Biology subjects

Fournier, A.

Publications and source records attributed to Fournier, A..

6 recordsLinked to original sources

bioRxiv2025

Fecal proteomics of wild capuchins reveals impacts of season, diet, age, and, sex on gut physiology

Understanding how the physiology of free-ranging mammals is impacted by environmental stressors is a major focus of ecological research. However, the constraints of non-invasive sampling pose serious challenges to the acquisition of physiological data from most species of primates. As a result, little is known about how the gut responds to ecological stimuli at the cellular level in wild populations. Recent research has demonstrated that proteomics could fill this knowledge gap by sequencing and quantifying proteins directly from primate feces. In order to ascertain how the gut of free-ranging white-faced capuchin monkeys (C. imitator) is influenced by environmental heterogeneity, diet, age, and sex, we sequenced 45 fecal proteomes from 24 individuals from the Sector Santa Rosa population in Costa Rica, using liquid chromatography-tandem mass spectrometry with label-free quantification. Fecal proteins assigned to C. imitator were strongly localized to gut tissues and functionally enriched for digestive and immune functions. We identified 41 capuchin candidate proteins linked to seasonality, age, sex, and diet. We also quantified abundances of dietary fruit, dietary insects, helminth gut parasites, and gut microbes. Our results demonstrate the viability of using quantitative fecal proteomics in free-ranging populations of mammals to integrate host physiology, diet, and microbial ecology through non-invasive means.

ecology↗

bioRxiv2024

Uncovering immune characteristics of neurons in the context of multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an immune-mediated disease characterized by chronic inflammation and damage to the central nervous system, and substantial characterization of molecular signatures of glial and immune cells in the disease has been conducted. However, comparatively less well characterized is the molecular signature of pathologically inflamed neurons. Here, we accessed multi-omic high-throughput transcriptomic and epigenomic data to investigate the molecular signature of neurons from progressive MS patients and from mice subjected to experimental autoimmune encephalomyelitis (EAE). Our results indicate a shared and consistent neuronal gene expression signature in MS and EAE samples including a notable upregulation of immune system related genes and processes. Analysis of immune-enriched pathways in retinal ganglion cells (RGCs) and motor neurons from mice subjected to EAE revealed enrichment for the major histocompatibility complex class I pathway and interferon response genes in both types of neurons, and ATAC-seq analysis confirmed the accessibility of these genes. Parallel analyses of neurons from MS patients identified a signature of 48 commonly upregulated immune genes in neurons. Prediction of transcriptional regulators of these genes identified key upstream regulators including signal transducer and activation of transcription 1 (STAT1) and interferon response factor 5 (IRF5), highly involved in immune-related processes, with significant gene expression changes in both RGCs and motor neurons. Protein-protein interaction analyses among the transcriptional regulators unveiled intricate interactions among transcription factors, especially from the IRF and STAT families, suggesting their importance in regulating immune gene expression in inflamed neurons. Small molecule inhibition of IRF5 in inflamed neurons in vitro promoted cell survival and reduced the expression of the immune gene signature, supporting the biological relevance of IRF5 in mediating the neuronal inflammatory response. Together, this study identifies regulated immune processes in neurons from EAE mice and from MS patient samples suggesting potential roles for neuronal immune molecules in disease progression, as revealed by transcriptomic, epigenomic, and experimental approaches. Further, the results strongly implicate active interferon signaling in neurons driving immune related changes in gene expression through IRF5 and STAT1 transcription factor activity, potentially impacting downstream neuronal survival through IRF5 activity.

neuroscience↗

bioRxiv2024

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis.

The role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Here, the effect of a bioinformatically-rationalized senolytic was tested in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). Single-cell analysis from brain tissue isolated from mice subjected to EAE identified microglia with a strong senescence signature including the presence of BCL2-family member transcripts. Cells expressing Bcl2l1 had higher expression of pro-inflammatory and senescence genes than their negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were strongly enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune related genes suggesting they may contribute to the active lesion pathology and tissue damage in chronic active lesions. Employing a small molecule BCL2 inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice, decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. Together, these results provide evidence to support the idea that senescent glia may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease and that removing them may ameliorate disease.

neuroscience↗

bioRxiv2022

Spatial Scale of Non-Target Effects of Cotton Insecticides

Plot size is of practical importance in any integrated pest management (IPM) study that has a field component. Such studies need to be conducted at a scale relevant to species dynamics because their abundance and distribution in plots might vary according to plot size. An adequate plot size is especially important for researchers, technology providers and regulatory agencies in understanding effects of various insect control technologies on non-target arthropods. Plots that are too small might fail to detect potential harmful effects of these technologies due to arthropod movement and redistribution among plots, or from untreated areas and outside sources. The Arizona cotton system is heavily dependent on technologies for arthropod control, thus we conducted a 2-year replicated field experiment to estimate the optimal plot size for non-target arthropod studies in our system. Experimental treatments consisted of plot sizes and insecticides in a full factorial. We established three plot sizes that measured 144 m2, 324 m2 and 576 m2. For insecticides, we established an untreated check, a positive control insecticide with known negative effects on the arthropod community and a selective insecticide. We investigated how plot size impacts the estimation of treatment effects relative to community structure (27 taxa), community diversity, individual abundance, effect sizes, biological control function and success of arthropod taxa with a wide range of mobility, including Collops spp., Orius tristicolor, Geocoris spp., Misumenops celer, Drapetis nr. divergens and Chrysoperla carnea. The 144 m2 plots supported similar results for all parameters compared to larger plots, thus being sufficiently large to measure insecticidal effects on non-target arthropods in Arizona cotton. Though results might be system-specific, they point to a scale of testing that should be considered when developing any IPM guidelines, especially for systems that share a similar fauna of predators and pests.

ecology↗

bioRxiv2020

Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands

Over the last decade, the urotensinergic system has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases and also cancer. Significant investment toward the development of clinically relevant UT ligands for therapeutic intervention has been made but have met little to no success to date. The UT system, which has yet to be effectively targeted, therefore remains to be therapeutically exploited. The discovery of allosteric sites that allow modulation of receptor activity will increase the searchable chemical space against a disease-relevant target. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics. Therefore, pepducins derived from the human urotensin II receptor might represent unique tools to generate signaling bias and study UT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of UT, respectively, have been synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp1, Leu2]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and to a lesser extent, IP1 production, stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate hUII- and URP-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue to design allosteric ligands selectively targeting UT signaling that could prove to be useful for the treatment of hUT-associated diseases.

pharmacology and toxicology↗

bioRxiv2018

MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and neurodegeneration in the brain, spinal cord and optic nerve. Neuronal degeneration and death underlie progressive forms of MS and cognitive dysfunction. Neuronal damage is triggered by numerous harmful factors in the brain that engage diverse signalling cascades in neurons thus therapeutic approaches to protect neurons will need to focus on agents that can target broad biological processes. To target the broad spectrum of signaling events that mediate neurodegeneration in MS we have focused on non-coding small microRNAs (miRNAs). microRNAs are epigenetic regulators of protein expression, targeting messenger RNAs (mRNAs) and inhibiting their translation. Dysregulation of miRNAs has been described in many neurodegenerative diseases including MS. In this study we identified two miRNAs, miR-223-3p and miR-27a-3p, that were upregulated in neurons in the experimental autoimmune encephalomyelitis (EAE) mouse model of CNS inflammation and in active MS lesions. Overexpression of miR-27a-3p or miR-223-3p protected dissociated cortical neurons from degeneration in response to peripheral blood mononuclear cell conditioned media (PBMC-CM). Introduction of miR-223-3p in vivo in mouse retinal ganglion cells (RGCs) protected RGC axons from degeneration in the EAE model. By in silico analysis we found that mRNAs in the glutamate receptor (GluR) pathway are enriched in miR-27a-3p and miR-223-3p targets. Antagonism of the GluR pathway protected neurons from PBMC-CM-dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by downregulating mRNAs involved in GluR signalling.

neuroscience↗