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1. French COhoRte Extra-Vascular Implantable CardiovErter DefibrillatoR (FOREVER)

Author

European Georges Pompidou Hospital, University Hospital, Grenoble, University Hospital, Clermont-Ferrand, Centre Hospitalier Universitaire de Rouen, Centre Hospitalier Universitaire de Besancon, Clinique du Millenaire, Institut Mutualiste Montsouris, Groupe Hospitalier Pitie-Salpetriere, University Hospital, Lille, University Hospital, Caen, Hospices Civils de Lyon, CHU de la Timone, Marseille, France, Centre Cardio-Thoracique de Monaco, Hospital of Lens, Institute Arnault Tzanck, France, University Hospital, Strasbourg, France, University Hospital, Limoges, University Hospital, Montpellier, Clinique Pasteur Toulouse, University Hospital, Bordeaux, University Hospital, Toulouse, Institut Jacques Cartier - Massy, Clinique Saint Augustin - Bordeaux, Rennes University Hospital, Clinique de la Sauvegarde, University Hospital of Saint-Etienne, Centre Hospitalier Universitaire, Amiens, Poitiers University Hospital, Clinique Saint-Gatien - Tours, CHU de Reims, Centre Hospitalier Universitaire Dijon, Hospital St. Joseph, Marseille, France, Centre Hospitalier Annecy Genevois, Clinique St Pierre, Perpignan, France, Bichat Hospital, Universite de La Reunion, University Hospital Center of Martinique, Henri Mondor University Hospital, University Hospital, Angers, Central Hospital, Nancy, France, Hôpital privé Clairval - Marseille, Médipôle Lyon-Villeurbanne, Hôpital Privé Les Franciscaines, Hospital Ambroise Paré Paris, Central Hospital, Metz Thionville, France, Hopital Prive Saint Martin - Bordeaux, Hôpital Privé de Parly II - Le Chesnay, and Marijon, Head of Cardiology Division

Published
2024

5. Sepsis in the ICU-II

Author

CHU Dijon Bourgogne, Ryhov Hospital, Jönköping, Bicetre Hospital, Hôpital Européen George Pompidou, APHP, Paris, France, and Michelle Chew, Professor

Published
2024

8. Bevacizumab-based Chemotherapy Adapted to Bevacizumab Pharmacokinetics in 1st-line Treatment (PHARBEVACOL)

Author

CHU DE BESANCON, Gustave Roussy, Cancer Campus, Grand Paris, CHU de Clermont-Ferrand, CHU de Reims, CHU de Brest, AP-HP, Hôpital Pitié- Salpétrière, CHU de Rouen, Poitiers University Hospital, Institut Paoli-Calmettes, Rennes University Hospital, University Hospital, Toulouse, AP-HP, Hôpital Saint-Louis, HCL Hôpital Edouard Hériot, Centre Hospitalier Universitaire Dijon, Nantes University Hospital, Centre Hospitalier Universitaire, Amiens, Hôpital Privé Jean Mermoz, AP-HP, Hôpital Henri Mondor, AP-HP, Hôpital Paul Brousse, CHG de St-Malo, Polyclinique de Blois, University Hospital, Caen, and CHU de Nancy

Published
2024

9. Determining the Most Efficient Screening Cut Off Levels for Phenylketonuria (PKU)

Author

University Hospital, Lille, Hospices Civils de Lyon, University Hospital, Strasbourg, France, CHU de Reims, Centre Hospitalier Universitaire, Amiens, Centre Hospitalier Universitaire Dijon, Nantes University Hospital, University Hospital, Tours, Clinical Research Center of Reunion island, University Hospital, Caen, Rennes University Hospital, University Hospital, Bordeaux, University Hospital, Toulouse, University Hospital, Montpellier, and HESS Valentin, MD, Principal Investigator

Published
2024

10. Amikacin Liposome Inhalation Suspension for Treatment of Mycobacterium Xenopi Pulmonary Infection (AKAPI)

Author

University Hospital, Angers, Hospital Avicenne, University Hospital, Bordeaux, University Hospital, Brest, CH Compiègne, Créteil Hospital, Centre Hospitalier Universitaire Dijon, University Hospital, Grenoble, Centre Hospitalier le Mans, Hôpital de la Croix-Rousse, APHM - Nord, Hôpital Saint Joseph, CH Mulhouse, CH Orléans, Tenon Hospital, Paris, Hôpital Necker-Enfants Malades, CH PERPIGNAN, Poitiers University Hospital, CH Pontoise, CHU de Reims, Rennes University Hospital, CHU de Rouen - Accueil, Central Hospital Saint Quentin, IHU Strasbourg, University Hospital, Tours, CH Abbeville, and CH Cannes

Published
2024

14. Hydration of biologically relevant tetramethylammonium cation by neutron scattering and molecular dynamics

Author

Mason, Philip, Martinek, Tomas, Fábián, Balázs, Vazdar, Mario, Jungwirth, Pavel, Tichacek, Ondrej, Duboué-Dijon, Elise, and Martinez-Seara, Hector

Subjects
Physics - Chemical Physics
Abstract

Neutron scattering and molecular dynamics studies were performed on a concentrated aqueous tetramethylammonium (TMA) chloride solution to gain insight into the hydration shell structure of TMA, which is relevant for understanding its behavior in biological contexts of, e.g., properties of phospholipid membrane headgroups or interactions between DNA and histones. Specifically, neutron diffraction with isotopic substitution experiments were performed on TMA and water hydrogens to extract the specific correlation between hydrogens in TMA ($\mathrm{H_{TMA}}$) and hydrogens in water ($\mathrm{H_{W}}$). Classical molecular dynamics simulations were performed to help interpret the experimental neutron scattering data. Comparison of the hydration structure and simulated neutron signals obtained with various force field flavors (e.g. overall charge, charge distribution, polarity of the CH bonds and geometry) allowed us to gain insight into how sensitive the TMA hydration structure is to such changes and how much the neutron signal can capture them. We show that certain aspects of the hydration, such as the correlation of the hydrogen on TMA to hydrogen on water, showed little dependence on the force field. In contrast, other correlations, such as the ion-ion interactions, showed more marked changes. Strikingly, the neutron scattering signal cannot discriminate between different hydration patterns. Finally, ab initio molecular dynamics was used to examine the three-dimensional hydration structure and thus to benchmark force field simulations. Overall, while neutron scattering has been previously successfully used to improve force fields, in the particular case of TMA we show that it has only limited value to fully determine the hydration structure, with other techniques such as ab initio MD being of a significant help.

Published
2023

15. Blood and urine multi-omics analysis of the impact of e-vaping, smoking, and cessation: from exposome to molecular responses

Author

Poussin, Carine, Titz, Bjoern, Xiang, Yang, Baglia, Laurel, Berg, Rachel, Bornand, David, Choukrallah, Mohammed-Amin, Curran, Timothy, Dijon, Sophie, Dossin, Eric, Dulize, Remi, Etter, Doris, Fatarova, Maria, Medlin, Loyse Felber, Haiduc, Adrian, Kishazi, Edina, Kolli, Aditya R., Kondylis, Athanasios, Kottelat, Emmanuel, Laszlo, Csaba, Lavrynenko, Oksana, Eb-Levadoux, Yvan, Nury, Catherine, Peric, Dariusz, Rizza, Melissa, Schneider, Thomas, Guedj, Emmanuel, Calvino, Florian, Sierro, Nicolas, Guy, Philippe, Ivanov, Nikolai V., Picavet, Patrick, Spinelli, Sherry, Hoeng, Julia, and Peitsch, Manuel C.

Published
2024
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19. Place of Nasogastric Tube in Uncomplicated Adhesive Small Bowel Obstruction (BOWNTI)

Author

Centre Hospitalier de Beauvais, CHU de Rouen - Accueil, Hospital Avicenne, Centre Hospitalier Universitaire Dijon, University Hospital, Limoges, Saint Antoine University Hospital, Centre Hospitalier Universitaire de Besancon, Hôpital Cochin, University Hospital, Toulouse, CH Abbeville, and University Hospital, Angers

Published
2024

24. French National Observatory on Infective Endocarditis (ObservatoireEI)

Author

Bichat Hospital, Centre Hospitalier Universitaire de Pointe-a-Pitre, Centre Hospitalier Universitaire de Besancon, Hospices Civils de Lyon, University Hospital, Montpellier, Rennes University Hospital, Hôpital Saint André, Reims, Henri Mondor University Hospital, Polyclinique Courlancy, Reims, Centre Hospitalier Universitaire de Saint Etienne, Bicetre Hospital, Centre Hospitalier Universitaire, Amiens, Centre Hospitalier Universitaire Dijon, Centre Hospitalier Annecy Genevois, Centre Hospitalier de Roanne, Centre hospitalier Pierre Oudot Bourgoin-Jallieu, L'hôpital Nord-Ouest - Villefranche Villefranche sur Saône, Hôpital d'Instruction des Armées Desgenettes, Hôpital intercommunal Sud Léman Valserine, Saint Julien en Genevois, University Hospital, Grenoble, Centre Cardiologique du Nord, Centre Hospitalier Intercommunal Robert Ballanger, Raincy Montfermeil Hospital Group, Pitié-Salpêtrière Hospital, Hôpital Cochin, Hospital Avicenne, Beaujon Hospital, European Georges Pompidou Hospital, Hopital Foch, Hotel Dieu Hospital, Hôpital Jean Verdier, Hopital Lariboisière, Hôpital Necker-Enfants Malades, Fondation Hôpital Saint-Joseph, Saint-Louis Hospital, Paris, France, Tenon Hospital, Paris, Saint Antoine University Hospital, Centre hospitalier de Saint Dié des Vosges, Centre Hospitalier Régional Metz-Thionville, Hôpital d'Instruction des Armées Legouest, Hôpital sainte Blandine Metz, Hôpital-clinique Claude Bernard, Metz, Polyclinique Louis Pasteur Essey-les-Nancy, Hopital Nord Franche-Comte, Lons le Saunier hospital, Pontarlier hospital, Epernay hospital, Chalons en Champagne hospital, Clinique Saint Vincent Epernay, Hôpital Maison Blanche Reims, Hopital Universitaire Robert-Debre, Beziers Hospital, Louis Pasteur hospital, Bagnols sur Cèze, Centre hospitalier de Perpignan, Narbonne Hospital, Clinique du Millenaire, Centre Hospitalier Universitaire de Nīmes, Saint Malo hospital, HIA Begin, Saint Mandé, Centre Hospitalier d'Alès-Cévennes, University Hospital, Bordeaux, Centre hospitalier de Chambéry, Poitiers University Hospital, Centre Hospitalier Intercommunal Villeneuve Saint Georges, Centre Hospitalier Argenteuil, Hospital St. Joseph, Marseille, France, Centre hospitalier de Vannes, University Hospital, Strasbourg, France, Centre Hospitalier Régional d'Orléans, and Christine Selton-Suty, Dr

Published
2024

25. Effect of Long-term Carvedilol to Prevent Decompensation or Death in Patients With Asymptomatic Child-Pugh A5 to B8 Cirrhosis and Clinically Significant Portal Hypertension: a Multicenter Double-blind Randomized Control Trial (CARVECIR)

Author

Centre Hospitalier Universitaire Amiens Picardie, Centre Hospitalier Universitaire Angers, Assistance Publique Hopitaux Paris BEAUJON, Centre Hospitalier Universitaire Caen, Centre Hospitalier intercommunal de Créteil, Hospices Civils de Lyon, Centre Hospitalier Universitaire Grenoble, Centre Hospitalier Universitaire Haut Lévêque, Centre Hospitalier Régional Universitaire Lille, Centre Hospitalier Universitaire Jean Minjoz, Assistance Publique Hopitaux Paris AVICENNE, Centre Hospitalier Universitaire Clermont Ferrand, Assistance Publique Hopitaux Paris LA PITIE SALPETRIERE, Centre Hospitalier Universitaire Pontchaillou, Assistance Publique Hopitaux Paris ST ANTOINE, Assistance Publique Hopitaux Paris PAUL BROUSSE, University Hospital, Montpellier, Assistance Publique Hopitaux Paris HENRI MONDOR, Centre Hospitaliser Départemental de Vendée, Nantes University Hospital, Centre Hospitalier Universitaire Dijon, CHU de Reims, Hôpitaux Universitaires de Strasbourg, and University Hospital, Toulouse

Published
2024

28. Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin Carboxy-terminal Hydrolase L1 (UCH-L1) to Exclude Lesions Linked to Significant Traumatic Brain Injuries (GUEST)

Author

BioMérieux, Assistance Publique - Hôpitaux de Paris, University Hospital, Clermont-Ferrand, Hospices Civils de Lyon, Poitiers University Hospital, University Hospital, Angers, Centre Hospitalier Universitaire de Nīmes, Centre Hospitalier Universitaire de Nice, Nantes University Hospital, University Hospital, Montpellier, Centre Hospitalier Universitaire Dijon, University Hospital, Grenoble, Fondation Hôpital Saint-Joseph, and CHU de Tours

Published
2024

29. Multicenter Prospective Cohort of Informal Caregivers in Burgundy and Franche-Comté (ICE)

Author

Methodological and quality of life unit in oncology (CHRU de Besançon), University of Franche-Comté, University of Burgundy, Pôle de Gérontologie Interrégional Bourgogne et Franche-Comté, CARSAT Bourgogne et Franche-Comté, CCAS of Dijon, CCAS of Besançon, CCAS of Montbéliard, Burgundy Regional Council, Franche-Comté Regional Council, The Municipality of Besançon, The Municipality of Dijon, General Council of the Doubs, General Council of the Territoire de Belfort, Collectif Inter Associatif Sur la Sante Bourgogne, Union Régionale Interfédérale des Œuvres et Organismes Privés Sanitaires Bourgogne, Association Gérontopôle Pierre Pfitzenmeyer, Pôle de compétitivité Vitagora Goût-Nutrition-Santé, National Old Age Insurance Fund for Employees (CNAVTS), Sheerbrooke Gérontopôle, France Alzheimer, Institut Régional de Vieillissement (IRV), Novartis Pharmaceuticals, Roche Foundation, Ligue contre le cancer, France, National Cancer Institute, France, Quality of life and cancer clinical research platform, and National Research Agency, France

Published
2023

30. Experimental evidence of the effect of nuclear shells on fission dissipation and time

Author

Ramos, D., Caamano, M., Farget, F., Rodriguez-Tajes, C., Lemasson, A., Schmitt, C., Audouin, L., Benlliure, J., Casarejos, E., Clement, E., Cortina, D., Delaune, O., Derkx, X., Dijon, A., Dore, D., Fernandez-Dominguez, B., de France, G., Heinz, A., Jacquot, B., Paradela, C., Rejmund, M., Roger, T., and Salsac, M. -D.

Subjects
Nuclear Experiment, Nuclear Theory
Abstract

Nuclear fission is still one of the most complex physical processes we can observe in nature due to the interplay of macroscopic and microscopic nuclear properties that decide the result. An example of this coupling is the presence of nuclear dissipation as an important ingredient that contributes to drive the dynamics and has a clear impact on the time of the process. However, different theoretical interpretations, and scarce experimental data make it poorly understood. In this letter, we present the first experimental determination of the dissipation energy in fission as a function of the fragment split, for three different fissioning systems. The amount of dissipation was obtained through the measurement of the relative production of fragments with even and odd atomic numbers with respect to different initial fission energies. The results reveal a clear effect of particular nuclear shells on the dissipation and fission dynamics. In addition, the relative production of fragments with even and odd atomic numbers appears as a potential contributor to the long-standing problem of the time scale in fission.

Published
2023
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35. French Cohort Evaluating the effectiveneSs of Atrioventricular Synchrony by the micRa AV (AV-CESAR)

Author

CHU de Tours, European Georges Pompidou Hospital, Hôpital privé Clairval - Marseille, Clinique Pasteur Toulouse, University Hospital, Bordeaux, Infirmerie Protestante Lyon, Institut Jacques Cartier - Massy, University Hospital, Grenoble, Hôpital de la Timone, University Hospital, Toulouse, Hopital Prive Saint Martin - Bordeaux, Hospices Civils de Lyon, CHU de Rouen - Accueil, University Hospital, Caen, Médipôle Lyon-Villeurbanne, Hospital Ambroise Paré Paris, Clinique Saint Augustin - Bordeaux, Rennes University Hospital, Clinique de la Sauvegarde - Lyon, University Hospital of Saint-Etienne, Hôpital Privé de Parly II - Le Chesnay, Institut Mutualiste Montsouris, Centre Hospitalier Universitaire, Amiens, University Hospital, Clermont-Ferrand, Centre Hospitalier Régional et Universitaire de Brest, Poitiers University Hospital, Clinique Saint-Gatien - Tours, CHU de Reims, Centre Hospitalier Universitaire de Besancon, Centre Hospitalier Universitaire Dijon, Hôpital Privé de Lille Métropole, University Hospital, Montpellier, University Hospital, Strasbourg, France, Nantes University Hospital, Centre Cardio-Thoracique de Monaco, Hospital St. Joseph, Marseille, France, Centre Hospitalier Régional Metz-Thionville, Centre Hospitalier Annecy Genevois, Clinique du Millenaire, University Hospital, Limoges, Clinique Saint Pierre - Perpignan, Bichat Hospital, Universite de La Reunion, CHU de Lille, Institute Arnault Tzanck, France, Hôpital Privé Les Franciscaines, CHU de Fort de France - Martinique, Henri Mondor University Hospital, University Hospital, Angers, Centre Hospitalier de Lens, and Central Hospital, Nancy, France

Published
2023

36. A Procalcitonin-based Algorithm in Adhesion-related Small Bowel Obstruction (ALPROC)

Author

Centre Hospitalier de Beauvais, Centre Hospitalier Universitaire de Rouen, University Hospital, Caen, University Hospital, Lille, Groupe Hospitalier Pitie-Salpetriere, Centre Hospitalier Universitaire Dijon, University Hospital, Limoges, Saint Antoine University Hospital, University Hospital, Clermont-Ferrand, Hôpital Cochin, University Hospital, Toulouse, Centre Hospitalier de PAU, Hopital Lariboisière, Tourcoing Hospital, and Central Hospital Saint Quentin

Published
2023

38. Blood and urine multi-omics analysis of the impact of e-vaping, smoking, and cessation: from exposome to molecular responses

Author

Carine Poussin, Bjoern Titz, Yang Xiang, Laurel Baglia, Rachel Berg, David Bornand, Mohammed-Amin Choukrallah, Timothy Curran, Sophie Dijon, Eric Dossin, Remi Dulize, Doris Etter, Maria Fatarova, Loyse Felber Medlin, Adrian Haiduc, Edina Kishazi, Aditya R. Kolli, Athanasios Kondylis, Emmanuel Kottelat, Csaba Laszlo, Oksana Lavrynenko, Yvan Eb-Levadoux, Catherine Nury, Dariusz Peric, Melissa Rizza, Thomas Schneider, Emmanuel Guedj, Florian Calvino, Nicolas Sierro, Philippe Guy, Nikolai V. Ivanov, Patrick Picavet, Sherry Spinelli, Julia Hoeng, and Manuel C. Peitsch

Subjects
Medicine, Science
Abstract

Abstract Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for smokers who would otherwise continue to smoke. A key challenge for the clinical assessment of NCAs is that self-reported product use can be unreliable, compromising the proper evaluation of their risk reduction potential. In this cross-sectional study of 205 healthy volunteers, we combined comprehensive exposure characterization with in-depth multi-omics profiling to compare effects across four study groups: cigarette smokers (CS), e-vapor users (EV), former smokers (FS), and never smokers (NS). Multi-omics analyses included metabolomics, transcriptomics, DNA methylomics, proteomics, and lipidomics. Comparison of the molecular effects between CS and NS recapitulated several previous observations, such as increased inflammatory markers in CS. Generally, FS and EV demonstrated intermediate molecular effects between the NS and CS groups. Stratification of the FS and EV by combustion exposure markers suggested that this position on the spectrum between CS and NS was partially driven by non-compliance/dual use. Overall, this study highlights the importance of in-depth exposure characterization before biological effect characterization for any NCA assessment study.

Published
2024
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39. Study Among People Living With HIV and Their Health Professionals of Associated Factors of Resilience to Self-stigma (RESILSTIGMA)

Author

Poitiers University Hospital, Poissy-Saint Germain Hospital, Centre Hospitalier Universitaire Dijon, Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer, Hopital Antoine Beclere, Nantes University Hospital, Hospital, La Roche sur Yon, Hôpital Necker-Enfants Malades, Centre Hospitalier de Bretagne Sud, Reims University Hospital, Groupe Hospitalier de la Rochelle Ré Aunis, Hospital Laennec, Quimper, University Hospital, Brest, Hospital Cornouaille, Quimper, Centre Hospitalier de Cholet, University Hospital, Strasbourg, CH Annecy Genevois, Centre hospitalier de Perpignan, Centre Hospitalier le Mans, Centre Hospitalier VALENCIENNES, Bicetre Hospital, Centre Hospitalier Universitaire de Nice, University Hospital, Marseille, Jacques Lacarin Hospital Center, L'hôpital Nord-Ouest - Villefranche Villefranche sur Saône, Centre Hospitalier Universitaire de Besancon, Hospital, Vannes, Moulins Hospital, Hospital, Montluçon, Centre Hospitalier de Niort, Hôpital Edouard Herriot, Hospital La Source, Orléans, Centre Hospitalier du Pays d'Aix, Hospital Andre Mignot, Le Chesnay, Hôpital Raymond Poincaré, University Hospital, Angers, University Hospital, Pointe-à-Pitre, Centre Hospitalier des Pays de Morlaix, Hospital Foch, Suresnes, Tenon Hospital, Paris, University Hospital of Saint-Etienne, Centre Hospitalier de Saint-Denis, and University Hospital, Mulhouse

Published
2023

40. Cardiac biogenic amine profile and its relationship with parameters of cardiovascular disease in obesity

Author

Belin, Matheus Antônio Filiol, Vieira, Taynara Aparecida, Grandini, Núbia Alves, Siqueira, Juliana Silva, Palacio, Thiago Luiz Novaga, Cruzeiro, Jordanna, Sormani, Luis Eduardo, Tanganini, Murilo Dalarme, Barbosa, Gabriela Souza, Gregolin, Cristina Schmitt, de Campos, Dijon Henrique Salomé, Bazan, Silmeia Garcia Zanati, Minatel, Igor Otávio, Lima, Giuseppina Pace Pereira, and Correa, Camila Renata

Published
2024
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42. Cardiac dysfunction in sucrose-fed rats is associated with alterations of phospholamban phosphorylation and TNF-α levels

Author

Gregolin, Cristina Schmitt, do Nascimento, Milena, de Souza, Sérgio Luiz Borges, Mota, Gustavo Augusto Ferreira, Luvizotto, Renata de Azevedo Melo, Sugizaki, Mário Mateus, Bazan, Silméia Garcia Zanati, de Campos, Dijon Henrique Salomé, Camacho, Camila Renata Corrêa, Cicogna, Antonio Carlos, and do Nascimento, André Ferreira

Published
2024
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43. The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis

Author

Emanuela Talamonti, Jelena Davegardh, Anastasia Kalinovich, Sten M.M. van Beek, Nodi Dehvari, Carina Halleskog, Hamza M. Bokhari, Dana S. Hutchinson, Seungmin Ham, Laura J. Humphrys, Nicola C. Dijon, Aikaterini Motso, Anna Sandstrom, Evelyn Zacharewicz, Ilga Mutule, Edgars Suna, Jana Spura, Karolina Ditrychova, Leigh A. Stoddart, Nicholas D. Holliday, Shane C. Wright, Volker M. Lauschke, Soren Nielsen, Camilla Scheele, Elizabeth Cheesman, Joris Hoeks, Peter Molenaar, Roger J. Summers, Benjamin Pelcman, Gopala K. Yakala, and Tore Bengtsson

Subjects
Obesity, Type 2 diabetes, β-Adrenergic agonists, Hepatic steatosis, Skeletal muscle, Internal medicine, RC31-1245
Abstract

Objective: Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs – and thus inducing cardiovascular complications – are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models. Methods: In the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis. Results: Exposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis. Conclusions: Our results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Published
2024
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44. The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis

Author

Talamonti, Emanuela, Davegardh, Jelena, Kalinovich, Anastasia, van Beek, Sten M.M., Dehvari, Nodi, Halleskog, Carina, Bokhari, Hamza M., Hutchinson, Dana S., Ham, Seungmin, Humphrys, Laura J., Dijon, Nicola C., Motso, Aikaterini, Sandstrom, Anna, Zacharewicz, Evelyn, Mutule, Ilga, Suna, Edgars, Spura, Jana, Ditrychova, Karolina, Stoddart, Leigh A., Holliday, Nicholas D., Wright, Shane C., Lauschke, Volker M., Nielsen, Soren, Scheele, Camilla, Cheesman, Elizabeth, Hoeks, Joris, Molenaar, Peter, Summers, Roger J., Pelcman, Benjamin, Yakala, Gopala K., and Bengtsson, Tore

Published
2024
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45. Novel complementation biosensors to investigate G protein-coupled receptor kinetics and signalling bias

Author

Dijon, Nicola C.

Subjects
QP501 Animal biochemistry
Abstract

G protein coupled receptors (GPCRs) signal through a complex cellular network, with a range of temporally variable signalling responses generated by GPCR activation. Characterisation of GPCR ligands is generally taken from the ligand "affinity", the ability to bind the receptor, and the ligand "efficacy", the ability to activate signalling from the receptor. Often single timepoints are used to quantify ligand affinity and efficacy by being applied to pharmacological models. Biased ligands, which have been suggested to preferentially activate one signalling pathway over another, are often identified from comparisons of concentration response data of an agonist between single timepoints of assays measuring the activation of different signalling proteins. Existing pharmacological models, which estimate ligand potencies, efficacies and ligand bias, such as the Black and Leff operational model, from functional data assume system equilibrium, yet often concentration response data at early timepoints are taken from hemi-equilibrium conditions. More recently, appreciation of agonist binding kinetics and signalling kinetics at GPCRs has increased, enhancing the extent of ligand characterisation and used to investigate discrepancies in ligand bias between different experimental systems. The origin of ligand bias has been suggested to be conformational, where the agonist binds the receptor to allosterically promote the formation of a conformation which preferentially activates one signalling pathway over another. It has also been suggested that bias originates from different receptor binding kinetics, which produce different profiles of signalling and can confound comparisons of bias - especially when bias is compared from a single timepoint. In this thesis we investigate how signalling kinetics and binding kinetics can influence measures of ligand affinities, efficacy and bias using experimental system monitoring dynamic protein:protein and ligand-receptor interactions. Firstly, we established a NanoBiT complementation assay to monitor agonist-stimulated recruitment of effector proteins, either β-arrestin2 or a synthetic mini Gαs protein, at β adrenoceptor subtypes. Recruitment profiles of β-arrestin2 recruitment produced a transient "rise and fall to plateau" profile, peaking at 3 minutes, whilst the mini Gαs protein was recruited to the receptor rapidly in the first 1-5 minutes and then plateaued and/or steadily increased over the timecourse. This experimental system allowed for dynamic agonist-stimulated recruitment profiles to be monitored over time and concentration response data to be gathered from multiple timepoints. Concentration response data from each timepoint was then applied to the Black and Leff operational models to compare how direct comparisons of ligand bias can change in magnitude and direction over time. Full kinetic signalling profiles were then applied to a kinetic operational model, which takes hemi-equilibrium conditions into account, to estimate agonist affinities and efficacies from β-arrestin2 recruitment data. Agonist affinities estimated from the kinetic operational model were strongly correlated with values obtained in a time-resolved fluorescence resonance energy transfer (TR-FRET) binding assays, highlighting the model's value in obtaining drug potency and affinity from a single functional recruitment assay. Secondly, we investigated the value of the NanoBiT complementation assays in monitoring receptor antagonism and how the kinetic context may misrepresent the mechanism of action of the antagonist ligands: propranolol, ICI-118,551 and CGP-12177. Schild-Gaddum based experiments were applied and monitored over a 61 minute timecourse, at β2 adrenoceptors. All antagonists at early timepoints (3 minutes) produced insurmountable antagonism of the formoterol response, with only propranolol demonstrating surmountable antagonism at 61 minutes. The extent of insurmountability correlated with a decreased dissociation rate (kOFF) of the antagonist, with kOFF estimated from a kinetic TR-FRET assay. The signalling profiles of antagonism of mini Gαs protein recruitment at the β2 adrenoceptor were applied to an antagonist form of the kinetic operational model, to provide similar estimates of antagonist affinity in comparison to values obtained in Schild-based and TR-FRET assays. The kinetic operational model also provided estimates of antagonist association (kON) and kOFF, though these were not comparable to estimates from the kinetic TR-FRET assay and highlight the need for model modification for accurate estimates of kinetic values. Lastly, this thesis investigated how the conformation of the receptor can influence binding properties of β2 adrenoceptor ligands. High affinity variants of the NanoBiT complementation fragments (LgBiT and HiBiT) were used to stabilise the β2 adrenoceptor in complex with an effector protein to form effector driven receptor conformations. Initially, high affinity NanoBiT fragments were genetically tagged to the β2 adrenoceptor and either β-arrestin2 or mini Gαs and expressed in dual-expression cell lines. However, unbalanced expression of the proteins resulted in insufficient formation of NanoBiT stabilised receptor-effector conformations. To resolve this issue, the HiBiT-tagged mini Gαs protein was bacterially expressed and purified and added to membranes expressing LgBiT-tagged β2 adrenoceptors, saturating the receptor population. The complimented NanoBiT fragments were used as the donor species to excite an extracellular fluorescent ligand bound to the receptor, to establish a novel transmembrane bioluminescence resonance energy transfer (TM-BRET) assay. In TM-BRET assays, β2 adrenoceptor-mini Gαs protein "high affinity" conformations were shown to have increase affinity for agonist ligands, compared to the receptor alone, whilst antagonist ligands were unchanged. Kinetic TR-FRET assays were used to monitor the kinetic binding properties of β2 adrenoceptor ligands and demonstrated that the increase in agonist affinity at receptor-mini Gαs protein complexes was driven by a decrease in agonist kOFF and that the extent of the decrease in kOFF rate was correlated with ligand efficacy. The findings presented in this thesis highlight the value of kinetic signalling data and binding kinetics in assessing ligand pharmacology, including measures of ligand bias. This thesis went onto to highlight how differences in receptor conformation drive changes in agonist kOFF, combining conformational and kinetic explanations of ligand bias.

Published
2022

46. Building intuition for binding free energy calculations: bound state definition, restraints, and symmetry

Author

Duboué-Dijon, Elise and Hénin, Jérôme

Subjects
Physics - Chemical Physics
Abstract

The theory behind computation of absolute binding free energies using explicit-solvent molecular simulations is well-established, yet somewhat complex, with counter-intuitive aspects. This leads to frequent frustration, common misconceptions, and sometimes, erroneous numerical treatment. To improve this, we present the main practically relevant segments of the theory with constant reference to physical intuition. We pinpoint the role of the implicit or explicit definition of the bound state (or the binding site), to make a robust link between an experimental measurement and a computational result. We clarify the role of symmetry, and discuss cases where symmetry number corrections have been misinterpreted. In particular, we argue that symmetry corrections as classically presented are a source of confusion, and could be advantageously replaced by restraint free energy contributions. We establish that contrary to a common intuition, partial or missing sampling of some modes of symmetric bound states does not affect the calculated decoupling free energies. Finally, we review these questions and pitfalls in the context of a few common practical situations: binding to a symmetric receptor (equivalent binding sites), binding of a symmetric ligand (equivalent poses), and formation of a symmetric complex, in the case of homodimerization.

Published
2021
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49. Bergamot by-product, a source of biogenic amines, reduces hypertension induced by high sugar-fat diet

Author

Belin, Matheus Antônio Filiol, Siqueira, Juliana Silva, Vieira, Taynara Aparecida, Grandini, Núbia Alves, Palacio, Thiago Luiz Novaga, Nakandakare-Maia, Erika Tiemi, de Campos, Dijon Henrique Salomé, Francisqueti-Ferron, Fabiane Valentini, Bombardelli, Ezio, Minatel, Igor Otávio, Aldini, Giancarlo, Lima, Giuseppina Pace Pereira, and Correa, Camila Renata

Published
2024
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50. The influence of dapagliflozin on cardiac remodeling, myocardial function and metabolomics in type 1 diabetes mellitus rats

Author

Eder Anderson Rodrigues, Camila Moreno Rosa, Dijon Henrique Salome Campos, Felipe Cesar Damatto, Gilson Masahiro Murata, Lidiane Moreira Souza, Luana Urbano Pagan, Mariana Gatto, Jessica Yumi Brosler, Hebreia Oliveira Almeida Souza, Mario Machado Martins, Luciana Machado Bastos, Suzana Erico Tanni, Katashi Okoshi, and Marina Politi Okoshi

Subjects
SGLT2 inhibitors, Streptozotocin, Papillary muscle, Ventricular function, Myocardial metabolomics, Echocardiogram, Nutritional diseases. Deficiency diseases, RC620-627
Abstract

Abstract Background Sodium-glucose cotransporter (SGLT)2 inhibitors have displayed beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, their effects in Type 1 DM have not been established. Objective To evaluate the influence of long-term treatment with SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, energy metabolism, and metabolomics in rats with Type 1 DM. Methods Male Wistar rats were divided into groups: Control (C, n = 15); DM (n = 15); and DM treated with dapagliflozin (DM + DAPA, n = 15) for 30 weeks. DM was induced by streptozotocin. Dapagliflozin 5 mg/kg/day was added to chow. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn. Results DM + DAPA presented lower glycemia and higher body weight than DM. Echocardiogram showed DM with left atrium dilation and left ventricular (LV) hypertrophy, dilation, and systolic and diastolic dysfunction. In LV isolated papillary muscles, DM had reduced developed tension, +dT/dt and -dT/dt in basal condition and after inotropic stimulation. All functional changes were attenuated by dapagliflozin. Hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) activity was lower in DM than C, and PFK and PK activity higher in DM + DAPA than DM. Metabolomics revealed 21 and 5 metabolites positively regulated in DM vs. C and DM + DAPA vs. DM, respectively; 6 and 3 metabolites were negatively regulated in DM vs. C and DM + DAPA vs. DM, respectively. Five metabolites that participate in cell membrane ultrastructure were higher in DM than C. Metabolites levels of N-oleoyl glutamic acid, chlorocresol and N-oleoyl-L-serine were lower and phosphatidylethanolamine and ceramide higher in DM + DAPA than DM. Conclusion Long-term treatment with dapagliflozin attenuates cardiac remodeling, myocardial dysfunction, and contractile reserve impairment in Type 1 diabetic rats. The functional improvement is combined with restored pyruvate kinase and phosphofructokinase activity and attenuated metabolomics changes.

Published
2023
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