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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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14. 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

Abstract

BackgroundThe COVID-19 pandemic emphasised the importance of access to reliable real-time forecasts for key epidemiological indicators. Given the strong heterogeneity between regions, providing forecasts at the local level is essential for health professionals.MethodsWe developed a SARS-CoV-2 transmission model in France, COVIDici, that performs parameter estimation using up-to-date vaccination coverage and hospital data to provide forecasts up to a four-week horizon based on the current epidemic trend. We present the model, its associated online tool and perform a retrospective evaluation of the forecasts provided from January to December 2021 by comparing to three standard statistical forecasting methods (auto-regression, exponential smoothing, and ARIMA) at the national and regional levels.ResultsCOVIDici allowed simultaneous real-time visualisation of several indicators of the COVID-19 epidemic at the sub-national level. For anticipating risk of critical care unit overload, it performed worse compared to the baseline methods for forecasts under the three-week horizon, but had better point forecasts at the longest horizons (e.g. four weeks) for 8 of the 13 regions considered depending on the metric.ConclusionsEffective communication between modelers and clinicians is essential for utilising forecasts for health care planning. Online visualisation tools and consideration of how metrics can be affected by distortion from non-pharmaceutical government interventions facilitate this dialogue.What is already known on this topicThe US and European Covid-19 Forecast Hubs publish real-time COVID-19 forecasts on the national level for new deaths, new cases, and hospital admissions, but not more direct measurements of hospital strain like critical care bed occupancy.In France, statistical modelling approaches have been proposed to anticipate hospital stain at the sub-national level but are limited by a two-week forecast horizon.What this study addsWe present a sub-national French modelling framework and online application for anticipating hospital strain at the four-week horizon that can account for abrupt changes in key epidemiological parameters.It was the only publicly available real-time non-Markovian mechanistic model for the French epidemic when implemented in January 2021 and, to our knowledge, it still was at the time it stopped in early 2022.How this study might affect research, practice or policyFurther adaptations of this surveillance system can serve as an anticipation tool for hospital strain across sub-national localities to aid in the prevention of short-noticed ward closures and patient transfers.

Published
2023

23. Oropharyngeal squamous cell carcinoma: p16/p53 immunohistochemistry as a strong predictor of HPV tumour status

Author

Pierre Philouze, Jonathan Lopez, Nazim Benzerdjeb, Yahia Mekki, Mojgan Devouassoux-Shisheboran, Juliet Tantot, and Christophe Blanchet

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Histology, Tp53 mutation, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, Biomarkers, Tumor, Humans, Medicine, Oropharyngeal squamous cell carcinoma, P53 expression, Cyclin-Dependent Kinase Inhibitor p16, Polymerase chain reaction, Human papillomavirus 16, Squamous Cell Carcinoma of Head and Neck, business.industry, Surrogate endpoint, Papillomavirus Infections, HPV infection, General Medicine, Prognosis, medicine.disease, Immunohistochemistry, Oropharyngeal Neoplasms, P53 immunohistochemistry, 030104 developmental biology, 030220 oncology & carcinogenesis, DNA, Viral, Carcinoma, Squamous Cell, Female, Tumor Suppressor Protein p53, business, Tumour status
Abstract

AIMS Oropharyngeal squamous cell carcinomas (OPSCC) related to human papillomavirus (HPV) infection have a better prognosis than those without HPV infection. Although p16INK4a overexpression is used as a surrogate marker for HPV infection, 5-20% of p16-positive OPSCC are described as being unrelated to HPV infection, with worse overall survival compared to OPSCC-related HPV. There is therefore a risk of undertreating a proportion of OPSCC patients falsely considered to be HPV-driven because of p16 positivity. TP53 mutations are highly prevalent in OPSCC driven by mutagens in tobacco and alcohol. We describe herein a combined p16/p53 algorithm to predict HPV tumour status in OPSCC. METHODS AND RESULTS A total of 110 OPSCC were identified in the database of the pathology department and were studied using p16 and p53 immunohistochemistry. For p16-positive or p16-negative/wild-type patterns-p53 (WT-p53) cases (n = 63), DNA in-situ hybridisation for high-risk HPV was performed, and if negative the HPV status was controlled by HPV DNA polymerase chain reaction (PCR) (n = 19). A significant association between TP53 mutation and pattern of p53 expression was found (WT-p53, seven of 16, P

Published
2021

25. 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

26. 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

27. 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

29. Scientific workflows for computational reproducibility in the life sciences: Status, challenges and opportunities

Author

Olivier Collin, Sarah Cohen-Boulakia, Konrad Hinsen, Alban Gaignard, Khalid Belhajjame, Pierre Larmande, Fabien Mareuil, Christine Froidevaux, Frédéric Lemoine, Christophe Blanchet, Jérôme Chopard, Christophe Pradal, Hervé Ménager, Yvan Le Bras, Scientific Data Management (ZENITH), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'analyse et modélisation de systèmes pour l'aide à la décision (LAMSADE), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Plateforme bioinformatique GenOuest [Rennes], 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), 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)-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 Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-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), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Mathématiques, Informatique et STatistique pour l'Environnement et l'Agronomie (MISTEA), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Centre hospitalier universitaire de Nantes (CHU Nantes), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Diversité, adaptation, développement des plantes (UMR DIADE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Bioinformatique évolutive - Evolutionary Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre d'Informatique pour la Biologie, Institut Pasteur [Paris] (IP), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Modeling plant morphogenesis at different scales, from genes to phenotype (VIRTUAL PLANTS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de la Recherche Agronomique (INRA)-Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), 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), The authors acknowledge the support of GDR CNRS MaDICS, pro-gramme CPER Region Bretagne 'CeSGO', and programme Region Paysde la Loire 'Connect Talent' (SyMeTRIC). We acknowledge funding by thecall Infrastructures in Biology and Health' in the framework of the FrenchInvestments for the Future' (ANR-11-INBS-0012 and ANR-11-INBS-0013).This work was conducted in part at the IBC (Institute of Computational Bi-ology) in Montpellier, France., ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Inria Sophia Antipolis - Méditerranée (CRISAM), CentraleSupélec-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®-Inria Rennes – Bretagne Atlantique, 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)-Université de Rennes 1 (UR1), 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 national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), 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 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), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS), 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), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Inria Sophia Antipolis - Méditerranée (CRISAM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), 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), ANR-11-INBS-0013/11-INBS-0013,ReNaBi-IFB,Institut français de bioinformatique(2011), ANR-11-INBS-0011/11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Cohen-Boulakia, Sarah, Infrastructures - Institut français de bioinformatique - - IFB (ex Renabi-IFB)2011 - ANR-11-INBS-0013 - INBS - VALID, and Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID

Subjects
0301 basic medicine, Scientific Workflows, Computer Networks and Communications, Computer science, [INFO.INFO-DS]Computer Science [cs]/Data Structures and Algorithms [cs.DS], [INFO.INFO-DS] Computer Science [cs]/Data Structures and Algorithms [cs.DS], Context (language use), 02 engineering and technology, Domain (software engineering), 03 medical and health sciences, 0202 electrical engineering, electronic engineering, information engineering, [INFO.INFO-DB] Computer Science [cs]/Databases [cs.DB], Packaging environments, Use case, Set (psychology), environments, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Reproducibility, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Data science, 030104 developmental biology, Workflow, C30 - Documentation et information, Packaging, 13. Climate action, Hardware and Architecture, Scientific workflows, Provenance, [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], 020201 artificial intelligence & image processing, [INFO.INFO-IR] Computer Science [cs]/Information Retrieval [cs.IR], U30 - Méthodes de recherche, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Software
Abstract

International audience; With the development of new experimental technologies, biologists are faced with an avalanche of data to be computationally analyzed for scientific advancements and discoveries to emerge. Faced with the complexity of analysis pipelines, the large number of computational tools, and the enormous amount of data to manage, there is compelling evidence that many if not most scientific discoveries will not stand the test of time: increasing the reproducibility of computed results is of paramount importance. The objective we set out in this paper is to place scientific workflows in the context of reproducibility. To do so, we define several kinds of repro-ducibility that can be reached when scientific workflows are used to perform experiments. We characterize and define the criteria that need to be catered for by reproducibility-friendly scientific workflow systems, and use such criteria to place several representative and widely used workflow systems and companion tools within such a framework. We also discuss the remaining challenges posed by reproducible scientific workflows in the life sciences. Our study was guided by three use cases from the life science domain involving in silico experiments.

Published
2017

31. 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

32. 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
Full Text
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33. 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

34. L’inclusion au prisme du confinement

Author

Jean-Claude Métraux and Christophe Blanchet

Subjects
Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published
2020

35. 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

36. 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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37. 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

38. 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

39. List of Contributors

Author

Ahmad Anbar, Haytham Assem, Christophe Blanchet, Teodora S. Buda, Jiannong Cao, Chuan-Yu Chang, Jinjun Chen, Cen Chen, Szu-Ta Chen, Kang Chen, Zixue Cheng, Cees de Laat, Yuri Demchenko, Mingxing Duan, Tarek El-Ghazawi, Weiwei W. Fang, Edmond J. Golden, Chu-Cheng Hsieh, Ching-Hsien Hsu, Hui-Huang Hsu, Qian Huang, Tian-Hsiang Huang, Chih-Chieh Hung, Pravin Kakar, Shonali Krishnaswamy, Chung-Nan Lee, Kenli Li, Keqin Li, Xiao-Li Li, Qingyong Y. Li, Hai-Ning Liang, Chen Lin, Xuefeng Liu, Ming Liu, Charles Loomis, Chao Lu, Ka L. Man, Martial Michel, Vijayakumar Nanjappan, Minh N. Nguyen, Declan O'Sullivan, Phyo P. San, Olivier Serres, Kathiravan Srinivasan, Ming-Chun Tsai, Fatih Turkmen, Wei Wang, Junbo Wang, Yilang Wu, Chen-Ming Wu, Lei Xu, Chi Yang, Jian-Bo Yang, and Zhangdui D. Zhong

Published
2017

40. 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

41. Cloud based big data infrastructure: Architectural components and automated provisioning

Author

Fatih Turkmen, Yuri Demchenko, Cees de Laat, Christophe Blanchet, Charles Loomis, and Information Systems

Subjects
Database, Computer science, business.industry, Data management, Big data, Interoperability, Intercloud Architecture Framework (ICAF), Provisioning, Cloud computing, 02 engineering and technology, Big Data Architecture Framework, SlipStream Cloud Automation platform, computer.software_genre, Data structure, Big Data Infrastructure, Big Data Architecture Framework, Big Data Infrastructure, Multi-cloud Services Provisioning Automation, SlipStream Cloud Automation platform, Intercloud Architecture Framework (ICAF), 020204 information systems, 0202 electrical engineering, electronic engineering, information engineering, Data analysis, 020201 artificial intelligence & image processing, Data architecture, Software engineering, business, computer, Multi-cloud Services Provisioning Automation
Abstract

This paper describes the general architecture and functional components of the cloud based Big Data Infrastructure (BDI). The proposed BDI architecture is based on the analysis of the emerging Big Data and data intensive technologies and supported by the definition of the Big Data Architecture Framework (BDAF) that defines the following components of the Big Data technologies: Big Data definition, Data Management including data lifecycle and data structures, Big Data Infrastructure (generically cloud based), Data Analytics technologies and platforms, and Big Data security, compliance and privacy. The paper provides example of requirements analysis and implementation of two bioinformatics use cases on cloud and using SlipStream based cloud applications deployment and management automation platform being developed in the CYCLONE project. The paper also refers to importance of standardisation of all components of BDAF and BDI and provides short overview of the NIST Big Data Interoperability Framework (BDIF). The paper discusses importance of automation of all stages of the Big Data applications developments, deployment and management and refers to existing cloud automation tools and new developments in the SlipStream cloud automation platform that allows multi-cloud applications deployment and management

Published
2016

42. CYCLONE: A Multi-cloud Federation Platform for Complex Bioinformatics and Energy Applications (Short Paper)

Author

M. Biancani, D. Gallico, Jean-François Gibrat, M. Kourkouli, J. I. A. Baranda, Christophe Blanchet, M. Bedri, and D. Hacker

Subjects
Service (systems architecture), Computer science, business.industry, Testbed, 020206 networking & telecommunications, Cloud computing, 02 engineering and technology, Slipstream (computer science), Bioinformatics, Network management, Elasticity (cloud computing), Software deployment, 0202 electrical engineering, electronic engineering, information engineering, Cyclone, business
Abstract

Multi-cloud applications delivered acrossheterogeneous public cloud service providers poses differenttechnical and operational challenges in terms of resourcebrokering, integration, implementation of security trusts, etc. Inthis paper we describe the federation approach taken in theH2020 CYCLONE project, which designed a multi-cloudplatform integrating and orchestrating different open-sourcecloud and network management tools (Openstack, OpenNaaS, SlipStream and TCTP). Some real-life use-cases in the scientificarea of energy optimization and bioinformatics are in use tovalidate the CYCLONE architecture and integrated platform, from the viewpoints of service deployment, service availability, elasticity and security. These validation activities are carried outin the CYCLONE shared testbed infrastructure, whose high-leveldescription is also presented in this paper. Initial feedbacks onthe validation of the CYCLONE federation approach will beavailable at the beginning of Q4-2016, when the CYCLONE usecaseportfolio will be extended to increase external users'involvement and attempt validation of the federation approachfrom real world market.

Published
2016
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43. 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

44. Neurexin-Neuroligin Adhesions Capture Surface-Diffusing AMPA Receptors through PSD-95 Scaffolds

Author

Christel Poujol, Olivier Thoumine, Eric Hosy, Christophe Blanchet, Béatrice Tessier, Magali Mondin, Virginie F. Labrousse, Martin Heine, Florian Levet, and Daniel Choquet

Subjects
Male, Patch-Clamp Techniques, Cell Adhesion Molecules, Neuronal, Primary Cell Culture, Neurexin, Neuroligin, AMPA receptor, Neurotransmission, Transfection, Inhibitory postsynaptic potential, Hippocampus, Synaptic Transmission, Membrane Potentials, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Receptors, AMPA, Neural Cell Adhesion Molecules, 030304 developmental biology, Mice, Knockout, Membrane potential, 0303 health sciences, Chemistry, musculoskeletal, neural, and ocular physiology, General Neuroscience, Calcium-Binding Proteins, Glutamate receptor, Membrane Proteins, Articles, Rats, nervous system, Mutation, Excitatory postsynaptic potential, Biophysics, Female, Disks Large Homolog 4 Protein, Guanylate Kinases, Neuroscience, 030217 neurology & neurosurgery
Abstract

The mechanisms governing the recruitment of functional glutamate receptors at nascent excitatory postsynapses following initial axon-dendrite contact remain unclear. We examined here the ability of neurexin/neuroligin adhesions to mobilize AMPA-type glutamate receptors (AMPARs) at postsynapses through a diffusion/trap process involving the scaffold molecule PSD-95. Using single nanoparticle tracking in primary rat and mouse hippocampal neurons overexpressing or lacking neuroligin-1 (Nlg1), a striking inverse correlation was found between AMPAR diffusion and Nlg1 expression level. The use of Nlg1 mutants and inhibitory RNAs against PSD-95 demonstrated that this effect depended on intact Nlg1/PSD-95 interactions. Furthermore, functional AMPARs were recruited within 1 h at nascent Nlg1/PSD-95 clusters assembled by neurexin-1β multimers, a process requiring AMPAR membrane diffusion. Triggering novel neurexin/neuroligin adhesions also caused a depletion of PSD-95 from native synapses and a drop in AMPAR miniature EPSCs, indicating a competitive mechanism. Finally, both AMPAR level at synapses and AMPAR-dependent synaptic transmission were diminished in hippocampal slices from newborn Nlg1 knock-out mice, confirming an important role of Nlg1 in driving AMPARs to nascent synapses. Together, these data reveal a mechanism by which membrane-diffusing AMPARs can be rapidly trapped at PSD-95 scaffolds assembled at nascent neurexin/neuroligin adhesions, in competition with existing synapses.

Published
2011

45. CURVES+ web server for analyzing and visualizing the helical, backbone and groove parameters of nucleic acid structures

Author

Richard Lavery, Krystyna Zakrzewska, Christophe Blanchet, and Marco Pasi

Subjects
Web server, business.industry, Protein Data Bank (RCSB PDB), Articles, Biology, computer.software_genre, Bioinformatics, Visualization, Computational science, Set (abstract data type), User-Computer Interface, Upload, Software, Genetics, Nucleic Acid Conformation, Nucleic acid structure, business, Base Pairing, computer, Groove (engineering), Algorithms
Abstract

Curves+, a revised version of the Curves software for analyzing the conformation of nucleic acid structures, is now available as a web server. This version, which can be freely accessed at http://gbio-pbil.ibcp.fr/cgi/Curves_plus/, allows the user to upload a nucleic acid structure file, choose the nucleotides to be analyzed and after optionally setting a number of input variables, view the numerical and graphic results online or download files containing a set of helical, backbone and groove parameters that fully describe the structure. PDB format files are also provided for offline visualization of the helical axis and groove geometry.

Published
2011

46. BioXSD: the common data-exchange format for everyday bioinformatics web services

Author

Jon Ison, Alexandre Joseph, Armin Töpfer, Matúš Kalaš, Prabakar Venkataraman, Kristoffer Rapacki, Pæl Puntervoll, Steve Pettifer, Edita Bartaševičiūtė, Christophe Blanchet, Jan Christian Bryne, and Inge Jonassen

Subjects
Statistics and Probability, Web standards, Computer science, Molecular Sequence Data, 0206 medical engineering, Interoperability, Information Storage and Retrieval, 02 engineering and technology, Ontology (information science), computer.software_genre, Bioinformatics, Biochemistry, Eccb 2010 Conference Proceedings September 26 to September 29, 2010, Ghent, Belgium, Workflow, World Wide Web, 03 medical and health sciences, Annotation, Text mining, Web page, Amino Acid Sequence, XML schema, Molecular Biology, Semantic Web, 030304 developmental biology, computer.programming_language, Internet, 0303 health sciences, business.industry, Computational Biology, Original Papers, Semantics, Computer Science Applications, Computational Mathematics, Computational Theory and Mathematics, Data exchange, Ontology, Programming Languages, Web service, business, computer, Text Mining, Ontologies and Databases, Software, 020602 bioinformatics
Abstract

Motivation: The world-wide community of life scientists has access to a large number of public bioinformatics databases and tools, which are developed and deployed using diverse technologies and designs. More and more of the resources offer programmatic web-service interface. However, efficient use of the resources is hampered by the lack of widely used, standard data-exchange formats for the basic, everyday bioinformatics data types. Results: BioXSD has been developed as a candidate for standard, canonical exchange format for basic bioinformatics data. BioXSD is represented by a dedicated XML Schema and defines syntax for biological sequences, sequence annotations, alignments and references to resources. We have adapted a set of web services to use BioXSD as the input and output format, and implemented a test-case workflow. This demonstrates that the approach is feasible and provides smooth interoperability. Semantics for BioXSD is provided by annotation with the EDAM ontology. We discuss in a separate section how BioXSD relates to other initiatives and approaches, including existing standards and the Semantic Web. Availability: The BioXSD 1.0 XML Schema is freely available at http://www.bioxsd.org/BioXSD-1.0.xsd under the Creative Commons BY-ND 3.0 license. The http://bioxsd.org web page offers documentation, examples of data in BioXSD format, example workflows with source codes in common programming languages, an updated list of compatible web services and tools and a repository of feature requests from the community. Contact: matus.kalas@bccs.uib.no; developers@bioxsd.org; support@bioxsd.org

Published
2010

47. 3D Structure Determination of the Crh Protein from Highly Ambiguous Solid-State NMR Restraints

Author

Thérèse E. Malliavin, Benjamin Bardiaux, Michael Nilges, Carole Gardiennet, Antoine Loquet, Anja Böckmann, Christophe Blanchet, Marc Baldus, 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), Bioinformatique Structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Protein Folding, Magnetic Resonance Spectroscopy, Protein Conformation, Dihedral angle, 010402 general chemistry, 01 natural sciences, Biochemistry, Resonance (particle physics), Catalysis, 03 medical and health sciences, Colloid and Surface Chemistry, Bacterial Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, Spins, Chemistry, Chemical shift, General Chemistry, Reference Standards, Phosphoproteins, Protein Structure, Tertiary, 0104 chemical sciences, Transport protein, Crystallography, Solid-state nuclear magnetic resonance, Structural biology, Spin diffusion
Abstract

International audience; In a wide variety of proteins, insolubility presents a challenge to structural biology, as X-ray crystallography and liquid-state NMR are unsuitable. Indeed, no general approach is available as of today for studying the three-dimensional structures of membrane proteins and protein fibrils. We here demonstrate, at the example of the microcrystalline model protein Crh, how high-resolution 3D structures can be derived from magic-angle spinning solid-state NMR distance restraints for fully labeled protein samples. First, we show that proton-mediated rare-spin correlation spectra, as well as carbon-13 spin diffusion experiments, provide enough short, medium, and long-range structural restraints to obtain high-resolution structures of this 2 x 10.4 kDa dimeric protein. Nevertheless, the large number of 13C/15N spins present in this protein, combined with solid-state NMR line widths of about 0.5-1 ppm, induces substantial ambiguities in resonance assignments, preventing 3D structure determination by using distance restraints uniquely assigned on the basis of their chemical shifts. In the second part, we thus demonstrate that an automated iterative assignment algorithm implemented in a dedicated solid-state NMR version of the program ARIA permits to resolve the majority of ambiguities and to calculate a de novo 3D structure from highly ambiguous solid-state NMR data, using a unique fully labeled protein sample. We present, using distance restraints obtained through the iterative assignment process, as well as dihedral angle restraints predicted from chemical shifts, the 3D structure of the fully labeled Crh dimer refined at a root-mean-square deviation of 1.33 A.In a wide variety of proteins, insolubility presents a challenge to structural biology, as X-ray crystallography and liquid-state NMR are unsuitable. Indeed, no general approach is available as of today for studying the three-dimensional structures of membrane proteins and protein fibrils. We here demonstrate, at the example of the microcrystalline model protein Crh, how high-resolution 3D structures can be derived from magic-angle spinning solid-state NMR distance restraints for fully labeled protein samples. First, we show that proton-mediated rare-spin correlation spectra, as well as carbon-13 spin diffusion experiments, provide enough short, medium, and long-range structural restraints to obtain high-resolution structures of this 2 x 10.4 kDa dimeric protein. Nevertheless, the large number of 13C/15N spins present in this protein, combined with solid-state NMR line widths of about 0.5-1 ppm, induces substantial ambiguities in resonance assignments, preventing 3D structure determination by using distance restraints uniquely assigned on the basis of their chemical shifts. In the second part, we thus demonstrate that an automated iterative assignment algorithm implemented in a dedicated solid-state NMR version of the program ARIA permits to resolve the majority of ambiguities and to calculate a de novo 3D structure from highly ambiguous solid-state NMR data, using a unique fully labeled protein sample. We present, using distance restraints obtained through the iterative assignment process, as well as dihedral angle restraints predicted from chemical shifts, the 3D structure of the fully labeled Crh dimer refined at a root-mean-square deviation of 1.33 A.

Published
2008

48. Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma

Author

Anna Kruczynski, Julie Meilleroux, Janick Selves, Laurent Créancier, Isabelle Vandenberghe, Rosine Guimbaud, Caroline Dejean, Jean-Christophe Blanchet, and Bruno Gomes

Subjects
Cancer Research, Colorectal cancer, Molecular Sequence Data, Mice, Nude, Tropomyosin, Tropomyosin receptor kinase A, Biology, Translocation, Genetic, Thyroid carcinoma, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Biomarkers, Tumor, Animals, Humans, Kinase activity, Receptor, trkA, Lung cancer, Gene Rearrangement, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Cancer, NTRK1 Gene, Gene rearrangement, Sequence Analysis, DNA, medicine.disease, Molecular biology, Immunohistochemistry, Nuclear Pore Complex Proteins, Oncology, Tissue Array Analysis, Gene Fusion, Colorectal Neoplasms
Abstract

Chromosomal rearrangements of the NTRK1 gene, which encodes the high affinity nerve growth factor receptor (tropomyosin related kinase, TRKA), have been observed in several epithelial cancers, such as colon cancer, papillary thyroid carcinoma or non small cell lung cancer. The various NTRK1 fusions described so far lead to constitutive activation of TRKA kinase activity and are oncogenic. We further investigated here the existence and the frequency of NTRK1 gene rearrangements in colorectal cancer. Using immunohistochemistry and quantitative reverse transcriptase PCR, we analyzed a series of human colorectal cancers. We identified two TRKA positive cases over 408, with NTRK1 chromosomal rearrangements. One of these rearrangements is a TPM3-NTRK1 fusion already observed in colon cancer, while the second one is a TPR-NTRK1 fusion never described in this type of cancer. These findings further confirm that translocations in the NTRK1 gene are recurring events in colorectal cancer, although occurring at a low frequency (around 0.5%).

Published
2015

49. Short-Term Regulation of Information Processing at the Corticoaccumbens Synapse

Author

Christophe Mulle, Christophe Blanchet, and Guillaume Casassus

Subjects
Cerebral Cortex, Neuronal Plasticity, Time Factors, Chemistry, General Neuroscience, Models, Neurological, Glutamate receptor, Stimulation, Long-term potentiation, In Vitro Techniques, Neurotransmission, Nucleus accumbens, Synaptic Transmission, Nucleus Accumbens, Tonic (physiology), Mice, Inbred C57BL, Mice, Bursting, Synapses, Animals, Prefrontal cortex, Neuroscience, Cellular/Molecular
Abstract

In relation to expectation and delivery of reward, pyramidal neurons of the prefrontal cortex either switch from a single spiking mode to transient phasic bursting, or gradually increase their sustained tonic activity. Here, we examined how switching between firing modes affects information processing at the corticoaccumbens synapse. We report that increasing presynaptic firing frequency in a tonic manner either depresses or facilitates synaptic transmission, depending on initial probability of release. In contrast, repeated bursts of stimulation of cortical afferents trigger a new form of short-term potentiation of synaptic transmission (RB-STP) in the nucleus accumbens (NAc). RB-STP involves the regulation of axonal excitability mediated by 4-AP-sensitive potassium channels in afferent cortical neurons. Thus, in a tonic mode, information flow is tightly controlled by regulatory mechanisms at the level of presynaptic terminals, whereas switching to a bursting mode reliably enhances efficacy of information processing for all cortical afferents to NAc neurons.

Published
2005

50. Donitriptan Decreases Jugular Venous Oxygen Saturation in Rats in the Absence of Cranial Vasoconstriction: An Overlooked Mechanism of Antimigraine Action?

Author

Gareth W. John, Estelle Sole, Bruno Le Grand, Robert Létienne, and Jean-Christophe Blanchet

Subjects
Male, medicine.drug_class, Migraine Disorders, Piperazines, Rats, Sprague-Dawley, Donitriptan, Nitriles, Heart rate, medicine, Animals, GR-127935, Pharmacology, Oxadiazoles, Sumatriptan, Chemistry, Hemodynamics, Venous blood, Receptor antagonist, Tryptamines, Rats, Serotonin Receptor Agonists, Oxygen, Blood pressure, Regional Blood Flow, Vasoconstriction, Cerebrovascular Circulation, Anesthesia, Molecular Medicine, Serotonin Antagonists, Blood Gas Analysis, Jugular Veins, medicine.symptom, medicine.drug
Abstract

The aim of the present study was to determine whether donitriptan and sumatriptan decreased jugular venous oxygen saturation and increased carbon dioxide partial pressure in venous blood. However, previous studies conducted with these compounds cannot discriminate whether the decrease of venous oxygen saturation is dependent of cranial vasoconstrictor. In the present study, vehicle (n = 10), donitriptan (2.5, 10, and 40 microg/kg; n = 8) or sumatriptan (630 microg/kg; n = 8) were infused into the carotid artery in the anesthetized rat. Regional blood flows were evaluated in the presence of donitriptan (10 microg/kg; n = 6) or vehicle (n = 6). Jugular venous oxygen saturation was significantly decreased by donitriptan (from 10 microg/kg) with maximal changes of -32.9 +/- 8.0%. Jugular carbon dioxide partial pressure was increased by donitriptan, reaching maximal changes of 17.7 +/- 4.6% (P0.05 versus vehicle). Similarly, sumatriptan significantly decreased venous oxygen saturation and increased jugular carbon dioxide partial pressure. These changes induced by donitriptan are abolished by the 5-hydroxytryptamine (5-HT)(1B/1D) receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2-[-methyl-4(5-methyl-1,2,4)-oxadiazol-3-yl]-(1,1 biphenyl)-4-carboxamide dihydrochloride). In addition, donitriptan was devoid of significant effects on systemic arterial pressure, heart rate, or regional blood flows, including systemic arterial-jugular venous anastomotic, systemic, or cranial. The results demonstrate that donitriptan increases cerebral oxygen consumption by 5-HT(1B/1D) receptor activation in the absence of cranial vasoconstriction.

Published
2005

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