Master regulators of biological systems in higher dimensions

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(51)

Published: Dec. 14, 2023

A longstanding goal of biology is to identify the key genes and species that critically impact evolution, ecology, health. Network analysis has revealed keystone regulate ecosystems master regulators cellular genetic networks. Yet these studies have focused on pairwise biological interactions, which can be affected by context background other present, generating higher-order interactions. The important interactions are unstudied. To address this, we applied a high-dimensional geometry approach quantifies epistasis in fitness landscape ask how individual influence rest network. We then generated also reanalyzed 5-dimensional datasets (two genetic, two microbiome). identified (e.g., rbs locus pykF) Lactobacilli) control many species. These induce or suppress evolutionary ecological diversification controlling topography landscape. Thus, provide method mathematical justification for exploration networks higher dimensions.

Language: Английский

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Ageing leads to reduced specificity of antimicrobial peptide responses in Drosophila melanogaster

Proceedings of the Royal Society B Biological Sciences, Journal Year: 2022, Volume and Issue: 289(1987)

Published: Nov. 16, 2022

Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to deregulations immune system. A potential outcome such is inability produce specific immunity against target pathogens. We tested this possibility by infecting multiple Drosophila melanogaster lines (with bacterial pathogens) across age groups, where either individual or different combinations Imd- and Toll-inducible antimicrobial peptides (AMPs) were deleted using CRISPR gene editing. show high degree non-redundancy pathogen-specificity AMPs young flies: some cases, even single AMP could confer complete resistance. However, ageing led drastic reductions specificity pathogens, warranting action Imd Toll pathways. Moreover, use diverse lacked survival benefits accompanied costs post-infection. These features also sexually dimorphic: females required larger repertoire than males but extracted equivalent benefits. Finally, age-specific expansion AMP-repertoire was with ageing-induced downregulation negative-regulators pathway damage renal function post-infection, as poorly regulated immunity. Overall, we highlight potentially non-adaptive role producing less-specific responses, sexes

Language: Английский

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Ageing leads to nonspecific antimicrobial peptide responses in Drosophila melanogaster

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: June 28, 2022

ABSTRACT Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to deregulations immune system. A potential outcome such immune-deregulation is inability produce specific immunity against target pathogens. We tested this possibility by infecting multiple Drosophila melanogaster lines (with bacterial pathogens) across age-groups, where either individual or different combinations Imd- and Toll-inducible antimicrobial peptides (AMPs) were deleted using CRISPR gene editing. show high degree non-redundancy pathogen-specificity AMPs young flies: some cases, even single AMP could confer complete resistance. In contrast, ageing led loss specificity, warranting action Toll-pathways during infections. Moreover, use diverse had no survival benefits, accompanied costs post-infection. These features also sexually dimorphic: females expressed larger repertoire than males, but extracted equivalent benefits. Finally, age-specific expansion AMP-pool was associated with downregulation negative-regulators Imd-pathway damage renal function, as poorly-regulated immunity, Overall, we establish an important driver nonspecific responses, sexes

Language: Английский

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Insect Models in Nutrition Research

Biomolecules, Journal Year: 2022, Volume and Issue: 12(11), P. 1668 - 1668

Published: Nov. 11, 2022

Insects are the most diverse organisms on earth, accounting for ~80% of all animals. They valuable as model organisms, particularly in context genetics, development, behavior, neurobiology and evolutionary biology. Compared to other laboratory animals, insects advantageous because they inexpensive house breed large numbers, making them suitable high-throughput testing. also have a short life cycle, facilitating analysis generational effects, fulfil 3R principle (replacement, reduction refinement). Many insect genomes now been sequenced, highlighting their genetic physiological similarities with humans. These factors make favorable whole-animal models nutritional research. In this review, we discuss impact science, focusing studies investigating role nutrition metabolic diseases aging/longevity. We consider food toxicology use study gut microbiome. The benefits relationship between biological markers fitness longevity can be exploited improve human health.

Language: Английский

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Drosophila melanogaster Systemic Infection Model to Study Altered Virulence during Polymicrobial Infection by Aeromonas

Pathogens, Journal Year: 2023, Volume and Issue: 12(3), P. 405 - 405

Published: March 2, 2023

Polymicrobial infections are complex associated with worse outcomes compared to monomicrobial infections. We need simple, fast, and cost-effective animal models assess their still poorly known pathogenesis.We developed a Drosophila melanogaster polymicrobial infection model for opportunistic pathogens assessed its capacity discriminate the effects of bacterial mixtures taken from cases human by Aeromonas strains. A systemic was obtained needle pricking dorsal thorax flies, fly survival monitored over time. Different lineages flies were infected single strain or paired strains (strain ratio 1:1).Individual killed more than 80% in 20 h. The course could be altered microbial mix. distinguish between diverse (synergistic, antagonistic, no difference) that resulted milder, severe, similar infection, depending on considered. then investigated determinants effects. maintained deficient main signaling pathways (Toll IMD deficient), which suggests an active microbe/microbe/host interaction.These results indicate D. is consistent study infection.

Language: Английский

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Geroprotection from ergothioneine treatment in Drosophila melanogaster by improving intestinal barrier and activation of intestinal autophagy

Deleted Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

Ergothioneine is a natural amino acid with powerful antioxidant activity. Previous studies have demonstrated that ergothioneine can increase the lifespan of Drosophila melanogaster and Caenorhabditis elegans, and enhance telomerase In present study, metagenomics sequencing qRT-PCR analysis were employed to characterize composition diversity gut microbiome in aging flies. And alterations barrier, morphology, other physiological indicators flies evaluated. Here, results showed EGT induced little variations microbiota at mid-life, significant populations only observed late-life. attenuated age-related injuries, including decreasing reactive oxygen species levels intestinal enterocytes, reduction cells death, preservation integrity also improved morphology by preserving structure shape cell organelles inducing autophagy. activation autophagy contributed longevity effect mediated an unidentified mechanism.

Language: Английский

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Astragalus membranaceus Extract Prevents Calcium Oxalate Crystallization and Extends Lifespan in a Drosophila Urolithiasis Model

Life, Journal Year: 2022, Volume and Issue: 12(8), P. 1250 - 1250

Published: Aug. 16, 2022

Approximately 1 in 20 people develops kidney stones at some point their life. Although the surgical removal of is common, recurrence rate remains high and it therefore important to prevent occurrence stones. We chose Astragalus membranaceus (AM), which a traditional Chinese medicine, study prevention urolithiasis using Drosophila model based on our previous screening herbs. Wild-type melanogaster Canton-S adult fruit flies were used this study. Ethylene glycol (EG, 0.5%) was added food as lithogenic agent. The positive control agent (2% potassium citrate (K-citrate)) then compared with AM (2, 8, 16 mg/mL). After 21 days, sacrificed under carbon dioxide narcotization, Malpighian tubules dissected, removed, processed for polarized light microscopy examination observe calcium oxalate (CaOx) crystallization. Then, ex vivo dissolution crystals between K-citrate AM. Survival analysis EG, K-citrate, groups also performed. Both 2% (16 mg/mL) significantly inhibited EG-induced CaOx crystal formation. Mean lifespan reduced by administration results reversed (8 groups. However, extract did not directly dissolve vivo. In conclusion, decreased ratio crystallization ameliorated reduction lifespan. prevented formation model.

Language: Английский

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Intake of caffeine containing sugar diet remodels gut microbiota and perturbs Drosophila melanogaster immunity and lifespan

Microbes and Infection, Journal Year: 2023, Volume and Issue: 25(7), P. 105149 - 105149

Published: May 9, 2023

Language: Английский

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Recurrent Phases of Strict Protein Limitation Inhibit Tumor Growth and Restore Lifespan in A Drosophila Intestinal Cancer Model

Aging and Disease, Journal Year: 2023, Volume and Issue: 15(1), P. 226 - 226

Published: Oct. 19, 2023

Diets that restrict caloric or protein intake offer a variety of benefits, including decreasing the incidence cancer. However, whether such diets pose substantial therapeutic benefit as auxiliary cancer treatments remains unclear. We determined effects severe depletion on tumorigenesis in Drosophila melanogaster intestinal tumor model, using human RAF gain-of-function allele. Severe and continuous restriction significantly reduced growth but resulted premature death. Therefore, we developed diet which short periods alternated cyclically with complete feeding. This nutritional regime mass, restored gut functionality, rescued lifespan oncogene-expressing flies to levels observed healthy continuous, fully nutritious diet. Furthermore, this chemotherapy-induced stem cell activity associated recurrence. Transcriptome analysis revealed long-lasting changes expression key genes involved multiple major developmental signaling pathways. Overall, data suggest recurrent effectively mimics health benefits restriction, without undesired shortcomings. provides seminal insights into mechanisms memory effect required maintain positive throughout phases full Finally, repetitive form strict is an ideal strategy for adjuvant therapy useful many contexts.

Language: Английский

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Antimicrobial peptides do not directly contribute to aging inDrosophila, but improve lifespan by preventing dysbiosis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 25, 2022

Abstract Antimicrobial peptides (AMPs) are innate immune effectors first studied for their role in host defense against bacterial and fungal infections. Recent studies have implicated these the clearance of aberrant cells various neurological processes including neurodegenerative syndromes. In Drosophila , an array AMPs produced downstream Toll Imd NF-κB pathways response to infection. Many suggested a pathway aging this insect, supported by upregulation with (so-called “inflammaging”). However, functional using RNAi or over-expression been inconclusive on whether how impact aging. Leveraging new set single compound AMP gene deletions controlled genetic background, we investigated contribute Overall, found no major effect individual lifespan, possible exception Defensin . ΔAMP14 flies lacking 14 genes from seven families display reduced lifespan. Interestingly, increased load food medium aged flies, suggesting that lifespan reduction was due failure controlling microbiome. Consistent idea, use germ-free conditions extends flies. our results do not point overt Instead, find collectively preventing dysbiosis over This is consistent previous study showing control gut microbiome, many works detrimental upon course experiments, also uncovered strong nora virus infection share experience reconciling data given confounding cryptic factor.

Language: Английский

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