In vivo evidence for quasispecies distributions in the bovine respiratory syncytial virus genome

We analyzed the genetic evolution of bovine respiratory syncytial virus (BRSV) isolate W2-00131, from its isolation in bovine turbinate (BT) cells to its inoculation in calves. Results showed that the BRSV genomic region encoding the highly variable glycoprotein G remains genetically stable after virus isolation and over 10 serial infections in BT cells, as well as following experimental inoculation in calves. This remarkable genetic stability led us to examine the mutant spectrum of several populations derived from this field isolate. Sequence analysis of molecular clones revealed an important genetic heterogeneity in G coding region of each population, with mutation frequencies ranging from 6.8 to 10.1 10-4 substitutions/nucleotide. The non-synonymous mutations of the mutant spectrum mapped preferentially within the two variable antigenic regions of the ectodomain or close to the highly conserved domain. These results suggest that RSV populations may evolve as complex and dynamic mutant swarms, despite apparent genetic stability

Retention of the virus-derived sequences in the nuclear genome of grapevine as a potential pathway to virus resistance

<p>Abstract</p> <p>Background</p> <p>Previous studies have revealed a wide-spread occurence of the partial and complete genomes of the reverse-transcribing pararetroviruses in the nuclear genomes of herbaceous plants. Although the absence of the virus-encoded integrases attests to the random and incidental incorporation of the viral sequences, their presence could have functional implications for the virus-host interactions.</p> <p>Hypothesis</p> <p>Analyses of two nuclear genomes of grapevine revealed multiple events of horizontal gene transfer from pararetroviruses. The ~200–800 bp inserts that corresponded to partial ORFs encoding reverse transcriptase apparently derived from unknown or extinct caulimoviruses and tungroviruses, were found in 11 grapevine chromosomes. In contrast to the previous reports, no reliable cases of the inserts derived from the positive-strand RNA viruses were found. Because grapevine is known to be infected by the diverse positive-strand RNA viruses, but not pararetroviruses, we hypothesize that pararetroviral inserts have conferred host resistance to these viruses. Furthermore, we propose that such resistance involves RNA interference-related mechanisms acting via small RNA-mediated methylation of pararetroviral DNAs and/or via degradation of the viral mRNAs.</p> <p>Conclusion</p> <p>The pararetroviral sequences in plant genomes may be maintained due to the benefits of virus resistance to this class of viruses conferred by their presence. Such resistance could be particularly significant for the woody plants that must withstand years- to centuries-long virus assault. Experimental research into the RNA interference pathways involving the integrated pararetroviral inserts is required to test this hypothesis.</p> <p>Reviewers</p> <p>This article was reviewed by Arcady R. Mushegian, I. King Jordan, and Eugene V. Koonin.</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The addition of dairy lipids and L. fermentum in infant formulas programs adult gut microbiota and physiology : study in a minipig model

La nutrition postnatale précoce conditionne la santé du futur adulte du fait de son rôle déterminant dans l’implantation du microbiote intestinal et le développement de la physiologie de l’hôte. L’objectif de mon travail de thèse a été d’évaluer les conséquences de la réintroduction de matière grasse laitière associée ou non au probiotique Lactobacillus fermentum dans des préparations pour nourrissons, sur le microbiote, la physiologie intestinale et le métabolisme de l’adulte, en utilisant le miniporc Yucatan comme modèle de l’Homme. Nos travaux ont montré un renforcement des défenses non spécifiques intestinales chez le jeune et une amélioration des fonctions endocrine et immunitaire intestinales de l’adulte soumis à un régime hyper-énergétique, réduisant ainsi le risque de développer une inflammation et des désordres métaboliques. Ces effets ont été associés à une modification de la digestion des préparations chez le jeune et à une modulation de la composition et de l’activité métabolique du microbiote intestinal. Des effets spécifiques de la matière grasse laitière et de L. fermentum, et d’autres complémentaires, ont été observés, suggérant des mécanismes d’action différents. Les modifications induites par la composition des préparations pour nourrissons étaient site- et âge-spécifiques, le comportement du microbiote caecal se rapprochant du microbiote fécal. En conclusion, l’optimisation des préparations pour nourrissons pourrait passer par l’ajout de matière grasse laitière et du probiotique L. fermentum.Early postnatal nutrition programs adult health owing to its crucial role in gut microbiota colonization and host physiology development. The objective of my thesis was to investigate the consequences of dairy lipid addition with or without probiotic Lactobacillus fermentum in infant formulas on adult gut microbiota, physiology and metabolism, using Yucatan minipig as a model for humans. We demonstrated increased non-specific intestinal defences in piglets and improved intestinal endocrine and immune functions in adults submitted to a high-energy diet, which may protect them from inflammation and metabolic disorders. These effects were associated in piglets to changes in digestion and gut microbiota composition and metabolism. We observed specific and complementary effects of dairy lipids and L. fermentum, suggesting different mechanisms of action. The infant formula composition had site- and age-specific effects, the caecal microbiota being closer to the faecal one. To conclude, the addition of dairy lipids and L. fermentum in infant formulas is an effective way to improve infant formulas

L’incorporation de matière grasse laitière et de <em>L. fermentum</em> dans des préparations pour nourrissons programme le microbiote et la physiologie intestinale de l’adulte : étude dans un modèle miniporc

Early postnatal nutrition programs adult health owing to its crucial role in gut microbiota colonization and host physiology development. The objective of my thesis was to investigate the consequences of dairy lipid addition with or without probiotic Lactobacillus fermentum in infant formulas on adult gut microbiota, physiology and metabolism, using Yucatan minipig as a model for humans. We demonstrated increased non-specific intestinal defences in piglets and improved intestinal endocrine and immune functions in adults submitted to a high-energy diet, which may protect them from inflammation and metabolic disorders. These effects were associated in piglets to changes in digestion and gut microbiota composition and metabolism. We observed specific and complementary effects of dairy lipids and L. fermentum, suggesting different mechanisms of action. The infant formula composition had site- and age-specific effects, the caecal microbiota being closer to the faecal one. To conclude, the addition of dairy lipids and L. fermentum in infant formulas is an effective way to improve infant formulas.La nutrition postnatale précoce conditionne la santé du futur adulte du fait de son rôle déterminant dans l’implantation du microbiote intestinal et le développement de la physiologie de l’hôte. L’objectif de mon travail de thèse a été d’évaluer les conséquences de la réintroduction de matière grasse laitière associée ou non au probiotique Lactobacillus fermentum dans des préparations pour nourrissons, sur le microbiote, la physiologie intestinale et le métabolisme de l’adulte, en utilisant le miniporc Yucatan comme modèle de l’Homme. Nos travaux ont montré un renforcement des défenses non spécifiques intestinales chez le jeune et une amélioration des fonctions endocrine et immunitaire intestinales de l’adulte soumis à un régime hyper-énergétique, réduisant ainsi le risque de développer une inflammation et des désordres métaboliques. Ces effets ont été associés à une modification de la digestion des préparations chez le jeune et à une modulation de la composition et de l’activité métabolique du microbiote intestinal. Des effets spécifiques de la matière grasse laitière et de L. fermentum, et d’autres complémentaires, ont été observés, suggérant des mécanismes d’action différents. Les modifications induites par la composition des préparations pour nourrissons étaient site- et âge-spécifiques, le comportement du microbiote caecal se rapprochant du microbiote fécal. En conclusion, l’optimisation des préparations pour nourrissons pourrait passer par l’ajout de matière grasse laitière et du probiotique L. fermentum

Health benefits of dairy lipids and MFGM in infant formula

Human breast milk (HBM) is the gold standard for the early nutrition of the neonates. The best way to improve infant formulas (IFs) is to mimic both the composition and the structure of HBM components. Supplementation of IF with dairy lipids or bovine milk components such as milk fat globule membrane (MFGM), in partial replacement of plant oils that are currently mainly used, has health benefits for infants. In this article, results of clinical studies on the impact of IF supplementation with MFGM and dairy lipids on psychomotor development and infectious disease prevalence in infants are reviewed and supported by recent pre-clinical studies. Numerous human studies have reported beneficial effects of MFGM supplementation on neurocognitive development and protection against infectious agents without deleterious impact on growth. Based on rodent and porcine studies, benefits of adding bovine MFGM and dairy lipids in IFs on gut digestion, physiology and protection against pathogens and inflammatory challenges have also been highlighted. However, more randomized controlled trials testing IF supplementation with bovine milk fat, and specifically apolar lipids and associated glycoproteins, must be performed to increase scientific-based knowledge, address safety concerns, and study its potential programming role of adult health

Health benefits of dairy lipids and MFGM in infant formula

Human breast milk (HBM) is the gold standard for the early nutrition of the neonates. The best way to improve infant formulas (IFs) is to mimic both the composition and the structure of HBM components. Supplementation of IF with dairy lipids or bovine milk components such as milk fat globule membrane (MFGM), in partial replacement of plant oils that are currently mainly used, has health benefits for infants. In this article, results of clinical studies on the impact of IF supplementation with MFGM and dairy lipids on psychomotor development and infectious disease prevalence in infants are reviewed and supported by recent pre-clinical studies. Numerous human studies have reported beneficial effects of MFGM supplementation on neurocognitive development and protection against infectious agents without deleterious impact on growth. Based on rodent and porcine studies, benefits of adding bovine MFGM and dairy lipids in IFs on gut digestion, physiology and protection against pathogens and inflammatory challenges have also been highlighted. However, more randomized controlled trials testing IF supplementation with bovine milk fat, and specifically apolar lipids and associated glycoproteins, must be performed to increase scientific-based knowledge, address safety concerns, and study its potential programming role of adult health

Quels bénéfices santé de la matière grasse laitière et des membranes des globules gras du lait (MFGM) dans les préparations pour nourrissons ?

International audienceHuman breast milk (HBM) is the gold standard for the early nutrition of the neonates. The best way to improve infant formulas (IFs) is to mimic both the composition and the structure of HBM components. Supplementation of IF with dairy lipids or bovine milk components such as milk fat globule membrane (MFGM), in partial replacement of plant oils that are currently mainly used, has health benefits for infants. In this article, results of clinical studies on the impact of IF supplementation with MFGM and dairy lipids on psychomotor development and infectious disease prevalence in infants, are reviewed and supported by recent pre-clinical studies. Numerous human studies have reported beneficial effects of MFGM supplementation on neurocognitive development and protection against infectious agents without deleterious impact on growth. Based on rodent and porcine studies, benefits of adding bovine MFGM and dairy lipids in IFs on gut digestion, physiology and protection against pathogens and inflammatory challenges have also been highlighted. However, more randomized controlled trials testing IF supplementation with bovine milk fat, and specifically apolar lipids and associated glycoproteins, are to be performed to increase scientific-based knowledge, address safety concerns, and study its potential programming role of adult health.Le lait de femme est l’aliment le mieux adapté aux besoins du nouveau-né. Il est ainsi l’aliment de référence tant du point de vue de sa composition nutritionnelle que de celui de ses propriétés fonctionnelles, pour améliorer la formulation des préparations pour nourrissons (PPN). L’incorporation dans les PPN de matière grasse provenant de lait de vache ou de certains de ses composants tels que les membranes des globules gras du lait (MFGM pour milk fat globule membrane), en remplacement partiel des huiles végétales qui sont actuellement principalement utilisées, a des effets bénéfiques sur la santé du nouveau-né. Dans cette revue, les résultats des études cliniques sur l’impact des MFGM et de la matière grasse laitière introduits dans les PPN sur le développement psychomoteur et la prévalence des maladies infectieuses et digestives infantiles sont rapportés et étayés par les résultats d’études pré-cliniques récentes. L’incorporation de MFGM dans les PPN apporte un bénéfice sur le développement neurocognitif de l’enfant et une protection vis-à-vis d’agents infectieux, sans modifier sa croissance. L’effet bénéfique de la supplémentation des PPN avec de la matière grasse laitière et des MFGM d’origine bovine sur la digestion et la physiologie intestinale, ainsi que la protection contre des challenges inflammatoires est par ailleurs mis en évidence dans des études précliniques réalisées chez les rongeurs et le porc. Des études complémentaires restent nécessaires pour affiner nos connaissances sur les mécanismes à l’origine de la fonctionnalité spécifique de la matière grasse laitière et en particulier des lipides apolaires et des glycoprotéines associés aux MFGM, et sur leurs effets potentiels sur la programmation de la santé de l’adulte