Biology subjects

Vidoudez, C.

Publications and source records attributed to Vidoudez, C..

11 recordsLinked to original sources

bioRxiv2026

Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells

Though cancer cells altered metabolism has been recognized for a century, the clinical success of metabolic targeting remains limited due to metabolic plasticity. Here, we use acute myeloid leukemia (AML) as a model to investigate this adaptability through combinatorial metabolic compound screening. Synthetic lethality emerged when AML cells were simultaneously treated with a glutaminase inhibitor and TOFA, a hypolipidemic agent. Sensitivity to this combination was also seen in primary patient samples and in other cancer types, while healthy hematopoietic progenitors were not affected. Unexpectedly, we discovered that TOFA acts through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain mitochondrial respiration upon glutaminolysis inhibition. Healthy cells in contrast have high intrinsic metabolic flexibility independent of S-acylation. Our results expose a unique mechanism of metabolic plasticity in cancer that could be targeted to enhance metabolic anti-cancer therapies.

cancer biology↗

bioRxiv2025

JNK signaling regulates reproductive trade-offs after Plasmodium infection in the malaria mosquito

Environmental stress can limit mammalian reproduction by affecting production of sexual steroid hormones. Here we reveal a similar mechanism in the malarial mosquito Anopheles gambiae: activation of the stress-sensitive c-Jun N-terminal kinase, JNK, constrains reproductive investment by suppressing production of ecdysteroids that orchestrate egg development in this species. We show that infection with Plasmodium berghei parasites increases JNK signalling in the reproductive tract causing a JNK-dependent reduction in both egg development and mosquito survival. Moreover, JNK signaling supresses expression of Cyp315a1 (AGAP000284), a rate-limiting enzyme in ecdysteroid synthesis, a transcriptional change reflected in reduced ecdysteroid production following an infected blood meal. A similar mechanism limits egg production under other stressors (heat stress, or ectopic activation of JNK signaling). Together, these data reveal a regulatory circuit whereby Plasmodium infection curtails reproductive investment in an important vector of human malaria, one that may be applicable to environmental stressors more generally.

zoology↗

bioRxiv2023

Interplay between nutrient transporters ensures fertility in the malaria mosquito Anopheles gambiae

Females from many mosquito species feed on blood to acquire nutrients for egg development. The oogenetic cycle has been characterized in the arboviral vector Aedes aegypti, where after a bloodmeal, the lipid transporter lipophorin (Lp) shuttles lipids from the midgut and fat body to the ovaries, and a yolk precursor protein, vitellogenin (Vg), is deposited into the oocyte by receptor-mediated endocytosis. Our understanding of how the roles of these two nutrient transporters are mutually coordinated is however limited in this and other mosquito species. Here, we demonstrate that in the malaria mosquito Anopheles gambiae, Lp and Vg are reciprocally regulated in a timely manner to optimize egg development and ensure fertility. Defective lipid transport via Lp silencing triggers abortive ovarian follicle development, leading to misregulation of Vg and aberrant yolk granules. Conversely, depletion of Vg causes an upregulation of Lp in the fat body in a manner that appears to be at least partially dependent on target of rapamycin (TOR) signaling, resulting in excess lipid accumulation in the developing follicles. Embryos deposited by Vg-depleted mothers are completely infertile, and are arrested early during development, likely due to severely reduced amino acid levels and protein synthesis. Our findings demonstrate that the mutual regulation of these two nutrient transporters is essential to safeguard fertility by ensuring correct nutrient balance in the developing oocyte, and validate Vg and Lp as two potential candidates for mosquito control. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/543516v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1c9b326org.highwire.dtl.DTLVardef@1109e59org.highwire.dtl.DTLVardef@c263borg.highwire.dtl.DTLVardef@1a1f9df_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Selection for insecticide resistance can promote Plasmodium falciparum infection in Anopheles

Insecticide resistance is under strong selective pressure in Anopheles mosquitoes due to widespread usage of insecticides in vector control strategies. Resistance mechanisms likely cause changes that profoundly affect mosquito physiology, yet it remains poorly understood how selective pressures imposed by insecticides may alter the ability of the mosquito to host and transmit a Plasmodium infection. From pyrethroid-resistant field-derived Anopheles gambiae s.l. mosquitoes, we performed selection experiments to establish resistant (RES) and susceptible (SUS) colonies by either selection for, or loss of, insecticide resistance. We show increased prevalence, intensity, and oocyst growth rate of Plasmodium falciparum infection in RES females compared to SUS. The increase in infection intensity in RES females was not associated with the presence of the kdrL1014F mutation, and was not impacted by inhibition of Cytochrome P450s. The lipid transporter lipophorin (Lp), which was upregulated in RES compared to SUS, was at least partly implicated in the increased intensity of P. falciparum but not directly in the insecticide resistance phenotype. Interestingly, we observed that although P. falciparum infections were not affected when RES females were exposed to permethrin, these females had decreased lipid abundance in the fat body following exposure, pointing to a possible role for lipid mobilization in response to damage caused by insecticide challenge. The finding that selection for insecticide resistance can increase P. falciparum infection intensities and growth rate reinforces the need to assess the overall impact on malaria transmission dynamics of selective pressures mosquitoes experience during repeated insecticide challenge. Significance StatementInsecticide resistance poses a severe threat for malaria control. Resistance to pyrethroid insecticides, the active component of most insecticide-treated nets, is now widespread in sub-Saharan Africa, reducing the efficacy of these crucial tools. Despite significant research characterizing insecticide resistance mechanisms, it remains unknown how these traits influence Plasmodium falciparum infections in malaria-transmitting Anopheles mosquitoes. We established a pyrethroid-resistant and pyrethroid-susceptible population of Anopheles gambiae derived from the same genetic background and performed experimental infections with P. falciparum. We found that the pyrethroid-resistant population was more supportive of malaria parasites compared to the susceptible population. This was not caused by well-known insecticide resistance mechanisms, but linked with a lipid transporter, lipophorin, which may play an indirect role in resistance.

molecular biology↗

bioRxiv2022

Tissue- and sex-specific DNA damage tracks aging in rodents and humans

DNA damage causes genomic instability underlying many human diseases. Traditional approaches to DNA damage analysis provide minimal insights into the spectrum of disease-driving DNA lesions and the mechanisms causing imbalances in damage formation and repair. Here we used untargeted mass spectrometry-based adductomics1 to discover 114 putative DNA lesions and modifications consistently detected in humans and two independent analyses in rats, showing species-, tissue-, age-, and sex-biases. As evidence of methodologic rigor, 10 selected adductomic signals were structurally validated as epigenetic marks: 5-MdC, 5-HMdC, 5-FdC; DNA damage products: N2-CMdG, 1,N6 {varepsilon}-dA, 3,N4-{varepsilon}dC, M1dG, O6/N2-MdG, and 8-Oxo-dG; and established analytical artifacts: cyclobutane dimers of 2-deoxycytosine. With steady-state levels of putative DNA adducts integrating multiple cell types in each tissue, there was strong age-dependent variation for many putative adducts, including N2-CMdG, 5-HMdC, and 8-Oxo-dG in rats and 1,N6 {varepsilon}-dA in human heart, as well as sex biases for 67 putative adducts in rat tissues. These results demonstrate the potential of untargeted adductomic analysis for defining DNA adducts as disease determinants, assigning substrates to DNA repair pathways, discovering new metabolically-driven DNA lesions, and quantifying inter-individual variation in DNA damage and repair across populations.

biochemistry↗

bioRxiv2020

Pumiliotoxin metabolism and molecular physiology in a poison frog

Poison frogs bioaccumulate alkaloids for chemical defense from their arthropod diet. Although many alkaloids are accumulated without modification, some poison frog species can metabolize pumiliotoxin (PTX 251D) into the more potent allopumiliotoxin (aPTX 267A). Despite extensive research characterizing the chemical arsenal of poison frogs, the physiological mechanisms involved in the sequestration and metabolism of individual alkaloids remain unclear. We first performed a feeding experiment with the Dyeing poison frog (Dendrobates tinctorius) to ask if this species can metabolize PTX 251D into aPTX 267A and what gene expression changes are associated with PTX 251D exposure in the intestines, liver, and skin. We found that D. tinctorius can metabolize PTX 251D into aPTX 267A, and that PTX 251D exposure changed the expression level of genes involved in immune system function and small molecule metabolism and transport. To better understand the functional significance of these changes in gene expression, we then conducted a series of high-throughput screens to determine the molecular targets of PTX 251D and identify potential proteins responsible for metabolism of PTX 251D into aPTX 267A. Although screens of PTX 251D binding human voltage-gated ion channels and G-protein coupled receptors were inconclusive, we identified human CYP2D6 as a rapid metabolizer of PTX 251D in a cytochrome P450 screen. Furthermore, a CYP2D6-like gene had increased expression in the intestines of animals fed PTX, suggesting this protein may be involved in PTX metabolism. These results show that individual alkaloids can modify gene expression across tissues, including genes involved in alkaloid metabolism. More broadly, this work suggests that specific alkaloid classes in wild diets may induce physiological changes for targeted accumulation and metabolism.

physiology↗

bioRxiv2019

Microstructures amplify seemingly honest signals in carotenoid-colored tanagers

Red, orange, and yellow carotenoid-colored plumages have been considered honest signals of condition. We comprehensively quantified carotenoid signals in the social, sexually-dimorphic tanager genus Ramphocelus using scanning electron microscopy (SEM), finite-difference time-domain (FDTD) optical modeling, liquid chromatography-mass spectrometry (LC-MS), and spectrophotometry. Despite males having significantly more saturated color patches, males and females within a species have equivalent amounts and types of carotenoids. Male, but not female, feathers have elaborate microstructures which amplify color appearance. Expanded barbs enhance color saturation (for the same amount of pigment) by increasing the transmission of optical power through the feather. Dihedral barbules (vertically-angled, strap-shaped barbules) reduce total reflectance to generate "super black" plumage, an optical illusion to enhance nearby color. Dihedral barbules paired with red carotenoid pigment produce "velvet red" plumage. Together, our results suggest that a widely cited index of honesty--carotenoid pigments--cannot fully explain male appearance. We propose that males are selected to evolve amplifiers of honest signals--in this case, microstructures that enhance appearance --that are not necessarily themselves linked to quality.

evolutionary biology↗

bioRxiv2019

Land use impacts poison frog chemical defenses through changes in leaf litter ant communities

Much of the worlds biodiversity is held within tropical rainforests, which are increasingly fragmented by agricultural practices. In these threatened landscapes, there are many organisms that acquire chemical defenses from their diet and are therefore intimately connected with their local food webs. Poison frogs (Family Dendrobatidae) are one such example, as they acquire alkaloid-based chemical defenses from their diet of leaf litter ants and mites. It is currently unknown how habitat fragmentation impacts chemical defense across trophic levels, from arthropods to frogs. We examined the chemical defenses and diets of the Diablito poison frog (Oophaga sylvatica), and the diversity of their leaf litter ant communities in secondary forest and reclaimed cattle pasture. Notably, this research was performed in collaboration with two high school science classrooms. We found that the leaf litter of forest and pasture frog habitats differed significantly in ant community structure. We also found that forest and pasture frogs differed significantly in diet and alkaloid profiles, where forest frogs contained more of specific alkaloids and ate more ants in both number and volume. Finally, ant species composition of frog diets resembled the surrounding leaf litter, but diets were less variable. This suggests that frogs tend to consume particular ant species within each habitat. To better understand how ants contribute to the alkaloid chemical profiles of frogs, we chemically profiled several ant species and found some alkaloids to be common across many ant species while others are restricted to a few species. At least one alkaloid (223H) found in ants from disturbed sites was also found in skins from pasture. Our experiments are the first to link anthropogenic land use changes to dendrobatid poison frog chemical defenses through variation in leaf litter communities, which has implications for conservation management of these threatened amphibians.

ecology↗

bioRxiv2019

Mechanisms of convergent egg-provisioning in poison frogs

Parental provisioning of offspring with physiological products occurs in many animals. Within amphibians, maternal provisioning has evolved multiple times, including in South American dendrobatid and Malagasy mantellid poison frogs. In some of these species, mothers feed unfertilized eggs to their developing tadpoles for several months until tadpoles complete metamorphosis. We conducted field studies in Ecuador and Madagascar to ask whether convergence at the behavioral level provides similar benefits to offspring and whether nursing behavior relies on shared neural mechanisms across frogs and vertebrates more broadly. At an ecological level, we found that nursing allows poison frog mothers to provide chemical defenses to their tadpoles in both species. At the level of brain regions, nursing behavior was associated with increased neural activity in the lateral septum and preoptic area in both species, demonstrating recruitment of shared brain regions in the convergent evolution of maternal care within frogs and across vertebrates. In contrast at a molecular level, only mantellids showed increased oxytocin neuron activity akin to that in nursing mammals. Taken together, our findings demonstrate that convergently evolved maternal provisioning behavior provides similar benefits to offspring and relies on similar brain regions. However, the molecular mechanisms underlying the convergence in nursing behavior may be different, suggesting evolutionary versatility in the mechanisms promoting maternal behavior.

neuroscience↗

bioRxiv2019

Molecular physiology of chemical defenses in a poison frog

Poison frogs sequester small molecule lipophilic alkaloids from their diet of leaf litter arthropods for use as chemical defenses against predation. Although the dietary acquisition of chemical defenses in poison frogs is well-documented, the physiological mechanisms of alkaloid sequestration has not been investigated. Here, we used RNA sequencing and proteomics to determine how alkaloids impact mRNA or protein abundance in the Little Devil Frog (Oophaga sylvatica) and compared wild caught chemically defended frogs to laboratory frogs raised on an alkaloid-free diet. To understand how poison frogs move alkaloids from their diet to their skin granular glands, we focused on measuring gene expression in the intestines, skin, and liver. Across these tissues, we found many differentially expressed transcripts involved in small molecule transport and metabolism, as well as sodium channels and other ion pumps. We then used proteomic approaches to quantify plasma proteins, where we found several protein abundance differences between wild and laboratory frogs, including the amphibian neurotoxin binding protein saxiphilin. Finally, because many blood proteins are synthesized in the liver, we used thermal proteome profiling as an untargeted screen for soluble proteins that bind the alkaloid decahydroquinoline. Using this approach, we identified several candidate proteins that interact with this alkaloid, including saxiphilin. These transcript and protein abundance patterns suggest the presence of alkaloids influences frog physiology and that small molecule transport proteins may be involved in toxin bioaccumulation in dendrobatid poison frogs.\n\nResumenLas ranas venenosas obtienen moleculas lipofilicas a partir de su dieta de artropodos que luego usan como una defensa quimica contra depredadores. Mientras que la acumulacion de toxinas dieteticas ha sido bien documentada, el mecanismo fisiologico de obtencion de alcaloides no ha sido investigado. En este estudio usamos secuenciacion de RNA y proteomica para determinar como la presencia de alcaloides afecta la abundancia de mRNA y proteinas en ranas diablito (Oophaga sylvatica) silvestres con defensas quimicas en comparacion a ranas diablito criadas en laboratorio con una dieta sin alcaloides. Para entender como las ranas venenosas mueven los alcaloides de su dieta a las glandulas granulares en su piel, nos enfocamos en medir la expresion de genes en tres tejidos: intestinos, piel e higado. En estos tejidos, encontramos varios transcriptomas regulados diferencialmente que tienen actividades involucradas con el transporte y metabolismo de pequenas moleculas, ademas de canales de sodio y bombas de iones. Luego usamos metodos proteomicos para cuantificar proteinas en plasma, donde encontramos varias diferencias en abundancia de proteinas entre las ranas silvestres y de laboratorio, incluyendo la proteina anfibia de fijacion de toxinas, saxifilina. Finalmente, debido a que muchas proteinas encontradas en la sangre se sintetizan en el higado, usamos la tecnica de perfilacion proteomica termal para seleccionar imparcialmente las proteinas solubles que fijan el alcaloide decahydroquinolina. Usando este metodo, identificamos varias posibles proteinas que interactuan con este alcaloide, incluyendo saxifilina. Estos patrones de cambios en abundancia de transcriptomas y proteinas en ranas con y sin defensas quimicas sugieren que la presencia de alcaloides influye en la fisiologia de las ranas y que moleculas proteicas pequenas de transporte podrian estar involucradas en la bioacumulacion de toxinas en ranas venenosas dendrobatidos.\n\nSummary StatementChemically defended wild poison frogs have gene expression and protein abundance differences across several tissue systems compared to poison frogs reared on an alkaloid-free diet.

physiology↗

bioRxiv2018

Seasonal changes in diet and toxicity in the Climbing Mantella frog (Mantella laevigata)

Poison frogs acquire chemical defenses from the environment for protection against potential predators. These defensive chemicals are lipophilic alkaloid toxins that are sequestered by poison frogs from dietary arthropods and stored in skin glands. Despite decades of research focusing on identifying poison frog toxins, we know relatively little about how environmental variation and subsequent arthropod availability impacts toxicity in poison frogs. We investigated how seasonal environmental variation influences poison frog toxin profiles through changes in the diet of the Climbing Mantella (Mantella laevigata). We collected M. laevigata females on the Nosy Mangabe island reserve in Madagascar during the wet and dry seasons and tested the hypothesis that seasonal differences in rainfall is associated with changes in the diet and skin toxin profiles of M. laevigata. The arthropod diet of each frog was characterized into five groups (i.e. ants, termites, mites, insect larvae, or other) using visual identification and cytochrome oxidase 1 DNA barcoding. We found that frog diet differed between the wet and dry seasons, where frogs had a more diverse diet in the wet season and consumed a higher percentage of ants in the dry season. To determine if seasonality was associated with variation in frog defensive chemical composition, we used gas chromatography / mass spectrometry to quantify toxins from individual skin samples. Although the assortment of identified toxins was similar across seasons, we detected significant differences in the abundance of certain alkaloids, which we hypothesize reflects seasonal variation in the diet of M. laevigata. We suggest that these variations could originate from seasonal changes in either arthropod leaf litter composition or changes in frog behavioral patterns. Although additional studies are needed to understand the consequences of long-term environmental shifts, this work suggests that toxin profiles are relatively robust against short-term environmental perturbations.

ecology↗