A puzzling anomaly in the 4-mer composition of the giant pandoravirus genomes reveals a stringent new evolutionary selection process

International audienceThe Pandoraviridae is a rapidly growing family of giant viruses, all of which have been isolated using laboratory strains of Acanthamoeba. The genomes of ten distinct strains have been fully characterized, reaching up to 2.5 Mb in size. These double-stranded DNA genomes encode the largest of all known viral proteomes and are propagated in oblate virions that are among the largest ever-described (1.2 μm long and 0.5 μm wide). The evolutionary origin of these atypical viruses is the object of numerous speculations. Applying the Chaos Game Representation to the pandoravirus genome sequences, we discovered that the tetranucleotide (4-mer) "AGCT" is totally absent from the genomes of 2 strains (P. dulcis and P. quercus) and strongly underrepresented in others. Given the amazingly low probability of such an observation in the corresponding randomized sequences, we investigated its biological significance through a comprehensive study of the 4-mer compositions of all viral genomes. Our results indicate that "AGCT" was specifically eliminated during the evolution of the Pandoraviridae and that none of the previously proposed host-virus antagonistic relationships could explain this phenomenon. Unlike the three other families of giant viruses (Mimiviridae, Pithoviridae, Molliviridae) infecting the same Acanthamoeba host, the pandoraviruses exhibit a puzzling genomic anomaly suggesting a highly specific DNA editing in response to a new kind of strong evolutionary pressure.IMPORTANCE The recent years have seen the discovery of several families of giant DNA viruses all infecting the ubiquitous amoebozoa of the genus Acanthamoeba. With dsDNA genomes reaching 2.5 Mb in length packaged in oblate particles the size of a bacterium, the pandoraviruses are the most complex and largest viruses known as of today. In addition to their spectacular dimensions, the pandoraviruses encode the largest proportion of proteins without homolog in other organisms which are thought to result from a de novo gene creation process. While using comparative genomics to investigate the evolutionary forces responsible for the emergence of such an unusual giant virus family, we discovered a unique bias in the tetranucleotide composition of the pandoravirus genomes that can only result from an undescribed evolutionary process not encountered in any other microorganism

Expression of mitofusin 2R94Q in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A

Charcot-Marie-Tooth disease type 2A is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene. Mitofusin 2 encodes a mitochondrial outer membrane protein that participates in mitochondrial fusion in mammalian cells. How mutations in this protein lead to Charcot-Marie-Tooth disease type 2A pathophysiology remains unclear. We have generated a transgenic mouse expressing either a mutated (R94Q) or wild-type form of human mitofusin 2 in neurons to evaluate whether the R94Q mutation was sufficient for inducing a Charcot-Marie-Tooth disease type 2A phenotype. Only mice expressing mitofusin 2R94Q developed locomotor impairments and gait defects thus mimicking the Charcot-Marie-Tooth disease type 2A neuropathy. In these animals, the number of mitochondria per axon was significantly increased in the distal part of the sciatic nerve axons with a diameter smaller than 3.5 μm. Importantly, the analysis of R94Q transgenic animals also revealed an age-related shift in the size of myelinated axons leading to an over-representation of axons smaller than 3.5 μm. Together these data suggest a link between an increased number of mitochondria in axons and a shift in axonal size distribution in mitofusin 2R94Q transgenic animals that may contribute to their neurological phenotyp

Approches quantitatives de l'analyse des pr{\'e}dictions en traduction automatique neuronale (TAN)

As part of a larger project on optimal learning conditions in neural machine translation, we investigate characteristic training phases of translation engines. All our experiments are carried out using OpenNMT-Py: the pre-processing step is implemented using the Europarl training corpus and the INTERSECT corpus is used for validation. Longitudinal analyses of training phases suggest that the progression of translations is not always linear. Following the results of textometric explorations, we identify the importance of the phenomena related to chronological progression, in order to map different processes at work in neural machine translation (NMT).Comment: in French. JADT 2020 : 15{\`e}mes Journ{\'e}es Internationales d'Analyse statistique des Donn{\'e}es Textuelles, Universit{\'e} de Toulouse, Jun 2020, Toulouse, Franc

Safety and Efficacy of Adding a Single Low Dose of Primaquine to the Treatment of Adult Patients With Plasmodium falciparum Malaria in Senegal, to Reduce Gametocyte Carriage: A Randomized Controlled Trial.

Introduction: More information is needed about the safety of low-dose primaquine in populations where G6PD deficiency is common. Methods: Adults with Plasmodium falciparum malaria were randomized to receive 1 of 3 artemisinin combination therapies (ACTs) with or without primaquine (0.25 mg/kg). Glucose-6-phosphate dehydrogenase (G6PD) status was determined using a rapid test. Patients were followed for 28 days to record hemoglobin concentration, adverse events, and gametocyte carriage. The primary end point was the change in Hb at day 7. Results: In sum, 274 patients were randomized, 139 received an ACT alone, and 135 received an ACT + primaquine. The mean reduction in Hb at day 7 was similar in each group, a difference in the ACT + PQ versus the ACT alone group of -0.04 g/dL (95% confidence interval [CI] -0.23, 0.31), but the effect of primaquine differed according to G6PD status. In G6PD-deficient patients the drop in Hb was 0.63 g/dL (95% CI 0.03, 1.24) greater in those who received primaquine than in those who received an ACT alone. In G6PD-normal patients, the reduction in Hb was 0.22 g/dL (95% CI -0.08, 0.52) less in those who received primaquine (interaction P = .01). One G6PD normal patient who received primaquine developed moderately severe anaemia (Hb < 8 g/dL). Dark urine was more frequent in patients who received primaquine. Primaquine was associated with a 73% (95% CI 24-90) reduction in gametocyte carriage (P = .013). Conclusion: Primaquine substantially reduced gametocyte carriage. However, the fall in Hb concentration at day 7 was greater in G6PD-deficient patients who received primaquine than in those who did not and one patient who received primaquine developed moderately severe anemia. Clinical Trial registration: PACTR201411000937373 (www.pactr.org)

Pandoravirus Celtis Illustrates the Microevolution Processes at Work in the Giant Pandoraviridae Genomes

With genomes of up to 2.7 Mb propagated in μm-long oblong particles and initially predicted to encode more than 2000 proteins, members of the Pandoraviridae family display the most extreme features of the known viral world. The mere existence of such giant viruses raises fundamental questions about their origin and the processes governing their evolution. A previous analysis of six newly available isolates, independently confirmed by a study including three others, established that the Pandoraviridae pan-genome is open, meaning that each new strain exhibits protein-coding genes not previously identified in other family members. With an average increment of about 60 proteins, the gene repertoire shows no sign of reaching a limit and remains largely coding for proteins without recognizable homologs in other viruses or cells (ORFans). To explain these results, we proposed that most new protein-coding genes were created de novo, from pre-existing non-coding regions of the G+C rich pandoravirus genomes. The comparison of the gene content of a new isolate, pandoravirus celtis, closely related (96% identical genome) to the previously described p. quercus is now used to test this hypothesis by studying genomic changes in a microevolution range. Our results confirm that the differences between these two similar gene contents mostly consist of protein-coding genes without known homologs, with statistical signatures close to that of intergenic regions. These newborn proteins are under slight negative selection, perhaps to maintain stable folds and prevent protein aggregation pending the eventual emergence of fitness-increasing functions. Our study also unraveled several insertion events mediated by a transposase of the hAT family, 3 copies of which are found in p. celtis and are presumably active. Members of the Pandoraviridae are presently the first viruses known to encode this type of transposase

PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cell

Bibliothèques et sciences de l\u27information : quel dialogue ? - Programme

Face aux évolutions technologiques, scientifiques, économiques, sociales, culturelles et politiques de leur environnement, les bibliothèques en tant qu\u27organismes culturels et scientifiques doivent repenser leurs pratiques, leur positionnement économique, politique et institutionnel, et leur rôle social, culturel et scientifique. Dans ce contexte, qu\u27attendent les bibliothèques de la recherche ? Quels thématiques et projets de recherche répondraient à leurs besoins ? Les sciences de l\u27information peuvent-elles apporter des réponses aux enjeux actuels ? Pour répondre aux interrogations posées par ces nouveaux défis, le colloque croise les approches et expériences de bibliothécaires et chercheurs en sciences de l\u27information de nombreux pays ( France, Canada, Etats-Unis, Allemagne, Royaume-Uni...

International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders

Introduction: Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting actions, for the treatment of these sleep disturbances in psychiatric disorders.Methods: To this aim, we conducted a systematic review according to PRISMA on the use of melatonin for the treatment of insomnia and circadian sleep disorders in neuropsychiatry. We expressed recommendations for the use of melatonin in psychiatric clinical practice for each disorder using the RAND/UCLA appropriateness method.Results: We selected 41 studies, which included mood disorders, schizophrenia, substance use disorders, attention deficit hyperactivity disorders, autism spectrum disorders, neurocognitive disorders, and delirium; no studies were found for both anxiety and eating disorders.Conclusion: The administration of prolonged release melatonin at 2–10 mg, 1–2 h before bedtime, might be used in the treatment of insomnia symptoms or comorbid insomnia in mood disorders, schizophrenia, in adults with autism spectrum disorders, neurocognitive disorders and during sedative-hypnotics discontinuation. Immediate release melatonin at &lt;1 mg might be useful in the treatment of circadian sleep disturbances of neuropsychiatric disorders