Virtual Constraints and Hybrid Zero Dynamics for Realizing Underactuated Bipedal Locomotion

Underactuation is ubiquitous in human locomotion and should be ubiquitous in bipedal robotic locomotion as well. This chapter presents a coherent theory for the design of feedback controllers that achieve stable walking gaits in underactuated bipedal robots. Two fundamental tools are introduced, virtual constraints and hybrid zero dynamics. Virtual constraints are relations on the state variables of a mechanical model that are imposed through a time-invariant feedback controller. One of their roles is to synchronize the robot's joints to an internal gait phasing variable. A second role is to induce a low dimensional system, the zero dynamics, that captures the underactuated aspects of a robot's model, without any approximations. To enhance intuition, the relation between physical constraints and virtual constraints is first established. From here, the hybrid zero dynamics of an underactuated bipedal model is developed, and its fundamental role in the design of asymptotically stable walking motions is established. The chapter includes numerous references to robots on which the highlighted techniques have been implemented.Comment: 17 pages, 4 figures, bookchapte

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Étude globale de deux nouveaux bactériophages : caractérisations transcriptomique, mécanistique et perspectives évolutives

Previous investigations in the field of phage therapy led to the discovery of two new genera of bacteriophages (phages), namely Kpp10virus and Pakpunavirus whose infection mechanisms are unknown. It is acknowledged that a successful infection is notably ensured by an effective takeover of host cell resources, leading to its transformation into a virocell, a cellular organism exclusively dedicated to the production of progeny phages.This PhD work aims to provide a comprehensive view of molecular strategies set up by Kpp10virus and Pakpunavirus (represented by phages PAK_P3 and PAK_P4, respectively) to infect the opportunist pathogen Pseudomonas aeruginosa.First, we assessed phage intrinsic properties by analyzing their genomic content, evaluating their host range and growth parameters and identifying their bacterial receptor.Then, by coupling transcriptomics and metabolomics approaches, we found that both viruses have similar transcriptional programs, with a temporal regulation of their gene expression and production of antisense transcripts. They both strikingly prompt a rapid degradation of 90% of host mRNAs, which are eventually replaced by viral RNAs. Despite this extensive degradation, we found that both phages do not shutoff host metabolism but redirect biosynthesis pathways, however through different mechanisms. In addition, we found that a common host response is elicited upon both PAK_P3 and PAK_P4 infections and hypothesized it represents an attempt of the host to repair extensive RNA damage.Finally, we investigated the functions of an early produced phage protein (Gp92), broadly conserved in both phage genera, in order to identify particular mechanisms of host subversion used by these phages. When expressed alone in the host, Gp92 alters cell morphology and interacts with the bacterial regulatory complex sigma/anti-sigma involved in stress response (namely AlgU- MucA). Our study suggests a potential role of Gp92 in alleviating the stress caused by phage infection.This manuscript provides a model of virocell transformation upon infection of P. aeruginosa by PAK_P3 or PAK_P4. In addition, by comparing their reproductive strategies, it addresses the evolution of infection mechanisms in virulent phages deriving from a common ancestorSoutenue par le renouveau de la phagothérapie, la découverte de nouveaux bactériophages (phages) nous a permis de définir deux nouveaux genres de virus dénommés Kpp10virus et Pakpunavirus dont les mécanismes infectieux sont inconnus. Il est admis que le succès d’un cycle infectieux est notamment assuré par une réappropriation efficace des ressources de la cellule hôte, conduisant à sa transformation en « virocellule », c’est-à-dire, un organisme cellulaire exclusivement dédié à la production de particules virales. Ce travail de thèse a pour objectif d’apporter une vision globale des stratégies moléculaires utilisées par les virus appartenant aux genres Kpp10virus et Pakpunavirus (respectivement représentés par les phages PAK_P3 et PAK_P4) pour infecter le pathogène opportuniste Pseudomonas aeruginosa. Dans un premier temps, nous avons évalué leurs propriétés intrinsèques en analysant le contenu de leurs génomes, leurs spectres d’hôtes, leurs paramètres de croissance ainsi qu’en identifiant leur récepteur bactérien. Dans un second temps, une combinaison d’approches transcriptomiques et métabolomiques a permis de montrer que ces deux virus ont des programmes transcriptionnels similaires, incluant notamment une régulation temporelle de leur expression génétique et la production de transcrits antisens. De plus, ils provoquent tous deux la dégradation rapide de 90% des ARNm de l’hôte, qui sont alors remplacés par des ARNm viraux. Malgré cette dégradation, nous avons constaté que ces deux phages redirigent les voies de biosynthèse bactériennes plutôt que de provoquer une extinction totale du métabolisme cellulaire, en utilisant cependant des mécanismes différents. De plus, nous avons détecté l’activation, par l’hôte, d’une réponse commune en réponse à une infection par PAK_P3 ou PAK_P4 et avons émis l’hypothèse qu’il s’agit d’une tentative de réparation des importants dommages ARN induits par l’infection virale. Enfin, nous avons étudié les fonctions d’une protéine virale (Gp92), largement conservée chez les virus appartenant à ces deux genres et qui est produite au stade précoce du cycle infectieux. Lorsqu’elle est produite seule chez l’hôte, cette protéine altère la morphologie cellulaire et interagit avec un complexe de régulation bactérien de type sigma/anti-sigma impliqué dans la réponse au stress (appelé AlgU-MucA). Notre étude suggère un rôle potentiel de Gp92 dans l’atténuation du stress provoqué par l’infection virale. Ce manuscrit fournit un modèle de transformation d’une cellule de P. aeruginosa en « virocellule » au cours de l’infection par PAK_P3 ou PAK_P4. De plus, la comparaison des stratégies de ces deux virus, vraisemblablement issus d’un ancêtre commun, nous a permis de discuter l’évolution des mécanismes infectieux chez les phages virulent

Étude globale de deux nouveaux bactériophages : caractérisations transcriptomique, mécanistique et perspectives évolutives

Soutenue par le renouveau de la phagothérapie, la découverte de nouveaux bactériophages (phages) nous a permis de définir deux nouveaux genres de virus dénommés Kpp10virus et Pakpunavirus dont les mécanismes infectieux sont inconnus. Il est admis que le succès d’un cycle infectieux est notamment assuré par une réappropriation efficace des ressources de la cellule hôte, conduisant à sa transformation en « virocellule », c’est-à-dire, un organisme cellulaire exclusivement dédié à la production de particules virales. Ce travail de thèse a pour objectif d’apporter une vision globale des stratégies moléculaires utilisées par les virus appartenant aux genres Kpp10virus et Pakpunavirus (respectivement représentés par les phages PAK_P3 et PAK_P4) pour infecter le pathogène opportuniste Pseudomonas aeruginosa. Dans un premier temps, nous avons évalué leurs propriétés intrinsèques en analysant le contenu de leurs génomes, leurs spectres d’hôtes, leurs paramètres de croissance ainsi qu’en identifiant leur récepteur bactérien. Dans un second temps, une combinaison d’approches transcriptomiques et métabolomiques a permis de montrer que ces deux virus ont des programmes transcriptionnels similaires, incluant notamment une régulation temporelle de leur expression génétique et la production de transcrits antisens. De plus, ils provoquent tous deux la dégradation rapide de 90% des ARNm de l’hôte, qui sont alors remplacés par des ARNm viraux. Malgré cette dégradation, nous avons constaté que ces deux phages redirigent les voies de biosynthèse bactériennes plutôt que de provoquer une extinction totale du métabolisme cellulaire, en utilisant cependant des mécanismes différents. De plus, nous avons détecté l’activation, par l’hôte, d’une réponse commune en réponse à une infection par PAK_P3 ou PAK_P4 et avons émis l’hypothèse qu’il s’agit d’une tentative de réparation des importants dommages ARN induits par l’infection virale. Enfin, nous avons étudié les fonctions d’une protéine virale (Gp92), largement conservée chez les virus appartenant à ces deux genres et qui est produite au stade précoce du cycle infectieux. Lorsqu’elle est produite seule chez l’hôte, cette protéine altère la morphologie cellulaire et interagit avec un complexe de régulation bactérien de type sigma/anti-sigma impliqué dans la réponse au stress (appelé AlgU-MucA). Notre étude suggère un rôle potentiel de Gp92 dans l’atténuation du stress provoqué par l’infection virale. Ce manuscrit fournit un modèle de transformation d’une cellule de P. aeruginosa en « virocellule » au cours de l’infection par PAK_P3 ou PAK_P4. De plus, la comparaison des stratégies de ces deux virus, vraisemblablement issus d’un ancêtre commun, nous a permis de discuter l’évolution des mécanismes infectieux chez les phages virulentsPrevious investigations in the field of phage therapy led to the discovery of two new genera of bacteriophages (phages), namely Kpp10virus and Pakpunavirus whose infection mechanisms are unknown. It is acknowledged that a successful infection is notably ensured by an effective takeover of host cell resources, leading to its transformation into a virocell, a cellular organism exclusively dedicated to the production of progeny phages.This PhD work aims to provide a comprehensive view of molecular strategies set up by Kpp10virus and Pakpunavirus (represented by phages PAK_P3 and PAK_P4, respectively) to infect the opportunist pathogen Pseudomonas aeruginosa.First, we assessed phage intrinsic properties by analyzing their genomic content, evaluating their host range and growth parameters and identifying their bacterial receptor.Then, by coupling transcriptomics and metabolomics approaches, we found that both viruses have similar transcriptional programs, with a temporal regulation of their gene expression and production of antisense transcripts. They both strikingly prompt a rapid degradation of 90% of host mRNAs, which are eventually replaced by viral RNAs. Despite this extensive degradation, we found that both phages do not shutoff host metabolism but redirect biosynthesis pathways, however through different mechanisms. In addition, we found that a common host response is elicited upon both PAK_P3 and PAK_P4 infections and hypothesized it represents an attempt of the host to repair extensive RNA damage.Finally, we investigated the functions of an early produced phage protein (Gp92), broadly conserved in both phage genera, in order to identify particular mechanisms of host subversion used by these phages. When expressed alone in the host, Gp92 alters cell morphology and interacts with the bacterial regulatory complex sigma/anti-sigma involved in stress response (namely AlgU- MucA). Our study suggests a potential role of Gp92 in alleviating the stress caused by phage infection.This manuscript provides a model of virocell transformation upon infection of P. aeruginosa by PAK_P3 or PAK_P4. In addition, by comparing their reproductive strategies, it addresses the evolution of infection mechanisms in virulent phages deriving from a common ancesto

“French Phage Network” Annual Conference—Seventh Meeting Report

The French Phage Network (Phages.fr) has continuously grown since its foundation, eight years ago. The annual conference, held at the Institut Pasteur in Paris, attracted 164 participants from the 11th to the 13th of October 2022. Researchers from academic laboratories, hospitals and private companies shared their ongoing projects and breakthroughs in the very institute where Felix d’Hérelle developed phage therapy over a century ago. The conference was divided into four thematic sessions, each opened by a keynote lecture: “Interaction between phages, mobile genetic elements and bacterial immune system,” “Ecology and evolution of phage–bacteria interactions,” “Molecular interplay between phages and their hosts” and “Therapeutic and biotechnological applications of phages.” A total of 32 talks and 33 posters were presented during the conference

“French Phage Network” Annual Conference—Seventh Meeting Report

The French Phage Network (Phages.fr) has continuously grown since its foundation, eight years ago. The annual conference, held at the Institut Pasteur in Paris, attracted 164 participants from the 11th to the 13th of October 2022. Researchers from academic laboratories, hospitals and private companies shared their ongoing projects and breakthroughs in the very institute where Felix d’Hérelle developed phage therapy over a century ago. The conference was divided into four thematic sessions, each opened by a keynote lecture: “Interaction between phages, mobile genetic elements and bacterial immune system,” “Ecology and evolution of phage–bacteria interactions,” “Molecular interplay between phages and their hosts” and “Therapeutic and biotechnological applications of phages.” A total of 32 talks and 33 posters were presented during the conference

Comparative transcriptomics analyses reveal the conservation of an ancestral infectious strategy in two bacteriophage genera

Although the evolution of tailed bacteriophages has increasingly been better understood through comparisons of their DNA sequences, the functional consequences of this evolution on phage infectious strategies have remained unresolved. In this study, we comprehensively compared the transcriptional strategies of two related myoviruses, PAK_P3 and PAK_P4, infecting the same Pseudomonas aeruginosa host strain. Outside of the conservation of their structural clusters, their highly syntenic genomes display only limited DNA similarity. Despite this apparent divergence, we found that both viruses follow a similar infection scheme, relying on a temporal regulation of their gene expression, likely involving the use of antisense transcripts, as well as a rapid degradation of 90% of the host non-ribosomal mRNA, as previously reported for PAK_P3. However, the kinetics of the mRNA degradation is remarkably faster during PAK_P4 infection. Moreover, we found that each virus has evolved specific adaptations, as exemplified by the distinct patterns of their core genes expression as well as the specific manipulation of the expression of iron-related host genes by PAK_P4. This study enhances our understanding of the evolutionary process of virulent phages, which relies on adjusting globally conserved ancestral infection mechanisms.The ISME Journal advance online publication, 12 May 2017; doi:10.1038/ismej.2017.63.status: publishe

Phage Therapy of Pneumonia Is Not Associated with an Overstimulation of the Inflammatory Response Compared to Antibiotic Treatment in Mice

International audienceSupported by years of clinical use in some countries and more recently by literature on experimental models, as well as its compassionate use in Europe and in the United States, bacteriophage (phage) therapy is providing a solution for difficult-to-treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce. Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) was treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (ceftriaxone, cefoxitin, or imipenem-cilastatin; intraperitoneal). Healthy mice also received phages alone. The severity of pulmonary edema, acute inflammatory cytokine concentration (blood and lung homogenates), complete blood counts, and bacterial and bacteriophage counts were determined at early (Յ12 h) and late (Ն20 h) time points. The efficacy of bacteriophage to decrease bacterial load was faster than with antibiotics, but the two displayed similar endpoints. Bacteriophage treatment was not associated with overinflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities than did antibiotics. In the absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of antiviral cytokines (gamma interferon [IFN-␥] and interleukin-12 [IL-12]) and chemokines in the lungs but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals. The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to that with antibiotic treatment

Self-synchronization and Self-stabilization of Walking Gaits Modeled by the 3D LIP Model

International audienc