HAL-Pasteur
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Transcriptional landscape of the cell cycle in a model thermoacidophilic archaeon reveals similarities to eukaryotes
No full textInternational audienceSimilar to many eukaryotes, the thermoacidophilic archaeon Saccharolobus islandicus follows a defined cell cycle program, with two growth phases, G1 and G2, interspersed by a chromosome replication phase (S), and followed by genome segregation and cytokinesis (M-D) phases. To study whether and which other processes are cell cycle-coordinated, we synchronized cultures of S. islandicus and performed an in-depth transcriptomic analysis of samples enriched in cells undergoing the M-G1, S, and G2 phases, providing a holistic view of the S. islandicus cell cycle. We show that diverse metabolic pathways, protein synthesis, cell motility and even antiviral defense systems, are expressed in a cell cycle-dependent fashion. Moreover, application of a transcriptome deconvolution method defined sets of phase-specific signature genes, whose peaks of expression roughly matched those of yeast homologs. Collectively, our data elucidates the complexity of the S. islandicus cell cycle, suggesting that it more closely resembles the cell cycle of certain eukaryotes than previously appreciated
In-host evolution of Yersinia enterocolitica during a chronic human infection
No full textInternational audienceBacteria exhibit remarkable adaptability in response to selective pressures encountered during infection and antibiotic treatment. We characterize four Yersinia enterocolitica clonal isolates from successive bacteremia episodes that evolved within an elderly patient over 14 years. Their common evolution is characterized by a genome size reduction resulting in the loss of about a hundred genes and a so far undescribed deletion in the DNA gyrase gene gyrA conferring quinolone resistance. Third-generation cephalosporin resistance of the last isolate correlates with a truncation of OmpF in synergy with an increased production of BlaA and AmpC β-lactamases. A strong proteome remodeling of the isolates reveals a perturbed stringent response, as well as impaired metabolism which substantiate their severe growth defects in vitro, accounting for antibiotics tolerance and possibly therapeutic failure. This study documents previously unreported genetic and phenotypic changes associated with in-host adaptation of a pathogenic Yersinia species under antibiotic pressure
BFVD—a large repository of predicted viral protein structures
No full textInternational audienceThe AlphaFold Protein Structure Database (AFDB) is the largest repository of accurately predicted structures with taxonomic labels. Despite providing predictions for over 214 million UniProt entries, the AFDB does not cover viral sequences, severely limiting their study. To address this, we created the Big Fantastic Virus Database (BFVD), a repository of 351 242 protein structures predicted by applying ColabFold to the viral sequence representatives of the UniRef30 clusters. By utilizing homology searches across two petabases of assembled sequencing data, we improved 36% of these structure predictions beyond ColabFold’s initial results. BFVD holds a unique repertoire of protein structures as over 62% of its entries show no or low structural similarity to existing repositories. We demonstrate how a substantial fraction of bacteriophage proteins, which remained unannotated based on their sequences, can be matched with similar structures from BFVD. In that, BFVD is on par with the AFDB, while holding nearly three orders of magnitude fewer structures. BFVD is an important virus-specific expansion to protein structure repositories, offering new opportunities to advance viral research. BFVD can be freely downloaded at bfvd.steineggerlab.workers.dev and queried using Foldseek and UniProt labels at bfvd.foldseek.com
A multicountry evaluation of the Xpert MTB/RIF assay for the diagnosis of intrathoracic tuberculosis in children using alternative specimens (nasopharyngeal aspirate and stool): A prospective cohort study conducted in Madagascar, Ivory Coast and Cameroon (TB KIDS project)
No full textInternational audienceBackgroundAmidst a global resurgence of diphtheria cases with numerous outbreaks recorded worldwide since 2000, a better understanding of this vaccine-preventable disease's circulation is needed. Methods We retrospectively analyzed sera from 2 sero-epidemiological cross-sectional studies in Madagascar and Cambodia on fully primo-vaccinated 3- to 15-year-olds. Using enzyme-linked immunosorbent assay (ELISA) and seroneutralization (Vero Cell TNT) for the 3- to 8-year-olds with low ELISA titration values (<0.01 IU/mL), we assessed (i) the duration of protection by primary vaccination for 3- to 8-year-olds and (ii) the level of diphtheria in children and adolescents. Seropositivity was defined as a titration value (by ELISA or TNT) of at least 0.1 IU/mL and was used as a proxy for diphtheria infection among individuals >6 years postvaccination. Results Seven hundred forty-five children in Cambodia and 949 children in Madagascar were included. Our results show significantly more unprotected children among the 5- to 6-year-olds than among the 3- to 4-year-olds, with 41.1% (39/95) vs 26.7% (27/101; P = .03) in Cambodia and 21.4% (27/126) vs 8.0% (9/113; P < .01) in Madagascar. In Cambodia and Madagascar, respectively, 27.8% and 20.7% of the participants whose primary vaccination was performed >6 years earlier were seropositive, suggesting diphtheria infection. In both countries, we observed a higher rate of infected children when the last vaccine injection had been received 7–8 years or 11–12 years earlier vs 5–6 years earlier. Conclusions Our data show that the disease is present at high levels in Cambodia and Madagascar and that the national recommendation—primary vaccination—is not sufficient: Booster doses appear necessary at around 6 years of age and for adolescents, as recommended by the World Health Organization
Strain phylogroup and environmental constraints shape Escherichia coli dynamics and diversity over a 20-year human gut time series
No full textInternational audienceEscherichia coli is an increasingly antibiotic-resistant opportunistic pathogen. Few data are available on its ecological and evolutionary dynamics in its primary commensal niche, the vertebrate gut. Using Illumina and/or Nanopore technologies, we sequenced whole genomes of 210 E. coli isolates from 22 stools sampled during a 20-year period from a healthy man (ED) living in Paris, France. All phylogroups, except C, were represented, with a predominance of B2 (34.3%), followed by A and F (19% each) phylogroups. Thirty-five clones were identified based on their haplogroup and pairwise genomic single nucleotide polymorphism distance and classified in three phenotypes according to their abundance and residence time: 25 sub-dominant/transient (52 isolates), five dominant/transient (48 isolates) and five dominant/resident (110 isolates). Four over five dominant/resident clones belonged to B2 and closely related F phylogroups, whereas sub-dominant/transient clones belonged mainly to B1, A and D phylogroups. The long residence times of B2 clones seemed to be counterbalanced by lower colonization abilities. Clones with larger within-host frequency persisted for longer. By comparing ED strain genomes to a collection of commensal E. coli genomes from 359 French individuals, we identified ED-specific genomic properties including an enrichment in genes involved in a metabolic pathway (mhp cluster) and the presence of a very rare antiviral defense island. The E. coli colonization within the gut microbiota was shaped by both the intrinsic properties of the strain lineages, in particular longer residence of phylogroup B2, and the environmental constraints such as diet or phages
Seroprevalence of diphtheria in Antananarivo, Madagascar and Cambodia
No full textInternational audienceBackground amidst a global resurgence of diphtheria cases with numerous outbreaks recorded worldwide since 2000, better understanding of this vaccine-preventable disease’s circulation is needed. Methods we analyzed retrospectively sera from two sero-epidemiological cross-sectional studies in Madagascar and Cambodia on fully primo-vaccinated three to fifteen year olds. Using ELISA and seroneutralization (Vero Cell TNT) for the three to eight year olds with low ELISA titration values (<0.01 IU/mL), we assessed the (i) duration of protection by primary vaccination for three to eight year olds, and (ii) level of diphtheria in children and adolescents. Seropositivity was defined as a titration value (by ELISA or TNT) of at least 0.1 IU/mL, and was used as a proxy for diphtheria infection among individuals more than 6 years post vaccination. Results 745 children in Cambodia and 949 children in Madagascar were included. Our results show significantly more unprotected children among the five/six year olds than among the three/four year olds, with 41.1% (39/95) vs. 26.7% (27/101) (p=0.03) in Cambodia and 21.4% (27/126) vs. 8.0 % (9/113) (p<0.01) in Madagascar. In Cambodia and Madagascar, respectively 27.8% and 20.7% of the participants whose primary vaccination was performed more than 6 years earlier were seropositive, suggesting diphtheria infection. In both countries, we observed a higher rate of infected children when the last vaccine injection had been received 7–8 years or 11–12 years vs. 5–6 years earlier. Conclusion Our data show that the disease is present at high levels in Cambodia and Madagascar and that the national recommendation—primary vaccination—is not sufficient: booster doses appear necessary at around six years of age and for adolescents, as recommended by WHO
Interféron γ et persistance du virus SARS-CoV-2: Entre contrôle de la réplication virale et évasion immunitaire
No full textInternational audienceNo abstract availabl
Prescription Trends of Medications Used to Treat Sleep Disturbances in School-aged Children: An Interrupted Time-Series Analysis in France, 2016-2023
No full textInternational audienceObjectiveTo assess rates and trends of hypnotic medication prescriptions for children and adolescents.Study designCross-sectional study of national dispensing data between January 1, 2016, and December 31, 2023, in France. Prescriptions of hypnotic medications (hydroxyzine, alimemazine, melatonin, and Z-drugs) dispensed to children aged 6 to 17 years were analyzed. Monthly rates of hypnotic prescriptions per 1,000 children were modeled before and after the pandemic onset (March 2020) to assess rate and trend changes. Rate ratios (RR) were calculated between estimated and expected prescription rates.ResultsOverall, 2,675,142 prescriptions were dispensed to an average yearly population of 9,963,497 children. In January 2016, prescription rate of hypnotic medications was estimated at 1.9 per 1,000 and at 6.8 per 1,000 in December 2023, with post-pandemic onset rates exceeding the expected by 131% (RR: 2.31, 95%CI: 2.08; 2.54). Prescription trends increased for all medications from -0.1% (95%CI: -0.2;0.1%) per month pre-pandemic to +1.4% (95%CI: 1.2;1.6%) after the pandemic onset for hydroxyzine; +0.1% (95%CI: 0.0;0.2%) to +0.9% (95%CI: 0.7;1.0%) for alimemazine; +2.2% (95%CI: 2.0;2.3%) to +4.4% (95%CI: 3.9;4.9%) for melatonin; and -3.2% (95%CI: -3.6;-2.8%) to +1.8% (95%CI: 1.4;2.2%) for Z-drugs. Monthly prescription rates exceeded the expected by 38% (RR: 1.38, 95%CI: 1.31;1.46) for hydroxyzine; 19% (RR: 1.19, 95%CI: 1.15;1.22) for alimemazine; 344% (RR: 4.44, 95%CI: 4.07;4.80) for melatonin; and 419% (RR: 5.19, 95%CI: 4.24;6.14) for Z-drugs.ConclusionsRecent substantial increases in hypnotic medication prescribing for children are possibly related to their persistently deteriorating mental health, changes in prescribing strategies, and/or unmet pre-existing needs
Contributions of Common Genetic Variants to Constitutional Delay of Puberty and Idiopathic Hypogonadotropic Hypogonadism
No full textInternational audienceAbstract Context Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found. Objective To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. Design Case-control study. Participants 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome (KS); control genotyping data from unrelated studies. Main Outcome Measures Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). Results The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.67, P = 1 × 10−10; for AAM, d = 0.85, P = 1 × 10−16). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, P = .003; AAM d = 0.10, P = .055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.05, P = .45; AAM d = 0.03, P = .56). Conclusion Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct
Unravelling the role of alpha7 nicotinic acetylcholine receptors in inhibitory control in physiological and pathological contexts, using transgenic rats and touchscreen technology
No full textInternational audienceDysfunctional α7 nicotinic acetylcholine receptors (α7*nAChRs) and their genetic regulation have been associated with several neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). Preclinical studies revealed that α7*nAChR ligands can improve executive function, commonly impaired across neuropsychiatric disorders. Yet, a translational gap prevents these findings from resulting into clinically effective treatments. To tackle this translational gap, we combine approaches such as pharmacological modulation, transgenic rats and touchscreen-based behavioral assays to investigate the role of these receptors notably with region-specific resolution. Our findings show that rats knockout for the α7 subunit gene (α7KO) present a general deficit in inhibitory control as observed in the continuous performance task and the differential reinforcement of low-rates of responding task, which seems unrelated to deficits in attention, learning or motivation. In a second set of experiments, we aim at identifying the contribution of α7*nAChRs to the development of cognitive deficits in the context of amyloid beta-mediated diseases, and the putative interaction between these receptors and the amyloid beta peptide in a rat model. Indeed, a particular role of α7*nAChRs has been suggested in Alzeihmer’s disease with fewer of these receptors observed in patients and their putative blockade by amyloid beta. To untangle this relationship, we use a viral vector-mediated local gene expression to express a mutated form of the human APP leading to an over production of amyloid beta. So far, our approach has revealed a crucial role of α7*nAChRs in response inhibition and represents a promising tool to screen new α7*nAChR ligands for therapeutical purposes