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1. Real-time forecasting of COVID-19-related hospital strain in France using a non-Markovian mechanistic model.

Author

Alexander Massey, Corentin Boennec, Claudia Ximena Restrepo-Ortiz, Christophe Blanchet, Samuel Alizon, and Mircea T Sofonea

Subjects
Biology (General), QH301-705.5
Abstract

Projects such as the European Covid-19 Forecast Hub publish forecasts on the national level for new deaths, new cases, and hospital admissions, but not direct measurements of hospital strain like critical care bed occupancy at the sub-national level, which is of particular interest to health professionals for planning purposes. We present a sub-national French framework for forecasting hospital strain based on a non-Markovian compartmental model, its associated online visualisation tool and a retrospective evaluation of the real-time forecasts it provided from January to December 2021 by comparing to three baselines derived from standard statistical forecasting methods (a naive model, auto-regression, and an ensemble of exponential smoothing and ARIMA). In terms of median absolute error for forecasting critical care unit occupancy at the two-week horizon, our model only outperformed the naive baseline for 4 out of 14 geographical units and underperformed compared to the ensemble baseline for 5 of them at the 90% confidence level (n = 38). However, for the same level at the 4 week horizon, our model was never statistically outperformed for any unit despite outperforming the baselines 10 times spanning 7 out of 14 geographical units. This implies modest forecasting utility for longer horizons which may justify the application of non-Markovian compartmental models in the context of hospital-strain surveillance for future pandemics.

Published
2024
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2. A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer

Author

Claire Bonneau, Antoine Eliès, Yann Kieffer, Brigitte Bourachot, Sylvain Ladoire, Floriane Pelon, Delphine Hequet, Jean-Marc Guinebretière, Christophe Blanchet, Anne Vincent-Salomon, Roman Rouzier, and Fatima Mechta-Grigoriou

Subjects
Luminal breast cancer, Metastases, Cancer-associated fibroblasts, Stroma, CDH11, Cadherin 11, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. Methods Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5–2 cm without lymph node metastasis) with metastatic recurrence (“cases”) and corresponding “controls” (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). Results We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that “cases” are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. Conclusions This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.

Published
2020
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3. The bio.tools registry of software tools and data resources for the life sciences

Author

Jon Ison, Hans Ienasescu, Piotr Chmura, Emil Rydza, Hervé Ménager, Matúš Kalaš, Veit Schwämmle, Björn Grüning, Niall Beard, Rodrigo Lopez, Severine Duvaud, Heinz Stockinger, Bengt Persson, Radka Svobodová Vařeková, Tomáš Raček, Jiří Vondrášek, Hedi Peterson, Ahto Salumets, Inge Jonassen, Rob Hooft, Tommi Nyrönen, Alfonso Valencia, Salvador Capella, Josep Gelpí, Federico Zambelli, Babis Savakis, Brane Leskošek, Kristoffer Rapacki, Christophe Blanchet, Rafael Jimenez, Arlindo Oliveira, Gert Vriend, Olivier Collin, Jacques van Helden, Peter Løngreen, and Søren Brunak

Subjects
Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Bioinformaticians and biologists rely increasingly upon workflows for the flexible utilization of the many life science tools that are needed to optimally convert data into knowledge. We outline a pan-European enterprise to provide a catalogue (https://bio.tools) of tools and databases that can be used in these workflows. bio.tools not only lists where to find resources, but also provides a wide variety of practical information.

Published
2019
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4. WellInverter: a web application for the analysis of fluorescent reporter gene data

Author

Yannick Martin, Michel Page, Christophe Blanchet, and Hidde de Jong

Subjects
Fluorescent reporter gene data, Microplate reader, Quantitative modeling of gene expression, Estimation, Web application, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Fluorescent reporter genes have become widely used for monitoring gene expression in living cells. When a microbial strain carrying a reporter gene is grown in a microplate reader, the fluorescence and the absorbance (optical density) of the culture can be automatically measured every few minutes in a highly parallelized way. The extraction of useful information from the resulting large amounts of data is not easy to achieve, because the fluorescence and absorbance measurements are only indirectly related to promoter activities and protein concentrations, requiring mathematical models of the expression of reporter genes for their interpretation. Although the principles of the analysis of reporter gene data are well-established today, there is a lack of general-purpose bioinformatics tools based on generic measurement models and sound inference procedures. This has motivated the development of WellInverter, a web application based on well-known methods for regularized linear inversion. Results We present a new version of WellInverter that considerably improves the performance and usability of the original application. In particular, we have put in place a parallel computing architecture with a load balancer to distribute analysis queries over several back-end servers, we have completely redesigned the graphical user interface to better support the different analysis steps, and we have developed a plug-in system for the parsing of data files produced by microplate readers from different manufacturers. We illustrate the functioning of WellInverter by analyzing data of the expression of a fluorescent reporter gene controlled by a phage promoter in growing Escherichia coli populations. We show that the expression pattern in different growth media, supporting different growth rates, corresponds to the pattern expected for a constitutive gene. Conclusions The new version of WellInverter is a robust, easy-to-use and scalable web application, which has been deployed on two publicly accessible web servers and which can also be installed locally. A demo version of the application with two sample datasets is available on-line.

Published
2019
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5. Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

Author

Clotilde Guyon, Nada Jmari, Francine Padonou, Yen-Chin Li, Olga Ucar, Noriyuki Fujikado, Fanny Coulpier, Christophe Blanchet, David E Root, and Matthieu Giraud

Subjects
self-antigens, immunological tolerance, Aire, 3'UTR shortening, mTEC, thymus, Medicine, Science, Biology (General), QH301-705.5
Abstract

The ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3’end processing complex, suggesting they might impact transcript stability and levels through an effect on 3’UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3’UTR transcript isoforms in mTECs, a feature preceding Aire’s expression and correlated with the preferential selection of proximal polyA sites by the 3’end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3’UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.

Published
2020
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6. Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors

Author

Silvia Viana da Silva, Matthias Georg Haberl, Pei Zhang, Philipp Bethge, Cristina Lemos, Nélio Gonçalves, Adam Gorlewicz, Meryl Malezieux, Francisco Q. Gonçalves, Noëlle Grosjean, Christophe Blanchet, Andreas Frick, U Valentin Nägerl, Rodrigo A. Cunha, and Christophe Mulle

Subjects
Science
Abstract

Hippocampal synaptic dysfunctions are an early symptom of Alzheimer’s disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.

Published
2016
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7. BioShaDock: a community driven bioinformatics shared Docker-based tools registry [version 1; referees: 2 approved]

Author

François Moreews, Olivier Sallou, Hervé Ménager, Yvan Le bras, Cyril Monjeaud, Christophe Blanchet, and Olivier Collin

Subjects
Bioinformatics, Medicine, Science
Abstract

Linux container technologies, as represented by Docker, provide an alternative to complex and time-consuming installation processes needed for scientific software. The ease of deployment and the process isolation they enable, as well as the reproducibility they permit across environments and versions, are among the qualities that make them interesting candidates for the construction of bioinformatic infrastructures, at any scale from single workstations to high throughput computing architectures. The Docker Hub is a public registry which can be used to distribute bioinformatic software as Docker images. However, its lack of curation and its genericity make it difficult for a bioinformatics user to find the most appropriate images needed. BioShaDock is a bioinformatics-focused Docker registry, which provides a local and fully controlled environment to build and publish bioinformatic software as portable Docker images. It provides a number of improvements over the base Docker registry on authentication and permissions management, that enable its integration in existing bioinformatic infrastructures such as computing platforms. The metadata associated with the registered images are domain-centric, including for instance concepts defined in the EDAM ontology, a shared and structured vocabulary of commonly used terms in bioinformatics. The registry also includes user defined tags to facilitate its discovery, as well as a link to the tool description in the ELIXIR registry if it already exists. If it does not, the BioShaDock registry will synchronize with the registry to create a new description in the Elixir registry, based on the BioShaDock entry metadata. This link will help users get more information on the tool such as its EDAM operations, input and output types. This allows integration with the ELIXIR Tools and Data Services Registry, thus providing the appropriate visibility of such images to the bioinformatics community.

Published
2015
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8. Spectral photon-counting CT imaging of colorectal peritoneal metastases: initial experience in rats

Author

Vahan Kepenekian, Philippe Douek, Pascal Rousset, Pierre-Emmanuel Bonnot, Loic Boussel, Salim Si-Mohamed, Arnaud Thivolet, Christophe Blanchet, Bodescot, Myriam, In Vivo Spectral Photon Counting CT Molecular Imaging in Cardio- and Neuro-Vascular Diseases - SPCCT - - H20202016-01-01 - 2019-12-31 - 668142 - VALID, Radiology Department [Lyon], Hospices Civils de Lyon (HCL), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université de Lyon, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Surgical Department [Lyon], Pathology Department [Lyon], Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), This work was supported by European Union Horizon 2020 grant No 668142, France Life Imaging (FLI)., European Project: 668142,H2020,H2020-PHC-2015-two-stage,SPCCT(2016), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
0301 basic medicine, Male, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Gadolinium, chemistry.chemical_element, Contrast Media, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Distribution (pharmacology), Medicine, Animals, Cancer models, lcsh:Science, Peritoneal Neoplasms, Photons, Multidisciplinary, business.industry, Significant difference, Contrast resolution, lcsh:R, Rats, Inbred Strains, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Colorectal cancer, Photon counting, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Disease Models, Animal, 030104 developmental biology, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, chemistry, Preclinical research, Surgical oncology, Immunohistochemistry, Cancer imaging, lcsh:Q, Tomography, Ct imaging, business, Nuclear medicine, Colorectal Neoplasms, Tomography, X-Ray Computed, 030217 neurology & neurosurgery, Neoplasm Transplantation
Abstract

Computed tomography imaging plays a major role in the preoperative assessment of tumor burden by providing an accurate mapping of the distribution of peritoneal metastases (PM). Spectral Photon Counting Computed Tomography (SPCCT) is an innovative imaging modality that could overcome the current limitations of conventional CT, offering not only better spatial resolution but also better contrast resolution by allowing the discrimination of multiple contrast agents. Based on this capability, we tested the feasibility of SPCCT in the detection of PM at different time of tumor growth in 16 rats inoculated with CC531 cells using dual-contrast injection protocols in two compartments (i.e. intravenous iodine and intraperitoneal gadolinium or the reverse protocol), compared to surgery. For all peritoneal regions and for both protocols, sensitivity was 69%, specificity was 100% and accuracy was 80%, and the correlation with surgical exploration was strong (p = 0.97; p = 0.0001). No significant difference was found in terms of diagnostic performance, quality of peritoneal opacification or diagnostic quality between the 2 injection protocols. We also showed poor vascularization of peritoneal metastases by measuring low concentrations of contrast agent in the largest lesions using SPCCT, which was confirmed by immunohistochemical analyses. In conclusion, SPCCT using dual-contrast agent injection protocols in 2 compartments is a promising imaging modality to assess the extent of PM in a rat model.

Published
2020

9. A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer

Author

Yann Kieffer, Fatima Mechta-Grigoriou, Jean Marc Guinebretière, Roman Rouzier, Delphine Hequet, Floriane Pelon, Sylvain Ladoire, Christophe Blanchet, Anne Vincent-Salomon, Antoine Elies, Claire Bonneau, Brigitte Bourachot, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut Curie [Paris], Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut National de la Santé et de la Recherche Médicale, Inserm ANR-10-EQPX-03, INCa-DGOS-Inserm-12554, STROMAE INCa-DGOS-9963 Institut National Du Cancer, INCa: INCa-11692, INCa-DGOS-4654, INCa-DGOS-9963 Fondation pour la Recherche Médicale, FRM Institut Curie: PIC3i CAFi Ligue Contre le Cancer: PC201317 Fondation Simone et Cino Del Duca, C.B. was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm, Plan Cancer - Formation à la recherche translationnelle), A.E. by the association d’aide en Cancérologie de Saint-Cloud (ARCS), and Y.K. by the Institut National du Cancer, INCa (INCa-DGOS-9963, INCa-11692), SIRIC (INCa-DGOS-4654), and the Fondation pour la Recherche Medicale (FRM). The experimental work was supported by grants from the Ligue Nationale Contre le Cancer (Labelisation), Inserm (PC201317), Institut Curie (Incentive and Cooperative Program Tumor Micro-environment PIC TME/T-MEGA, PIC3i CAFi), ICGex (ANR-10-EQPX-03), SIRIC (INCa-DGOS-4654), and INCa (STROMAE INCa-DGOS-9963, CaLYS INCa-11692, INCa-DGOS-Inserm-12554). F.M-G acknowledges both the Association 'Le cancer du sein, Parlons-en' and the Simone and Cino del Duca Foundation for attribution of their 'Grand Prix'. F.M-G is very grateful to all her funders for providing support throughout the years., and F.M-G. received research support from Innate-Pharma, Roche and Bristol-Myers-Squibb (BMS). R. R received financial support for research (travel reimbursement) and speaker honoraria from Nanostring Technologies. Other authors declare no potential conflict of interest.

Subjects
Oncology, CDH11, Receptor, ErbB-2, Stroma, Metastases, 0302 clinical medicine, Luminal breast cancer, Surgical oncology, Tumor Microenvironment, Aged, 80 and over, 0303 health sciences, Carcinoma, Ductal, Breast, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Combined Modality Therapy, 3. Good health, Tumor infiltrating lymphocytes, Survival Rate, Cadherin 11, Receptors, Estrogen, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Receptors, Progesterone, Research Article, Adult, medicine.medical_specialty, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, Lymphocytes, Tumor-Infiltrating, Internal medicine, medicine, Biomarkers, Tumor, Humans, Clinical significance, TILs, Cancer-associated fibroblasts, 030304 developmental biology, Aged, business.industry, Tumor-infiltrating lymphocytes, medicine.disease, Carcinoma, Lobular, Tumor micro-environment, Case-Control Studies, Cancer cell, Cancer-Associated Fibroblasts, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

BackgroundEarly luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients.MethodsOur study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5–2 cm without lymph node metastasis) with metastatic recurrence (“cases”) and corresponding “controls” (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF).ResultsWe found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that “cases” are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients.ConclusionsThis study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.

Published
2020

10. Aire-dependent genes undergo Clp1-mediated 3'UTR shortening associated with higher transcript stability in the thymus

Author

Fanny Coulpier, Li Yen-Chin, Christophe Blanchet, Olga Ucar, Clotilde Guyon, Francine Padonou, Matthieu Giraud, Noriyuki Fujikado, Nada Jmari, David E. Root, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Harvard Medical School [Boston] (HMS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Français de Bioinformatique (IFB-CORE), Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], the European Commission CIG grant PCIG9-GA-2011-294212 786, the Fondation pour la Recherche Médicale FDT20150532551 and ING20121226316, ANR-06-NEUR-0044,SCANEPI,Conséquences à long terme de l'exposition péripubertaire aux cannabinoides: étude comportementale et transcriptionnelle chez le rat et analyse moléculaire chez l'homme(2006), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Le Bihan, Sylvie, Neurosciences, neurologie et psychiatrie - Conséquences à long terme de l'exposition péripubertaire aux cannabinoides: étude comportementale et transcriptionnelle chez le rat et analyse moléculaire chez l'homme - - SCANEPI2006 - ANR-06-NEUR-0044 - NEURO - VALID, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
QH301-705.5, Science, [SDV]Life Sciences [q-bio], Thymus Gland, Biology, Transcript isoforms, immunology, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Immunology and Inflammation, thymus, Gene expression, medicine, genomics, Animals, genetics, Biology (General), Gene, self-antigens, 3' Untranslated Regions, mouse, 030304 developmental biology, Autoimmune disease, 0303 health sciences, Thymocytes, Three prime untranslated region, Genetics and Genomics, Cell Differentiation, Epithelial Cells, mTEC, medicine.disease, Cell biology, Rnai screen, [SDV] Life Sciences [q-bio], Gene Expression Regulation, inflammation, Aire, Medicine, immunological tolerance, 3'UTR shortening, 030217 neurology & neurosurgery, Research Article
Abstract

The ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3’end processing complex, suggesting they might impact transcript stability and levels through an effect on 3’UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3’UTR transcript isoforms in mTECs, a feature preceding Aire’s expression and correlated with the preferential selection of proximal polyA sites by the 3’end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3’UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.

Published
2020

11. Hippocampal Mossy Fibers Synapses in CA3 Pyramidal Cells Are Altered at an Early Stage in a Mouse Model of Alzheimer's Disease

Author

Virginie F. Labrousse, Silvia Viana da Silva, Noelle Grosjean, Christophe Blanchet, Matthias G. Haberl, Christophe Mulle, Pei Zhang, Andreas Frick, Department of Microbiology and Immunology, Division of Infectious Diseases, Walther Oncology Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Nutrition et Neurobiologie intégrée (NutriNeur0), and Ecole nationale supérieure de chimie, biologie et physique-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1-Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2

Subjects
0301 basic medicine, Mossy fiber (hippocampus), Male, hippocampus, Long-Term Potentiation, Hippocampus, CA3, Neurotransmission, Biology, Hippocampal formation, Synapse, 03 medical and health sciences, Mice, 0302 clinical medicine, Alzheimer Disease, synapse, mossy fiber, Animals, Research Articles, mouse, General Neuroscience, Dentate gyrus, Pyramidal Cells, musculoskeletal, neural, and ocular physiology, Excitatory Postsynaptic Potentials, Long-term potentiation, CA3 Region, Hippocampal, Disease Models, Animal, 030104 developmental biology, nervous system, Synaptic plasticity, Mossy Fibers, Hippocampal, Synapses, Alzheimer, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery
Abstract

Early Alzheimer's disease (AD) affects the brain non-uniformly, causing hippocampal memory deficits long before wide-spread brain degeneration becomes evident. Here we addressed whether mossy fiber inputs from the dentate gyrus onto CA3 principal cells are affected in an AD mouse model before amyloid β plaque deposition. We recorded from CA3 pyramidal cells in a slice preparation from 6-month-old male APP/PS1 mice, and studied synaptic properties and intrinsic excitability. In parallel we performed a morphometric analysis of mossy fiber synapses following viral based labeling and 3D-reconstruction. We found that the basal structural and functional properties as well as presynaptic short-term plasticity at mossy fiber synapses are unaltered at 6 months in APP/PS1 mice. However, transient potentiation of synaptic transmission mediated by activity-dependent release of lipids was abolished. Whereas the presynaptic form of mossy fiber long-term potentiation (LTP) was not affected, the postsynaptic LTP of NMDAR-EPSCs was reduced. In addition, we also report an impairment in feedforward inhibition in CA3 pyramidal cells. This study, together with our previous work describing deficits at CA3–CA3 synapses, provides evidence that early AD affects synapses in a projection-dependent manner at the level of a single neuronal population.SIGNIFICANCE STATEMENTBecause loss of episodic memory is considered the cognitive hallmark of Alzheimer's disease (AD), it is important to study whether synaptic circuits involved in the encoding of episodic memory are compromised in AD mouse models. Here we probe alterations in the synaptic connections between the dentate gyrus and CA3, which are thought to be critical for enabling episodic memories to be formed and stored in CA3. We found that forms of synaptic plasticity specific to these synaptic connections are markedly impaired at an early stage in a mouse model of AD, before deposition of β amyloid plaques. Together with previous work describing deficits at CA3–CA3 synapses, we provide evidence that early AD affects synapses in an input-dependent manner within a single neuronal population.

Published
2019

12. The bio.tools registry of software tools and data resources for the life sciences

Author

Piotr Jaroslaw Chmura, Salvador Capella, Rob Hooft, Søren Brunak, Tomáš Raček, Inge Jonassen, Rodrigo Lopez, Jacques van Helden, Bengt Persson, Hedi Peterson, Brane Leskošek, Alfonso Valencia, Heinz Stockinger, Hervé Ménager, Emil Karol Rydza, Matúš Kalaš, Josep Lluís Gelpí, Tommi Nyrönen, Hans Ienasescu, Christophe Blanchet, Rafael C. Jimenez, Björn Grüning, Jon Ison, Babis Savakis, Radka Svobodová Vařeková, Arlindo L. Oliveira, Peter Løngreen, Niall Beard, Gert Vriend, Veit Schwämmle, Jiří Vondrášek, Séverine Duvaud, Federico Zambelli, Ahto Salumets, Kristoffer Rapacki, Olivier Collin, Technical University of Denmark [Lyngby] (DTU), University of Copenhagen = Københavns Universitet (KU), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], University of Bergen (UIB), University of Southern Denmark (SDU), Albert-Ludwigs-Universität Freiburg, University of Manchester [Manchester], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Swiss Institute of Bioinformatics - Lausanne (SIB), Swiss Institute of Bioinformatics, Uppsala University, Central European Institute of Technology [Brno] (CEITEC), Czech Academy of Sciences [Prague] (ASCR), University of Tartu, Dutch Techcentre for Life Sciences [Utrecht], Center for Science (CSC-IT), CSC-IT Center for Science, Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Università degli studi di Milano [Milano], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), University of Ljubljana, Institut Français de Bioinformatique - UMS CNRS 3601 (IFB-CORE), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de la Recherche Agronomique (INRA), ELIXIR Hub [Cambridge], Instituto de Engenharia de Sistemas e Computadores Investigação e Desenvolvimento em Lisboa (INESC-ID), Instituto Superior Técnico, Universidade Técnica de Lisboa (IST)-Instituto de Engenharia de Sistemas e Computadores (INESC), Nijmegen Medical Centre [Nijmegen], Plateforme bioinformatique GenOuest [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Danish Ministry of Higher Education and Science, European Project: 676559,H2020,H2020-INFRADEV-1-2015-1,ELIXIR-EXCELERATE(2015), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UiB), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Czech Academy of Sciences [Prague] (CAS), Università degli Studi di Milano [Milano] (UNIMI), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), University of Copenhagen = Københavns Universitet (UCPH), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Università degli Studi di Milano = University of Milan (UNIMI), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), and Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1)

Subjects
lcsh:QH426-470, Databases, Factual, Bioinformatics, [SDV]Life Sciences [q-bio], MEDLINE, Biology, Biological Science Disciplines, 03 medical and health sciences, 0302 clinical medicine, Software, Bioinformàtica, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, Internet, business.industry, Biochemistry and Molecular Biology, Data science, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Data resources, Variety (cybernetics), lcsh:Genetics, Workflow, lcsh:Biology (General), The Internet, Open Letter, business, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Biokemi och molekylärbiologi, 030217 neurology & neurosurgery
Abstract

Bioinformaticians and biologists rely increasingly upon workflows for the flexible utilization of the many life science tools that are needed to optimally convert data into knowledge. We outline a pan-European enterprise to provide a catalogue (https://bio.tools) of tools and databases that can be used in these workflows. bio.tools not only lists where to find resources, but also provides a wide variety of practical information. Electronic supplementary material The online version of this article (10.1186/s13059-019-1772-6) contains supplementary material, which is available to authorized users.

Published
2019
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13. Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors

Author

Adam Gorlewicz, Francisco Q. Gonçalves, Noelle Grosjean, Silvia Viana da Silva, Matthias G. Haberl, Nélio Gonçalves, Rodrigo A. Cunha, Philipp Bethge, Meryl Malezieux, Pei Zhang, Christophe Mulle, U. Valentin Nägerl, Andreas Frick, Cristina Lemos, and Christophe Blanchet

Subjects
0301 basic medicine, Dendritic spine, Long-Term Potentiation, General Physics and Astronomy, Adenosine A2A receptor, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Postsynaptic potential, Medicine, RNA, Small Interfering, Episodic memory, Multidisciplinary, Triazines, Long-term potentiation, CA3 Region, Hippocampal, Adenosine A2 Receptor Antagonists, Neuroprotective Agents, NMDA receptor, Alzheimer's disease, Signal Transduction, Receptor, Adenosine A2A, Dendritic Spines, Memory, Episodic, Science, Mice, Transgenic, Receptors, N-Methyl-D-Aspartate, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Alzheimer Disease, mental disorders, Presenilin-1, Animals, Humans, business.industry, General Chemistry, Triazoles, medicine.disease, Disease Models, Animal, 030104 developmental biology, Pyrimidines, nervous system, Gene Expression Regulation, Synaptic plasticity, Immunology, Synapses, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients., Hippocampal synaptic dysfunctions are an early symptom of Alzheimer's disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.

Published
2016

14. A reusable tree-based web-visualization to browse EDAM ontology, and contribute to it

Author

Hervé Ménager, Christophe Blanchet, Bryan Brancotte, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Français de Bioinformatique - UMS CNRS 3601 (IFB-CORE), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Ménager, Hervé

Subjects
0301 basic medicine, Interface (Java), Computer science, javascript, 02 engineering and technology, Ontology (information science), computer.software_genre, JavaScript, 03 medical and health sciences, Controlled vocabulary, 0202 electrical engineering, electronic engineering, information engineering, d3.js, ontology, visualization, computer.programming_language, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], d3js, Information retrieval, edamontology, Toolbar, 020207 software engineering, bioinformatics, 030104 developmental biology, Search box, Web service, User interface, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer
Abstract

International audience; The EDAM Browser is a client-side web-based visualization javascript widget for the navigation of the EDAM ontology (Ison et al. 2013). EDAM is a structured and controlled vocabulary describing bioinformatics and computational biology concepts. It is used to annotate resource descriptions (tools, web services) for discovery (Ison et al. 2015) and integration in platforms such as galaxy (Afgan et al. 2016). The EDAM Browser provides users a simple and performant interface to explore EDAM when annotating or searching for bioinformatics resources. User interface and functionalities The user interface (see Fig. 1) is divided in two main panels, a tree representation of the ontology on the left, and a properties card on the right. The tree on the left represents the different parts of the ontology (formats, data, operations and topics). By expanding or closing the nodes, users explore the hierarchy of the EDAM concepts. The selected concept is displayed in bold, and all the path(s) leading from the root to it are highlighted. The properties card panel on the right displays the main properties of the concept, such as its definition, comments, synonyms, and its non-hierarchical relations to other concepts (e.g. an operation has inputs, outputs, and belongs to a given topic). It also includes counts and links to entries in various databases that use this term, such as bio.tools, BioSphere (Brancotte et al. 2017), BioWeb and TeSS. The user may directly suggest a modification on a concept by clicking on the "edit" icons at the top-right corner of this panel ; creating a new concept is also possible thanks to the "add a child" button. Both lead the user to a form that directly formats suggestions as github issues ready to be submitted by the user (see Fig. 2). Additional components of the interface include a full-text search box to search for concepts on their names, synonyms or descriptions; a navigation toolbar to toggle the display of specific parts of the ontology only, or load locally modified versions of the ontology; and a history stack of the concepts that have been seen previously to the one currently selected, below the properties card panel.

Published
2018

15. Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK

Author

Jamie L. Lim, Roy Augustinus, Jaap J. Plomp, Kasra Roya-Kouchaki, Dana L. E. Vergoossen, Yvonne Fillié-Grijpma, Josephine Struijk, Rachel Thomas, Daniela Salvatori, Christophe Steyaert, Christophe Blanchetot, Roeland Vanhauwaert, Karen Silence, Silvère M. van der Maarel, Jan J. Verschuuren, and Maartje G. Huijbers

Subjects
Medicine, Science
Abstract

Abstract Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise.

Published
2023
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16. Combined genetic approaches yield a 48% diagnostic rate in a large cohort of French hearing-impaired patients

Author

Z. Azher, Gema García-García, L. Lambert, B. Isidor, Christel Vaché, M. Moclyn, M. Mondain, M. Nizon, Marie-Claire Vincent, David Baux, R. Touraine, C. Calais, Y. Perdomo-Trujillo, Anne-Françoise Roux, Corinne Baudoin, F. Giuliano, Mireille Claustres, D. Dupin-Deguine, Sandra Mercier, Marjolaine Willems, Michel Koenig, Valérie Faugère, Christophe Blanchet, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'ORL, Hôpital Gui de Chauliac (CHRU de Montpellier), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, CHU Saint-Etienne, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Strasbourg, Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
0301 basic medicine, Male, DNA Copy Number Variations, Hearing loss, Genetic counseling, lcsh:Medicine, Bioinformatics, Sensitivity and Specificity, Connexins, White People, Article, Cohort Studies, 03 medical and health sciences, medicine, OTOF, otorhinolaryngologic diseases, Humans, Computer Simulation, Genetic Predisposition to Disease, Copy-number variation, Genetic Testing, Hearing Loss, lcsh:Science, Genetic testing, Multidisciplinary, Massive parallel sequencing, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], medicine.diagnostic_test, business.industry, Genetic heterogeneity, lcsh:R, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, 3. Good health, Connexin 26, 030104 developmental biology, Early Diagnosis, Mutation, lcsh:Q, France, medicine.symptom, business, STRC
Abstract

Hearing loss is the most common sensory disorder and because of its high genetic heterogeneity, implementation of Massively Parallel Sequencing (MPS) in diagnostic laboratories is greatly improving the possibilities of offering optimal care to patients. We present the results of a two-year period of molecular diagnosis that included 207 French families referred for non-syndromic hearing loss. Our multi-step strategy involved (i) DFNB1 locus analysis, (ii) MPS of 74 genes, and (iii) additional approaches including Copy Number Variations, in silico analyses, minigene studies coupled when appropriate with complete gene sequencing, and a specific assay for STRC. This comprehensive screening yielded an overall diagnostic rate of 48%, equally distributed between DFNB1 (24%) and the other genes (24%). Pathogenic genotypes were identified in 19 different genes, with a high prevalence of GJB2, STRC, MYO15A, OTOF, TMC1, MYO7A and USH2A. Involvement of an Usher gene was reported in 16% of the genotyped cohort. Four de novo variants were identified. This study highlights the need to develop several molecular approaches for efficient molecular diagnosis of hearing loss, as this is crucial for genetic counselling, audiological rehabilitation and the detection of syndromic forms.

Published
2017

17. CYCLONE: The Multi-Cloud Middleware Stack for Application Deployment and Management

Author

Yuri Demchenko, Alexy Ilyushkin, Cees de Laat, Charles Loomis, Fatih Turkmen, Mathias Slawik, Christophe Blanchet, and System and Network Engineering (IVI, FNWI)

Subjects
Computer science, business.industry, 020206 networking & telecommunications, 020207 software engineering, Access control, Cloud computing, 02 engineering and technology, computer.software_genre, SlipStream Cloud Management platform, Network management, Resource (project management), CYCLONE cloud automation platform for scientific application, Trust Bootstrapping in Federated Clouds, Software deployment, Cyclone (programming language), Middleware (distributed applications), Middleware, Intercloud Access Control, 0202 electrical engineering, electronic engineering, information engineering, CYCLONE Network Services Manager and Orchestrator (CNSMO), DevOps, business, Software engineering, computer, computer.programming_language
Abstract

DevOps teams have to consider many technology and platform aspects when developing, deploying and operating cloud based applications: application deployments need to work everywhere on different cloud platforms, identities need to come from anywhere, and networks need to connect to anyone. The CYCLONE middleware is a holistic middleware stack that allows deploying and managing cloud based applications on multiple clouds and multiple cloud platforms. It includes a deployment manager, a practical identity federation, as well as a network manager that connects VMs independent of any specific infrastructure. This article explains the CYCLONE middleware stack, and what it can offer for application developers and operators. The paper describes in details the main bioinformatics use cases that evolve from a single VM installation for simple microbial research to multicloud infrastructure for advanced genomic resource. The paper also describes the CYCLONE federated identity management and access control infrastructure that significantly simplifies access for institutional users.

Published
2017

18. An economical security architecture for multi-cloud application deployments in federated environments

Author

Christophe Blanchet, Begüm İlke Zilci, Axel Küpper, Jean-François Gibrat, Yuri Demchenko, Fatih Turkmen, Mathias Slawik, Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), Technische Universität Berlin (TUB), University of Amsterdam, Centre National de la Recherche Scientifique (CNRS), UE, ProdInra, Archive Ouverte, Technische Universität Berlin (TU), and University of Amsterdam [Amsterdam] (UvA)

Subjects
Development environment, 021110 strategic, defence & security studies, Computer science, business.industry, [SDV]Life Sciences [q-bio], 0211 other engineering and technologies, Cloud computing, security architectures, 02 engineering and technology, Enterprise information security architecture, Architecture design, Computer security, computer.software_genre, Cloud federation, multi-cloud application, [SDV] Life Sciences [q-bio], federated Bioinformatics applications, Software, Risk analysis (engineering), 13. Climate action, 020204 information systems, 0202 electrical engineering, electronic engineering, information engineering, Architecture, business, computer
Abstract

Contemporary multi-cloud application deployments require increasingly complex security architectures, especially within federated environments. However, increased complexity often leads to higher efforts and raised costs for managing and securing those applications. This publication establishes an economical and comprehensive security architecture that is readily instantiable, pertinent to concrete users’ requirements, and builds upon up-to-date protocols and software. We highlight its feasibility by applying the architecture within the CYCLONE innovation action, deploying federated Bioinformatics applications within a cloud production environment. At last, we put special emphasis on the reduced management efforts to highlight the economic benefit of following our approach.

Published
2016

19. CYCLONE: A Platform for Data Intensive Scientific Applications in Heterogeneous Multi-cloud/Multi-provider Environment

Author

Yuri Demchenko, Christophe Blanchet, Charles Loomis, Rob Branchat, Mathias Slawick, Ilke Zilci, Mohamed Bedri, Jean-Francois Gibrat, Oleg Lodygensky, Miroslav Zivkovic, Cees de Laat, Jose Ignacio Aznar Baranda, System and Network Engineering (IVI, FNWI), Theory of Computer Science (IVI, FNWI), University of Amsterdam [Amsterdam] (UvA), Centre National de la Recherche Scientifique (CNRS), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), Sunder Lal Jain Hospital, Technical University Berlin, and SixSq Sàrl

Subjects
0301 basic medicine, Computer science, [SDV]Life Sciences [q-bio], Cloud computing, Access control, Data intensive scientific applications requirements, 02 engineering and technology, World Wide Web, SlipStream Cloud Management platform, 03 medical and health sciences, CYCLONE cloud automation platform for scientific application, 0202 electrical engineering, electronic engineering, information engineering, Data Protection Act 1998, Use case, [INFO]Computer Science [cs], [MATH]Mathematics [math], 020203 distributed computing, Data processing, business.industry, Intercloud Architecture Framework (ICAF), Federated Cloud Infrastructure, Slipstream (computer science), Automation, 030104 developmental biology, 13. Climate action, Systems engineering, Intercloud, business
Abstract

International audience; This paper presents results of the ongoing development of the CYCLONE as a platform for scientific applications in heterogeneous multi-cloud/multi-provider environment. The paper explains the general use case that provides a general motivation for the CYCLONE architecture and provides detailed analysis of the bioinformatics use cases that define specific requirements to the CYCLONE infrastructure components. Special attention is given to the federated access control and security infrastructure that must provide consistent security and data protection for distributed bioinformatics data processing infrastructure and distributed cross-organisations collaborating teams of scientists. The paper provides information about selected use cases implementation using SlipStream cloud automation and management platform with application recipe example. The paper also addresses requirements for providing dedicated intercloud network infrastructure which is currently not addressed by cloud providers (both public and scientific/community)

Published
2016

20. BioShaDock: a community driven bioinformatics shared Docker-based tools registry

Author

Hervé Ménager, François Moreews, Cyril Monjeaud, Olivier Collin, Christophe Blanchet, Olivier Sallou, Yvan Le Bras, Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Service Expérimentation et Développement (SED [Rennes]), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria), Plateforme bioinformatique GenOuest [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®-Inria Rennes – Bretagne Atlantique, Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Centre d'Informatique pour la Biologie, Institut Pasteur [Paris], Institut Français de Bioinformatique - UMS CNRS 3601 (IFB-CORE), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), projet e-science des régions Bretagne te Pays de Loire, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®-Inria Rennes – Bretagne Atlantique, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Pasteur [Paris] (IP), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Moreews, Francois

Subjects
workflow, Interoperability, interoperability, Biology, Ontology (information science), registry, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Controlled vocabulary, deployment, High-throughput computing, General Pharmacology, Toxicology and Pharmaceutics, 030304 developmental biology, computer.programming_language, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, General Immunology and Microbiology, Software Tool Article, maintainability, General Medicine, Articles, bioinformatics, container, docker, Metadata, Workflow, community driven registry, Elixir (programming language), Data as a service, meta-données, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030217 neurology & neurosurgery
Abstract

International audience; Linux container technologies, as represented by Docker, provide an alternative to complex and time-consuming installation processes needed for scientific software. The ease of deployment and the process isolation they enable, as well as the reproducibility they permit across environments and versions, are among the qualities that make them interesting candidates for the construction of bioinformatic infrastructures, at any scale from single workstations to high throughput computing architectures. The Docker Hub is a public registry which can be used to distribute bioinformatic software as Docker images. However, its lack of curation and its genericity make it difficult for a bioinformatics user to find the most appropriate images needed. BioShaDock is a bioinformatics-focused Docker registry, which provides a local and fully controlled environment to build and publish bioinformatic software as portable Docker images. It provides a number of improvements over the base Docker registry on authentication and permissions management, that enable its integration in existing bioinformatic infrastructures such as computing platforms. The metadata associated with the registered images are domain-centric, including for instance concepts defined in the EDAM ontology, a shared and structured vocabulary of commonly used terms in bioinformatics. The registry also includes user defined tags to facilitate its discovery, as well as a link to the tool description in the ELIXIR registry if it already exists. If it does not, the BioShaDock registry will synchronize with the registry to create a new description in the Elixir registry, based on the BioShaDock entry metadata. This link will help users get more information on the tool such as its EDAM operations, input and output types. This allows integration with the ELIXIR Tools and Data Services Registry, thus providing the appropriate visibility of such images to the bioinformatics community.

Published
2015

21. Appliance Management for Federated Cloud Environments

Author

Christophe Blanchet, Stuart Kenny, Charles Loomis, Mohammed Airaj, LAL - Sce Informatique, Laboratoire de l'Accélérateur Linéaire (LAL), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), 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), School of Computer Science and Statistics [Dublin], Trinity College Dublin, Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), INFSO-RI-261552, StratusLab, European Project: 261552,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2010-2,STRATUSLAB(2010), Laboratoire de l'Accélérateur Linéaire ( LAL ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), 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-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), and European Project : 261552,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2010-2,STRATUSLAB ( 2010 )

Subjects
Service (systems architecture), Computer science, computer.internet_protocol, Cloud computing, 02 engineering and technology, Computer security, computer.software_genre, Electronic mail, [ INFO.INFO-DC ] Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Server, 0202 electrical engineering, electronic engineering, information engineering, cloud, RDF, appliance, business.industry, federated cloud, Infrastructure as a Service, IaaS, 020206 networking & telecommunications, computer.file_format, Scalability, [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], business, StratusLab, computer, XML
Abstract

International audience; Cloud infrastructures provide compelling features for scientific and engineering applications. Federated clouds additionally promise improved scalability via access to a larger pool of resources and improved service availability through geographically distributed redundant servers. Effective use of federated clouds requires the creation of portable appliances and consistent appliance management techniques. The StratusLab Marketplace, a platform-agnostic appliance registry, facilitates appliance management in a federated environment. This paper describes the Marketplace design goals, implementation, and security concerns. It also covers the planned improvements based on our experience of running this service in production for more than two years.

Published
2013

22. VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

Author

Jennifer Bosco, Zhiwei Zhou, Sofie Gabriëls, Mayank Verma, Nan Liu, Brian K. Miller, Sheng Gu, Dianna M. Lundberg, Yan Huang, Eilish Brown, Serene Josiah, Muthuraman Meiyappan, Matthew J. Traylor, Nancy Chen, Atsushi Asakura, Natalie De Jonge, Christophe Blanchetot, Hans de Haard, Heather S. Duffy, and Dennis Keefe

Subjects
Duchenne muscular dystrophy, angiogenesis, monoclonal antibody, vascular endothelial growth factor, fibrosis, Genetics, QH426-470, Cytology, QH573-671
Abstract

Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling. The lead chimeric mAb, 21B3, had high affinity and specificity for both human and mouse sFlt-1 and inhibited VEGF binding to sFlt-1 in a competitive manner. Proof-of-concept studies in the mdx mouse model of Duchenne muscular dystrophy showed that intravenous administration of 21B3 led to elevated VEGF levels, increased vascularization and blood flow to muscles, and decreased fibrosis after 6–12 weeks of treatment. Greater muscle strength was also observed after 4 weeks of treatment. A humanized form of the mAb, 27H6, was engineered and demonstrated a comparable pharmacologic effect. Overall, administration of anti-Flt-1 mAbs in mdx mice inhibited the VEGF:Flt-1 interaction, promoted angiogenesis, and improved muscle function. These studies suggest a potential therapeutic benefit of Flt-1 inhibition for patients with Duchenne muscular dystrophy.

Published
2021
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23. Towards Scalable Data Management for Map-Reduce-based Data-Intensive Applications on Cloud and Hybrid Infrastructures

Author

Gabriel Antoniu, Julien Bigot, Christophe Blanchet, Luc Bougé, François Briant, Franck Cappello, Alexandru Costan, Frédéric Desprez, Gilles Fedak, Sylvain Gault, Kate Keahey, Bogdan Nicolae, Christian Pérez, Anthony Simonet, Frédéric Suter, Bing Tang, Raphael Terreux, Scalable Storage for Clouds and Beyond (KerData), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SYSTÈMES LARGE ÉCHELLE (IRISA-D1), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Algorithms and Software Architectures for Distributed and HPC Platforms (AVALON), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de l'Informatique du Parallélisme (LIP), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), IBM PSSC Montpellier - Innovation Lab., IBM PSSC Montpellier, Global parallel and distributed computing (GRAND-LARGE), Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria), Joint Laboratory for Petascale Computing [Illinois] (JLPC), Institut National de Recherche en Informatique et en Automatique (Inria)-University of Illinois at Urbana-Champaign [Urbana], University of Illinois System-University of Illinois System, Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Argonne National Laboratory [Lemont] (ANL), Centre de Calcul de l'IN2P3 (CC-IN2P3), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), ANR-10-SEGI-0001,MapReduce,Traitement intensif de données à très grande échelle à l'aide du paradigme MapReduce sur des infrastructures de type cloud et hybrides(2010), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Mathematics and Computer Science Division [ANL] (MCS), IBM Research - Ireland, IBM, CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Paris-Sud - Paris 11 (UP11)-Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec, and University of Illinois at Urbana Champaign (UIUC)

Subjects
BlobSeer, hybrid infrastructures, HLCM, cloud computing, BitDew, Grid'5000, Map-Reduce, MapReduce, [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Nimbus, ComputingMilieux_MISCELLANEOUS, data-intensive computing
Abstract

International audience; As Map-Reduce emerges as a leading programming paradigm for data-intensive computing, today's frameworks which support it still have substantial shortcomings that limit its potential scalability. In this paper we discuss several directions where there is room for such progress: they concern storage efficiency under massive data access concurrency, scheduling, volatility and fault-tolerance. We place our discussion in the perspective of the current evolution towards an increasing integration of large-scale distributed platforms (clouds, cloud federations, enterprise desktop grids, etc.). We propose an approach which aims to overcome the current limitations of existing Map-Reduce frameworks, in order to achieve scalable, concurrency-optimized, fault-tolerant Map-Reduce data processing on hybrid infrastructures. This approach will be evaluated with real-life bio-informatics applications on existing Nimbus-powered cloud testbeds interconnected with desktop grids.

Published
2012

24. Deficits in Morphofunctional Maturation of Hippocampal Mossy Fiber Synapses in a Mouse Model of Intellectual Disability

Author

Virginie F. Labrousse, Christophe Mulle, Elisabeth Normand, Christophe Blanchet, Frederic Lanore, Zsolt Szabo, Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)

Subjects
N-Methylaspartate, Presynaptic Terminals, Kainate receptor, Neurotransmission, Synapse, Mice, 03 medical and health sciences, 0302 clinical medicine, Receptors, Kainic Acid, Intellectual Disability, Synaptic augmentation, Animals, Outbred Strains, Excitatory Amino Acid Agonists, Animals, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, 030304 developmental biology, Hippocampal mossy fiber, Mice, Knockout, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, General Neuroscience, Excitatory Postsynaptic Potentials, Articles, Disease Models, Animal, Synaptic fatigue, nervous system, Mossy Fibers, Hippocampal, Synapses, Synaptic plasticity, NMDA receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

Thegrik2gene, coding for the kainate receptor subunit GluK2 (formerly GluR6), is associated with autism spectrum disorders and intellectual disability. Here, we tested the hypothesis that GluK2 could play a role in the appropriate maturation of synaptic circuits involved in learning and memory. We show that both the functional and morphological maturation of hippocampal mossy fiber to CA3 pyramidal cell (mf-CA3) synapses is delayed in mice deficient for the GluK2 subunit (GluK2−/−). In GluK2−/−mice this deficit is manifested by a transient reduction in the amplitude of AMPA-EPSCs at a critical time point of postnatal development, whereas the NMDA component is spared. By combining multiple probability peak fluctuation analysis and immunohistochemistry, we have provided evidence that the decreased amplitude reflects a decrease in the quantal size per mf-CA3 synapse and in the number of active synaptic sites. Furthermore, we analyzed the time course of structural maturation of CA3 synapses by confocal imaging of YFP-expressing cells followed by tridimensional (3D) anatomical reconstruction of thorny excrescences and presynaptic boutons. We show that major changes in synaptic structures occur subsequently to the sharp increase in synaptic transmission, and more importantly that the course of structural maturation of synaptic elements is impaired in GluK2−/−mice. This study highlights how a mutation in a gene linked to intellectual disability in the human may lead to a transient reduction of synaptic strength during postnatal development, impacting on the proper formation of neural circuits linked to memory.

Published
2012

25. NMDA receptor–dependent metaplasticity at hippocampal mossy fiber synapses

Author

Nelson Rebola, Mario Carta, Frederic Lanore, Christophe Mulle, Christophe Blanchet, and Indisciplinary Institute for Neuroscience, UMR 5297

Subjects
Mossy fiber (hippocampus), Long-Term Potentiation, AMPA receptor, Hippocampal formation, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, Glutamatergic, Mice, 0302 clinical medicine, mental disorders, Metaplasticity, Animals, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Hippocampal mossy fiber, 0303 health sciences, Neuronal Plasticity, Chemistry, musculoskeletal, neural, and ocular physiology, General Neuroscience, Excitatory Postsynaptic Potentials, Long-term potentiation, nervous system, Mossy Fibers, Hippocampal, Synapses, Excitatory postsynaptic potential, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery
Abstract

Hippocampal mossy fiber synapses have been reported to lack NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA excitatory postsynaptic currents (EPSCs), unlike conventional glutamatergic synapses. An explanation for this difference may reside in the relatively low number of NMDARs at these synapses. Because mossy fiber synapses display LTP selective for NMDARs, we examined whether this would affect the plasticity rules at mossy fiber-CA3 synapses in mouse hippocampal slices. We found that LTP of NMDARs serves as a metaplastic switch making mossy fiber synapses competent for generating NMDAR-dependent LTP of AMPA EPSCs.

Published
2011

26. Verification of parameters semantic compatibility for semi-automatic web service composition: a generic case study

Author

Julie Chabalier, Olivier Dameron, Anita Burgun, Nicolas Lebreton, Daniela Barreiro Claro, Christophe Blanchet, Modélisation Conceptuelle des Connaissances Biomédicales, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), BioSciences Lyon-Gerland (BLG), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Natural Solutions, Laboratoire d'Informatique Médicale (LIM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Brébion, Alice, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Rennes (UR), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1)

Subjects
[SDV.IB] Life Sciences [q-bio]/Bioengineering, medicine.medical_specialty, Information retrieval, Database, Computer science, business.industry, computer.software_genre, Web API, Social Semantic Web, Web page, medicine, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Semantic Web Stack, Web service, business, computer, Semantic Web, Web modeling, Data Web
Abstract

We propose an algorithm for checking the semantic compatibility of Web service parameters and for suggesting compatible parameters pairings between two Web services semi-automatically. This algorithm supports semi-automatic Web service composition in workflows where the order of the Web service is known. In our use case, we used the OWL-S semantic description of Web service. We automatically generated a Taverna-compatible Xscufl file whenever possible.

Published
2010

27. Kainate Receptors Act as Conditional Amplifiers of Spike Transmission at Hippocampal Mossy Fiber Synapses

Author

Shankar Sachidhanandam, Christophe Mulle, Christophe Blanchet, Yoon H. Cho, and Yannick Jeantet

Subjects
Mice, Knockout, General Neuroscience, Action Potentials, Excitatory Postsynaptic Potentials, Kainate receptor, Long-term potentiation, Articles, Biology, Neurotransmission, Granule cell, Synaptic Transmission, Mice, Inbred C57BL, Mice, Protein Subunits, medicine.anatomical_structure, Receptors, Kainic Acid, Postsynaptic potential, Mossy Fibers, Hippocampal, Synapses, Excitatory postsynaptic potential, medicine, Animals, Spike (software development), Neuroscience, Hippocampal mossy fiber
Abstract

Hippocampal mossy fiber (Mf) synapses are viewed as conditional detonators, assisting CA3 cells in complex network functions. By analyzing mice deficient for GluK2 (GluR6), GluK3 (GluR7) and GluK5 (KA2) genes we show that kainate receptors (KARs) play a crucial role in the control of synaptic integration and spike transmission efficacy at Mf synapses. We dissected out the role of the different KAR functions at Mf synapses and we show that presynaptic and postsynaptic KARs concur to amplify unitary Mf synaptic inputs to trigger spike discharge within a wide range of frequencies (from 1 to 50 Hz). Moreover, KARs strongly favor spike transmission in response to patterns of presynaptic activity mimickingin vivodentate granule cell activity. By amplifying spike transmission, KARs also facilitate the induction of associative long-term potentiation in CA3. Hence the actions of KARs as amplifiers of spike transmission contribute largely to the “conditional detonator” function of Mf synapses and are likely important for spatial information processing.

Published
2009

28. Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice

Author

Kevin Wickman, Hans G Cruz, Marco Pravetoni, Frédérique Berton, Christophe Blanchet, Christian Lüscher, and Monica Sollini

Subjects
medicine.medical_specialty, Benzylamines, Benzylamines/pharmacology, Substance-Related Disorders, Narcotic Antagonists, Neurotoxins, Adrenergic, (+)-Naloxone, Pharmacology, In Vitro Techniques, Neurotoxins/pharmacology, Inhibitory postsynaptic potential, G Protein-Coupled Inwardly-Rectifying Potassium Channels/deficiency, Mice, Postsynaptic potential, Naloxone/pharmacology, Internal medicine, medicine, Neurotoxin, Animals, G protein-coupled inwardly-rectifying potassium channel, Narcotic Antagonists/pharmacology, Locus Coeruleus/metabolism/physiopathology, ddc:612, Mice, Knockout, Morphine, business.industry, Naloxone, Analgesics, Opioid/adverse effects, General Neuroscience, Neural Inhibition, Articles, Adrenergic Fibers/drug effects, Substance Withdrawal Syndrome, Analgesics, Opioid, Electrophysiology, Endocrinology, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Locus coeruleus, Locus Coeruleus, Morphine/adverse effects, Substance Withdrawal Syndrome/metabolism/physiopathology, Analgesia, business, Adrenergic Fibers, medicine.drug, Substance-Related Disorders/metabolism/physiopathology
Abstract

Although morphine induces both analgesia and dependence through μ-opioid receptors (MORs), the respective contributions of the intracellular effectors engaged by MORs remain unknown. To examine the contribution of G-protein-gated inwardly rectifying K+(GIRK, Kir3) channels to morphine dependence and analgesia, we quantified naloxone-precipitated withdrawal behavior and morphine analgesia using GIRK knock-out (−/−) mice. The morphine withdrawal syndrome was strongly attenuated, whereas morphine analgesia was mostly preserved in mice lacking both GIRK2 and GIRK3 (GIRK2/3−/−mice). In acute slices containing the locus ceruleus (LC) from GIRK2/3−/−mice, the increase in spontaneous firing typically associated with morphine withdrawal was absent. Moreover, although morphine elicited normal presynaptic inhibition in the LC, postsynaptic GIRK currents were completely abolished in GIRK2/3−/−mice. Altogether, these data suggested that morphine-evoked postsynaptic inhibition of the LC was required for the induction of dependence. Consistent with this hypothesis, morphine withdrawal behavior was rescued in GIRK2/3−/−mice by ablation of adrenergic fibers using the neurotoxinN-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. Our data suggest that inhibition of adrenergic tone is required for the induction of dependence, and that channels containing GIRK2 and GIRK3 serve as an inhibitory gate.

Published
2008

29. GPS@ bioinformatics portal: from network to EGEE grid

Author

Christophe Blanchet, Vincent LEFORT, Christophe Combet, Gilbert Deléage, and Deleage, Gilbert

Subjects
Europe, Internet, User-Computer Interface, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Computational Biology, Genomics
Abstract

Bioinformatics analysis of data produced by complete genome sequencing projects is one of the major challenges of the current years. Integrating up-to-date databanks and relevant algorithms is a clear requirement of such analysis. Grid computing would be a viable solution to distribute data, algorithms, computing and storage resources for Genomics. Providing bioinformaticians with a good interface to grid infrastructure, such as the one provided by the EGEE European project, is also a challenge to take up. The GPS@ web portal, "Grid Protein Sequence Analysis", aims to provide such a user-friendly interface for these grid genomic resources on the EGEE grid.Bioinformatics analysis of data produced by complete genome sequencing projects is one of the major challenges of the current years. Integrating up-to-date databanks and relevant algorithms is a clear requirement of such analysis. Grid computing would be a viable solution to distribute data, algorithms, computing and storage resources for Genomics. Providing bioinformaticians with a good interface to grid infrastructure, such as the one provided by the EGEE European project, is also a challenge to take up. The GPS@ web portal, "Grid Protein Sequence Analysis", aims to provide such a user-friendly interface for these grid genomic resources on the EGEE grid.

Published
2006

30. Integrated databanks access and sequence/structure analysis services at the PBIL

Author

Manolo Gouy, Guy Perrière, Christophe Combet, Jean Thioulouse, Julien Grassot, Céline Charavay, Christophe Blanchet, Laurent Duret, Gilbert Deléage, Simon Penel, Christophe Geourjon, Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Ecologie quantitative et évolutive des communautés, Département écologie évolutive [LBBE], Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Models, Molecular, Protein Conformation, Sequence analysis, Nearest neighbor search, 030303 biophysics, Sequence Homology, Sequence alignment, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Protein Structure, Secondary, User-Computer Interface, 03 medical and health sciences, Sequence Analysis, Protein, Nucleic Acids, Databases, Genetic, Genetics, Data bank, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Sequence (medicine), Internet, 0303 health sciences, Information retrieval, Sequence Analysis, RNA, business.industry, Proteins, Articles, Sequence Analysis, DNA, Protein structure prediction, Systems Integration, GenBank, The Internet, business, Sequence Alignment, Software
Abstract

International audience; The World Wide Web server of the PBIL (Pole Bioinformatique Lyonnais) provides on-line access to sequence databanks and to many tools of nucleic acid and protein sequence analyses. This server allows to query nucleotide sequence banks in the EMBL and GenBank formats and protein sequence banks in the SWISS-PROT and PIR formats. The query engine on which our data bank access is based is the ACNUC system. It allows the possibility to build complex queries to access functional zones of biological interest and to retrieve large sequence sets. Of special interest are the unique features provided by this system to query the data banks of gene families developed at the PBIL. The server also provides access to a wide range of sequence analysis methods: similarity search programs, multiple alignments, protein structure prediction and multivariate statistics. An originality of this server is the integration of these two aspects: sequence retrieval and sequence analysis. Indeed, thanks to the introduction of re-usable lists, it is possible to perform treatments on large sets of data. The PBIL server can be reached at: http://pbil.univ-lyon1.fr.The World Wide Web server of the PBIL (Pole Bioinformatique Lyonnais) provides on-line access to sequence databanks and to many tools of nucleic acid and protein sequence analyses. This server allows to query nucleotide sequence banks in the EMBL and GenBank formats and protein sequence banks in the SWISS-PROT and PIR formats. The query engine on which our data bank access is based is the ACNUC system. It allows the possibility to build complex queries to access functional zones of biological interest and to retrieve large sequence sets. Of special interest are the unique features provided by this system to query the data banks of gene families developed at the PBIL. The server also provides access to a wide range of sequence analysis methods: similarity search programs, multiple alignments, protein structure prediction and multivariate statistics. An originality of this server is the integration of these two aspects: sequence retrieval and sequence analysis. Indeed, thanks to the introduction of re-usable lists, it is possible to perform treatments on large sets of data. The PBIL server can be reached at: http://pbil.univ-lyon1.fr.

Published
2003

31. Desensitization of mu-opioid receptor-evoked potassium currents: initiation at the receptor, expression at the effector

Author

Christophe Blanchet and Christian Lüscher

Subjects
GTP-Binding Proteins/ physiology, medicine.medical_specialty, Potassium Channels, G protein, medicine.drug_class, Receptor expression, Population, Receptors, Opioid, mu, Rats, Sprague-Dawley, Desensitization (telecommunications), Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology, GTP-Binding Proteins, Postsynaptic potential, Opioid receptor, Internal medicine, medicine, Animals, G protein-coupled inwardly-rectifying potassium channel, education, Receptors, Opioid, mu/ physiology, education.field_of_study, Multidisciplinary, Chemistry, urogenital system, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology, Enkephalin, Ala(2)-MePhe(4)-Gly(5), Biological Sciences, Potassium channel, Cell biology, ddc:616.8, Rats, Endocrinology, Guanosine 5'-O-(3-Thiotriphosphate), Potassium Channels/ physiology
Abstract

Many G protein-coupled receptor-mediated responses desensitize within minutes. Sustained stimulation of μ-opioid receptors (MORs), which primarily signal through G i/o proteins, leads to activation and subsequent desensitization of G protein-coupled inwardly rectifying potassium (GIRK) currents. We observed that in neurons of the locus coeruleus, which express among the highest levels of MORs in the brain, the degree of desensitization depended on the intensity of receptor stimulation, indicating that the process is initiated at the receptor. Interestingly, while GIRK-mediated postsynaptic inhibition substantially desensitized within 15 min, presynaptic inhibition of afferent transmission, which involves other effector systems, remained constant, suggesting that the postsynaptic desensitization we observed is expressed at the effector. We show that desensitized GIRK currents can gradually be reactivated by additional G protein signals of increasing intensity and present evidence that desensitization is a G protein-mediated process. Finally, desensitization of MOR-induced GIRK currents had heterologous effects on responses mediated by other G protein-coupled receptors converging onto the same population of GIRK channels. Taken together, our results provide evidence for a form of desensitization mediated by a slowly developing G protein-dependent pathway, initiated at the MORs and leading to competitive inhibition of GIRK channel activation. This implies that MORs exert a bidirectional action on GIRK channels.

Published
2002

32. MPSA: integrated system for multiple protein sequence analysis with client/server capabilities

Author

Christophe Geourjon, Christophe Blanchet, Gilbert Deléage, Christophe Combet, Deleage, Gilbert, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Statistics and Probability, Web server, Computer science, MESH: Sequence Analysis, Protein, Protein sequence analysis, computer.software_genre, Computing Methodologies, Biochemistry, Client–server model, 03 medical and health sciences, MESH: Software, Software, Sequence Analysis, Protein, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, Graphical user interface, Unix, Internet, 0303 health sciences, business.industry, 030302 biochemistry & molecular biology, Computer Science Applications, Computational Mathematics, MESH: Internet, Computational Theory and Mathematics, MESH: Computing Methodologies, Operating system, business, computer
Abstract

Summary: MPSA is a stand-alone software intended to protein sequence analysis with a high integration level and Web clients/server capabilities. It provides many methods and tools, which are integrated into an interactive graphical user interface. It is available for most Unix/Linux and non-Unix systems. MPSA is able to connect to a Web server (e.g. http://pbil.ibcp.fr/NPSA) in order to perform large-scale sequence comparison on up-to-date databanks. Availability: Free to academic http://www.ibcp.fr/mpsa/ Contact: c.blanchet@ibcp.fr

Published
2000

33. Kinetics of PKCε activating and inhibiting llama single chain antibodies and their effect on PKCε translocation in HeLa cells.

Author

Milla Summanen, Niko Granqvist, Raimo K Tuominen, Marjo Yliperttula, C Theo Verrips, Johannes Boonstra, Christophe Blanchetot, and Elina Ekokoski

Subjects
Medicine, Science
Abstract

Dysregulation of PKCε is involved in several serious diseases such as cancer, type II diabetes and Alzheimer's disease. Therefore, specific activators and inhibitors of PKCε hold promise as future therapeutics, in addition to being useful in research into PKCε regulated pathways. We have previously described llama single chain antibodies (VHHs) that specifically activate (A10, C1 and D1) or inhibit (E6 and G8) human recombinant PKCε. Here we report a thorough kinetic analysis of these VHHs. The inhibiting VHHs act as non-competitive inhibitors of PKCε activity, whereas the activating VHHs have several different modes of action, either increasing V(max) and/or decreasing K(m) values. We also show that the binding of the VHHs to PKCε is conformation-dependent, rendering the determination of affinities difficult. Apparent affinities are in the micromolar range based on surface plasmon resonance studies. Furthermore, the VHHs have no effect on the activity of rat PKCε nor can they bind the rat form of the protein in immunoprecipitation studies despite the 98% identity between the human and rat PKCε proteins. Finally, we show for the first time that the VHHs can influence PKCε function also in cells, since an activating VHH increases the rate of PKCε translocation in response to PMA in HeLa cells, whereas an inhibiting VHH slows down the translocation. These results give insight into the mechanisms of PKCε activity modulation and highlight the importance of protein conformation on VHH binding.

Published
2012
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34. Membrane Lipids Tune Synaptic Transmission by Direct Modulation of Presynaptic Potassium Channels

Author

Christophe Mulle, Mario Carta, Joana Lourenço, Silvia Viana DaSilva, Nelson Rebola, Zsolt Szabo, Christophe Blanchet, Carsten Schultz, André Nadler, Agathe Verraes, Frederic Lanore, Indisciplinary Institute for Neuroscience, UMR 5297, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), INSERM ERL U950, Membrane Traffic in Neuronal and Epithelial Morphogenesis, Institut National de la Santé et de la Recherche Médicale (INSERM), European Molecular Biology Laboratory [Heidelberg] (EMBL), and EIF Fellowship (project name KARTRAF), SYNSCAFF, the Conseil Regional of Aquitaine, the Fondation pour le Recherche Medicale, VANR ASD/LD, Dalhousie University, ESF EuroMembrane program (TraPPs)

Subjects
MESH: Hippocampus, Potassium Channels, Long-Term Potentiation, MESH: Neurons, Gating, Hippocampus, Synaptic Transmission, MESH: Synapses, Mice, 0302 clinical medicine, Postsynaptic potential, MESH: Animals, Neurons, 0303 health sciences, Chemistry, General Neuroscience, Pyramidal Cells, MESH: Electric Stimulation, Long-term potentiation, MESH: Potassium Channels, Potassium channel, medicine.anatomical_structure, Modulation, Mossy Fibers, Hippocampal, Excitatory postsynaptic potential, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Membrane lipids, Neuroscience(all), Neurotransmission, Biology, 03 medical and health sciences, Membrane Lipids, MESH: Long-Term Potentiation, MESH: Mice, Inbred C57BL, medicine, MESH: Synaptic Transmission, Animals, MESH: Excitatory Postsynaptic Potentials, MESH: Mice, 030304 developmental biology, Post-tetanic potentiation, MESH: Mossy Fibers, Hippocampal, Excitatory Postsynaptic Potentials, MESH: Pyramidal Cells, Electric Stimulation, Mice, Inbred C57BL, Synaptic plasticity, Synapses, Biophysics, Retrograde signaling, Neuron, MESH: Membrane Lipids, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission.

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35. Actinic keratosis modelling in mice: A translational study.

Author

Arnaud Pillon, Bruno Gomes, Isabelle Vandenberghe, Valérie Cartron, Patrick Cèbe, Jean-Christophe Blanchet, Vincent Sibaud, Nicolas Guilbaud, Laurent Audoly, Laurence Lamant, and Anna Kruczynski

Subjects
Medicine, Science
Abstract

Actinic keratoses (AK) are pre-malignant cutaneous lesions caused by prolonged exposure to ultraviolet radiation. As AKs lesions are generally accepted to be the initial lesions in a disease continuum that progresses to squamous cell carcinoma (SCC), AK lesions have to be treated. They are also the second most common reason for visits to the dermatologist. Several treatments are available but their efficacy still needs to be improved. The UV-B-induced KA lesion mouse model is used in preclinical studies to assess the efficacy of novel molecules, even though it is often more representative of advanced AK or SCC.Here we report on a translational study, comparing the various stages of AK development in humans and in the UV-B irradiated mouse model, as well as the optimization of photograph acquisition of AK lesions on mouse skin.Human and mouse skin lesions were analysed by histology and immunohistochemistry. Mouse lesions were also assessed using a digital dermatoscope.An histological and phenotypic analysis, including p53, Ki67 and CD3 expression detection, performed on human and mouse AK lesions, shows that overall AK modelling in mice is relevant in the clinical situation. Some differences are observed, such as disorganization of keratinocytes of the basal layer and a number of atypical nuclei which are more numerous in human AK, whereas much more pronounced acanthosis is observed in skin lesion in mice. Thanks to this translational study, we are able to select appropriate experimental conditions for establishing either early or advanced stage AK or an SCC model. Furthermore, we optimized photograph acquisition of AK lesions on mouse skin by using a digital dermatoscope which is also used in clinics and allows reproducible photograph acquisition for further reliable assessment of mouse lesions. Use of this camera is illustrated through a pharmacological study assessing the activity of CARAC®.These data demonstrate that this mouse model of UV-B-induced skin lesions is predictive for the identification of novel therapeutic treatments for both early and advanced stages of the disease.

Published
2017
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36. Présentation des Centres Bioinformatiques Régionaux : RENABI-GO

Author

Martin, Tiphaine, Caron, Christophe, Collin, Olivier, Modèles et algorithmes pour la Bioinformatique et la Visualisation d'informations, (MABIOVIS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), 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), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Biological systems and models, bioinformatics and sequences (SYMBIOSE), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria), GIS IBISA GRISBI, Christophe Blanchet and Christophe Caron and Olivier Collin and Stéphane Delmotte and Clément Gauthey and Tiphaine Martin and Franck Samson and Bruno Spataro, 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), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique

Subjects
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2011

37. CBIB/MaBioVis : noeud Bordelais de GRISBI

Author

Martin, Tiphaine, Modèles et algorithmes pour la Bioinformatique et la Visualisation d'informations, (MABIOVIS), 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)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Christophe CARON and Olivier COLLIN and Antoine de DARUVAR and Gael EVEN and Hugues LEROY and Tiphaine MARTIN and Claudine MEDIGUE and Frédéric PLEWNIAK and Bruno SPATARO and Christophe BLANCHET, and Martin, Tiphaine

Subjects
[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [INFO.INFO-DC] Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract

National audience

Published
2008

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