Biology subjects

Baudry, J.

Publications and source records attributed to Baudry, J..

16 recordsLinked to original sources

bioRxiv2026

Acetate promotes nutritional adaptation in Escherichia coli

The long-held view that acetate, one of the main fermentation by-products of Escherichia coli, is toxic to microbial growth is currently challenged. Here, we demonstrate that acetate promotes E. coli adaptation to nutrient changes by accelerating growth resumption, with as little as 250 {micro}M acetate being sufficient to shorten the lag phase by several hours. Acetate was found to be consumed via acetyl-CoA synthetase very early after the nutrient change. Transcriptomics, metabolomics and 13C-isotope labeling experiments show that acetate replenishes metabolic pools in the tricarboxylic acid cycle and upper glycolysis. Single-cell analyses reveal that acetate increases the adaptation speed of individual cells switching to the new nutrient. We conclude that the reuse of excreted acetate by E. coli facilitates metabolic adaptation by transiently replenishing central metabolite pools. This work identifies an unexpected role of acetate in the nutritional adaptation of E. coli, providing new insights into the physiological relevance of overflow metabolism. HighlightsO_LIAcetate facilitates E. coli adaptation from one nutrient to another. C_LIO_LILess than 250 {micro}M acetate is sufficient to halve lag times. C_LIO_LIAcetate helps replenish metabolite pools in central carbon metabolism. C_LIO_LIAcetate excretion is an adaptative strategy to overcome resource fluctuations. C_LI

systems biology↗

bioRxiv2026

A Multi-Modal AI/ML-based Framework for Protein Conformation Selection and Prediction in Drug Discovery Applications

The development of pharmaceutical drugs is a time-intensive and costly process, with more than 90% of drug candidates failing during preclinical or clinical testing. A major challenge lies in accurately predicting protein-ligand interactions, especially given that traditional computational methods often rely on a single protein conformation, failing to capture biologically relevant structural variability. To address this, we present an AI/ML-based multi-modal framework based on Graph Convolutional Network (GCN) that integrates both global and local protein descriptors to classify binding and non-binding conformations more effectively. Global descriptors capture overarching physico-chemical and structural properties of proteins, while local descriptors--such as pharmacophores--provide site-specific information crucial for modeling ligand interactions. Our GCN based approach demonstrates that integrating local and global structural perspectives significantly improves predictive accuracy and robustness. By enabling more reliable protein conformation classification, this work contributes toward scalable, AI-driven drug discovery--an increasingly critical goal in response to global health challenges.

molecular biology↗

bioRxiv2023

Near infrared spectroscopic characterization of sesamin, a dietary lignan natural product

Sesamin, a lignan component of sesame seed oil, has shown pharmacologic benefits, such as anti-oxidative and anti-inflammatory qualities. However, the amount of data available to the field is surprisingly sparse, as for instance there is no known spectroscopic characterization of sesamin. This work provides the first experimental near infrared spectrum of sesamin. Sesamin powder was subjected to experimental Fourier-transform infrared spectroscopy, and the resulting spectrum was compared to quantum chemical calculations of sesamins stereoisomers in various hydration states. Major peaks of sesamin were assigned vibrational modes through comparison of computed and observed spectra. Multiple sesamin species may be present in a typical powder sample, coexisting with potential trace hydration.

biochemistry↗

bioRxiv2023

Fatty Acid Metabolism and The Oxidative Stress Response Support Bacterial Predation

Despite growing awareness of their importance in soil ecology, the genetic and physiological traits of bacterial predators are still relatively poorly understood. In the course of a Myxococcus xanthus predator evolution experiment, we discovered a class of genotypes leading to enhanced predation against diverse species. RNA-seq analysis demonstrated that this phenotype is linked to the constitutive activation of a predation-specific program. Functional analysis of the mutations accumulated across the evolutionary time in a two- component system and Acyl-CoA-manipulating enzymes revealed the critical roles of fatty acid metabolism and antioxidant gene induction. The former likely adapts the predator to metabolites derived from the prey while the latter protects predatory cells from reactive oxygen species (ROS) generated by prey cells under stress and released upon lysis during predation. These findings reveal interesting parallels between bacterial predator-prey dynamics and pathogen-host cell interactions. Significance StatementThis study illuminates the largely unexplored genetic and metabolic strategies used by bacterial predators in soil ecosystems. Through experimental evolution in Myxococcus xanthus, we discovered that more efficient predators accumulate mutations that activate a genetic program for predation. This program simultaneously triggers a metabolic shift favoring fatty acid degradation for energy production and upregulates antioxidant gene expression, enhancing protection against reactive oxygen species generated during prey cell lysis. This adaptive mechanism proves advantageous across a wide range of prey species, suggesting that metabolic adaptation plays a crucial role in the evolutionary trajectory of bacterial predators within their natural ecological niche.

microbiology↗

bioRxiv2022

Conservation networks do not match ecological requirements of amphibians

O_LIAmphibians are among the most threatened taxa as they are highly sensitive to habitat degradation and fragmentation. They are considered as model species to evaluate habitats quality in agricultural landscapes. In France, all amphibian species have a protected status requiring recovery plans for their conservation. Conservation networks combining protected areas and green infrastructure can help the maintenance of their habitats while favouring their movement in fragmented landscapes such as farmlands. Yet, assessing the effectiveness of conservation networks is challenging. C_LIO_LIHere, we compared the ecological requirements of amphibian species with existing conservation network coverage in a human-dominated region of western France. First, we mapped suitable habitat distributions for nine species of amphibian with varying ecological requirements and mobility. Second, we used stacking species distribution modelling (SSDM) to produce multi-species habitat suitability maps. Then, to identify spatial continuity in suitable habitats at the regional scale, we defined species and multi-species core habitats to perform a connectivity analysis using Circuitscape theory. Finally, we compared different suitability maps with existing conservation networks to assess conservation coverage and efficiency. C_LIO_LIWe highlighted a mismatch between the most suitable amphibian habitats at the regional scale and the conservation network, both for common species and for species of high conservation concern. We also found two bottlenecks between areas of suitable habitat which might be crucial for population movements induced by global change, especially for species associated with hedgerow mosaic landscapes. These bottlenecks were not covered by any form of protection and are located in an intensive farmland context. C_LIO_LISynthesis and applications - We advocate the need to better integrate agricultural landscape mosaics into species conservation planning as well as to protect and promote agroecological practices suitable for biodiversity, including mixed and extensive livestock farming. We also emphasize the importance of interacting landscape elements of green infrastructure for amphibian conservation and the need for these to be effectively considered in land-use planning policies. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/500425v4_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@1b6446forg.highwire.dtl.DTLVardef@146e7c7org.highwire.dtl.DTLVardef@1ad210org.highwire.dtl.DTLVardef@d545a0_HPS_FORMAT_FIGEXP M_FIG C_FIG PCI recommendation : https://ecology.peercommunityin.org/articles/rec?id=504

ecology↗

bioRxiv2022

Structure-based discovery of selective histone deacetylase (HDAC) 3 and 4 inhibitors

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. Here, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the NCOR protein. These pockets were then targeted using an ensemble docking approach combined with consensus scoring to identify compounds with a different mechanism of binding than the currently known HDAC modulators. Using this approach, 18 compounds predicted in silico to bind to HDAC4s novel pockets were tested in vivo testing on two cancer cell lines. Of these, 5 compounds decreased cell viability to less than 60%. One inhibited the catalytic activity of HDAC4 but not HDAC3, which belongs to a different family of HDACs (Class I). The most potent compound has an IC50 comparable to the FDA-approved compound SAHA (Vorinostat). While there are currently no known inhibitors reported to bind highly selectively to HDAC4, the present result suggests potential mechanistic and chemical approaches for the development of selective HDAC4 modulators.

cancer biology↗

bioRxiv2022

Single cell profiling reveals functional heterogeneity and serial killing in human peripheral and ex vivo-generated CD34+ progenitor derived Natural Killer cells

Increasing evidence suggest that Natural killer (NK) cells are composed of distinct functional subsets. This multi-functional role displayed by NK cells have made them an attractive choice for anti-cancer immunotherapy. A functional NK cell repertoire is generated through cellular education, resulting in heterogeneous NK cell population with distinct capabilities to respond to different stimuli. The application of a high-throughput droplet-based microfluidic platform allows monitoring of NK cell-target cell interactions at single-cell level and in real-time. Through fluorescence-based screening of around 80,000 droplets, with different Effector:Target ratios, a fully automated image analysis allows for the assessment of individual killing events in each droplet over time. We observed a variable response of single NK cells towards different target cells and identified a distinct population of NK cells capable of inducing multiple target lysis, coined as serial killers. To meet the increasing clinical demand for NK cells several sources, such as umbilical cord blood (UCB), have successfully been explored. By assessing the cytotoxic dynamics, we showed that single UCB-derived CD34+ hematopoietic progenitor (HPC)-NK cells display superior anti-tumor cytotoxicity. Additionally, with an integrated analysis of cytotoxicity and cytokine secretion we showed that target cell interactions augmented cytotoxic as well as secretory behavior of NK cells. By providing an in-depth assessment over NK cell functions, this study provides crucial information on diversity and functional characteristics of peripheral blood NK cells and ex vivo-generated HPC-NK cells to develop and improve of NK cell-based cancer immunotherapy.

immunology↗

bioRxiv2021

Single-cell analyses of immune thrombocytopenic patients reveal multiorgan dissemination of high-affinity autoreactive plasma cells

The major therapeutic goal for immune thrombocytopenia (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. 80% of patients possess anti-integrin IIb{beta}3 (GPIIbIIIa) IgG autoantibodies causing platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in ~50% of patients to recover a normal platelet count after anti-CD20 Rituximab-mediated B cell depletion and splenectomy suggest that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SC) reside in other anatomical compartments. We analyzed >3,300 single IgG-SC from spleen, bone marrow and/or blood of 27 patients with ITP revealing high inter-individual variability in affinity for GPIIbIIIa with variations over 3 logs. IgG-SC dissemination and range of affinities were however similar per patient. Longitudinal analysis of autoreactive IgG-SC upon treatment with anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti-GPIIbIIIa IgG-SC in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.

immunology↗

bioRxiv2020

Sequential dynamics of Stearoyl-CoA Desaturase-1 (SCD1) /ligand binding and unbinding mechanism: A computational study

Stearoyl-CoA desaturase-1 (SCD1 or delta-9 desaturase, D9D) is a key metabolic protein that modulates cellular inflammation and stress, but overactivity of SCD1 is associated with diseases including cancer and metabolic syndrome. This transmembrane endoplasmic reticulum protein converts saturated fatty acids into monounsaturated fatty acids, primarily stearoyl-CoA into oleoyl-CoA, which are critical products for energy metabolism and membrane composition. The present computational molecular dynamics study characterizes the molecular dynamics of SCD1 with substrate, product, and as apoprotein. The modeling of SCD1:fatty acid interactions suggests that 1) SCD1:CoA moiety interactions open the substrate binding tunnel, 2) SCD1 stabilizes a substrate conformation favorable for desaturation, and 3) SCD1:product interactions result in an opening of the tunnel, possibly allowing product exit into the surrounding membrane. Together, these results describe a highly dynamic series of SCD1 conformations resulting from the enzyme:cofactor:substrate interplay that inform drug-discovery efforts.

biochemistry↗

bioRxiv2020

How citizen science could improve Species Distribution Models and their independent assessment for conservation

AO_SCPLOWBSTRACTC_SCPLOWSpecies distribution models (SDM) have been increasingly developed in recent years but their validity is questioned. Their assessment can be improved by the use of independent data but this can be difficult to obtain and prohibitive to collect. Standardized data from citizen science may be used to establish external evaluation datasets and to improve SDM validation and applicability. We used opportunistic presence-only data along with presence-absence data from a standardized citizen science program to establish and assess habitat suitability maps for 9 species of amphibian in western France. We assessed Generalized Additive and Random Forest Models performance by (1) cross-validation using 30% of the opportunistic dataset used to calibrate the model or (2) external validation using different independent data sets derived from citizen science monitoring. We tested the effects of applying different combinations of filters to the citizen data and of complementing it with additional standardized fieldwork. Cross-validation with an internal evaluation dataset resulted in higher AUC (Area Under the receiver operating Curve) than external evaluation causing overestimation of model accuracy and did not select the same models; models integrating sampling effort performed better with external validation. AUC, specificity and sensitivity of models calculated with different filtered external datasets differed for some species. However, for most species, complementary fieldwork was not necessary to obtain coherent results, as long as the citizen science data was strongly filtered. Since external validation methods using independent data are considered more robust, filtering data from citizen sciences may make a valuable contribution to the assessment of SDM. Limited complementary fieldwork with volunteers participation to complete ecological gradients may also possibly enhance citizen involvement and lead to better use of SDM in decision processes for nature conservation.

ecology↗

bioRxiv2020

Quantitative modeling of the effect of antigen dosage on B-cell affinity distributions in maturating germinal centers

Affinity maturation is a complex dynamical process allowing the immune system to generate antibodies capable of recognizing antigens. We introduce a model for the evolution of the distribution of affinities across the antibody population in germinal centers. The model is amenable to detailed mathematical analysis, and gives insight on the mechanisms through which antigen availability controls the rate of maturation and the expansion of the antibody population. It is also capable, upon maximum-likelihood inference of the parameters, to reproduce accurately the distributions of affinities of IgG-secreting cells we measure in mice immunized against Tetanus Toxoid under largely varying conditions (antigen dosage, delay between injections). Both model and experiments show that the average population affinity depends non-monotonically on the antigen dosage. We show that combining quantitative modelling and statistical inference is a concrete way to investigate biological processes underlying affinity maturation (such as selection permissiveness), hardly accessible through measurements.

immunology↗

bioRxiv2020

Structure based virtual screening identifies novel competitive inhibitors for the sialoglycan binding protein Hsa

Infective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that a serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialyated glycans displayed on human platelets. Despite its important role in disease progression, there are currently no anti-adhesive drugs available on the market. Here, we performed structure-based virtual screening using an ensemble docking approach followed by consensus scoring to identify novel inhibitors against the sialoglycan binding domain of the SRR adhesin protein Hsa from the S. gordonii strain DL1. In silico cross screening against the glycan binding domains of closely related SRR proteins from five other S. gordonii or S. sanguinis strains was also performed to further reduce false positives. Using our in silico screening strategy we successfully predicted nine compounds which were able to displace the native ligand (sialyl-T antigen) in an in vitro assay and bind competitively to adhesin protein Hsa ([~]20% hit rate).

microbiology↗

bioRxiv2020

Tree diversity and the temporal stability of mountain forest productivity: testing the effect of species composition, through asynchrony and overyielding

Climate change modifies ecosystem processes directly through its effect on environmental conditions, but also indirectly by changing community composition. Theoretical studies and grassland experiments suggest that diversity may increase and stabilize communities productivity over time. Few recent studies on forest ecosystems suggested the same pattern but with a larger variability between the results. In this paper, we aimed to test stabilizing diversity effect for two kinds of mixtures (Fagus sylvatica - Quercus pubescens and Fagus sylvatica - Abies alba), and to assess how climate may affect the patterns. We used tree ring data from forest plots distributed along a latitudinal gradient across French Alps. We found that diversity effect on stability in productivity varies with stand composition. Most beech-fir stands showed a greater stability in productivity over time than monocultures, while beech-oak stands showed a less stable productivity. Considering non-additive effects, no significant trends were found, regardless the type of mixed stands considered. We further highlighted that these patterns could be partially explained by asynchrony between species responses to annual climatic conditions (notably to variation in temperature or precipitation), overyielding, and climatic conditions. We also showed that the intensity of the diversity effect on stability varies along the ecological gradient, consistently with the stress gradient hypothesis for beech-oak forests, but not for beech-fir forests. This study showed the importance of the species identity on the relationships between diversity, climate and stability of forest productivity. Better depicting diversity and composition effects on forest ecosystem functioning appears to be crucial for forest managers to promote forest adaptation and maintain timber resource in the context of on-going climate change.

ecology↗

bioRxiv2019

Selectivity and engineering of the sialoglycan-binding spectrum in Siglec-like adhesins

The Siglec-like Serine-Rich Repeat (SRR) adhesins mediate bacterial attachment to mammalian hosts via sialoglycan receptors. Here, we combine structural, computational, biochemical, and phylogenetic approaches to elucidate the determinants of the sialoglycan-binding spectrum across the family of Siglec-like SRR adhesins. We further identified mutable positions that disproportionately affect sialoglycan selectivity, as demonstrated by increases in binding to alternative ligands of 2- to 3-orders of magnitude. Biologically, these studies highlight how bacteria nimbly modulate the receptor interaction during coevolution of host and pathogen. These studies additionally created binding proteins specific for sialyl-T antigen or 6S-sialyl LewisX that can recognize glycosylation of human plasma proteins. The engineered binding proteins can facilitate the characterization of normal cellular glycan modifications or may be used as diagnostic tools in disease states with altered glycosylation.\n\nSignificanceThe ability of bacteria to bind selectively to host receptors underlies both commensalism and pathogenesis. Here, we identify the molecular basis for receptor selectivity in streptococci that bind to sialoglycan receptors. This revealed how to convert these adhesins into selective probes that measure triand tetrasacharides within the context of larger glycosylations. These probes that can be used in a laboratory with no specialized equipment and can be used to address biological questions relating to sialoglycan-dependent signaling and adhesion.

biochemistry↗

bioRxiv2019

Interdimer zipping in the chemoreceptor signaling domain revealed by molecular dynamics simulations

Chemoreceptors are principal components of the bacterial sensory system that modulates cellular motility. They detect changes in the environment and transmit information to CheA histidine kinase, which ultimately controls cellular flagellar motors. The prototypical Tsr chemoreceptor in E. coli is a homodimer containing two principal functional modules: (i) a periplasmic ligand-binding domain and (ii) a cytoplasmic signaling domain. Chemoreceptor dimers are arranged into a trimer of dimers at the tip of the signaling domain comprising a minimal physical unit essential for enhancing the CheA activity several hundredfold. Trimers of dimers are arranged into highly ordered hexagon arrays at the cell pole; however, the mechanism underlying the trimer-of-dimer and higher order array formation remains unclear. Furthermore, molecular mechanisms of signal transduction that are likely to involve inter-dimer interactions are not fully understood. Here we apply all-atom, microsecond-time scale molecular dynamics simulations of the Tsr trimer of dimers atomic model in order to obtain further insight into potential interactions within the chemoreceptor signaling unit. We show extensive interactions between homodimers at the hairpin tip of the signaling domain, where strong hydrophobic interactions maintain binding. A subsequent zipping of homodimers is facilitated by electrostatic interactions, in particular by polar solvation energy and salt bridges that stabilize the final compact structure, which extends beyond the kinase interacting subdomain. Our study provides evidence that interdimer interactions within the chemoreceptor signaling domain are more complex than previously thought.

biophysics↗

bioRxiv2019

Metabolic Cost of Rapid Adaptation of Single Yeast Cells Under Unforeseen Challenge

Cells can rapidly adapt to changing environments through non-genetic processes; however, the metabolic cost of such adaptation has never been considered. Here we demonstrate metabolic coupling in a remarkable, rapid adaptation process (10-3cells/hour) by simultaneously measuring metabolism and division of thousands of individual Saccharomyces cerevisiae cells using a droplet microfluidic system. Following a severe challenge, most cells, while not dividing, continue to metabolize, displaying a remarkably wide diversity of metabolic trajectories from which adaptation events can be anticipated. Adaptation requires the consumption of a characteristic amount of energy, indicating that it is an active process. The demonstration that metabolic trajectories predict a priori adaptation events provides the first evidence of tight energetic coupling between metabolism and regulatory reorganization in adaptation.\n\nOne Sentence SummaryDemonstration of the tight coupling between metabolic activity and regulatory processes during rapid adaptation at the single-cell level.

systems biology↗