributed to Foley, A..

5 recordsLinked to original sources

bioRxiv2024

Systemic extracellular acidification is a hallmark of aging

Understanding the critical pathophysiological processes that promote age-related disease is needed to uncover effective targets for preventive medicine. Here, we investigate how extracellular pH changes with age and its impact on longevity, using fly and mouse models. We find that extracellular acidification occurs in flies during aging and correlates to mortality rate. With age, flies also become more susceptible to die from acidotic stress, which can be prevented by alkalotic treatment. Acidification is caused by insufficient acid elimination, linked to downregulation of genes in the fly excretory tract that control pH and ATP production, essential for active secretion initiation. In mice, we show that lymph-drained interstitial fluids acidify with age. Expression of genes, whose pathogenic loss-of-function variants cause tubular acidosis in humans, is decreased in the kidneys of aging mice. Overall, this study sheds light on dysregulated systemic acid-base balance as a conserved pathophysiological mechanism of aging.

physiology↗

bioRxiv2021

Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Mutations in SET binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging pre-clinical data for the use of trametinib in SETBP1-mutant disease.

cancer biology↗

bioRxiv2019

Enhancing autophagy by redox regulation extends lifespan in Drosophila

Dysregulation of redox homeostasis has been implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2 in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in flies. As anticipated, these flies were strongly resistant to a range of oxidative stress challenges, but interestingly were sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan upon catalase up-regulation, as the survival benefits were completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.

molecular biology↗

bioRxiv2019

Identifying Clostridioides difficile-inhibiting gut commensals using culturomics, phenotyping, and combinatorial community assembly

A major function of the gut microbiota is to provide colonization resistance, wherein pathogens are inhibited or suppressed below infectious level. However, the fraction of gut microbiota required for colonization resistance remains unclear. We used culturomics to isolate a gut microbiota culture collection comprising 1590 isolates belonging to 102 species. Estimated by metagenomic sequencing of fecal samples used for culture, this culture collection represents 50.73% of taxonomic diversity and 70% functional capacity. Using whole genome sequencing we characterized species representatives from this collection, and predicted their phenotypic traits, further characterizing isolates by defining nutrient utilization profile and short chain fatty acid (SCFA) production. When screened using a co-culture assay, 66 species in our culture collection inhibited C. difficile. Several phenotypes, particularly, growth rate, production of SCFAs, and the utilization of mannitol, sorbitol or succinate correlated with C. difficile inhibition. We used a combinatorial community assembly approach to formulate defined bacterial mixes inhibitory to C. difficile. When 256 combinations were tested, we found both species composition and blend size to be important in inhibition. Our results show that the interaction of bacteria with each other in a mix and with other members of gut commensals must be investigated for designing defined bacterial mixes for inhibiting C. difficile in vivo.\n\nIMPORTANCEAntibiotic treatment causes instability of gut microbiota and the loss of colonization resistance, allowing pathogens such as C. difficile to colonize, causing recurrent infection and mortality. Although fecal microbiome transplantation has shown to be an effective treatment for C. difficile infection (CDI), a more desirable approach would be the use of a defined mix of inhibitory gut bacteria. C. difficile-inhibiting species and bacterial combinations we identify herein improve our understanding of the ecological interactions controlling colonization resistance against C. difficile, and could aid the design of defined bacteriotherapy as a non-antibiotic alternative against CDI.

microbiology↗

bioRxiv2019

Myeloid Lineage Enhancers Drive Oncogene Synergy in CEBPA/CSF3R Mutant Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. This finding of mutation-synergy is broadly applicable other mutations that activate the JAK/STAT pathway or disrupt CEBPA function (i.e. activating mutations in JAK3 and Core Binding Factor translocations). The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation, confirming predictions from clinical sequencing data. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.

cancer biology↗