Biology subjects

Ibanez, S.

Publications and source records attributed to Ibanez, S..

13 recordsLinked to original sources

bioRxiv2026

Acidosis-triggered fatty acid overload induces endothelial cell dysfunction.

Vascular ischemia is characterized not only by hypoxia but also by acidosis, which affects endothelial cells (ECs) due to increased H+ production from glycolysis and a deficit in H+ washout. We recently documented that an acidic environment facilitates the flip-flop transport of the non-ionized form of fatty acids (FAs) across the plasma membrane of cancer cells. In this study, we investigated how acidosis influences the capacity of highly glycolytic ECs to manage FAs and participates to endothelial dysfunction. We first tracked lipid droplet (LD) formation using Oil Red O staining and holotomographic microscopy. Purified monounsaturated oleate but also a mixture of FAs that reflect in vivo serum composition, resulted in dose- and time-dependent LD accumulation through FA transporter-independent mechanisms. Acid-exposed ECs exhibited enhanced mitochondrial respiration fueled by FAs, and endoplasmic reticulum (ER) stress, as indicated by the expression of ATF4 and CHOP. This phenotype was further associated with elevated reactive oxygen species production, which correlated with reduced nitric oxide (NO) availability. FA removal from EC culture media promoted lipolysis from LDs, supported by ATGL lipase induction which however slowed under acidic conditions. While ER stress persisted upon FA washout, NO availability was restored to levels comparable to those in FA-unexposed ECs. This observation coincided with dynamic mobilization of antioxidant defenses in acid-exposed ECs, as evidenced by low levels of reduced glutathione and enhanced cystine uptake, alongside a decrease in carnitine and FA-fueled mitochondrial respiration. Collectively, these data underscore the vulnerability of ECs to passive FA capture promoted by local acidosis, thereby contributing to a silent source of endothelial dysfunction in the postprandial state or during chronic exposure to elevated lipid levels.

cell biology↗

bioRxiv2025

UCL-MetIsoLib: A Public High-Resolution Tandem Mass Spectrometry Library for HILIC-Based Isomer-Resolved Profiling of Glycolysis, Central Carbon Metabolism, and Beyond in Urine, Plasma, Tissues, Cells, and Patient-Derived Organoids

We present UCL-MetIsoLib, a publicly accessible high-resolution tandem mass spectrometry (HRMS/MS) library developed for HILIC-based, ion-pairing free, isomer-resolved metabolomics using a bioinert UHPLC system and the Acquity Premier BEH Amide column. The platform integrates two complementary methods operating under distinct chromatographic conditions (pH 3.5, ESI+; pH 11.0, ESI-), enabling broad metabolic coverage. A total of 334 metabolites are annotated in the library structure, with thiol derivatization incorporated into the extraction protocol to mitigate redox-driven artifacts. Metabolite identification is supported by 245 authentic reference standards and curated according to MSI Level 1 and Level 2 criteria. Validation followed FDA guidelines for bioanalytical method validation and was performed across five biological matrices--urine, plasma, tissues, cultured cells, and patient-derived colorectal organoids--with a U-13C, U-15N-labeled Amino Acid Mixture used as an isotope labeled internal standard. The method demonstrated high precision (<15% RSD intra-/inter-day) and recovery (85-115% across all QC levels). To demonstrate biological applicability, UCL-MetIsoLib was applied to a case study comparing healthy and colorectal cancer-derived organoids. The method enabled confident annotation of metabolite isomers, including key glycolytic intermediates such as DHAP and GA3P, as well as sugar phosphates from the glycolysis and pentose phosphate pathways. Metabolic alterations were observed in tumor organoids, including accumulation of nucleotide derivatives and shifts in central carbon metabolism. These findings emphasize the value of isomer-resolved spectral libraries in detecting biologically meaningful differences that are often missed in conventional untargeted metabolomics workflows.

systems biology↗

bioRxiv2023

Myelin dystrophy in the aging prefrontal cortex leads to impaired signal transmission and working memory decline: a multiscale computational study

Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

neuroscience↗

bioRxiv2023

Is adaptive foraging adaptive? A resource-consumer eco-evolutionary model.

Phenotypic plasticity has important ecological and evolutionary consequences. In particular, behavioural phenotypic plasticity such as adaptive foraging (AF) by consumers, may enhance community stability. Yet little is known about the ecological conditions that favor the evolution of AF, and how the evolutionary dynamics of AF may modulate its effects on community stability. In order to address these questions, we constructed an eco-evolutionary model in which resource and consumer niche traits underwent evolutionary diversification. Consumers could either forage randomly, only as a function of resources abundance, or adaptatively, as a function of resource abundance, suitability and consumption by competitors. AF evolved when the niche breadth of consumers with respect to resource use was large enough and when the ecological conditions allowed substantial functional diversification. In turn, AF promoted further diversification of the niche traits in both guilds. This suggests that phenotypic plasticity can influence the evolutionary dynamics at the community-level. Faced with a sudden environmental change, AF promoted community stability directly and also indirectly through its effects on functional diversity. However, other disturbances such as persistent environmental change and increases in mortality, caused the evolutionary regression of the AF behaviour, due to its costs. The causal relationships between AF, community stability and diversity are therefore intricate, and their outcome depends on the nature of the environmental disturbance, in contrast to simpler models claiming a direct positive relationship between AF and stability.

ecology↗

bioRxiv2023

Neuronal properties of pyramidal cells in lateral prefrontal cortex of the aging rhesus monkey brain are associated with performance deficits on spatial working memory but not executive function.

Age-related declines in cognitive abilities occur as early as middle-age in humans and rhesus monkeys. Specifically, performance by aged individuals on tasks of executive function (EF) and working memory (WM) is characterized by greater frequency of errors, shorter memory spans, increased frequency of perseverative responses, impaired use of feedback and reduced speed of processing. However, how aging precisely differentially impacts specific aspects of these cognitive functions and the distinct brain areas mediating cognition are not well understood. The prefrontal cortex (PFC) is known to mediate EF and WM and is an area that shows a vulnerability to age-related alterations in neuronal morphology. In the current study, we show that performance on EF and WM tasks exhibited significant changes with age and these impairments correlate with changes in biophysical properties of L3 pyramidal neurons in lateral LPFC (LPFC). Specifically, there was a significant age-related increase in excitability of Layer 3 LPFC pyramidal neurons, consistent with previous studies. Further, this age-related hyperexcitability of LPFC neurons was significantly correlated with age-related decline on a task of WM, but not an EF task. The current study characterizes age-related performance on tasks of WM and EF and provides insight into the neural substrates that may underlie changes in both WM and EF with age.

neuroscience↗

bioRxiv2022

The contrasted impacts of grasshoppers on soil microbial activities in function of ecosystem productivity and herbivore diet

Herbivory can have contrasted impacts on soil microbes and nutrient cycling, which has stimulated the development of conceptual frameworks exploring the links between below- and aboveground processes. The "productivity model" predicts that herbivores stimulate microbial activities and accelerate nutrient mineralization in productive ecosystems, while they have an opposite effect in less productive ecosystems. In parallel, the "diet model" predicts that herbivores feeding on conservative plants accelerate nutrient cycling while those feeding on exploitative plants decelerate nutrient cycling, due to changes in litter inputs. Since these two frameworks can lead to conflicting predictions in some cases, experimental evidence combining herbivore diet and plant productivity is required. During two consecutive years, we conducted an experiment controlling the presence of three grasshopper species consuming either grasses, forbs or both in twelve natural and managed alpine grasslands with contrasted productivities. In order to assess the effects of herbivory on soil microbes, we measured their extracellular enzymatic activities, biomass and potential nitrogen mineralization (PNM). Soil and vegetation were also characterized to test how much they modulated the effects of herbivory on microbes. Contrary to the predictions of the diet model, the effects of herbivory on microbial characteristics did not depend on the herbivores diet, but were influenced by primary production, though in a way that differed from the productivity model. The most productive sites were constituted by exploitative plant species which depleted N resources in the soil, and by microbes producing relatively few extracellular enzymes, leading to a lower PNM. Herbivory increased microbial biomass and decreased the production of extracellular enzymes in those sites, possibly through the stimulation of root exudates produced by exploitative species. The least productive sites were characterized by conservative plants, high soil C content, and by microbes having a resource acquisition strategy (more extracellular enzymes, higher PNM). Herbivory decreased microbial biomass and increased the production of extracellular enzymes in those sites. This pattern can be explained by the loss of carbon associated with insect respiration, which increases the resource requirements of microbes and by a lower production of root exudates by conservative species. Therefore, the effects of two years of herbivory on soil microbes were at odds with the productivity model, which focuses instead on longer term effects corresponding to herbivory-induced changes in plant species composition. This highlights the multidimensional feature of the impacts of herbivory on ecosystem functioning, both in space and time.

ecology↗

bioRxiv2022

iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B), or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and either an abnormal TH proximodistal gradient (THDA), or neurite arborization defects (THDB). Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.

neuroscience↗

bioRxiv2021

Mutualists construct the ecological conditions that trigger the transition from parasitism

The evolution of mutualism between hosts and initially parasitic symbionts represents a major transition in evolution. Although vertical transmission of symbionts during host reproduction and partner control both favour the stability of mutualism, these mechanisms require specifically evolved features that may be absent in the first place. Therefore, the first steps of the transition from parasitism to mutualism may suffer from the cost of mutualism at the organismic level. We hypothesize that spatial structure can lead to the formation of higher selection levels favouring mutualism. This resembles the evolution of altruism, with the additional requirement that the offspring of mutualistic hosts and symbionts must co-occur often enough. Using a spatially explicit agent-based model we demonstrate that, starting from a parasitic system with global dispersal, the joint evolution of mutualistic effort and local dispersal of hosts and symbionts leads to a stable coexistence between parasites and mutualists. The evolution of local dispersal mimics vertical transmission and triggers the formation of mutualistic clusters, counteracting the organismic selection level of parasites that maintain global dispersal. The transition occurs when mutualistic symbionts increase the density of hosts, which strengthens competition between hosts and disfavours hosts inhabiting areas dominated by parasitic symbionts: mutualists construct the ecological conditions that allow their own spread. Therefore, the transition to mutualism may come from an eco-evolutionary feedback loop involving spatially structured population dynamics.

evolutionary biology↗

bioRxiv2020

Spatial structure of natural boxwood and the invasive box tree moth can promote coexistence

In the absence of top-down and bottom-up controls, herbivores eventually drive themselves to extinction by ex-hausting their host plants. Poorly mobile herbivores may experiment only local disappearance, because they can recolonize intact plant patches elsewhere, leaving time to previously over-exploited patches to regrow. However most herbivores such as winged insects are highly mobile, which may prevent the formation of spatial heterogeneity. We test if long-distance dispersal can preclude coexistence using the invasion of box tree moth (Cydalima perspectalis) in Europe as a model system. We build a lattice model and estimate the parameters with a combination of field measurements, experimental data and literature sources. Space corresponds either to a realistic boxwood landscape in the Alps, or to theoretical landscapes of various sizes. We find that both species persist under a large range of realistic parameter values, despite a severe reduction in boxwood biomass, with an alternation of outbreaks and near-to-extinction moth densities. Large landscapes are necessary for coexistence, allowing the formation of spatial structure. Slow plant regrowth combined with long-distance dispersal could drive moths to extinction, because of resources depletion at the global scale even without a complete synchronization of the local dynamics. The spatial dynamics leads to formation of small plant patches evenly distributed in the landscape, because of a combination of local plant dispersal and global indirect competition between plants through their positive effect on moth population size. Coexistence is favored by such heterogeneous landscapes, because empty patches increase moth mortality during dispersal: the system thus creates its own stability conditions.

ecology↗

bioRxiv2020

Discovery of cryptic plant diversity in one of the harshest environments: the rooftops of the Alps

High altitude temperate mountains have long been considered devoid of life owing to high extinction or low speciation rates during the Pleistocene. We performed a phylogenetic and population genomic investigation of an emblematic high-altitude plant clade (Androsace sect. Aretia, 31 currently recognized species), based on plant surveys conducted during alpinism expeditions. Surprisingly, we inferred that this clade originated in the Miocene and continued diversifying through Pleistocene glaciations, and discovered three novel species of Androsace dwelling on different bedrock types on the rooftops of the Alps. This suggests that temperate high mountains have been cradles of plant diversity even during the Pleistocene, with in-situ speciation driven by the combined action of geography and geology. Our findings have an unexpected historical relevance: H.-B. de Saussure likely observed one of these species during his 1788 expedition to the Mont Blanc and we describe it here, over two hundred years after its first sighting.

evolutionary biology↗

bioRxiv2019

In vivo characterisation of the toxicological properties of DPhP, one of the main degradation product of aryl phosphate esters.

BackgroundAryl phosphate esters (APEs), a main class of organophosphorus ester molecules, are widely used and commonly present in the environment. Health hazards associated with these compounds remain largely unknown and the effects of diphenyl phosphate (DPhP), one of their most frequent derivatives in human samples, are poorly characterised. ObjectiveOur aim was to investigate whether DPhP per se may represent a more relevant marker of exposure to APEs and determine its potential deleterious biological effects in chronically exposed mice. MethodsConventional animals (FVB mice) were acutely (intravenous or oral gavage) or chronically (0.1 mg.mL-1, 1 mg.mL-1, 10 mg.mL-1 in drink water) exposed to relevant doses of DPhP or triphenyl phosphate (TPhP), one of its main precursors in the environment. Both molecules were measured in blood and other relevant tissues by liquid chromatography-mass spectrometry (LC-MS). Biological effects of chronic DPhP exposure were addressed through liver multi-omics analysis combining mRNA extraction and sequencing to high resolution LC-MS to determine the corresponding metabolic profile. Deep statistical exploration was performed to extract correlated information, guiding further physiological analyses (immunohistochemistry (IHC) and animal growth measurement). ResultsAcute and chronic exposure to DPhP led to significant levels of this molecule in blood and other tissues, an effect missing with TPhP. Multi-omics analysis confirmed the existence of biological effects of DPhP, even at a very low dose of 0.1 mg.mL-1 in drinking water. Chemical structural homology and pathway mapping demonstrated a clear reduction of the fatty-acid catabolic processes centred on acylcarnitine and mitochondrial {beta}-oxidation. Interestingly, mRNA expression confirmed and extended these observations by demonstrating at all tested doses the overall repression of genes involved in lipid catabolic processes and regulated by PPAR, a master regulator of {beta}-oxidation and its associated ketogenesis. IHC analysis confirmed the alteration of these pathways by showing a specific downregulation of Hmgcs2, a kernel target gene of PPAR, at all doses tested, and surprisingly, a strong reduction of the lipid droplet content only at the highest dose. Overall, DPhP absorption led to weight loss, which was significant using the highest dose. ConclusionsOur results suggest that in mice, the effects of chronic exposure to DPhP, even at a low dose, are not negligible. Fatty acid metabolism in the liver in particular is essential for controlling fast and feast periods with adverse consequences on the overall physiology. Therefore, the impact of DPhP on circulating fat, cardiovascular and metabolic disease incidence deserves, in light of our results, further investigations.

pharmacology and toxicology↗

bioRxiv2019

Network models predict that pyramidal neuron hyperexcitability and synapse loss in the dlPFC lead to age-related spatial working memory impairment in rhesus monkeys

Behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlPFC) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased in vitro action potential firing rates (hyperexcitability), across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task (DRT), and introduce a model of memory retention in the DRSTsp. Persistent activity--and, in turn, cognitive performance--in both models was affected much more by hyperexcitability of pyramidal neurons than by a loss of synapses. Our DRT simulations predict that additional changes to the network, such as increased firing of inhibitory interneurons, are needed to account for lower firing rates during the DRT with aging reported in vivo. Synaptic facilitation was an essential feature of the DRSTsp model, but it did not compensate fully for the effects of the other age-related changes on DRT performance. Modeling pyramidal neuron hyperexcitability and synapse loss simultaneously led to a partial recovery of function in both tasks, with the simulated level of DRSTsp impairment similar to that observed in aging monkeys. This modeling work integrates empirical data across multiple scales, from synapse counts to cognitive testing, to further our understanding of aging in non-human primates.

neuroscience↗

bioRxiv2018

Tannin evolution by niche construction: a spatial stoichiometric model

Among plant traits, plant secondary metabolites such as tannins mediate plant-herbivore interactions but also have after-life effects on litter decomposition and nutrient cycling, which could influence their evolution. By modeling the flow of nitrogen and carbon through plants and soil in a spatially explicit context, we explored the relative contribution of herbivory and plant-soil feedbacks as drivers of tannin evolution. We assumed soil nitrogen to be composed of labile and recalcitrant compartments, the latter made of tannin-protein complexes accessible by plants via associations with mycorrhizal fungi. In unproductive environments and for plants with low biomass turnover rates, we show that when tannins modify soil properties locally, plant-soil feedbacks alone can drive their evolution. We further predict the existence of positive coevolutionary feedbacks between associations with mycorrhizae and tannins, possibly triggered by the evolution of the latter as protection against herbivores. In line with our theoretical results, tannins are mostly present in conservative plants, associated with mycorrhizae and inhabiting unproductive environments. Our work suggests that plant-soil feedbacks can enable niche construction mechanisms which can be key to the evolution of plant traits.

ecology↗