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1. A Long Journey into Reproducible Computational Neuroscience

Author

Meropi eTopalidou, Arthur eLeblois, Thomas eBoraud, Nicolas P Rougier, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Mnemonic Synergy (Mnemosyne), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2, Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2, Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria) - Institut National de Recherche en Informatique et en Automatique (Inria) - Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS) - Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Inria Bordeaux - Sud-Ouest, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and Rougier, Nicolas P.

Subjects
Computer science, Neuroscience (miscellaneous), [INFO] Computer Science [cs], Reproducible Neuroscience, Basal Ganglia, reproducible science, lcsh:RC321-571, Cellular and Molecular Neuroscience, Notebook, Python language, python language, Computational models, [INFO]Computer Science [cs], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Publication process, publication process, Cognitive science, Brain organization, Computational model, Computational neuroscience, General Commentary, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Data science, Public repository, public repository, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Version control, Neuroscience, Python
Abstract

Computational neuroscience, a relatively recent field, has gained fast ground and modelling is now widely 1 used to better understand individual and collective neuronal dynamics, and to propose new functions relying on 2 neural substrate. While the development of a model is initially tightly linked to the specific question asked by a given 3 group of researchers, further development of the model in different contexts is often possible and desired. When such 4 further development relies on new players, the continuity of the work requires proper validation, reproduction and 5 sharing of the models original equations and code. However, as they are published today, computational neuroscience 6 papers rarely include the sufficient material for the reproduction and sharing of the underlying model as a whole. 7 Here, we aim at showing the full extent of the problem, as well as state-of-the-art solutions, through the detailed story 8 of the reproduction of a computational modelling study by Guthrie et al. (2013) investigating the dynamics of basal 9 ganglia circuits and their function in multiple level action selection. In collaboration with the authors of the original 10 work, we first explain the difficulties encountered during the reproduction and validation of the initial model and 11 results. These difficulties led us to completely rewrite the model enforcing best software practices, relying on previous 12 attempts to provide a common framework for reproducible computational science and software sustainability. We 13 hereby detail these practices in the face of our practical example: the reproduction of the results from Guthrie et al. 14 (2013). In particular, these practices include: (i) a template for formal description of the model in a single table, 15 (ii) a public repository for shared software a proper version control, and (iii) an easy interface to run the underlying 16 code and reproduce figures. We finally propose new formats for communicating results allowing the replay of a code 17 while reading a computational study, in order to get a deeper understanding of the concepts being introduced. 18 Author Summary Computational sciences, such as bioinformatics, computational biology or computational neuro-19 science, are gaining fast ground in modern Life Sciences and new discoveries can be made thanks to computational 20 models or numerical simulations and analysis. The picture is not all bright however. The computational part in 21 computational sciences implies the use of computers, operating systems, tools, frameworks, libraries and data. This 22 leads to such a large number of combinations (taking into account the version for each components) that the chances 23 to have the exact same configuration as one of your colleague are nearly zero. This draws consequences in our 24 respective computational approaches in order to make sure models and simulations can be actually and faithfully 25 reproduced. If reproducibility is the hallmark of Science, computational sciences seems to be still in their infancy 26 in this domain, even though things have started to improve. This article highlights the extent of the problem based 27 on the reproduction of a model in computational neuroscience and show how to circumvent it using recommended 28 practices.

Published
2015
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2. A long journey into reproducible computational neuroscience research

Author

Topalidou, Meropi, Leblois, Arthur, Boraud, Thomas, Rougier, Nicolas P., Mnemonic Synergy (Mnemosyne), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Inria Bordeaux - Sud-Ouest, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Topalidou, Meropi, Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria) - Institut National de Recherche en Informatique et en Automatique (Inria) - Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS) - Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2, Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS)

Subjects
[INFO]Computer Science [cs], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [INFO] Computer Science [cs]
Abstract

International audience; In a previous modelling study, Leblois et al. (2006) demonstrated an action selection mechanism in cortico- basal ganglia loops based on competition between the positive feedback, direct pathway through the striatum and the negative feedback, hyperdirect pathway through the subthalamic nucleus. In Guthrie et al. (2013), authors investigated how multiple level action selection could be performed by the basal ganglia. To do this, the model has been extended in a manner consistent with known anatomy and electro-physiology in three main areas. Unfortunately, the information provided by the article were not sufficient to reproduce the model. If reproducibility is the hallmark of Science, non-reproducibility seems to be the hallmark of Computational Neurosciences. In that respect, Guthrie et al. (2013) is a prototypic case of such non-reproducible computational neuroscience research even though the proposed model gives a fair account of decision making in the basal ganglia complex. While trying to replicate results starting from the article description, we soon realised some information were undisclosed, some other were ambiguous and there were also some factual errors. Even after accessing the original sources (more than 6000 lines of Pascal), we were still unable to understand how the model worked. In the end, only the original material (a binary executable) and a direct contact with the authors allowed us to access the whole picture. After two months of intensive refactoring, we were finally able to replicate results using only 200 lines of Python. From this experience, which is unfortunately not an isolated case, we would like to share a simple message with the computational neuroscience community: designing computational models is not all about writing & running programs. If a model is to be reviewed, understood, used, replicated and integrated, it requires a minimal amount of coordinated efforts. Or the model will be soon forgotten, even by their own original designers.

Published
2014

3. The threonine degradation pathway of the Trypanosoma brucei procyclic form: the main carbon source for lipid biosynthesis is under metabolic control

Author

Yoann, Millerioux, Charles, Ebikeme, Marc, Biran, Pauline, Morand, Guillaume, Bouyssou, Isabel M, Vincent, Muriel, Mazet, Loïc, Riviere, Jean-Michel, Franconi, Richard J S, Burchmore, Patrick, Moreau, Michael P, Barrett, Frédéric, Bringaud, Centre de résonance magnétique des systèmes biologiques (CRMSB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Mucoviscidose et bronchopathies chroniques : biopathologie et phénotypes cliniques (EA 2511), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Service de Bactériologie [CHU Cochin, AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Geriatric Medicine, University of British Columbia (UBC), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Clermont-Ferrand (ICCF), Institut de Chimie du CNRS (INC)-SIGMA Clermont (SIGMA Clermont)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), Résonance magnétique des systèmes biologiques (RMSB), CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), Service de Bactériologie, CHU Cochin [AP-HP]-AP-HP, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Sigma CLERMONT (Sigma CLERMONT), Université de Bordeaux Ségalen [Bordeaux 2], Biologie végétale intégrative (BVI), Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, University of Glasgow, Agence Nationale de la Recherche (ANR) through grant ACETOTRYP of the ANR-BLANC-2010, Centre National de la Recherche Scientifique (CNRS), Universite Bordeaux Segalen, Conseil Regional d'Aquitaine, Laboratoire d'Excellence (LabEx) ParaFrap [ANR-11-LABX-0024], ParaMet PhD programme of Marie Curie Initial Training Network (FP7), Wellcome Trust through The Wellcome Trust Centre for Molecular Parasitology, Wellcome Trust [085349], Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), CHU Cochin [AP-HP] - AP-HP, Université Blaise Pascal - Clermont-Ferrand 2 (UBP) - Université d'Auvergne - Clermont-Ferrand I (UdA) - Centre National de la Recherche Scientifique (CNRS), CNRS-UMR 5234, Microbiologie fondamentale et Pathogénicité, University of Bordeaux 2, Bordeaux, France, Université Blaise Pascal - Clermont-Ferrand 2 (UBP) - Sigma CLERMONT (Sigma CLERMONT) - Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Microbiologie Fondamentale et Pathogénicité (MFP), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Threonine, Magnetic Resonance Spectroscopy, SUCCINATE COA-TRANSFERASE, [SDV]Life Sciences [q-bio], Trypanosoma brucei brucei, ENERGY-METABOLISM, TSETSE-FLY, Acetates, COMPARATIVE PROTEOMICS, BLOOD-STREAM FORM, AMINO-ACIDS, MOLECULAR CHARACTERIZATION, LEISHMANIA-MEXICANA, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Biotransformation, Research Articles, Lipid Metabolism, Carbon, Reverse Genetics, Culture Media, PROLINE METABOLISM, Glucose, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, FATTY-ACIDS, Gene Deletion, Metabolic Networks and Pathways
Abstract

International audience; The Trypanosoma brucei procyclic form resides within the digestive tract of its insect vector, where it exploits amino acids as carbon sources. Threonine is the amino acid most rapidly consumed by this parasite, however its role is poorly understood. Here, we show that the procyclic trypanosomes grown in rich medium only use glucose and threonine for lipid biosynthesis, with threonine's contribution being approximate to 2.5 times higher than that of glucose. A combination of reverse genetics and NMR analysis of excreted end-products from threonine and glucose metabolism, shows that acetate, which feeds lipid biosynthesis, is also produced primarily from threonine. Interestingly, the first enzymatic step of the threonine degradation pathway, threonine dehydrogenase (TDH, EC 1.1.1.103), is under metabolic control and plays a key role in the rate of catabolism. Indeed, a trypanosome mutant deleted for the phosphoenolpyruvate decarboxylase gene (PEPCK, EC 4.1.1.49) shows a 1.7-fold and twofold decrease of TDH protein level and activity, respectively, associated with a 1.8-fold reduction in threonine-derived acetate production. We conclude that TDH expression is under control and can be downregulated in response to metabolic perturbations, such as in the PEPCK mutant in which the glycolytic metabolic flux was redirected towards acetate production.

Published
2013
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4. Interaction Between Cognitive and Motor Cortico-Basal Ganglia Loops During Decision Making: A Computational Study

Author

Martin Guthrie, Thomas Boraud, Arthur Leblois, André Garenne, Garenne, André, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS), Mnemonic Synergy (Mnemosyne), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria) - Institut National de Recherche en Informatique et en Automatique (Inria) - Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS) - Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Inria Bordeaux - Sud-Ouest, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest

Subjects
Physiology, Dopamine, Decision Making, Models, Neurological, Action Potentials, Striatum, Action selection, Basal Ganglia, 03 medical and health sciences, Cognition, 0302 clinical medicine, Negative feedback, Basal ganglia, Animals, Learning, Direct pathway of movement, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Neurons, 0303 health sciences, Computational model, General Neuroscience, Motor Cortex, Subthalamic nucleus, Synapses, Macaca, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cues, Nerve Net, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; n a previous modeling study, Leblois et al. (2006) demonstrated an action selection mechanism in cortico-basal ganglia loops based on competition between the positive feedback, direct pathway through the striatum and the negative feedback, hyperdirect pathway through the subthalamic nucleus. The present study investigates how multiple level action selection could be performed by the basal ganglia. To do this, the model is extended in a manner consistent with known anatomy and electrophysiology in three main areas. First, two-level decision making has been incorporated, with a cognitive level selecting based on cue shape and a motor level selecting based on cue position. We show that the decision made at the cognitive level can be used to bias the decision at the motor level. We then demonstrate that, for accurate transmission of information between decision-making levels, low excitability of striatal projection neurons is necessary, a generally observed electrophysiological finding. Second, instead of providing a biasing signal between cue choices as an external input to the network, we show that the action selection process can be driven by reasonable levels of noise. Finally, we incorporate dopamine modulated learning at corticostriatal synapses. As learning progresses, the action selection becomes based on learned visual cue values and is not interfered with by the noise that was necessary before learning.

Published
2013

5. Health and aging in elderly farmers: the AMI cohort

Author

Pascale Barberger-Gateau, Isabelle Baldi, Hélène Amieva, Annie Fourrier-Réglat, Maryse Gaimard, Alexandra Foubert-Samier, Michèle Allard, Karine Pérès, Nicole Rascle, Cécile Delcourt, Isabelle Bourdel-Marchasson, Sonia Laberon, Virginie Postal, Jean-François Dartigues, Muriel Rainfray, Fanny Matharan, Cécilia Maubaret, Chantal Chantal, Valérie Bergua, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Ecole Pratique des Hautes Etudes, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Laboratoire de psychologie:Santé et qualité de vie, Université Bordeaux Segalen - Bordeaux 2, Service de médecine gériatrique, CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud-Hôpital Xavier Arnozan, Centre de résonance magnétique des systèmes biologiques (CRMSB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CIC - Bordeaux, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Émile Durkheim (CED), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Sciences Po Bordeaux - Institut d'études politiques de Bordeaux (IEP Bordeaux), The AMI project was funded by AGRICA (CAMARCA, CRCCA, CCPMA PREVOYANCE, CPCEA, AGRI PREVOYANCE), la Mutualité Sociale Agricole (MSA) de Gironde, la Caisse Centrale de la Mutualité Sociale Agricole (CCMSA). The AMImage1 project was funded by the Programme Hospitalier de Recherche Clinique - PHRC 2008 - Sponsor's code CHUBX 2008/13 - ClinicalTrials.gov Identifier NCT00951197. The AMImage2 project was funded by the Programme Hospitalier de Recherche Clinique - PHRC 2011 - Sponsor's code CHUBX 2011/15, BMC, Ed., Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Sciences Po Bordeaux - Institut d'études politiques de Bordeaux (IEP Bordeaux)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2 - Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED) - Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2 - Université Sciences et Technologies - Bordeaux 1 - SFR Bordeaux Neurosciences - Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux] - Groupe Hospitalier Sud - Hôpital Xavier Arnozan, Résonance magnétique des systèmes biologiques (RMSB), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2 - CHU Bordeaux [Bordeaux] - Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bordeaux (UB) - Sciences Po - Centre National de la Recherche Scientifique (CNRS)

Subjects
Gerontology, medicine.medical_specialty, Aging, Population, 03 medical and health sciences, Social support, Study Protocol, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, education, Aged, 2. Zero hunger, education.field_of_study, Interdisciplinary studies, Visual test, business.industry, Rural health, Public health, lcsh:Public aspects of medicine, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, Agriculture, 3. Good health, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort studies, Dementia, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Rural area, business, 030217 neurology & neurosurgery, Blood sampling, Cohort study, Follow-Up Studies
Abstract

Background The health of the agricultural population has been previously explored, particularly in relation to the farming exposures and among professionally active individuals. However, few studies specifically focused on health and aging among elders retired from agriculture. Yet, this population faces the long-term effects of occupational exposures and multiple difficulties related to living and aging in rural area (limited access to shops, services, and practitioners). However, these difficulties may be counter-balanced by advantages related to healthier lifestyle, richer social support and better living environment. The general aim of the AMI cohort was to study health and aging in elderly farmers living in rural area through a multidisciplinary approach, with a main focus on dementia. Methods/design The study initially included 1 002 participants, randomly selected from the Farmer Health Insurance rolls. Selection criteria were: being 65 years and older; living in rural area in Gironde (South-Western France); being retired from agriculture after at least 20 years of activity and being affiliated to the Health Insurance under own name. The study started in 2007, with two follow-up visits over 5 years. Baseline visits were conducted at home by a neuropsychologist then by a geriatrician for all cases suspected of dementia, Parkinson’s disease and depression (to confirm the diagnosis), and by a nurse for others. A large panel of data were collected through standardised questionnaires: complete neuropsychological assessment, material and social living environment, psychological transition to retirement, lifestyle (smoking, alcohol and diet), medications, disability in daily living, sensory impairments and some clinical measures (blood pressure, depression symptomatology, anxiety, visual test, anthropometry…). A blood sampling was performed with biological measurements and constitution of a biological bank, including DNA. Brain MRI were also performed on 316 of the participants. Finally, the three-year data on health-related reimbursements were extracted from the Health System database (medications, medical and paramedical consultations, biological examinations and medical devices), and the registered Long-Term Diseases (30 chronic diseases 100% covered by the Insurance System). Discussion AMI is the first French longitudinal study on health and aging set up in a population of elderly farmers living in rural area through a multidisciplinary approach.

Published
2012
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6. Sleep disorders and accidental risk in a large group of regular registered highway drivers

Author

Pierre Philip, Patricia Sagaspe, Jacques Taillard, Emmanuel Lagarde, Jacques Boussuge, Bernard Bioulac, Maurice M. Ohayon, Damien Leger, Sommeil, Addiction et Neuropsychiatrie [Bordeaux] (SANPSY), Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), Prévention et prise en charge des traumatismes [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre du Sommeil et de la Vigilance [Paris], Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), ASFA, Alicante [Seclin], Laboratoire Exploitation, Perception, Simulateurs et Simulations (LEPSIS), Laboratoire Central des Ponts et Chaussées (LCPC) - Institut National de Recherche sur les Transports et leur Sécurité (INRETS), Université Bordeaux Segalen - Bordeaux 2 - Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED) - Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Mouvement Adaptation Cognition (MAC), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Sommeil-Vigilance-Fatigue et Santé Publique (VIFASOM - EA 7330), Université Paris Descartes - Paris 5 (UPD5), Stanford Sleep Epidemiology Research Center, School of Medicine, GENPPHASS, Sommeil, Attention et Neuropsychiatrie [Bordeaux] (SANPSY), Laboratoire Central des Ponts et Chaussées (LCPC)-Institut National de Recherche sur les Transports et leur Sécurité (INRETS), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Institut de Recherche Biomédicale des Armées (IRBA)

Subjects
Male, MESH: Accidents, Traffic, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Sleep Apnea, Obstructive, Poison control, MESH: Logistic Models, 0302 clinical medicine, Risk Factors, MESH: Narcolepsy, MESH: Risk Factors, Surveys and Questionnaires, Insomnia, Prevalence, 030212 general & internal medicine, MESH: Sleep Disorders, MESH: Aged, Sleep disorder, Sleep Stages, Sleep Apnea, Obstructive, MESH: Middle Aged, MESH: Automobile Driving, Epworth Sleepiness Scale, Accidents, Traffic, Sleep apnea, General Medicine, Middle Aged, MESH: Young Adult, Female, Medical emergency, France, medicine.symptom, CONDUCTEUR, Adult, Sleep Wake Disorders, medicine.medical_specialty, Automobile Driving, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Adolescent, ACCIDENT DE LA ROUTE, Disorders of Excessive Somnolence, MESH: Multivariate Analysis, 03 medical and health sciences, Young Adult, medicine, Humans, Psychiatry, MESH: Prevalence, Aged, Narcolepsy, MESH: Adolescent, MESH: Humans, RISQUE ROUTIER, business.industry, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], MESH: Questionnaires, MESH: Adult, MESH: Sleep Stages, medicine.disease, MESH: Male, Obstructive sleep apnea, MESH: France, Logistic Models, Multivariate Analysis, business, human activities, MESH: Female, 030217 neurology & neurosurgery, MESH: Disorders of Excessive Somnolence
Abstract

Objective : Despite convincing evidence regarding the risk of highway accidents due to sleepiness at the wheel, highway drivers still drive while sleepy. Sleep disorders can affect driving skills, but the relative impact of sleep complaints among a large population of highway drivers is still unknown. Methods : Out of 37,648 questionnaires completed by frequent highway users (registered in an electronic payment system), we ran our analyses on 35,004 drivers who responded to all items. The questionnaire previously used in a telephone survey included socio-demographics, driving and sleep disorders items (Basic Nordic Sleep Questionnaire) and the Epworth Sleepiness Scale. Results : Of all drivers, 16.9% complained of at least one sleep disorder, 5.2% reported obstructive sleep apnea syndrome, 9.3% insomnia, and 0.1% narcolepsy and hypersomnia ; 8.9% of drivers reported experiencing at least once each month an episode of sleepiness at the wheel so severe they had to stop driving. One-third of the drivers (31.1%) reported near-miss accidents (50% being sleep-related), 2520 drivers (7.2%) reported a driving accident in the past year, and 146 (5.8%) of these driving accidents were sleep-related. The highest risk of accidents concerned patients suffering from narcolepsy and hypersomnia (odds ratio 3.16, p < .01) or multiple sleep disorders (odds ratio 1.46, p < .001). Other major risk factors were age [1830 years (OR 1.42, p < .001)] and being unmarried (OR 1.21-fold, p < .01). Conclusions : In regular highway drivers, sleepiness at the wheel or sleep disorders such as hypersomnia and narcolepsy are responsible for traffic accidents independent of age, sex, marital status or socioprofessional categories.

Published
2010
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7. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations

Author

Marion Sallée, Marie Essig, David Ribes, Marie-Agnès Dragon-Durey, Sophie Caillard, Eric Rondeau, Véronique Frémeaux-Bacchi, Fadi Fakhouri, Lionel Couzi, Lubka T. Roumenina, Franck Bridoux, François Provôt, Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2, ifr 66, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie, Dialyse, Transplantations [CHU Limoges], CHU Limoges, Laboratoire d'Immunologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP] - Assistance publique - Hôpitaux de Paris (AP-HP), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Université de Limoges (UNILIM) - CHU Limoges - Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Européen Georges Pompidou [APHP] (HEGP), and Université de Limoges (UNILIM) - Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503) - Centre National de la Recherche Scientifique (CNRS)

Subjects
Hemolytic anemia, MESH : Retrospective Studies, 030232 urology & nephrology, MESH : Hemolytic-Uremic Syndrome, MESH: Pregnancy Complications, Hematologic, 030204 cardiovascular system & hematology, Gene mutation, urologic and male genital diseases, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, hemic and lymphatic diseases, MESH : Female, MESH : Pregnancy Outcome, Pregnancy Outcome, General Medicine, MESH : Adult, 3. Good health, Nephrology, MESH: Hemolytic-Uremic Syndrome, MESH: Young Adult, MESH : Complement C3 Convertase, Alternative Pathway, Gestation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Thrombotic thrombocytopenic purpura, MESH : Young Adult, Preeclampsia, 03 medical and health sciences, Young Adult, MESH : Pregnancy Complications, Hematologic, Clinical Research, Internal medicine, Atypical hemolytic uremic syndrome, medicine, Humans, Retrospective Studies, Complement C3 Convertase, Alternative Pathway, MESH: Humans, business.industry, MESH : Humans, Pregnancy Complications, Hematologic, MESH: Complement C3 Convertase, Alternative Pathway, MESH: Adult, MESH: Retrospective Studies, medicine.disease, MESH: Pregnancy Outcome, MESH : Pregnancy, Immunology, Hemolytic-Uremic Syndrome, business, MESH: Female, Kidney disease
Abstract

International audience; In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n = 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.

Published
2010
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8. Molecular and biochemical characterization of a cathepsin B-like protease family unique to Trypanosoma congolense

Author

Edith Authié, Théo Baltz, Theresa H.T. Coetzer, Nicolas Biteau, Virginie Coustou, C. Giroud, Carlos Mendoza-Palomares, Alain Boulangé, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire biologie moléculaire et immunologie de protozoaires parasites, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Université de Lyon - Université de Lyon - Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Programme forêts naturelles (Cirad-Forêt programme Forêts naturelles), Département Forêt (Cirad-FORET), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Infectiologie Animale et Santé Publique (UR IASP), Institut National de la Recherche Agronomique (INRA), UMR Trypanosomes, Institut de Recherche pour le Développement (IRD)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)

Subjects
MESH : Molecular Sequence Data, Trypanosoma congolense, [SDV]Life Sciences [q-bio], Cathepsin E, MESH: Amino Acid Sequence, Cathepsin F, L73 - Maladies des animaux, Cathepsin A, Cathepsin B, Cathepsin C, MESH: Recombinant Proteins, 0302 clinical medicine, Cathepsin O, Cathepsin H, Cathepsin L1, Immunologie, MESH: Animals, MESH: Phylogeny, Phylogeny, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Sequence Alignment, Contrôle de maladies, MESH : Trypanosoma congolense, Cystéine, General Medicine, Articles, MESH: Trypanosoma congolense, Recombinant Proteins, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, PCR, Biochemistry, Multigene Family, Protéase, MESH : Recombinant Proteins, 030231 tropical medicine, Molecular Sequence Data, MESH : Multigene Family, MESH: Sequence Alignment, MESH : Cathepsins, Biology, Microbiology, 03 medical and health sciences, Animals, Peptidase, Amino Acid Sequence, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, 030304 developmental biology, MESH: Molecular Sequence Data, Anticorps, MESH : Phylogeny, Molecular biology, Cathepsins, MESH: Cathepsins, MESH: Multigene Family, MESH : Animals, Sequence Alignment
Abstract

Cysteine proteases have been shown to be essential virulence factors and drug targets in trypanosomatids and an attractive antidisease vaccine candidate forTrypanosoma congolense. Here, we describe an important amplification of genes encoding cathepsin B-like proteases unique toT. congolense. More than 13 different genes were identified, whereas only one or two highly homologous genes have been identified in other trypanosomatids. These proteases grouped into three evolutionary clusters: TcoCBc1 to TcoCBc5 and TcoCBc6, which possess the classical catalytic triad (Cys, His, and Asn), and TcoCBs7 to TcoCBs13, which contains an unusual catalytic site (Ser, Xaa, and Asn). Expression profiles showed that members of the TcoCBc1 to TcoCBc5 and the TcoCBs7 to TcoCBs13 groups are expressed mainly in bloodstream forms and localize in the lysosomal compartment. The expression of recombinant representatives of each group (TcoCB1, TcoCB6, and TcoCB12) as proenzymes showed that TcoCBc1 and TcoCBc6 are able to autocatalyze their maturation 21 and 31 residues, respectively, upstream of the predicted start of the catalytic domain. Both displayed a carboxydipeptidase function, while only TcoCBc1 behaved as an endopeptidase. TcoCBc1 exhibited biochemical differences regarding inhibitor sensitivity compared to that of other cathepsin B-like proteases. Recombinant pro-TcoCBs12 did not automature in vitro, and the pepsin-matured enzyme was inactive in tests with cathepsin B fluorogenic substrates. In vivo inhibition studies using CA074Me (a cell-permeable cathepsin B-specific inhibitor) demonstrated that TcoCB are involved in lysosomal protein degradation essential for survival in bloodstream form. Furthermore, TcoCBc1 elicited an important immune response in experimentally infected cattle. We propose this family of proteins as a potential therapeutic target and as a plausible antigen forT. congolensediagnosis.

Published
2008
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9. Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism

Author

Leblois, Arthur, Meissner, Wassilios, Bioulac, Bernard, Gross, Christian E, Hansel, David, Boraud, Thomas, Neurophysique et physiologie du système moteur (NPSM), Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS), Laboratoire Franco-Israelien de Neurophysiologie et Neurophysique des Systèmes, Université Paris Descartes - Paris 5 (UPD5), Laboratoire Mouvement Adaptation Cognition (MAC), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Neurons, Behavior, Animal, Tyrosine 3-Monooxygenase, Movement, MPTP Poisoning, Globus Pallidus, Macaca mulatta, Basal Ganglia, Electrophysiology, Disease Progression, Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cortical Synchronization, Parkinson Disease, Secondary, Algorithms
Abstract

Parkinson's disease is known to result from basal ganglia dysfunction. Electrophysiological recordings in parkinsonian patients and animals have shown the emergence of abnormal synchronous oscillatory activity in the cortico-basal ganglia network in the pathological condition. In addition, previous studies pointed out an altered response pattern during movement execution in the pallidum of parkinsonian animals. To investigate the dynamics of these changes during disease progression and to relate them to the onset of the motor symptoms, we recorded spontaneous and movement-related neuronal activity in the internal pallidum of nonhuman primates during a progressive dopamine depletion process. Parkinsonian motor symptoms appeared progressively during the intoxication protocol, at the end of which both animals displayed severe akinesia, rigidity and postural abnormalities. Spontaneous firing rates did not vary significantly after intoxication. During the early phase of the protocol, voluntary movements were significantly slowed down and delayed. At the same time, the neuronal response to movement execution was modified and inhibitory responses disappeared. In contrast, the unitary and collective dynamic properties of spontaneous neuronal activity, as revealed by spectral and correlation analysis, remained unchanged during this period. Spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor symptoms developed. Thus, a causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. The pathological disruption of movement-related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and stands as the best candidate to account for this motor symptom.

Published
2007
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10. Oxygen concentration influences mRNA processing and expression of the CD34 gene

Author

Brunet De La Grange, Philippe, Barthe, Christophe, Lippert, Eric, Hermitte, Francis, Belloc, Francis, Lacombe, Francis, Ivanovic, Zoran, Praloran, Vincent, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique et Physiologie du Poisson (G.P.P.), Université Sciences et Technologies - Bordeaux 1, Laboratoire d'hématologie, CHU Bordeaux [Bordeaux], Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Transfert de Genes a Visee Therapeutique Dans les Cellules Souches, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Transfusion Sanguine Aquitaine-Limousin (CTS AQUITAINE-LIMOUSIN), Centre de Transfusion Sanguine, Muniesa, Annie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), and Université Bordeaux Segalen - Bordeaux 2 - Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT]
Published
2006

11. Very low O2 concentration (0,1 %) favors G0 return of dividing CD34 + cells

Author

Philippe Brunet de la Grange, Zoran Ivanovic, Francis Hermitte, Francis Belloc, Vincent Praloran, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Transfert de Genes a Visee Therapeutique Dans les Cellules Souches, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Transfusion Sanguine Aquitaine-Limousin (CTS AQUITAINE-LIMOUSIN), Centre de Transfusion Sanguine, Muniesa, Annie, Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Université Bordeaux Segalen - Bordeaux 2 - Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Cell Survival, Cd34 cells, CD34, Antigens, CD34, Mice, SCID, Biology, Resting Phase, Cell Cycle, Andrology, Mice, Mice, Inbred NOD, medicine, Animals, Humans, Stem Cell Factor, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], Cell Cycle, Hematopoietic Stem Cell Transplantation, Hematopoietic stem cell, Bone Marrow Stem Cell, Cell Biology, Cell cycle, Hematopoietic Stem Cells, Oxygen, medicine.anatomical_structure, Cord blood, Immunology, Molecular Medicine, Interleukin-3, Bone marrow, Developmental Biology, Transforming growth factor
Abstract

Physiological bone marrow oxygen concentrations are everywhere lower than 4% and almost null in some areas. We compared the effects of 20%, 3%, and 0.1% O2 concentrations on cord blood CD34+ cell survival, cycle, and functionality in serum-free cultures for 72 hours with or without interleukin-3 (IL-3). As from 24 hours, IL-3 improved cell survival and proliferation in all conditions. After 72 hours, cells were 1.5 and 2.5 times more in quiescence (G0) at 3% and 0.1% O2, respectively, than at 20%; transforming growth factor-β signaling seemed not to be involved. To explore cell cycle further, fresh CD34+ cells were stained with PKH26 and cultured for 72 hours, and then undivided and divided cells were sorted. At 0.1% O2, 46.5% ± 19.1% of divided cells returned to G0 compared with 7.9% ± 0.3% at 20%. Colony formation and nonobese diabetic/severe combined immunodeficient mice engraftment efficiency were similar after 3 days at 20% and 0.1% O2 concentrations but lower than at T0. In conclusion, a low O2 concentration, close to those found in bone marrow stem cell niches, induces the G0 return of CD34+ cells without impairing their functional capacity.

Published
2006

12. Préservation des cellules souches hématopoïétiques (CHS) en hypoxie par le VEGF

Author

Debeissat, Christelle, Brunet de La Grange, Philippe, Ivanovic, Zoran, Praloran, Vincent, Muniesa, Annie, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Centre de Transfusion Sanguine Aquitaine-Limousin (CTS AQUITAINE-LIMOUSIN), Centre de Transfusion Sanguine, Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Published
2006

13. Age effect in recall performance according to the levels of processing, elaboration, and retrieval cues

Author

François Guillem, Hélène Sauzéon, Bernard Claverie, Bernard N'Kaoua, Veronique Lespinet, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de l'intégration, du matériau au système (IMS), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Programming Language Technology For Communication Services (Phoenix), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS) - École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB) - Université Sciences et Technologies - Bordeaux 1 - Université Bordeaux Segalen - Bordeaux 2 - Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria) - Institut National de Recherche en Informatique et en Automatique (Inria) - Handicap et système nerveux :Action, communication, interaction: rétablissement de la fonction et de la participation [Bordeaux] (EA4136), UFR Sciences médicales 3 [Bordeaux] - Université de Bordeaux Ségalen [Bordeaux 2] - UFR Sciences médicales 3 [Bordeaux] - Université de Bordeaux Ségalen [Bordeaux 2], Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Université Sciences et Technologies - Bordeaux 1 - Institut Polytechnique de Bordeaux - Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Aging, Context-dependent memory, Encoding specificity principle, Developmental psychology, Arts and Humanities (miscellaneous), Encoding (memory), Task Performance and Analysis, Humans, Levels-of-processing effect, General Psychology, Aged, Aged, 80 and over, Recall, Memoria, Cognition, Middle Aged, Free recall, [SCCO.PSYC] Cognitive science/Psychology, Mental Recall, [SCCO.PSYC]Cognitive science/Psychology, Female, Geriatrics and Gerontology, Psychology, Cognitive psychology
Abstract

International audience; The present study was conducted to investigate the incidence of several factors contributing to age-related memory decrement. Variables manipulated include quality (level of processing encoding conditions), the degree of effort and encoding quantitative elaboration (active/passive encoding conditions), and the influence of retrieval support (free-/cued recall conditions). In support of the environmental support hypothesis, middle-old and old subjects benefited more than young ones from cued recall in all the memory tests. Moreover, the results showed a differential (qualitative vs. quantitative) impairment of conceptual processing between the middle-old and the old-age groups. In the middle-olds, age differences were abolished by deep processing in old adults, age differences were attentuated only with deep and active processing associated with retrieval support. These gradual memory impairments are evaluated according to Mandler's model of memory (1979, In L. G. Nilsson [Ed.], Perspective in memory research. Hillsdale: Lawrence-Erlbaum), and the environmental support hypothesis is discussed in terms of the involvement of encoding and retrieval operations required by the memory task.

Published
2000
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14. Efficient and Specific Internal Cleavage of a Retroviral Palindromic DNA Sequence by Tetrameric HIV-1 Integrase

Author

Caroline Petit, Hervé Leh, Olivier Delelis, Vincent Parissi, Jean-François Mouscadet, Eric Deprez, Pierre Sonigo, Gladys Mbemba, Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan) - Centre National de la Recherche Scientifique (CNRS), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2 - Centre National de la Recherche Scientifique (CNRS), Bioalliancepharma, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie Fondamentale et Pathogénicité (MFP), and Brachet-Ducos, Corinne

Subjects
Sequence analysis, Stereochemistry, Inverted Repeat Sequences, Virus Integration, lcsh:Medicine, HIV Integrase, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Consensus sequence, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, HIV Long Terminal Repeat, 030304 developmental biology, Palindromic sequence, Genetics, 0303 health sciences, Multidisciplinary, Base Sequence, biology, lcsh:R, 030302 biochemistry & molecular biology, Long terminal repeat, Integrase, chemistry, DNA, Viral, HIV-1, biology.protein, lcsh:Q, DNA, Circular, DNA, Plasmids, Research Article
Abstract

BACKGROUND: HIV-1 integrase (IN) catalyses the retroviral integration process, removing two nucleotides from each long terminal repeat and inserting the processed viral DNA into the target DNA. It is widely assumed that the strand transfer step has no sequence specificity. However, recently, it has been reported by several groups that integration sites display a preference for palindromic sequences, suggesting that a symmetry in the target DNA may stabilise the tetrameric organisation of IN in the synaptic complex. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the ability of several palindrome-containing sequences to organise tetrameric IN and investigated the ability of IN to catalyse DNA cleavage at internal positions. Only one palindromic sequence was successfully cleaved by IN. Interestingly, this symmetrical sequence corresponded to the 2-LTR junction of retroviral DNA circles-a palindrome similar but not identical to the consensus sequence found at integration sites. This reaction depended strictly on the cognate retroviral sequence of IN and required a full-length wild-type IN. Furthermore, the oligomeric state of IN responsible for this cleavage differed from that involved in the 3'-processing reaction. Palindromic cleavage strictly required the tetrameric form, whereas 3'-processing was efficiently catalysed by a dimer. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that the restriction-like cleavage of palindromic sequences may be a general physiological activity of retroviral INs and that IN tetramerisation is strongly favoured by DNA symmetry, either at the target site for the concerted integration or when the DNA contains the 2-LTR junction in the case of the palindromic internal cleavage.

Published
2007
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