Biology subjects

Michel, L.

Publications and source records attributed to Michel, L..

14 recordsLinked to original sources

bioRxiv2026

Intrinsically disordered regions influence protein motif usage in Drosophila Ubx and AbdA Hox proteins

Hox proteins are evolutionary conserved transcription factors guiding morphogenesis in all bilaterian animals. Conservation mainly concerns the homeodomain (HD), a helix-turn-helix DNA binding motif and flanking sequences close by. Besides, sequences are poorly conserved and disordered. Here we investigate how poorly conserved Intrinsically Disordered Regions (IDRs) influence Hox protein activity, focusing on a closely related Drosophila Hox pair and using a wide range of in vivo function. Studying Drosophila Ultrabithorax (Ubx) and AbdominalA (AbdA) proteins, we find that conserved protein motifs close to the HD are differently used in Ubx and AbdA. Coarse-grained molecular dynamics simulations identify a large set of intra-molecular interactions, notably involving poorly conserved disordered regions upstream and downstream the HD. Swapping these regions in Ubx and AbdA alters protein functions and switches motif dependency in some biological situations. This suggests that IDRs, predicted to mediate large and dynamic sets of intramolecular interactions, influence protein motif usage in a context dependent manner.

developmental biology↗

bioRxiv2026

A microbiota-derived protease links phage susceptibility to host epithelial responses

Bacteriophages are major ecological drivers of gut microbial ecology, yet whether bacterial mechanisms that determine phage susceptibility have consequences for the mammalian host remains poorly understood. Here, we identify dipeptidyl peptidase 11 (Dpp11a), the predominant active serine protease of the prevalent gut commensal Phocaeicola vulgatus, as an unexpected bacterial defence factor. Dpp11a protects against environmental proteases and confers resistance to bacteriophage infection. Metatranscriptomic analyses further reveal increased expression of both dpp11a and P. vulgatus-associated phage transcripts in ulcerative colitis stool samples, indicating that both components of this interaction are transcriptionally active in disease-associated human microbiomes. Using the microfluidic gut-on-a-chip co-culture model HuMiX, we show that the absence of Dpp11 is accompanied by altered epithelial tight-junction remodelling during phage-bacterial infection. Together, our findings reveal that the consequences of bacterial phage defence can extend beyond phage-bacterium interactions to the mammalian epithelium.

microbiology↗

bioRxiv2026

Chemical Interrogation and Reprogramming of ATAT1-Mediated Tubulin Acetylation

Acetylation of -tubulin K40 by -tubulin acetyltransferase 1 (ATAT1) using acetyl-coenzyme A (Ac-CoA) marks stable microtubule populations, yet chemical tools to directly measure ATAT1 ligand engagement, inhibit its activity, or visualize ATAT1-mediated modification on intact microtubules remain limited. Through the development of a quantitative binding assay, we uncovered that ATAT1 can bind unnatural cofactors but fails to efficiently use them in acyl-transfer reactions. Structure-guided mutation subsequently yielded ATAT1-L163A, which successfully installed clickable handles at the native -tubulin K40 site of synthetic tubulin peptides, -tubulin, and intact microtubules. Cu(I)-catalyzed azide-alkyne cycloaddition enabled visualization of modified microtubules by in-gel fluorescence and microscopy. Moreover, we report a p11-CoA bisubstrate inhibitor that suppressed both native acetylation and engineered acylation. Together, these tools provide chemically controlled access to ATAT1 activity and a site-verified, clickable K40 modification on intact microtubules.

biochemistry↗

bioRxiv2026

Beige/brown fat-mediated cardiac protection from high-fat diet is dependent on adipocyte beta3-adrenergic receptor

Cardiometabolic diseases associated with obesity are continuously increasing worldwide. Yet, current therapeutic strategies remain insufficient to improve patient outcomes. The beta3-adrenergic receptor ({beta}3AR) promotes lipolysis in adipose tissue (AT) and thermogenesis specifically in brown adipose tissue (BAT). In mice, BAT activation also improves systemic metabolism and limits cardiometabolic damage. While BAT is limited in humans (e.g., with ageing and obesity), {beta}3AR activation induces beige adipocytes within white adipose depots with similar thermogenic properties. To study the role of adipocyte {beta}3AR in the regulation of cardiac metabolism and remodeling, mice with/without adipocyte-specific {beta}3AR genetic deletion were fed a high-fat-sucrose (HF-S) diet and treated with the selective {beta}3AR agonist CL316,243 (CL). The metabolic and cardiac protection following {beta}3AR activation was abrogated upon {beta}3AR deletion in adipocytes, together with the beiging of the epididymal (visceral) AT, highlighting a critical role of adipose {beta}3AR signalling in mediating these benefits. Multi-omic analysis of AT and cardiac samples identified CL-induced secreted mediators of the crosstalk between AT and the heart. Therefore, adipocyte {beta}3AR is critical for the adipose-cardiac communication and supports the therapeutic potential of targeting {beta}3AR for the management of obesity-related cardiometabolic diseases.

systems biology↗

bioRxiv2026

Personalized microbiotas (counter-)select for antibiotic resistant strains

Antibiotic resistant pathogens are an increasing public health threat, as development of novel therapeutics is outpaced by resistance emergence and dissemination. Approaches to slow down or even revert antibiotic resistance are necessary to maintain efficacy of both existing and new antibiotics. Such approaches exploit the fitness cost of resistance elements, but have largely relied on assessing this cost in laboratory conditions that poorly reflect the native context in which pathogens reside. Here we present a method that allows to investigate the influence of personalized human gut microbiota compositions on the competitive fitness of antibiotic resistant pathogens. Using fecal matter-derived microbiomes we identified a specific community that selected for a carbapenem-resistant Klebsiella pneumoniae strain. This selective advantage was due to mutations arising in a LacI-type transcriptional regulator, GlyR, which upregulated expression of the downstream glycoporin GlyP, causing the effect. By deconvoluting the microbiome composition, we identified a focal E. coli strain as a central driver of the selection, which was further modulated by other microbiota members. We further demonstrate that the selective advantage was due to carbohydrate competition, and in particular for glycerol-containing compounds. Importantly, glyR mutations are under strong positive but conditional selection in clinical K. pneumoniae isolates. This implies a reduced competitiveness in other environments, which we experimentally validated in vitro. Overall, this study offers a path to identify microbiome-specific interactions that modulate the competitiveness of antibiotic resistant pathogens.

microbiology↗

bioRxiv2026

RAPID DECLINE OF NESTING PEREGRINE FALCONS IN THE SAN FRANCISCO BAY REGION OF CALIFORNIA SYNCHRONOUS WITH AN H5N1 OUTBREAK

After rebounding from near extirpation during the organochlorine era, breeding Peregrine Falcons (Falco peregrinus) in California are again facing adversity, this time consistent with an outbreak of a highly pathogenic avian influenza. Following the first detection of the H5N1 variant clade 2.3.4.4b virus in California wild birds in July 2022, we assembled data from long-term monitoring (2000-2025) of peregrine breeding territory occupancy in the broad vicinity of San Francisco Bay to examine possible impacts on falcon populations. Prior to the outbreak, 47 focal breeding territories had shown nearly complete occupancy by pairs (98.5% of 390 site-years), with very few vacancies, single birds in attendance, or subadult pair members. Within 8 mo of the outbreak, occupancy had dropped to 65.1%, and 2 yrs later (2025), only 36.2% of sites remained occupied. An uptick in site-occupancy by single birds also occurred after the outbreak, but it is unclear whether these were survivors or floaters attempting to fill vacant territories where both pair members had perished. The high vacancy rates signaled an impact upon floaters (nonbreeding adults) that normally buffer breeding site-occupancy in healthy peregrine populations. From October 2022 through November 2025, 17 peregrine fatalities were diagnosed with H5N1 within the counties comprising our study area. Evidence that H5N1 caused these territory vacancies includes, (1) the striking temporal coincidence of occupancy loss with the outbreak, and (2) the lethality of the virus to peregrines and its confirmed presence in peregrine prey in our study area. Our study reaffirms the value of long-term territory occupancy monitoring in this sentinel species.

ecology↗

bioRxiv2024

The sensory shark: high-quality phenotypic, genomic and transcriptomic data for the small spotted catshark Scyliorhinus canicula reveal the molecular bases of sensory organ evolution in jawed vertebrates

Cartilaginous fishes (chimaeras and elasmobranchs -sharks, skates and rays) hold a key phylogenetic position to explore the origin and diversifications of jawed vertebrates. Here, we report and integrate reference genomic, transcriptomic and morphological data in the small-spotted catshark Scyliorhinus canicula to shed light on the evolution of sensory organs. We first characterise general aspects of the catshark genome, confirming the high conservation of genome organisation across cartilaginous fishes, and investigate population genomic signatures. Taking advantage of a dense sampling of transcriptomic data, we also identify gene signatures for all major organs, including chondrichthyan specializations, and evaluate expression diversifications between paralogs within major gene families involved in sensory functions. Finally, we combine these data with 3D synchrotron imaging and in situ gene expression analyses to explore chondrichthyan-specific traits and more general evolutionary trends of sensory systems. This approach brings to light, among others, novel markers of the ampullae of Lorenzini electro-sensory cells, a duplication hotspot for crystallin genes conserved in jawed vertebrates, and a new metazoan clade of the Transient-receptor potential (TRP) family. These resources and results, obtained in an experimentally tractable chondrichthyan model, open new avenues to integrate multiomics analyses for the study of elasmobranchs and jawed vertebrates.

evolutionary biology↗

bioRxiv2024

Exploring the role of cultivar, year and plot age in the incidence of grapevine trunk diseases: insights from 20 years of regional surveys in France

Grapevine trunk diseases cause yield losses and vine mortality in vineyards worldwide. However, there have been few quantitative studies evaluating grapevine dieback on a large spatial and temporal scale. Here, we consolidated and standardized databases from the 13 main wine regions of France, compiling records of leaf symptoms associated with esca and Eutypa dieback from 2082 plots and 36 cultivars over a 20-year period. This large dataset was used (a) for quantitative analysis of the prevalence (number of plots with at least one symptomatic plant) and incidence (percentage of symptomatic plants) of esca and Eutypa dieback; and (b) to decipher the effects of cultivar, year and plot age on both the prevalence and incidence of esca leaf symptoms by temporal Bayesian modelling. Esca was present on a mean of 74 {+/-} 2% plots annually, with an incidence of 3.1 {+/-} 0.1%. Eutypa dieback occurred in 41 {+/-} 3% of the plots, with an incidence of 1.4 {+/-} 0.1%. Our modelling approach revealed that the cultivar had a significant impact on the prevalence of esca, but not on its incidence when prevalence is greater than zero. Esca prevalence remained stable, whereas esca incidence was higher than the mean value in six of the years after 2012. We also found a significant non-linear effect of plot age, with 10- to 30-year-old plots significantly more susceptible, depending on the cultivar. This study clearly illustrates the importance of considering extensive and continuous monitoring to improve our understanding of the impact and evolution of crop diseases.

plant biology↗

bioRxiv2023

A NRF2/beta3-adrenoreceptor axis drives a sustained antioxidant and metabolic rewiring through the pentose-phosphate pathway to alleviate cardiac stress

BackgroundCardiac {beta}3-adrenergic receptors ({beta}3AR) are upregulated in diseased hearts and mediate antithetic effects to those of {beta}1AR and {beta}2AR. {beta}3AR agonists were recently shown to protect from myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. The underlying mechanisms, however, remain elusive. MethodsTo dissect functional, transcriptional and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a human ADRB3 transgene ({beta}3AR-Tg) and subjected to transverse aortic constriction (TAC) were assessed using echocardiography, RNAseq, PET scan, metabolomics, seahorse and metabolic flux analysis. Subsequently, signaling and metabolic pathways were investigated further in vivo in {beta}3AR-Tg and in vitro in neonatal rat ventricular myocytes adenovirally infected to express {beta}3AR and subjected to neurohormonal stress. These results were completed with an analysis of single nucleus RNAseq data from human cardiac myocytes from heart failure patients. ResultsCompared with WT littermate, {beta}3AR-Tg mice were protected from hypertrophy after transaortic constriction (TAC), while systolic function was preserved. {beta}3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the Pentose-Phosphate Pathway (PPP) in {beta}3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the PPP, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, while downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in {beta}3AR-Tg post-TAC compared to WT, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as upstream transcription factor which was functionally verified in {beta}3AR-expressing cardiac myocytes where its translocation and nuclear activity was dependent on {beta}3AR activation of nitric-oxide synthase (NOS) NO production. ConclusionModerate expression of cardiac {beta}3AR, at levels observed in human cardiac myocardium, exerts antioxidant effects through activation of the PPP and NRF2 pathway, thereby preserving myocardial oxidative metabolism, function and integrity under pathophysiological stress.

physiology↗

bioRxiv2023

Analysis of a shark reveals ancient habenular asymmetries in gnathostomes and points to Wnt regulation as a driving force in their diversification

The origin of left-right asymmetries in the vertebrate habenula remains largely unknown. Using a transcriptomic approach, we show that in a cartilaginous fish, the catshark Scyliorhinus canicula, habenulae exhibit marked asymmetries both in their medial and their lateral component. Comparisons across gnathostomes suggest that asymmetries in the catshark lateral habenulae reflect an ancestral gnathostome trait, independently lost in tetrapods and neopterygians. Analysis of the mechanisms underlying their formation highlights an essential role of Wnt signaling. Wnt activity is submitted to a dynamic, asymmetric regulation during habenula development, with a Nodal dependent left repression at a stage when precursors for lateral habenulae have exited cell cycles. Pharmacological treatments during this time window reveal that Wnt signaling promotes lateral right neuronal identities in the right lateral habenula, while its repression by Nodal in the left one promotes lateral left neuronal identities. Based on comparisons with the zebrafish and the mouse, we propose that habenular asymmetry formation and diversification in gnathostomes involve the same developmental logic, relying on a conserved temporal regulation of neurogenesis, shaping neuronal identities on both sides, and its modification by a dynamic Wnt activity, right-restricted in the ancestral state and prone to variations in time and space during evolution.

developmental biology↗

bioRxiv2023

3D RNA profile of habenulae in the catshark Scyliorhinus canicula: a reference in jawed vertebrates

We report the generation of a spatially resolved RNA profile of the habenulae in a chondrichthyan, the catshark Scyliorhinus canicula. The digital profiles obtained for candidate markers of the broad territories previously characterized in this species reflect their broad characteristics, including left- or right asymmetric distributions. We use spatial autocorrelation and autocorrelation as measures to analyze these data and identify novel territory markers. These analyses lead to a refined molecular characterization of catshark habenulae and lead to extended lists of markers for the major territories previously identified. They confirm the marked asymmetry of the catshark habenulae, both in its lateral and medial components. In addition, they highlight a bilateral lateral to medial organization in radial bands, which may reflect a temporal regulation of neurogenesis. These data lead to a novel reference to explore the lmode of evolution of habenulae and of their asymmetries across gnathostomes.

developmental biology↗

bioRxiv2023

Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells.

Caspase-8 deficiency in the epidermis (caspase-8EKO) results in cutaneous inflammation resembling pustular psoriasis, triggered by necroptotic cell death of keratinocytes. Necroptosis is a highly proinflammatory form of programmed necrosis due to the release of intracellular molecules called alarmins, which can act as inflammatory mediators. However, their role in necroptosis-induced skin inflammation remains unexplored. Here, we demonstrate that alarmin IL-33 and its receptor ST2 are essential early mediators of necroptosis-induced skin inflammation. Genetic ablation of Il-33 or St2 dramatically delays lesion development and improves survival of caspase-8EKO animals. IL-33 is highly expressed in necroptotic epidermis of caspase-8EKO mice and induces immune cell recruitment in the skin upon keratinocyte necroptosis. Impairment of the IL33-ST2 axis does not affect epidermal necroptosis but reduces the recruitment of TNF-producing infiltrating immune cells and subsequent amplification of cutaneous inflammation. Collectively, our findings highlight a pivotal role for IL-33 and ST2 in necroptosis-induced skin inflammation. TeaserInhibition of IL-33/ST2 axis alleviates necroptosis-induced skin inflammation by reducing TNF production in the dermis.

immunology↗

bioRxiv2023

Grey and white matter metrics demonstrate distinct and complementary prediction of differences in cognitive performance in children: Findings from ABCD (N= 11 876)

Individual differences in cognitive performance in childhood are a key predictor of significant life outcomes such as educational attainment and mental health. Differences in cognitive ability are governed in part by variations in brain structure. However, studies commonly focus on either grey or white matter metrics in humans, leaving open the key question as to whether grey or white matter microstructure play distinct or complementary roles supporting cognitive performance. To compare the role of grey and white matter in supporting cognitive performance, we used regularized structural equation models to predict cognitive performance with grey and white matter measures. Specifically, we compared how grey matter (volume, cortical thickness and surface area) and white matter measures (volume, fractional anisotropy and mean diffusivity) predicted individual differences in cognitive performance. The models were tested in 11,876 children (ABCD Study, 5680 female; 6196 male) at 10 years old. We found that grey and white matter metrics bring partly non-overlapping information to predict cognitive performance. The models with only grey or white matter explained respectively 15.4% and 12.4% of the variance in cognitive performance, while the combined model explained 19.0%. Zooming in we additionally found that different metrics within grey and white matter had different predictive power, and that the tracts/regions that were most predictive of cognitive performance differed across metric. These results show that studies focusing on a single metric in either grey or white matter to study the link between brain structure and cognitive performance are missing a key part of the equation. Significance StatementThis paper enriches the recent debates on the challenges of linking variation in brain structure to phenotypic differences (Marek et al., 2022). We demonstrate that using latent variables (to improve power), structural equation modelling (to allow greater flexibility in linking brain to behaviour), and by simultaneously incorporating multiple measures of grey and white matter in a large sample, we demonstrate relatively strong and robust brain-behaviour associations, which highlight the complementarity of grey and white matter metrics in predicting cognitive performance as well as the importance of incorporating the full complexity of these associations over 1-to-1 linkages. This finding should lead researchers to consider integrating both grey and white matter measures when demonstrating a more comprehensive picture of brain-cognition relationships.

neuroscience↗

bioRxiv2019

Vibrio cholerae Type VI Secretion System Auxiliary Cluster 3 is a Pandemic-associated Mobile Genetic Element

All sequenced Vibrio cholerae isolates encode a contact-dependent type VI secretion system (T6SS) in three loci that terminate in a toxic effector and cognate immunity protein (E/I) pair, allowing for competitor killing and clonal expansion in aquatic environments and the host gut. Recent studies have demonstrated variability in the toxic effectors produced by different V. cholerae strains and the propensity for effector genes to undergo horizontal gene transfer. Here we demonstrate that a fourth cluster, auxiliary cluster 3 (Aux3), encoding the E/I pair tseH/tsiH, is located directly downstream from two putative recombinases and is flanked by repeat elements resembling att sites. Genomic analysis of 749 V. cholerae isolates, including both pandemic and environmental strains, revealed that Aux3 exists in two states: a [~]40 kb prophage-like element in nine environmental isolates and a [~]6 kb element in pandemic isolates. These findings indicate that Aux3 in pandemic V. cholerae is evolutionarily related to an environmental prophage-like element. In both states, Aux3 excises from the chromosome via site-specific recombination to form a circular product, likely priming the module for horizontal transfer. Finally, we show that Aux3 can integrate into the Aux3-naive chromosome in an integrase-dependent, site-specific manner. This highlights the potential of Aux3 to undergo horizontal transfer by a phage-like mechanism, which based on pandemic coincidence may confer currently unknown fitness advantages to the recipient V. cholerae cell. Significance StatementV. cholerae is a human pathogen that causes pandemics affecting 2.8 million people annually (1). The O1 El Tor lineage is responsible for the current pandemic. A subset of non-O1 strains cause cholera-like disease by producing the major virulence factors cholera toxin and toxin co-regulated pilus but fail to cause pandemics. The full set of V. cholerae pandemic factors is unknown. Here we describe the type VI secretion system (T6SS) Aux3 element as a largely pandemic-specific factor that is evolutionarily related to an environmental prophage-like element circulating in non-pathogenic strains. These findings shed light on V. cholerae T6SS evolution and indicate the Aux3 element as a pandemic-enriched mobile genetic element.

microbiology↗