HAL ENVT (Ecole Nationale Vétérinaire de Toulouse)
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Multidimensional reference regions is a new tool to optimize the personalized care of patients
No full textInternational audienceMedical diagnostic processes often rely on comprehensive biological assessments, but current methods have drawbacks, such as insufficient consideration of variable dependence. Modern databases enable precise estimation of multidimensional variable distributions, prompting this study to enhance methodologies for biological variables. The focus is on establishing better reference regions and defining more accurate decision boundaries. Using an American database (1999-2017) with 19,231 healthy and 24,257 diseased individuals, the study examined plasma biochemical markers. The methodology involved constructing reference regions based on level sets of the healthy and diseased distributions and establishing decision boundaries. An example involved selecting diseased liver patients and considering 9 biological variables characterizing liver dysfunction. The proposed method is consistently more sensitive and specific than traditional approaches. Our results show that other biological functions, such as renal and cardiac functions, in a patient with liver dysfunction are also likely to be altered, even if the biochemical variables measuring these functions remain within the reference range. Therefore, it is preferable to consider a large panel of biological variables rather than just 9 to accurately characterize liver function. Despite potential limitations in identifying diseases, the proposed methodology provides valuable insights into physiological dysfunctions, enhancing early detection
PARSEC
No full textPARSEC is a bioinformatics pipeline designed to genotype large populations using low coverage sequencing dat
French‐Speaking Network of Pharmacogenetics (RNPGx) Recommendations for Clinical Use of Mavacamten
No full textInternational audienceMavacamten, the first drug in the class of β‐cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 poor metabolizers have increased exposure and are at increased risk of reduced cardiac hypercontractility. To ensure the safety of all patients, European Medicines Agency recommends CYP2C19 preemptive genotyping, and consecutively, to adapt maintenance and initial mavacamten doses, and to manage drug–drug interactions, according to CYP2C19 phenotype. In this article, we summarize evidence from the literature supporting the association between CYP2C19 phenotype and pharmacological features of mavacamten and provide, beyond biologic guidelines, therapeutic recommendations for the use of mavacamten based on CYP2C19 and CYP3A4/CYP3A5 genotype
Pairwise graph edit distance characterizes the impact of the construction method on pangenome graphs
No full textInternational audienceMotivation: Pangenome variation graphs are an increasingly used tool to perform genome analysis, aiming to replace a linear reference in a wide variety of genomic analyses. The construction of a variation graph from a collection of chromosome-size genome sequences is a difficult task that is generally addressed using a number of heuristics. The question that arises is to what extent the construction method influences the resulting graph, and the characterization of variability. Results: We aim to characterize the differences between variation graphs derived from the same set of genomes with a metric which expresses and pinpoint differences. We designed a pairwise variation graph comparison algorithm, which establishes an edit distance between variation graphs, threading the genomes through both graphs. We applied our method to pangenome graphs built from yeast and human chromosome collections, and demonstrate that our method effectively characterizes discordances between pangenome graph construction methods and scales to real datasets
Plasmids in Staphylococcus aureus: key vectors of antibiotic resistance genes dissemination
No full textInternational audienceBackground and objectives: Staphylococcus aureus (SA) possesses a wide variety of antibiotic resistance genes (ARGs), and their dissemination is closely associated with the high proportion of mobile genetic elements (MGEs) present in SA genomes (between 15 and 20%). To date, few data are available on the diversity of ARG-carrying MGEs in SA, and their impact on the spread of antibiotic resistance is poorly documented.Methods: An in silico analysis of 9054 human- and animal-associated SA genomes available in NCBI databases was carried out. An exhaustive mapping of associations between MGE, ARG and hosts was established using the ResFinder, RGI-CARD and MEFinder tools. In parallel, an in vitro analysis of 329 SA isolates collected from animals through the Resapath network between 2010 and 2021 and carrying ARGs was carried out. Plasmids were characterized by PFGE and the ARGs they carried determined by PCR. All identified plasmids were long-read sequenced (MinION) and a subset of 81 isolates were short-read sequenced (Illumina).Results: In silico analyses of SA genomes identified 88 different ARGs and 305 different MGEs, including 167 plasmids (identified using the rep gene), 25 transposons and 14 integrative and conjugative elements. Exploration of the MGE/ARG associations revealed that ARGs were predominantly present on plasmids (62%) and transposons (37%, with 2% associated with plasmids). Given their importance as ARG carriers, 211 plasmids collected from 329 SA isolates of animal origin in France over a ten-year period were characterized. The major families identified —rep7a, rep20, and rep10— were associated with specific resistance genes (str, cat, blaZ, erm(C)) and exhibited widespread horizontal transfer across different SA sequence types and animal hosts. Evolution of plasmids was observed, since the rep7a/str and rep7a/cat plasmids, circulating in horses, were progressively replaced by a rep7a plasmid carrying both str and cat genes. The study also highlighted the presence of mosaic (combining elements from different bacterial species/genera) and hybrid (displaying more than one rep gene) plasmids. Conclusions: The diversity of MGEs and the predominance of ARG/plasmid associations confirmed that MGEs, and plasmids in particular, play a key role in the transmission of resistance in SA, whatever the host. It is therefore essential to characterize the transmission mechanisms of these elements in order to understand and better control the spread of antibiotic resistance in this major pathogen
Protein signatures of feed restriction and spontaneous lipolysis in skimmed ewe milk
No full textInternational audienceMilk lipolysis refers to the breakdown of triacylglycerols by lipoprotein lipase. Our aim was to identify the drivers of spontaneous lipolysis in skimmed ewe milk. To achieve this, feed restriction was used as a lever to generate contrasting samples with respect to lipolysis. We combined multivariate statistical methods to identify the effects of feed restriction on ewes, the molecular composition of skim milk, and the drivers of spontaneous lipolysis in milk. The high spontaneous lipolysis in skimmed ewe milk was driven by a combination of variables consisting of 12 milk proteins (ANGPT1, FN1, COL14A1, W5PDQ9, W5QH04, CLSTN1, PPIB, PLIN3, ITIH2, ASAH1, SMPD1 and FST), 7 milk fatty acids (C6:0, C14:0, C14:1 cis9, C10:1 cis9, C10:0, C11:0 and C12:0), milk urea, plasma acetate, plasma urea, plasma IGF1, milk yield, and NEL. In particular, the proteins ANGPT1, SMPD1, and ASAH1 were identified as participants in the lipolytic process in milk, whatever the level of nutrition, which could be considered in future tools to manage milk lipolysis
Molecular responses of chicken embryos to maternal heat stress through DNA methylation and gene expression: a pilot study
No full textInternational audienceClimate change, with its repercussions on agriculture, is one of the most important adaptation challenges for livestock production. Poultry production is a major source of proteins for human consumption all over the world. With a growing human population, improving poultry's adaptation to environmental constraints becomes critical. Extensive evidence highlights the influence of environmental variations on epigenetic modifications. The aim of this paper is therefore to explore chickens' molecular response to maternal heat stress. We employed Reduced Representation Bisulfite Sequencing to generate genome-wide single-base resolution DNA methylation profiling and RNA sequencing to profile the transcriptome of the brains of embryos hatched from dams reared under either heat stress (32 ∘ C) or thermoneutrality (22 ∘ C). We detected 289 significant differentially methylated CpG sites (DMCs) and one differentially methylated region (DMR) between heat stressed and control groups. These DMCs were associated with 357 genes involved in processes such as cellular response to stimulus, developmental processes, and immune function. In addition, we identified 11 genes differentially expressed between the two groups of embryos, and identified ATP9A as a target gene of maternal heat stress on offspring. This study provides a body of fundamental knowledge on adaptive mechanisms concerning heat tolerance in chickens
Enhancing Biodiversity‐Function Relationships in Field Retting: Towards Key Microbial Indicators for Retting Control
No full textInternational audienceHemp field retting is a bioprocess that facilitates fibre extraction by degrading pectin and other matrix components surrounding fibre bundles. However, traditional methods rely on empirical practices, often resulting in inconsistent fibre quality. This study investigates the biodiversity–function relationship in the hemp retting ecosystem to identify microbial and enzymatic indicators for improved process control. Over six weeks of field retting, we monitored bacterial and fungal community dynamics using high‐throughput sequencing and assessed enzymatic activity profiles. Our results revealed a sequential enzymatic pattern: pectinases (e.g., polygalacturonase) dominated early stages, followed by hemicellulases (β‐xylosidase, β‐galactosidase), and later cellulases. These enzymatic shifts were reflected in the changes in microbial community composition, with pectinolytic bacteria (e.g., Proteobacteria ) dominating the initial phases and cellulolytic fungi (e.g., Ascomycota ) becoming more prevalent later. Our results identified specific microbial taxa correlated with optimal retting, suggesting their potential as bioindicators for monitoring retting. Specifically, key bacterial genera such as Pseudomonas and Sphingomonas , and fungal genera like Cladosporium , were associated with distinct enzymatic profiles. Our findings offer new insights into the microbial ecology of retting, providing both microbial and enzymatic indicators that could inform the development of monitoring strategies for process control, ultimately contributing to more consistent hemp fibre production
Biotechnological advances in 3D modeling of cancer initiation. Examples from pancreatic cancer research and beyond
No full textInternational audienceIn recent years, biofabrication technologies have garnered significant attention within the scientific community for their potential to create advanced in vitro cancer models. While these technologies have been predominantly applied to model advanced stages of cancer, there exists a pressing need to develop pertinent, reproducible, and sensitive 3D models that mimic cancer initiation lesions within their native tissue microenvironment. Such models hold profound relevance for comprehending the intricacies of cancer initiation, to devise novel strategies for early intervention, and/or to conduct sophisticated toxicology assessments of putative carcinogens. Here, we will explain the pivotal factors that must be faithfully recapitulated when constructing these models, with a specific focus on early pancreatic cancer lesions. By synthesizing the current state of research in this field, we will provide insights into recent advances and breakthroughs. Additionally, we will delineate the key technological and biological challenges that necessitate resolution in future endeavors, thereby paving the way for more accurate and insightful in vitro cancer initiation models
The glycosomal ATP-dependent phosphofructokinase of Trypanosoma brucei operates also in the gluconeogenic direction.
No full textInternational audienceIn the glucose-free environment of the midgut of the tsetse fly vector, the procyclic forms of Trypanosoma brucei primarily consume proline to feed its central carbon and energy metabolism. In this context, the parasite produces through gluconeogenesis, glucose 6-phosphate (G6P), the precursor of essential metabolic pathways, from proline catabolism. We show here that the parasite uses three different enzymes to perform the key gluconeogenic reaction producing fructose 6-phosphate (F6P) from fructose 1,6-bisphosphate, (i) fructose-1,6-bisphosphatase (FBPase), the canonical enzyme performing this reaction, (ii) sedoheptulose-1,7-bisphosphatase (SBPase), and (iii) more surprisingly ATP-dependent phosphofructokinase (PFK), an enzyme considered to irreversibly catalyze the opposite reaction involved in glycolysis. These three enzymes, as well as six other glycolytic/gluconeogenic enzymes, are located in peroxisome-related organelles, named glycosomes. Incorporation of 13C-enriched glycerol (a more effective alternative to proline for monitoring gluconeogenic activity) into F6P and G6P was more affected in the PFK null mutant than in the FBPase null mutant, suggesting the PFK contributes at least as much as FBPase to gluconeogenesis. We also showed that glucose deprivation did not affect the quantities of PFK substrates and products, whereas an approximately 500-fold increase in the substrate/product ratio was expected for PFK to carry out the gluconeogenic reaction. In conclusion, we show for the first time that ATP-dependent PFK can function in vivo in the gluconeogenic direction, even in the presence of FBPase activity. This particular feature, which precludes loss of ATP through a futile cycle involving PFK and FBPase working simultaneously in the glycolytic and gluconeogenic directions, respectively, is possibly due to the supramolecular organization of the metabolic pathway within glycosomes to overcome thermodynamic barriers through metabolic channeling