Biology subjects

Mathieu, A.

Publications and source records attributed to Mathieu, A..

10 recordsLinked to original sources

bioRxiv2026

An in-depth, updated benchmark for 16S amplicon sequencing

Amplicon-based techniques provide a rapid and cost-effective approach for profiling microbial communities. However, the observed microbial diversity is influenced by a wide range of factors, encompassing pre-analytical steps such as the choice of primers and target regions, as well as the bioinformatic pipeline, including the selection of tools, reference databases, and parameter settings. Several benchmarks are already available in the literature, but the updates to important tools and databases, namely LotuS3, the Ribosomal Database Project and GreenGenes2, prompted our investigation. In this study, we conducted a comprehensive benchmark of the main bioinformatic tools and databases. Using seven regions for three publicly available mock communities of increasing complexity, we tested 38 possible combinations of sequence resolution algorithms (DADA2 stand-alone, LotuS3 (DADA2/UPARSE)), taxonomic classifiers and search tools (Kraken2, DECIPHER, RDP, MMseqs2, Lambda, and Metaxa2), and databases (SILVA, GreenGenes2, RDP, RefSeq, and Metaxa2). The region V1-V3, coupled with DADA2+MMseqs2+SILVA, DADA2+Metaxa2, or LotuS3 (DADA2)+RDP yielded the highest-quality estimates of the true diversity according to the metrics. We also demonstrated that even certain dominant genera remain difficult to detect, and that the quantification of all genera can be substantially over- or under-estimated, even when using optimal combinations of tools and reference databases.

bioinformatics↗

bioRxiv2025

Tuned to explore: Increased phasic responses to auditory targets and novelty in children regardless of induced tonic arousal

The ability to focus on relevant information while ignoring distractions is critical during childhood, as it supports learning, social interaction, and adaptation to changing environments. This attentional balance is thought to depend in part on arousal regulation, mediated by the activity of the locus coeruleus norepinephrine (LC-NE) system. Moderate levels of arousal are typically associated with optimal cognitive performance. However, the interaction between arousal and attention remains poorly understood in humans, especially during development. In this study, we investigated whether experimentally modulating tonic arousal, the baseline level of physiological alertness, affects attentional processing in children (N = 44, aged 6-8) and adults (N = 46, aged 18-35). Participants performed an active auditory three-stimulus (standard, novel, target) oddball task, designed to assess selective attention to target tones and distraction by novel sounds. Prior to each task block, tonic arousal was manipulated using music or videos varying in arousing content. Physiological responses were recorded continuously (skin conductance, pupil dilation, heart rate) to index both tonic arousal and transient, phasic changes in arousal triggered by task events. While tonic arousal modulation was successful, as confirmed by skin conductance levels, Bayesian analyses provided evidence for no effect of this modulation on subsequent attentional processing. Importantly, children generally exhibited stronger phasic arousal responses, particularly to task-irrelevant novel sounds, reflecting less mature regulation of attention and arousal. These findings show developmental differences in physiological responses to unexpected environmental stimuli and provide physiological evidence of increased distractibility during childhood.

neuroscience↗

bioRxiv2025

Exploration of chemical probes and conformational flexibility of GID4 - the substrate receptor of human CTLH E3 ligase complex

The application of targeted protein degradation (TPD) is currently constrained by the limited availability of low-molecular-weight molecules that can recruit E3 ligases other than CRBN (Cereblon) or VHL (Von Hippel-Lindau ligase). In this study, we present the structure-based drug design (SBDD) of high-affinity ligands that engage E3 ligase GID4 (Glucose-induced degradation protein 4) in biophysical and cellular experiments. Through structural studies and molecular modeling, we identified three clusters of compounds that induce distinct conformations of GID4. We characterized potential exit vectors and used the most promising ligand as a building block to prepare bifunctional degraders in the form of proteolysis-targeting chimeras (PROTACs). Although ternary complex formation was successful in vitro, degradation of BRD4 was not observed, highlighting the need for further optimization of the degraders. Finally, we theoretically investigated the likelihood of the identified GID4 conformations participating in protein-protein interactions mediated by molecular glue mechanisms. We believe the expanded ligand diversity discovered in this study may pave the way for tuning the selectivity and efficacy of interactions involving GID4 and its neosubstrates. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/662521v3_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@19187e8org.highwire.dtl.DTLVardef@171abd1org.highwire.dtl.DTLVardef@1c75a5forg.highwire.dtl.DTLVardef@fe17fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Global and selective effects of auditory attention on arousal: insights from pupil dilation

Theoretical models of attention propose that norepinephrine (NE) can induce both a global boost of arousal and selective amplification of high-priority stimuli, yet few tasks have tested these dual effects in humans. Here, we used pupillometry in an auditory detection task, the Competitive Attention Test (CAT), previously performed in large cohort studies, to examine how task engagement (active vs. passive) and stimulus relevance (informative vs. uninformative cues) modulate arousal. Results showed that both relevant and irrelevant sounds elicited larger pupil dilation under active conditions, indicating a global arousal effect. Crucially, only relevant sounds benefited from an additional dilation when preceded by an informative cue, demonstrating a selective arousal mechanism associated to top-down attention. These findings illustrate the NEs dual role in boosting overall alertness while selectively enhancing high-priority stimuli. Beyond theoretical implications, this work highlights that the CAT captures measurable arousal components, reinforcing its utility for clinical assessments of attention-arousal clinical disruptions.

neuroscience↗

bioRxiv2024

Enhancing tonic arousal improves voluntary but not involuntary attention in humans

Arousal and attention are fundamental brain functions that play a critical role in optimizing performance. Kahnemans attention model (1973) theorizes a key interplay between attention and arousal, yet this relationship remains poorly understood. Using a multimodal approach, we investigated this interaction in healthy young adults performing an auditory attention task designed to simultaneously assess phasic arousal, voluntary attention, and involuntary attention. Furthermore, tonic arousal was experimentally modulated with low or high arousing music, as confirmed by changes in pupil size and heart rate. Behavioral data confirmed that informative cues enhanced voluntary attention, while unexpected salient task-irrelevant sounds (so-called distractors) produced either shortened or lengthened reaction times depending on their timing relative to target onset. Physiological data indicated that the facilitation effect of distractors on reaction times was driven by increases in phasic arousal. This benefit was further modulated by a dynamic interplay between phasic arousal and voluntary attention over time. Supporting Aston-Jones and Cohens theory, a fronto-central cortical response to distractors revealed that tonic and phasic arousal interact in line with an inverted U-shaped relationship. This study provides empirical evidence, in humans, that tonic arousal can optimize performance by tuning phasic arousal and attentional control.

neuroscience↗

bioRxiv2024

Comprehensive benchmark of integrative strategies for analyzing microbiome-metabolome relationships

BackgroundThe exponential growth of high-throughput sequencing technologies was an incredible opportunity for researchers to combine various -omics within computational frameworks. Among these, metagenomics and metabolomics data have gained an increasing interest due to their involvement in many complex diseases. However, currently, no standard seems to emerge for jointly integrating both microbiome and metabolome datasets within statistical models. ResultsThus, in this paper we comprehensively benchmarked nineteen different integrative methods to untangle the complex relationships between microorganisms and metabolites. Methods evaluated in this paper cover most of the researchers goals such as global associations, data summarization, individual associations, and feature selection. Through an extensive and realistic simulation we identified best methods across questions commonly encountered by researchers. We applied the most promising methods in an application to real gut microbial datasets, unraveling complementary biological processes involved between the two omics. We also provided practical guidelines for practitioners tailored to specific scientific questions and data types. ConclusionIn summary, our work paves the way toward establishing research standards when mutually analyzing metagenomics and metabolomics data, building foundations for future methodological developments.

bioinformatics↗

bioRxiv2019

A standardized gnotobiotic mouse model harboring a minimal 15-member mouse gut microbiota recapitulates SOPF phenotype

Mus musculus is the classic mammalian model for biomedical research. Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice remains a limitation. In an attempt to standardize the gut microbiome in preclinical mouse studies, we developed a simplified mouse microbiota composed of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal microbiota of C57BL/6J Specific (and Opportunistic) Pathogen-Free (SPF/SOPF) animals and derived a new standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome, and GM15 animals are phenotypically similar to SOPF or SPF animals in two different facilities. They are also less sensitive to the deleterious effects of post-weaning malnutrition. The GM15 model provides increased reproducibility and robustness of preclinical studies by limiting the confounding effect of fluctuation in microbiota composition, and offers new opportunities for research focused on how the microbiota shapes host physiology in health and disease.

microbiology↗

bioRxiv2019

The enemy from within: a prophage of Roseburia intestinalis systematically turns lytic in the mouse gut, driving bacterial adaptation by CRISPR spacer acquisition

Despite an overall stability in time of the human gut microbiota at the phylum level, strong temporal variations in species abundance have been observed. We are far from a clear understanding of what promotes or disrupts the stability of microbiome communities. Environmental factors, like food or antibiotic use, modify the gut microbiota composition, but their overall impacts remain relatively low. Phages, the viruses that infect bacteria, might constitute important factors explaining temporal variations in species abundance. Gut bacteria harbour numerous prophages, or dormant viruses. A breakdown of prophage dormancy can evolve through the selection of ultravirulent phage mutants, potentially leading to important bacterial death. Whether such phenomenon occurs in the mammals microbiota has been largely unexplored.\n\nHere we studied temperate phage-bacteria coevolution in gnotoxenic mice colonised with Escherichia coli and Roseburia intestinalis, a dominant symbiont of the human gut microbiota. We show that R. intestinalis harbors two active prophages, Jekyll and Shimadzu, and observed the systematic evolution of ultravirulent Shimadzu phage mutants, leading to a collapse of R. intestinalis population. In a second step, phage infection drove the fast evolution of host phage-resistance mainly through phage-derived spacer acquisition in a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) array. Alternatively, phage resistance was conferred by a prophage originating from an ultravirulent phage with a restored ability to lysogenize.\n\nOur results demonstrate that prophages are the potential source of ultravirulent phages that can successfully infect most of the susceptible bacteria. This suggests that prophages can play important roles in the short-term temporal variations observed in the composition of the gut microbiota.

microbiology↗

bioRxiv2018

Both rare and common genetic variants contribute to autism in the Faroe Islands

The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism compared to controls had a higher burden of copy-number variants (p < 0.05), higher inbreeding status (p < 0.005) and higher load of homozygous deleterious variants (p < 0.01). Our analysis supports the role of several genes/loci associated with autism (e.g. NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g. GRIK2, ROBO1, NINL and IMMP2L) or recessive deleterious variants (e.g. KIRELL3 and CNTNAP2) affecting autism-risk genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.

genetics↗

bioRxiv2017

A framework to identify modifier genes in patients with Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability, speech impairment, and autism spectrum disorders (ASD). It results from a deletion of the 22q13 locus that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors modulating the severity of the syndrome remain largely unknown. In this study, we investigated 85 PMS patients with different 22q13 rearrangements (78 deletions, 7 duplications). We first explored their clinical features and provide evidence for frequent corpus callosum abnormalities. We then mapped candidate genomic regions at the 22q13 locus associated with risk of clinical features, and suggest a second locus associated with absence of speech. Finally, in some cases, we identified additional rearrangements at loci associated with ASD, potentially modulating the severity of the syndrome. We also report the first SHANK3 deletion transmitted to five affected daughters by a mother without intellectual disability nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

genetics↗