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1. Prognosis of lasso-like penalized Cox models with tumor profiling improves prediction over clinical data alone and benefits from bi-dimensional pre-screening

Author

Rémy Jardillier, Dzenis Koca, Florent Chatelain, and Laurent Guyon

Subjects
Cox model, Prediction, Survival model, Penalized regression, Lasso, RNA-seq, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Prediction of patient survival from tumor molecular ‘-omics’ data is a key step toward personalized medicine. Cox models performed on RNA profiling datasets are popular for clinical outcome predictions. But these models are applied in the context of “high dimension”, as the number p of covariates (gene expressions) greatly exceeds the number n of patients and e of events. Thus, pre-screening together with penalization methods are widely used for dimensional reduction. Methods In the present paper, (i) we benchmark the performance of the lasso penalization and three variants (i.e., ridge, elastic net, adaptive elastic net) on 16 cancers from TCGA after pre-screening, (ii) we propose a bi-dimensional pre-screening procedure based on both gene variability and p-values from single variable Cox models to predict survival, and (iii) we compare our results with iterative sure independence screening (ISIS). Results First, we show that integration of mRNA-seq data with clinical data improves predictions over clinical data alone. Second, our bi-dimensional pre-screening procedure can only improve, in moderation, the C-index and/or the integrated Brier score, while excluding irrelevant genes for prediction. We demonstrate that the different penalization methods reached comparable prediction performances, with slight differences among datasets. Finally, we provide advice in the case of multi-omics data integration. Conclusions Tumor profiles convey more prognostic information than clinical variables such as stage for many cancer subtypes. Lasso and Ridge penalizations perform similarly than Elastic Net penalizations for Cox models in high-dimension. Pre-screening of the top 200 genes in term of single variable Cox model p-values is a practical way to reduce dimension, which may be particularly useful when integrating multi-omics.

Published
2022
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3. miR-600 Acts as a Bimodal Switch that Regulates Breast Cancer Stem Cell Fate through WNT Signaling

Author

Rita El Helou, Guillaume Pinna, Olivier Cabaud, Julien Wicinski, Ricky Bhajun, Laurent Guyon, Claire Rioualen, Pascal Finetti, Abigaelle Gros, Bernard Mari, Pascal Barbry, Francois Bertucci, Ghislain Bidaut, Annick Harel-Bellan, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, and Christophe Ginestier

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define this state are unclear. We have performed two microRNA (miRNA) gain- and loss-of-function screens to identify miRNAs that regulate the choice between bCSC self-renewal and differentiation. We find that micro-RNA (miR)-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal, leading to decreased in vivo tumorigenicity. miR-600 targets stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. In the absence of miR-600, WNT signaling is active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT and promotes bCSC differentiation. In a series of 120 breast tumors, we found that a low level of miR-600 is correlated with active WNT signaling and a poor prognosis. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decisions and influences tumor progression. : El Helou et al. identify miRNAs that are able to balance bCSC fate. They find that miR-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal. miR-600 was further found to regulate WNT signaling through SCD1, and miR-600 expression correlates with clinical outcome.

Published
2017
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4. Human Bone Marrow Mesenchymal Stem Cells Regulate Biased DNA Segregation in Response to Cell Adhesion Asymmetry

Author

Delphine Freida, Severine Lecourt, Audrey Cras, Valérie Vanneaux, Gaelle Letort, Xavier Gidrol, Laurent Guyon, Jerome Larghero, and Manuel Thery

Subjects
Biology (General), QH301-705.5
Abstract

Biased DNA segregation is a mitotic event in which the chromatids carrying the original template DNA strands and those carrying the template copies are not segregated randomly into the two daughter cells. Biased segregation has been observed in several cell types, but not in human mesenchymal stem cells (hMSCs), and the factors affecting this bias have yet to be identified. Here, we have investigated cell adhesion geometries as a potential parameter by plating hMSCs from healthy donors on fibronectin-coated micropatterns. On symmetric micropatterns, the segregation of sister chromatids to the daughter cells appeared random. In contrast, on asymmetric micropatterns, the segregation was biased. This sensitivity to asymmetric extracellular cues was reproducible in cells from all donors but was not observed in human skin-derived fibroblasts or in a fibroblastic cell line used as controls. We conclude that the asymmetry of cell adhesion is a major factor in the regulation of biased DNA segregation in hMSCs.

Published
2013
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5. Segmentation of Image Data from Complex Organotypic 3D Models of Cancer Tissues with Markov Random Fields.

Author

Sean Robinson, Laurent Guyon, Jaakko Nevalainen, Mervi Toriseva, Malin Åkerfelt, and Matthias Nees

Subjects
Medicine, Science
Abstract

Organotypic, three dimensional (3D) cell culture models of epithelial tumour types such as prostate cancer recapitulate key aspects of the architecture and histology of solid cancers. Morphometric analysis of multicellular 3D organoids is particularly important when additional components such as the extracellular matrix and tumour microenvironment are included in the model. The complexity of such models has so far limited their successful implementation. There is a great need for automatic, accurate and robust image segmentation tools to facilitate the analysis of such biologically relevant 3D cell culture models. We present a segmentation method based on Markov random fields (MRFs) and illustrate our method using 3D stack image data from an organotypic 3D model of prostate cancer cells co-cultured with cancer-associated fibroblasts (CAFs). The 3D segmentation output suggests that these cell types are in physical contact with each other within the model, which has important implications for tumour biology. Segmentation performance is quantified using ground truth labels and we show how each step of our method increases segmentation accuracy. We provide the ground truth labels along with the image data and code. Using independent image data we show that our segmentation method is also more generally applicable to other types of cellular microscopy and not only limited to fluorescence microscopy.

Published
2015
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8. Aberrant activation of Wnt/β-Catenin signaling pathway drives the expression of poor prognosis-associated microRNAs in adrenocortical cancer with a major impact on miR-139-5p and its host gene PDE2A

Author

Justine Cristante, Soha Reda El Sayed, Josiane Denis, Bruno Ragazzon, Constanze Hantel, Olivier Chabre, Laurent Guyon, and Nadia Cherradi

Abstract

Adrenocortical carcinoma (ACC) is a rare malignancy with dismal prognosis. Deregulated microRNA (miRNA) expression has been implicated in ACC aggressiveness. Nevertheless, the mechanisms underlying such deregulations remain unknown. Aberrant Wnt/β-Catenin signaling has been reported in about 40% of ACC and is associated with poor outcome. Here, we investigated the link between constitutive activation of Wnt/β-Catenin pathway and miRNA expression alterations in ACC. Inducible shRNA-mediated gene silencing of β-Catenin (β-Cat) was performed in ACC cells expressing constitutively active β-Catenin. The miRnome of ACC cells was analyzed using RNA-Sequencing. Selected miRNAs and mRNAs were validated using quantitative PCR and functional experiments with an emphasis on miR-139-5p, its host gene phosphodiesterase 2A (PDE2A) and its target gene N-Myc Downstream-Regulated Gene 4 (NDRG4). Prognostic values of Wnt/β-Catenin pathway components or mutational status and their correlations with miRNA/mRNA expressions were determined in COMETE-ENSAT and TCGA cohorts. We carried out the first miRnome analysis in β-Catenin-deficient (β-Cat-) ACC cells. Twelve upregulated miRNAs and 42 downregulated miRNAs among which miR-139-5p and miRNAs of the 14q32 locus were identified in β-Cat-cells. Downregulation of selected poor prognosis-associated miRNAs was confirmed using RT-qPCR. Remarkably, the expression of the intronic miR-139-5p was decreased by 90% in β-Cat-cells with a concomitant repression of its host gene PDE2A and upregulation of its target gene NDRG4. In ACC patients, miR-139-5p levels were highly correlated with the levels of PDE2A and anti-correlated with those of NDRG4. MiR-139-5p and PDE2A expressions were higher in patients with mutations in components of Wnt/β-Catenin signaling pathway or high expression of LEF1, with LEF1 proving a better predictor of prognosis than Wnt/β-Catenin signaling pathway mutational status. Our findings indicate that in addition to inducing protein-coding genes in ACC, constitutively active Wnt/β-Catenin signaling upregulates the expression of a subset of miRNAs involved in tumour aggressiveness and poor clinical outcome.

Published
2023

9. Optimal microRNA Sequencing Depth to Predict Cancer Patient Survival with Random Forest and Cox Models

Author

Rémy Jardillier, Dzenis Koca, Florent Chatelain, and Laurent Guyon

Subjects
Genetics, sequencing depth, cancer, microRNA, survival, Cox model, random survival forest model, Genetics (clinical)
Abstract

(1)Backgroundtumor profiling enables patient survival prediction. The two essential parameters to be calibrated when designing a study based on tumor profiles from a cohort are the sequencing depth of RNA-seq technology and the number of patients. This calibration is carried out under cost constraints, and a compromise has to be found. In the context of survival data, the goal of this work is to benchmark the impact of the number of patients and of the sequencing depth of miRNA-seq and mRNA-seq on the predictive capabilities for both the Cox model with elastic net penalty and random survival forest.(2)Resultswe first show that the Cox model and random survival forest provide comparable prediction capabilities, with significant differences for some cancers. Second, we demonstrate that miRNA and/or mRNA data improve prediction over clinical data alone. mRNA-seq data leads to slightly better prediction than miRNA-seq, with the notable exception of lung adenocarcinoma for which the tumor miRNA profile shows higher predictive power. Third, we demonstrate that the sequencing depth of RNA-seq data can be reduced for most of the investigated cancers without degrading the prediction abilities, allowing the creation of independent validation sets at lower cost. Finally, we show that the number of patients in the training dataset can be reduced for the Cox model and random survival forest, allowing the use of different models on different patient subgroups.(3)AvailabilityR script is available athttps://github.com/remyJardillier/Survival_seq_depth

Published
2022
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11. Mycoplasma hyopneumoniae J elicits an antioxidant response and decreases the expression of ciliary genes in infected swine epithelial cells

Author

Scheila G. Mucha, Sophie Rome, Marie-France Sagot, Laurent Guyon, Mariana Galvão Ferrarini, Carol Moraga, Florence Tardy, Alex Di Genova, Arnaldo Zaha, Centro de Biotecnologia [Porto Alegre] (CBiot), Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Mycoplasmoses des Ruminants - UMR (MYCO), Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CAPES782/13European Research Council (ERC)[247073]10CAPES CAPES-Cofecub doctoral fellowship CAPES post-doctoral fellowship (CAPES-Biologia Computacional) 611 23038.010043/2013-02CONICYT BECAS CHILE DOCTORADO 2016/FOLIO 72170320, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
0301 basic medicine, Swine, [SDV]Life Sciences [q-bio], lcsh:Medicine, Article, Antioxidants, 03 medical and health sciences, 0302 clinical medicine, Mycoplasma hyopneumoniae, Bacterial Proteins, Gene expression, microRNA, Animals, Cilia, RNA, Messenger, Transcriptomics, lcsh:Science, Gene, Pathogen, Transcription factor, Cells, Cultured, Regulation of gene expression, Multidisciplinary, biology, Gene Expression Profiling, lcsh:R, Bacteriology, Epithelial Cells, Pneumonia of Swine, Mycoplasmal, biology.organism_classification, 3. Good health, Cell biology, Gene expression profiling, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, miRNAs, lcsh:Q, Pathogens, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, Biomarkers
Abstract

Mycoplasma hyopneumoniae is the most costly pathogen for swine production. Although several studies have focused on the host-bacterium association, little is known about the changes in gene expression of swine cells upon infection. To improve our understanding of this interaction, we infected swine epithelial NPTr cells with M. hyopneumoniae strain J to identify differentially expressed mRNAs and miRNAs. The levels of 1,268 genes and 170 miRNAs were significantly modified post-infection. Up-regulated mRNAs were enriched in genes related to redox homeostasis and antioxidant defense, known to be regulated by the transcription factor NRF2 in related species. Down-regulated mRNAs were enriched in genes associated with cytoskeleton and ciliary functions. Bioinformatic analyses suggested a correlation between changes in miRNA and mRNA levels, since we detected down-regulation of miRNAs predicted to target antioxidant genes and up-regulation of miRNAs targeting ciliary and cytoskeleton genes. Interestingly, most down-regulated miRNAs were detected in exosome-like vesicles suggesting that M. hyopneumoniae infection induced a modification of the composition of NPTr-released vesicles. Taken together, our data indicate that M. hyopneumoniae elicits an antioxidant response induced by NRF2 in infected cells. In addition, we propose that ciliostasis caused by this pathogen is partially explained by the down-regulation of ciliary genes.

Published
2020

12. Cibler la dégradation des ARNms médiée par les éléments riches en A et U à l'aide d'une forme active tronquée de la protéine à doigts de zincs TIS11b/BRF1 affecte les principales propriétés de la tumorigenèse mammaire

Author

Nadia Cherradi, Josiane Denis, Laurent Guyon, Felicitas Rataj, Séverine Planel, Odile Filhol, Jean-Jacques Feige, Caroline Roelants, Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Invasion mechanisms in angiogenesis and cancer (IMAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
0301 basic medicine, Untranslated region, Cancer Research, Carcinogenesis, RNA Stability, Recombinant Fusion Proteins, [SDV]Life Sciences [q-bio], Tristetraprolin, Breast Neoplasms, Biology, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chlorocebus aethiops, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Animals, Humans, Protein Isoforms, Molecular Biology, Cells, Cultured, AU Rich Elements, AU-rich element, Mice, Inbred BALB C, TATA-Binding Protein Associated Factors, Tumor microenvironment, Tumor hypoxia, Cancer, Zinc Fingers, medicine.disease, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, Vascular endothelial growth factor, 030104 developmental biology, chemistry, Gain of Function Mutation, 030220 oncology & carcinogenesis, COS Cells, Cancer cell, Female
Abstract

International audience; Altered expression of regulatory RNA-binding proteins (RBPs) in cancer leads to abnormal expression of mRNAs encoding many factors involved in cancer hallmarks. While conventional anticancer therapies usually target one pathway at a time, targeting key RBP would affect multiple genes and thus overcome drug resistance. Among the Tristetraprolin family of RBP, TIS11b/BRF1/ZFP36L1 mediates mRNA decay through binding to Adenylate/Uridylate (AU-rich elements) in mRNA 3'-untranslated region and recruitment of mRNA degradation enzymes. Here, we show that TIS11b is markedly underexpressed in three breast cancer cell lines, as well as in breast tumor samples. We hypothesized that restoring intracellular TIS11b levels could impair cancer cell phenotypic traits. We thus generated a derivative of TIS11b called R9-ZnCS334D, by combining N-terminal domain deletion, serine-to-aspartate substitution at position 334 to enhance the function of the protein and fusion to the cell-penetrating peptide polyarginine R9. R9-ZnCS334D not only blunted secretion of vascular endothelial growth factor (VEGF) but also inhibited proliferation, migration, invasion, and anchorage-independent growth of murine 4T1 or human MDA-MB-231 breast cancer cells. Moreover, R9-ZnCS334D prevented endothelial cell organization into vessel-like structures, suggesting that it could potentially target various cell types within the tumor microenvironment. In vivo, injection of R9-ZnCS334D in 4T1 tumors impaired tumor growth, decreased tumor hypoxia, and expression of the epithelial-to-mesenchymal transition (EMT) markers Snail, Vimentin, and N-cadherin. R9-ZnCS334D also hindered the expression of chemokines and proteins involved in cancer-related inflammation and invasion including Fractalkine (CX3CL1), SDF-1 (CXCL12), MCP-1 (CCL2), NOV (CCN3), and Pentraxin-3 (PTX3). Collectively, our data indicate that R9-ZnCS334D counteracts multiple traits of breast cancer cell aggressiveness and suggest that this novel protein could serve as the basis for innovative multi-target therapies in cancer.

Published
2019

13. Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

Author

Yann Wallez, Laurent Guyon, Caroline Roelants, Christophe Battail, Q. Franquet, Frédéric Chalmel, Irinka Séraudie, Claude Cochet, Caroline Barette, Odile Filhol, Sofia Giacosa, Nicolas Peilleron, Marie-Odile Fauvarque, Catherine Pillet, Emmanuelle Soleilhac, Clément Sarrazin, Bertrand Evrard, Gaelle Fiard, Jean-Luc Descotes, Jean-Alexandre Long, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Invasion mechanisms in angiogenesis and cancer (IMAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Inovarion, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Genetics and Chemogenomics (GenChem), CHU Grenoble, Gestes Medico-chirurgicaux Assistés par Ordinateur (TIMC-GMCAO), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), UMR1036, Institut National de la Santé et de la Recherche Médicale, 2018, Groupement des Entreprises Françaises dans la lutte contre le Cancer, Isère, Ligue Contre le Cancer, 2017, Association Française d'Urologie, 2019, Centre Hospitalier Universitaire de Grenoble Alpes, ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Chard-Hutchinson, Xavier

Subjects
Cancer Research, kinase inhibitor, CK2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, urologic and male genital diseases, lcsh:RC254-282, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Article, NOX4, 03 medical and health sciences, 0302 clinical medicine, Mediator, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, ROS pathway, tumor tissue slices, 030304 developmental biology, 0303 health sciences, Kinase, ccRCC, apoptosis, Cancer, HIF-2α, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, Clear cell renal cell carcinoma, Oncology, Apoptosis, Cell culture, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, ATM, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ex vivo
Abstract

Simple Summary Renal cell carcinoma (RCC) is the eighth leading malignancy in the world, accounting for 4% of all cancers with poor outcome when metastatic. Protein kinases are highly druggable proteins, which are often aberrantly activated in cancers. The aim of our study was to identify candidate targets for metastatic clear cell renal cell carcinoma therapy, using chemo-genomic-based high-throughput screening. We found that the combined inhibition of the CK2 and ATM kinases in renal tumor cells and patient-derived tumor samples induces synthetic lethality. Mechanistic investigations unveil that this drug combination triggers apoptosis through HIF-2α-(Hypoxic inducible factor HIF-2α) dependent reactive oxygen species (ROS) overproduction, giving a new option for patient care in metastatic RCC. Abstract Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL− cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

Published
2021

14. A survey of IoT protocols and their security issues through the lens of a generic IoT stack

Author

Frédéric Le Mouël, Hicham Ben-Hassine, Jonathan Tournier, Laurent Guyon, François Lesueur, Dynamic Software and Distributed Systems (DYNAMID), CITI Centre of Innovation in Telecommunications and Integration of services (CITI), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria), and AlgoSecure

Subjects
Spoofing attack, IoT protocols, Computer science, Interoperability, IoT security, Cryptography, 02 engineering and technology, Man-in-the-middle attack, Computer security, computer.software_genre, IoT comparison, Protocol stack, [INFO.INFO-IU]Computer Science [cs]/Ubiquitous Computing, [INFO.INFO-MC]Computer Science [cs]/Mobile Computing, [INFO.INFO-CR]Computer Science [cs]/Cryptography and Security [cs.CR], [INFO.INFO-NI]Computer Science [cs]/Networking and Internet Architecture [cs.NI], Artificial Intelligence, Management of Technology and Innovation, 0202 electrical engineering, electronic engineering, information engineering, Computer Science (miscellaneous), Wireless, Engineering (miscellaneous), business.industry, Network packet, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, Generic approach, 020206 networking & telecommunications, IoT attacks, Computer Science Applications, Flooding (computer networking), Hardware and Architecture, 020201 artificial intelligence & image processing, business, computer, Software, Information Systems
Abstract

International audience; The Internet of things (IoT) is rapidly growing, and many security issues relate to its wireless technology. These security issues are challenging because IoT protocols are heterogeneous, suit different needs, and are used in different application domains. From this assessment, we identify the need to provide a homogeneous formalism applying to every IoT protocols. In this survey, we describe a generic approach with twofold challenges. The first challenge we tackle is the identification of common principles to define a generic approach to compare IoT protocol stack. We base the comparison on five different criteria: the range, the openness of the protocol, the interoperability, the topology and the security practices of these IoT protocols. The second challenge we consider is to find a generic way to describe fundamental IoT attacks regardless of the protocol used. This approach exposes similar attacks amongst different IoT protocols and is divided into three parts: attacks focusing on packets (passive and active cryptographic attacks), attacks focusing on the protocol (MITM, Flooding, Sybil, Spoofing, Wormhole attacks) and attacks focusing on the whole system (Sinkhole, Selective forwarding attacks). It also highlights which mechanisms are different between two protocols to make both of them vulnerable to an attack. Finally, we draw some lessons and perspectives from this transversal study.

Published
2020

15. Benchmark of lasso-like penalties in the Cox model for TCGA datasets reveal improved performance with pre-filtering and wide differences between cancers

Author

Rémy Jardillier, Laurent Guyon, and Florent Chatelain

Subjects
Elastic net regularization, Computer science, Proportional hazards model, business.industry, Dimensionality reduction, Univariate, Stability (learning theory), Feature selection, Machine learning, computer.software_genre, Lasso (statistics), Covariate, Artificial intelligence, business, computer
Abstract

MotivationPrediction of patient survival from tumor molecular ‘omics’ data is a key step toward personalized medicine. With this aim, the databases available are growing, with the collection of various ‘omics’ characterizations of patient tumors, together with their associated clinical outcomes for weeks to years of follow-up. Cox models with variable selection used with RNA profiling datasets are popular for identification of prognostic biomarkers and for clinical predictions. However, these models are confronted with the ‘curse of dimensionality’, as the number p of covariates (genes) can greatly exceed the number n of patients. To tackle this problem, variance-based pre-filtering and penalization methods are popular for dimension reduction. In the present paper, we study the impact of a pre-filtering step based on gene variability, and we evaluate the performance of the lasso penalization of the Cox model and four variants (i.e., elastic net, adaptive elastic net, ridge, univariate Cox) in terms of prediction, selection and stability.ResultsFirst, we show that the prediction capacity with the Cox penalties method is cancer dependent. Second, we develop a methodology to fix a threshold to filter out genes with low variability without losing prediction capacity. Third, we show that it is best not to use the Cox model to select prognostic biomarkers, as its false discovery proportion is always ≥ 50%. Finally, to predict overall survival, we can suggest the use of the ridge penalty, or the elastic net if a more parsimonious model is needed, after the pre-filtering step.AvailabilityWe provide the R script generated to reproduce all of the figures presented in this article.Supplementary informationSupplementary Figures and R scripts are available.

Published
2020
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16. Early postoperative circulating miR-483-5p is a prognosis marker for adrenocortical cancer

Author

Josiane Denis, Maurine Oreglia, Olivier Chabre, Martin Fassnacht, Justine Cristante, Silviu Sbiera, Nadia Cherradi, and Laurent Guyon

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, recurrence, Multivariate analysis, lcsh:RC254-282, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, adrenocortical carcinoma, early prognosis, medicine, Adrenocortical carcinoma, ddc:610, circulating microrna, mir-483-5p, business.industry, Hazard ratio, Area under the curve, Prognosis Marker, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, Real-time polymerase chain reaction, Oncology, 030220 oncology & carcinogenesis, biomarker, Biomarker (medicine), business, Adrenocortical cancer
Abstract

We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years, NR3yrs) from patients with poor prognosis (recurrence or death within 3 years after surgery, R &lt, 3yrs). We conducted a single-center retrospective analysis using sera from 48 patients with ACC that were initially non-metastatic and treated by surgery. Sera sampled within 3 months after surgery were available in 26 patients. MiR-483-5p absolute circulating levels were measured using quantitative PCR. Thirteen patients showed a recurrence before 3 years (=R &lt, 3yrs). Thirteen patients showed no recurrence within 3 years, including 11 patients with a follow-up longer than 3 years (=NR3yrs). Serum miR-483-5p levels were higher in R &lt, 3yrs than in NR3yrs: 1,541,990 &plusmn, 428,377 copies/mL vs. 388,457 &plusmn, 62,169 copies/mL (p = 0.002). Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R &lt, 3yrs from NR3yrs with 61.5% sensitivity (CI 31.6&ndash, 86.1) and 100% specificity (CI 71.5&ndash, 100) with an area under the curve of 0.853. Patients with a value below this threshold had a significantly longer recurrence-free and overall survival. In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p &lt, 0.011) but not for overall survival. Our study suggests that serum miR-483-5p is a potent early post-operative biomarker for ACC prognosis that might be a better predictor of RFS than currently used markers.

Published
2020

17. IoTMap: A protocol-agnostic multi-layer system to detect application patterns in IoT networks

Author

Laurent Guyon, Jonathan Tournier, François Lesueur, Frédéric Le Mouël, Hicham Ben-Hassine, Le Mouël, Frédéric, Dynamic Software and Distributed Systems (DYNAMID), CITI Centre of Innovation in Telecommunications and Integration of services (CITI), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria), and AlgoSecure

Subjects
IoT, Computer science, IoT security, 050801 communication & media studies, 02 engineering and technology, law.invention, Bluetooth, [INFO.INFO-IU]Computer Science [cs]/Ubiquitous Computing, [INFO.INFO-MC]Computer Science [cs]/Mobile Computing, [INFO.INFO-CR]Computer Science [cs]/Cryptography and Security [cs.CR], 0508 media and communications, [INFO.INFO-MC] Computer Science [cs]/Mobile Computing, law, 0202 electrical engineering, electronic engineering, information engineering, [INFO.INFO-DC] Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], Protocol (object-oriented programming), [INFO.INFO-CR] Computer Science [cs]/Cryptography and Security [cs.CR], business.industry, Network packet, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, 05 social sciences, [INFO.INFO-IU] Computer Science [cs]/Ubiquitous Computing, 020206 networking & telecommunications, IoT modelling, Pattern detection, [INFO.INFO-OS] Computer Science [cs]/Operating Systems [cs.OS], IoT networks, Heterogeneous networks, [INFO.INFO-OS]Computer Science [cs]/Operating Systems [cs.OS], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], business, 6LoWPAN, Internet of Things, Heterogeneous network, Computer network
Abstract

International audience; The growth of the Internet of Things (IoT) results in a proliferation of different protocols (ZigBee, Bluetooth, 6LowPAN, Z-Wave, Wi-Fi, etc.). Organizations tend to quickly deploy several IoT applications over time and thus face heterogeneous IoT systems, combining different IoT protocols in different places of the overall system. This heterogeneity of protocols makes these networks hard to monitor or control, and some misconfigurations or unexpected device behaviours may even expose users to security issues. In this work, we propose the IoTMap system. IoTMap models interconnected and heterogeneous IoT networks, combining different protocols, by providing a generic stack and a unified packet format. IoTMap builds an iterative graph model where high-level semantics can progressively be deduced, ranging from packet transmission to application-type analysis. As such, IoTMap detects application behaviours amongst devices implementing different protocols, interconnected through a multi-protocol hub. In its current implementation (available at https://github.com/AlgoSecure/iotmap), IoTMap can inspect Zig- Bee, BLE and 6LowPAN networks.

Published
2020

18. miRViz: a novel webserver application to visualize and interpret microRNA datasets

Author

Claire Picquenot, Lise Desquilles, Pierre Giroux, Ricky Bhajun, Christophe Ginestier, Stéphane Segard, Guillaume Pinna, Céline Charavay, Josiane Denis, Laurent Guyon, Nadia Cherradi, Guyon, Laurent, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)

Subjects
Web server, Computer science, AcademicSubjects/SCI00010, Phenotypic screening, Population, Datasets as Topic, Objective analysis, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Biology, computer.software_genre, Exosomes, 03 medical and health sciences, Mice, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Genetics, Adrenocortical Carcinoma, Animals, Humans, Relevance (information retrieval), Differential expression, education, Gene, 030304 developmental biology, education.field_of_study, 0303 health sciences, Internet, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Microvesicles, Adrenal Cortex Neoplasms, Rapid identification, MicroRNAs, Colonic Neoplasms, Web Server Issue, Neoplastic Stem Cells, Mature mirnas, DECIPHER, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, computer, 030217 neurology & neurosurgery, Software
Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the regulation of major pathways in eukaryotic cells through their binding to and repression of multiple mRNAs. With high-throughput methodologies, various outcomes can be measured that produce long lists of miRNAs that are often difficult to interpret. A common question is: after differential expression or phenotypic screening of miRNA mimics, which miRNA should be chosen for further investigation? Here, we present miRViz (http://mirviz.prabi.fr/), a webserver application designed to visualize and interpret large miRNA datasets, with no need for programming skills. MiRViz has two main goals: (i) to help biologists to raise data-driven hypotheses and (ii) to share miRNA datasets in a straightforward way through publishable quality data representation, with emphasis on relevant groups of miRNAs. MiRViz can currently handle datasets from 11 eukaryotic species. We present real-case applications of miRViz, and provide both datasets and procedures to reproduce the corresponding figures. MiRViz offers rapid identification of miRNA families, as demonstrated here for the miRNA-320 family, which is significantly exported in exosomes of colon cancer cells. We also visually highlight a group of miRNAs associated with pluripotency that is particularly active in control of a breast cancer stem-cell population in culture.

Published
2020

19. MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream-regulated gene family members in adrenocortical cancer

Author

Claire Agosta, Olivier Chabre, Jérôme Bertherat, Laurent Guyon, Bruno Boisson, Nadia Cherradi, Jean-Jacques Feige, Rossella Libé, Josiane Denis, Nathalie Sturm, and Jonathan Laugier

Subjects
0301 basic medicine, Cancer Research, Effector, Cell, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, Downregulation and upregulation, 030220 oncology & carcinogenesis, microRNA, Cancer research, medicine, Adrenocortical carcinoma, Gene family, Ectopic expression, N-Myc
Abstract

Adrenocortical carcinoma (ACC) is a tumor with poor prognosis in which overexpression of a panel of microRNAs has been associated with malignancy but a very limited number of investigations on their role in ACC pathogenesis have been conducted. We examined the involvement of miR-483-5p and miR-139-5p in adrenocortical cancer aggressiveness. Using bioinformatics predictions and mRNA/miRNA expression profiles, we performed an integrated analysis to identify inversely correlated miRNA-mRNA pairs in ACC. We identified N-myc downstream-regulated gene family members 2 and 4 (NDRG2 and NDRG4) as targets of miR-483-5p and miR-139-5p, respectively. NDRG2 and NDRG4 expressions were inversely correlated respectively with miR-483-5p and miR-139-5p levels in aggressive ACC samples from two independent cohorts of 20 and 44 ACC. Moreover, upregulation of miR-139-5p and downregulation of NDRG4 demonstrated a striking prognostic value. A direct interaction between miR-483-5p or miR-139-5p and their targets was demonstrated in reporter assays. Downregulation of miR-483-5p or miR-139-5p in the ACC cell lines NCI-H295R and SW13 increased NDRG2 or NDRG4 mRNA and protein expression, compromised adrenocortical cancer cell invasiveness and anchorage-independent growth. MiR-483-5p or miR-139-5p overexpression and NDRG2 or NDRG4 inhibition produce similar changes, which are rescued by NDRG2 or NDRG4 ectopic expression. We established that key factors mediating epithelial-to-mesenchymal transition are downstream effectors of miR-483-5p/NDRG2 and miR-139-5p/NDRG4 pathways. Collectively, our data show for the first time that miR-483-5p/NDRG2 and miR-139-5p/NDRG4 axes promote ACC aggressiveness, with potential implications for prognosis and therapeutic interventions in adrenocortical malignancies.

Published
2018

20. Incorporating interaction networks into the determination of functionally related hit genes in genomic experiments with Markov random fields

Author

Jaakko Nevalainen, Laurent Guyon, Sean Robinson, Anna Campalans, J. Pablo Radicella, Guillaume Pinna, Yhteiskuntatieteiden tiedekunta - Faculty of Social Sciences, Tampere University, University of Turku, Tampere School of Public Health, PARi (PARI), Département Plateforme (PF I2BC), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Statistics and Probability, Multivariate statistics, Netbio, Lymphoma, Computer science, [SDV]Life Sciences [q-bio], ta220, ta3111, computer.software_genre, Machine learning, Biochemistry, Biokemia, solu- ja molekyylibiologia - Biochemistry, cell and molecular biology, 03 medical and health sciences, 0302 clinical medicine, Tilastotiede - Statistics and probability, Gene interaction, RNA interference, Code (cryptography), Humans, ta219, Gene Regulatory Networks, Molecular Biology, Gene, ComputingMilieux_MISCELLANEOUS, ta113, ta112, Markov random field, Random field, Markov chain, business.industry, ta111, Matematiikka - Mathematics, ta1182, Genomics, Ismb/Eccb 2017: The 25th Annual Conference Intelligent Systems for Molecular Biology Held Jointly with the 16th Annual European Conference on Computational Biology, Prague, Czech Republic, July 21–25, 2017, Computer Science Applications, Computational Mathematics, Identification (information), 030104 developmental biology, Computational Theory and Mathematics, Artificial intelligence, Data mining, business, computer, 030217 neurology & neurosurgery, Algorithms, Signal Transduction
Abstract

Motivation Incorporating gene interaction data into the identification of ‘hit’ genes in genomic experiments is a well-established approach leveraging the ‘guilt by association’ assumption to obtain a network based hit list of functionally related genes. We aim to develop a method to allow for multivariate gene scores and multiple hit labels in order to extend the analysis of genomic screening data within such an approach. Results We propose a Markov random field-based method to achieve our aim and show that the particular advantages of our method compared with those currently used lead to new insights in previously analysed data as well as for our own motivating data. Our method additionally achieves the best performance in an independent simulation experiment. The real data applications we consider comprise of a survival analysis and differential expression experiment and a cell-based RNA interference functional screen. Availability and implementation We provide all of the data and code related to the results in the paper. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2017

21. miR-600 Acts as a Bimodal Switch that Regulates Breast Cancer Stem Cell Fate through WNT Signaling

Author

Pascal Finetti, Claire Rioualen, François Bertucci, Bernard Mari, Julien Wicinski, Abigaelle Gros, Ricky Bhajun, Christophe Ginestier, Pascal Barbry, Olivier Cabaud, Guillaume Pinna, Daniel Birnbaum, Laurent Guyon, Ghislain Bidaut, Annick Harel-Bellan, Rita El Helou, Emmanuelle Charafe-Jauffret, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Laboratoire de Biologie à Grande Échelle ( BGE - UMR S1038 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes [Saint Martin d'Hères]-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Epigenetique et Cancer, Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Bidaut, Ghislain

Subjects
0301 basic medicine, Carcinogenesis, Cellular differentiation, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Bioinformatics, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, Gene silencing, Humans, Wnt Signaling Pathway, lcsh:QH301-705.5, Wnt signaling pathway, Cell Differentiation, 3. Good health, Gene Expression Regulation, Neoplastic, Wnt Proteins, MicroRNAs, 030104 developmental biology, lcsh:Biology (General), Tumor progression, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cancer research, Neoplastic Stem Cells, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Stem cell, Signal transduction, Stearoyl-CoA Desaturase, Signal Transduction
Abstract

Summary: Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define this state are unclear. We have performed two microRNA (miRNA) gain- and loss-of-function screens to identify miRNAs that regulate the choice between bCSC self-renewal and differentiation. We find that micro-RNA (miR)-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal, leading to decreased in vivo tumorigenicity. miR-600 targets stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. In the absence of miR-600, WNT signaling is active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT and promotes bCSC differentiation. In a series of 120 breast tumors, we found that a low level of miR-600 is correlated with active WNT signaling and a poor prognosis. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decisions and influences tumor progression. : El Helou et al. identify miRNAs that are able to balance bCSC fate. They find that miR-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal. miR-600 was further found to regulate WNT signaling through SCD1, and miR-600 expression correlates with clinical outcome.

Published
2017
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22. Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Author

Laurent Blanchoin, Laetitia Kurzawa, Laurent Guyon, Yoran Margaron, Alice Pinheiro, Manuel Théry, Tomoaki Nagai, Anne-Pierre Morel, Fabien Reyal, and Alain Puisieux

Subjects
0303 health sciences, Chemistry, Mesenchymal stem cell, Cell, Cell biology, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Centrosome, 030220 oncology & carcinogenesis, medicine, Cell adhesion, Nucleus, Transcription factor, Intracellular, 030304 developmental biology
Abstract

Potential metastatic cells can dissociate from a primary breast tumor by undergoing an epithelial-to-mesenchymal transmission (EMT). Recent work has revealed that cells in intermediate states of EMT acquire an augmented capacity for tumor-cell dissemination. These states have been characterized by molecular markers, but the structural features and the cellular mechanisms that underlie the acquisition of their invasive properties are still unknown. Using human mammary epithelial cells, we generated cells in intermediate states of EMT through the induction of a single EMT-inducing transcription factor, ZEB1, and cells in a mesenchymal state by stimulation with TGFβ. In stereotypic and spatially-defined culture conditions, the architecture, internal organization and mechanical properties of cells in the epithelial, intermediate and mesenchymal state were measured and compared. We found that the lack of intercellular cohesiveness in epithelial and mesenchymal cells can be detected early by microtubule destabilization and the repositioning of the centrosome from the cell-cell junction to the cell center. Consistent with their high migration velocities, cells in intermediate states produced low contractile forces compared with epithelial and mesenchymal cells. The high contractile forces in mesenchymal cells powered a retrograde flow pushing the nucleus away from cell adhesion to the extracellular matrix. Therefore, cells in intermediate state had structural and mechanical properties that were distinct but not necessarily intermediate between epithelial and mesenchymal cells. Based on these observations, we found that a panel of triple-negative breast cancer lines had intermediate rather than mesenchymal characteristics suggesting that the structural and mechanical properties of the intermediate state are important for understanding tumor-cell dissemination.

Published
2019

23. Selective BMP-9 Inhibition Partially Protects Against Experimental Pulmonary Hypertension

Author

Raphaël Thuillet, Alice Huertas, Carole Phan, Ayumi Sekine, Christine Mallet, Ly Tu, Sabine Bailly, Christophe Guignabert, Laurent Savale, Olli Ritvos, Florian Robert, Jennifer Bordenave, Laurent Guyon, Agnès Desroches-Castan, Marc Humbert, Jean-Jacques Feige, Amélie Cumont, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre chirurgical Marie Lannelongue, Université Paris-Saclay, Service d'Anesthésie et de Soins Intensifs [Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Grenoble Alpes, Inserm, CEA, BIG-Biologie du Cancer et de l’Infection, Grenoble, France, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Invasion mechanisms in angiogenesis and cancer (IMAC), Department of Bacteriology and Immunology and Department of Physiology [Helsinki, Finland] (Faculty of Medicine), University of Helsinki, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Department of Bacteriology and Immunology [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Service de Pneumologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-DHU Thorax Innovation (TORINO), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, ANR-17-CE14-0006,B9inPAH,BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel(2017), Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Guignabert, Christophe, Albaret, Lucie, and BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel - - B9inPAH2017 - ANR-17-CE14-0006 - AAPG2017 - VALID

Subjects
0301 basic medicine, medicine.medical_specialty, Physiology, vascular remodeling, [SDV]Life Sciences [q-bio], Vasodilation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Right ventricular hypertrophy, medicine.artery, Internal medicine, pulmonary artery, medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, business.industry, animal model, growth differentiation factor 2, Hypoxia (medical), medicine.disease, Pulmonary hypertension, endothelial cells, BMPR2, Apelin, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Adrenomedullin, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, Pulmonary artery, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract

Rationale: Although many familial cases of pulmonary arterial hypertension exhibit an autosomal dominant mode of inheritance with the majority having mutations in essential constituents of the BMP (bone morphogenetic protein) signaling, the specific contribution of the long-term loss of signal transduction triggered by the BMPR2 (type 2 BMP receptor) remains poorly characterized. Objective: To investigate the role of BMP9, the main ligand of ALK1 (Activin receptor-like kinase 1)/BMPR2 heterocomplexes, in pulmonary hypertension. Method and Results: The absence of BMP9 in Bmp9 −/− mice and its inhibition in C57BL/6 mice using neutralizing anti-BMP9 antibodies substantially prevent against chronic hypoxia-induced pulmonary hypertension judged by right ventricular systolic pressure measurement, right ventricular hypertrophy, and pulmonary distal arterial muscularization. In agreement with these observations, we found that the BMP9/BMP10 ligand trap ALK1 ECD administered in monocrotaline or Sugen/hypoxia (SuHx) rats substantially attenuate proliferation of pulmonary vascular cells, inflammatory cell infiltration, and regresses established pulmonary hypertension in rats. Our data obtained in human pulmonary endothelial cells derived from controls and pulmonary arterial hypertension patients indicate that BMP9 can affect the balance between endothelin-1, apelin, and adrenomedullin. We reproduced these in vitro observations in mice chronically exposed to hypoxia, with Bmp9 −/− mice exhibiting lower mRNA levels of the vasoconstrictor peptide ET-1 (endothelin-1) and higher levels of the 2 potent vasodilator factors apelin and ADM (adrenomedullin) compared with Bmp9 +/+ littermates. Conclusions: Taken together, our data indicate that the loss of BMP9, by deletion or inhibition, has beneficial effects against pulmonary hypertension onset and progression.

Published
2019

24. MicroRNA degeneracy and pluripotentiality within a Lavallière-tie architecture confers robustness to gene expression networks

Author

Ricky Bhajun, Laurent Guyon, Xavier Gidrol, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Gene regulatory network, Computational biology, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Gene expression, microRNA, Humans, Gene Regulatory Networks, Degeneracy (biology), Molecular Biology, ComputingMilieux_MISCELLANEOUS, Pharmacology, Regulation of gene expression, Genetics, Visions and Reflections, Models, Genetic, Gene Expression Profiling, Robustness (evolution), Cell Biology, Gene expression profiling, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, Molecular Medicine, Signal transduction
Abstract

Modularity, feedback control, functional redundancy and bowtie architecture have been proposed as key factors that confer robustness to complex biological systems. MicroRNAs (miRNAs) are highly conserved but functionally dispensable. These antinomic properties suggest that miRNAs fine-tune gene expression rather than act as genetic switches. We synthesize published and unpublished data and hypothesize that miRNA pluripotentiality acts to buffer gene expression, while miRNA degeneracy tunes the expression of targets, thus providing robustness to gene expression networks. Furthermore, we propose a Lavallière-tie architecture by integrating signal transduction, miRNAs and protein expression data to model complex gene expression networks.

Published
2016

25. Bioinformatics Methods to Select Prognostic Biomarker Genes from Large Scale Datasets: A Review

Author

Florent Chatelain, Rémy Jardillier, Laurent Guyon, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), GIPSA - Signal et Automatique pour la surveillance, le diagnostic et la biomécanique (GIPSA-SAIGA), Département Automatique (GIPSA-DA), Grenoble Images Parole Signal Automatique (GIPSA-lab ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Grenoble Images Parole Signal Automatique (GIPSA-lab ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Département Images et Signal (GIPSA-DIS), and Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, False discovery rate, Databases, Factual, Computer science, Feature selection, Computational biology, 01 natural sciences, Applied Microbiology and Biotechnology, Models, Biological, Disease-Free Survival, 010104 statistics & probability, 03 medical and health sciences, Survival data, Lasso (statistics), Clinical information, Biomarkers, Tumor, Humans, Prognostic biomarker, 0101 mathematics, Computational Biology, Patient survival, General Medicine, Benchmarking, Prognosis, Kidney Neoplasms, 3. Good health, 030104 developmental biology, Molecular Medicine, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract

International audience; With the increased availability of survival datasets, that comprise both molecular information (e.g., gene expression), and clinical information (e.g., patient survival), numerous genes are proposed as prognostic biomarkers. Despite efforts and money invested, very few of these biomarkers have been clinically validated and are used routinely. A high false discovery rate is assumed to be largely responsible for this, in particular as the number of tested genes is extremely high relative to the number of patients followed. Here, after describing the historical methodologies on which recent developments have often been based, this review describes studies that have been performed in the last few years. The concepts will be illustrated for a renal cancer dataset, and the corresponding scripts are provided (Supporting Information). These new developments belong to three main fields of applications. First, variable selection concerns various improvements to lasso penalization. Second, accurate definition of p-values and control of the false discovery rate have also been the subject of many studies. Third, the incorporation of biological knowledge, often through the form of networks or pathways, can be used as an a priori and/or to reduce dimensionality. These new and promising developments deserve benchmarking by independent groups not involved in their development, with various independent datasets. Further work on the methodologies is also still required.

Published
2018

27. Indolizine-Based Scaffolds as Efficient and Versatile Tools: Application to the Synthesis of Biotin-Tagged Antiangiogenic Drugs

Author

Agnès Desroches-Castan, Jean-Jacques Feige, Sabine Brugière, Simon Bonte, Isabelle Baussanne, Yohann Couté, Martine Demeunynck, Laurent Guyon, Marie Arvin-Berod, Département de pharmacochimie moléculaire (DPM ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Département de pharmacochimie moléculaire (DPM), Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Etude de la dynamique des protéomes (EDyP), Invasion mechanisms in angiogenesis and cancer (IMAC), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Scaffold, General Chemical Engineering, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Article, lcsh:Chemistry, chemistry.chemical_compound, Biotin, Affinity chromatography, medicine, Placental Extracts, [CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS, 010405 organic chemistry, Biological activity, General Chemistry, Combinatorial chemistry, 0104 chemical sciences, lcsh:QD1-999, chemistry, Mechanism of action, Indolizine, medicine.symptom, Conjugate
Abstract

International audience; We describe the design and optimization of polyfunctional scaffolds based on a fluorescent indolizine core derivatized with various orthogonal groups (amines, esters, oximes, alkynes, etc.). To show one application as tools in biology, the scaffold was used to prepare drug-biotin conjugates that were then immobilized onto avidin-agarose for affinity chromatography. More specifically, the antiangiogenic drug COB223, whose mechanism of action remained unclear, was chosen as a proof-of-concept drug. The drug-selective discrimination of proteins observed after elution of the cell lysates through the affinity columns, functionalized either with the biologically active COB223 or a structurally related inactive analogue (COB236), is a clear indication that the presence of the indolizine core does not limit drug-protein interaction and confirms the usefulness of the indolizine scaffold. Furthermore, the separation of COB223-interacting proteins from human placental extracts unveiled unanticipated protein targets belonging to the family of regulatory RNA-binding proteins, which opens the way to new hypotheses on the mode of action of this antiangiogenic drug.

Published
2017

28. Microtubule stabilization drives 3D centrosome migration to initiate primary ciliogenesis

Author

Gaëlle Letort, Fabrice Senger, Xavier Gidrol, Laurent Guyon, Manuel Théry, Amandine Pitaval, James Sillibourne, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biologie du Cancer et de l'Infection (BCI ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Project: 310472,EC:FP7:ERC,ERC-2012-StG_20111109,SPICY(2012), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
0301 basic medicine, Axoneme, Time Factors, Cytoskeleton organization, Centrosome cycle, Retinal Pigment Epithelium, Microtubule dynamics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Transfection, Mechanotransduction, Cellular, Microtubules, Spindle pole body, Article, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Primary ciliogenesis, Centrosome migration, Intraflagellar transport, Microtubule, Ciliogenesis, Humans, Actin network, Cilia, Cytoskeleton, Research Articles, 030304 developmental biology, Microtubule nucleation, Centrosome, 0303 health sciences, Protein Stability, Tumor Suppressor Proteins, Epithelial Cells, Cell Biology, Actin cytoskeleton, Human cells, Cell biology, Actin Cytoskeleton, 030104 developmental biology, Microtubule Proteins, RNA Interference, Centrosome positioning regulation, 030217 neurology & neurosurgery
Abstract

The classical view of centrosome decentering and migration to the cell periphery during ciliogenesis is that it is pulled toward its final destination. Here, Pitaval et al. argue that microtubule stabilization in the early stages of ciliogenesis generates pushing forces that propel the centrosome toward the apical pole., Primary cilia are sensory organelles located at the cell surface. Their assembly is primed by centrosome migration to the apical surface, yet surprisingly little is known about this initiating step. To gain insight into the mechanisms driving centrosome migration, we exploited the reproducibility of cell architecture on adhesive micropatterns to investigate the cytoskeletal remodeling supporting it. Microtubule network densification and bundling, with the transient formation of an array of cold-stable microtubules, and actin cytoskeleton asymmetrical contraction participate in concert to drive apical centrosome migration. The distal appendage protein Cep164 appears to be a key actor involved in the cytoskeleton remodeling and centrosome migration, whereas intraflagellar transport 88’s role seems to be restricted to axoneme elongation. Together, our data elucidate the hitherto unexplored mechanism of centrosome migration and show that it is driven by the increase and clustering of mechanical forces to push the centrosome toward the cell apical pole.

Published
2017

29. Stem Cell-Like Properties of CK2β-down Regulated Mammary Cells

Author

Filhol, Eve Duchemin-Pelletier, Megghane Baulard, Elodie Spreux, Magali Prioux, Mithila Burute, Baharia Mograbi, Laurent Guyon, Manuel Théry, Claude Cochet, and Odile

Subjects
protein kinase CK2, stem cell, breast cancer, EMT, epithelial plasticity
Abstract

The ubiquitous protein kinase CK2 has been demonstrated to be overexpressed in a number of human tumours. This enzyme is composed of two catalytic α or α’ subunits and a dimer of β regulatory subunits whose expression levels are probably implicated in CK2 regulation. Several recent papers reported that unbalanced expression of CK2 subunits is sufficient to drive epithelial to mesenchymal transition, a process involved in cancer invasion and metastasis. Herein, through transcriptomic and miRNA analysis together with comparison of cellular properties between wild type and CK2β-knock-down MCF10A cells, we show that down-regulation of CK2β subunit in mammary epithelial cells induces the acquisition of stem cell-like properties associated with perturbed polarity, CD44high/CD24low antigenic phenotype and the ability to grow under anchorage-independent conditions. These data demonstrate that a CK2β level establishes a critical cell fate threshold in the control of epithelial cell plasticity. Thus, this regulatory subunit functions as a nodal protein to maintain an epithelial phenotype and its depletion drives breast cell stemness.

Published
2017
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30. The modulation of attachment, growth and morphology of cancerous prostate cells by polyelectrolyte nanofilms

Author

Xavier Gidrol, Ricky Bhajun, Philippe Cinquin, Nathalie Picollet-D'hahan, Eric Sulpice, Jean-Pierre Alcaraz, Frédérique Kermarrec, Jayesh Wagh, Donald K. Martin, Sophie Gerbaud, Patricia Obeid, Laurent Guyon, Monika E. Dolega, Laboratoire Biopuces (BIOPUCES), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Systèmes Nanobiotechnologiques et Biomimétiques (TIMC-IMAG-SyNaBi), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Structures et propriétés d'architectures moléculaire (SPRAM - UMR 5819), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-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 Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-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)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Male, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Materials science, Polymers, Carcinogenesis, Biophysics, Bioengineering, Epithelial cells, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Cell Line, Allylamine, Focal adhesion, Biomaterials, chemistry.chemical_compound, Animals, Cytotoxic T cell, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, Cell adhesion, Cell proliferation, biology, Cell growth, Prostate, Prostatic Neoplasms, Adhesion, Models, Theoretical, Layer-by-layer, 021001 nanoscience & nanotechnology, Polyelectrolytes, Rats, 0104 chemical sciences, Fibronectin, chemistry, Cell culture, Mechanics of Materials, Immunology, biology.protein, Ceramics and Composites, 0210 nano-technology
Abstract

free download pdf : http://ac.els-cdn.com/S0142961213010715/1-s2.0-S0142961213010715-main.pdf?_tid=af9b5ff8-4bae-11e3-b1b0-00000aab0f27&acdnat=1384270119_77de34b330a3942315169996314d8ce3; International audience; The behaviour of cancerous epithelial prostatic cells (PC3) growing on polyelectrolytes (PE) coatings was compared to the behaviour of immortalized normal prostatic cells (PNT-2). The cell behaviour was evaluated and quantified in terms of initial cell attachment, growth, metabolic activity, morphometry, adhesion, apoptosis and stress related gene expression. Both the anionic PSS (poly(sodium 4-styrenesulphonate))-terminated surface and cationic PAH (poly(allylamine hydrochloride))-terminated surfaces were not cytotoxic. The initial attachment of cells was better on the PAH-terminated surface compared to fibronectin. However, the proliferation rate of PC3 cells was reduced on the PAH-terminated surface and slightly increased on the PSS coatings. Only PAH prevented the clustering phenotype of PC3 and reduced the number of focal adhesion points as compared to fibronectin or PSS coatings. In contrast, none of the PE surfaces significantly affected the biological responses of PNT-2 cells. PAH-terminating films provide a tool to preferentially modulate the growth of some cancerous phenotypes, in this case as a micro-environment that reduces the growth of metastatic PC3 cells.

Published
2013
Full Text
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31. Distinct outcomes of CRL-Nedd8 pathway inhibition reveal cancer cell plasticity

Author

Anastasia V, Rulina, Frédérique, Mittler, Patricia, Obeid, Sophie, Gerbaud, Laurent, Guyon, Eric, Sulpice, Frédérique, Kermarrec, Nicole, Assard, Monika E, Dolega, Xavier, Gidrol, and Maxim Y, Balakirev

Subjects
Male, NEDD8 Protein, Transcription, Genetic, Cell Survival, Ubiquitin-Protein Ligases, Cell Plasticity, Prostatic Neoplasms, Cyclopentanes, Models, Biological, Pyrimidines, Transcriptional Regulator ERG, Receptors, Androgen, Cell Line, Tumor, Gene Knockdown Techniques, Spheroids, Cellular, Humans, Cell Lineage, Original Article, Ubiquitins, Cell Proliferation, Signal Transduction
Abstract

Inhibition of protein degradation by blocking Cullin-RING E3 ligases (CRLs) is a new approach in cancer therapy though of unknown risk because CRL inhibition may stabilize both oncoproteins and tumor suppressors. Probing CRLs in prostate cancer cells revealed a remarkable plasticity of cells with TMPRSS2-ERG translocation. CRL suppression by chemical inhibition or knockdown of RING component RBX1 led to reversible G0/G1 cell cycle arrest that prevented cell apoptosis. Conversely, complete blocking of CRLs at a higher inhibitor dose-induced cytotoxicity that was amplified by knockdown of CRL regulator Cand1. We analyzed cell signaling to understand how varying degrees of CRL inhibition translated to distinct cell fates. Both tumor suppressor and oncogenic cell signaling pathways and transcriptional activities were affected, with pro-metastatic Wnt/β-catenin as the most upregulated. Suppression of the NF-κB pathway contributed to anti-apoptotic effect, and androgen receptor (AR) and ERG played decisive, though opposite, roles: AR was involved in protective quiescence, whereas ERG promoted apoptosis. These data define AR–ERG interaction as a key plasticity and survival determinant in prostate cancer and suggest supplementary treatments that may overcome drug resistance mechanisms regulated by AR–ERG interaction.

Published
2016

32. Critical Behavior of the Liquid Gas Transition of 4He Confined in a Silica Aerogel

Author

Florence Despetis, Mathieu Melich, Fabien Bonnet, Geoffroy J. Aubry, Laurent Guyon, Pierre-Etienne Wolf, Hélium : du fondamental aux applications (HELFA), Institut Néel (NEEL), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and ANR-06-BLAN-0098,HEVEPOR,Un système modèle pour les transitions de phase en milieu désordonné : l'adsorption de l'hélium dans les aérogels(2006)

Subjects
Confined systems, Phase transition, Materials science, PACS numbers: 67.25.dr, 05.70.Jk, 64.60.My, 68.03.Fg, FOS: Physical sciences, Thermodynamics, Condensed Matter - Soft Condensed Matter, 01 natural sciences, Light scattering, 010305 fluids & plasmas, Equilibrium phase, Critical point (thermodynamics), 0103 physical sciences, RFIM, General Materials Science, [PHYS.COND.CM-SM]Physics [physics]/Condensed Matter [cond-mat]/Statistical Mechanics [cond-mat.stat-mech], Some Energy, 010306 general physics, Porosity, Condensed Matter - Statistical Mechanics, Statistical Mechanics (cond-mat.stat-mech), Liquid gas, Aerogel, Condensed Matter Physics, Critical behavior, Atomic and Molecular Physics, and Optics, Soft Condensed Matter (cond-mat.soft), [PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft]
Abstract

We have studied 4 He confined in a 95% porosity silica aerogel in the vicinity of the bulk liquid gas critical point. Both thermodynamic measurements and light scattering experiments were performed to probe the effect of a quenched disorder on the liquid gas transition, in relation with the Random Field Ising Model (RFIM). We find that the hysteresis between condensation and evaporation present at lower temperatures disappears at a temperature T ch between 25 and 30 mK below the critical point. Slow relaxations are observed for temperatures slightly below T ch , indicating that some energy barriers, but not all, can be overcome. Above T ch , no density step is observed along the (reversible) isotherms, showing that the critical behavior of the equilibrium phase transition in presence of disorder, if it exists, is shifted to smaller temperatures, where it cannot be observed due to the impossibility to reach equilibrium. Above T ch , light scattering exhibits a weak maximum close to the pressure where the isotherm slope is maximal. This behavior can be accounted for by a simple model incorporating the compression of 4 He close to the silica strands., Comment: 6 pages

Published
2012

33. Phi-score: A cell-to-cell phenotypic scoring method for sensitive and selective hit discovery in cell-based assays

Author

Ricky Bhajun, Stéphanie Combe, Jean-Philippe Vert, Eric Sulpice, J. Pablo Radicella, Philippe Rouillier, Christian Lajaunie, Mélissa Mary, Xavier Gidrol, Anna Campalans, Frédéric Fer, Guillaume Pinna, Patricia Obeid, Laurent Guyon, Laboratoire de Biologie à Grande Échelle ( BGE - UMR S1038 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes [Saint Martin d'Hères]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Centre de Bioinformatique ( CBIO ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Cellules Souches et Radiations ( SCSR - U 967 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), This work was funded by grants from the Agence Nationale de la Recherche (Investissements d’avenir), the pôle de compétitivité MEDICEN and CEA. The screen was funded by a grant from the Association pour la Recherche sur le Cancer (n°PJA 20131200165 to JPR)., Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre de Géosciences (GEOSCIENCES), PARi (PARI), Département Plateforme (PF I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Cellules Souches et Radiations (SCSR - U 967), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), PSL Research University (PSL)-MINES ParisTech - École nationale supérieure des mines de Paris, and Institut Curie

Subjects
[SDV]Life Sciences [q-bio], Phenotypic screening, Cell, Excision-Repair, Robust statistics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Population Context, 01 natural sciences, Article, 03 medical and health sciences, RNA interference, medicine, Statistical-Methods, Hit selection, Primary cell, Pathways, Patterns, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Scale RNAi Screens, Transfection, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure
Abstract

Phenotypic screening monitors phenotypic changes induced by perturbations, including those generated by drugs or RNA interference. Currently-used methods for scoring screen hits have proven to be problematic, particularly when applied to physiologically relevant conditions such as low cell numbers or inefficient transfection. Here, we describe the Φ-score, which is a novel scoring method for the identification of phenotypic modifiers or hits in cell-based screens. Φ-score performance was assessed with simulations, a validation experiment and its application to gene identification in a large-scale RNAi screen. Using robust statistics and a variance model, we demonstrated that the Φ-score showed better sensitivity, selectivity and reproducibility compared to classical approaches. The improved performance of the Φ-score paves the way for cell-based screening of primary cells, which are often difficult to obtain from patients in sufficient numbers. We also describe a dedicated merging procedure to pool scores from small interfering RNAs targeting the same gene so as to provide improved visualization and hit selection.

Published
2015

34. Segmentation of image data from complex organotypic 3D models of cancer tissues with Markov random fields

Author

Mervi Toriseva, Laurent Guyon, Matthias Nees, Sean Robinson, Jaakko Nevalainen, Malin Åkerfelt, University of Turku, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Tampere School of Public Health, Turku Centre for Biotechnology, University of Turku-Åbo Academy University, Medical Biotechnology, VTT Technical Research Centre of Finland (VTT), Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Cancer Research Institute Ghent (CRIG), Ghent University [Belgium] (UGENT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Terveystieteiden yksikkö - School of Health Sciences, and University of Tampere

Subjects
Male, Cell type, Biolääketieteet - Biomedicine, [SDV]Life Sciences [q-bio], ta220, lcsh:Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 02 engineering and technology, Biology, Bioinformatics, Models, Biological, 03 medical and health sciences, 3D cell culture, Imaging, Three-Dimensional, SDG 3 - Good Health and Well-being, Cell Line, Tumor, Image Interpretation, Computer-Assisted, 0202 electrical engineering, electronic engineering, information engineering, Humans, Entropy (information theory), Segmentation, lcsh:Science, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, ta113, ta112, 0303 health sciences, Ground truth, Multidisciplinary, Random field, Markov chain, business.industry, lcsh:R, ta111, ta1182, Prostatic Neoplasms, Pattern recognition, Image segmentation, ta3122, Coculture Techniques, Markov Chains, Microscopy, Fluorescence, Multiphoton, lcsh:Q, 020201 artificial intelligence & image processing, Artificial intelligence, business, Research Article
Abstract

Organotypic, three dimensional (3D) cell culture models of epithelial tumour types such as prostate cancer recapitulate key aspects of the architecture and histology of solid cancers. Morphometric analysis of multicellular 3D organoids is particularly important when additional components such as the extracellular matrix and tumour microenvironment are included in the model. The complexity of such models has so far limited their successful implementation. There is a great need for automatic, accurate and robust image segmentation tools to facilitate the analysis of such biologically relevant 3D cell culture models. We present a segmentation method based on Markov random fields (MRFs) and illustrate our method using 3D stack image data from an organotypic 3D model of prostate cancer cells co-cultured with cancer-associated fibroblasts (CAFs). The 3D segmentation output suggests that these cell types are in physical contact with each other within the model, which has important implications for tumour biology. Segmentation performance is quantified using ground truth labels and we show how each step of our method increases segmentation accuracy. We provide the ground truth labels along with the image data and code. Using independent image data we show that our segmentation method is also more generally applicable to other types of cellular microscopy and not only limited to fluorescence microscopy. Public Library of Science open access

Published
2015

35. A statistically inferred microRNA network identifies breast cancer target miR-940 as an actin cytoskeleton regulator

Author

Vincent Haguet, Stéphanie Combe, Ricky Bhajun, Christian Lajaunie, Xavier Gidrol, Amandine Pitaval, Eric Sulpice, Patricia Obeid, Laurent Guyon, Itebeddine Ghorbel, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR et CEA, Mines Paris - PSL (École nationale supérieure des mines de Paris), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Centre de Géosciences (GEOSCIENCES), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), and MINES ParisTech, Bibliothèque

Subjects
Kinase, Mesenchymal Transition, [SDV]Life Sciences [q-bio], Cells, Gene regulatory network, Gene-Expression, Breast Neoplasms, Biology, Discovery, Article, Cell Movement, Myosin, microRNA, Gene expression, Humans, Gene Regulatory Networks, Disease, ComputingMilieux_MISCELLANEOUS, Cellular Senescence, Cell Proliferation, Monomeric GTP-Binding Proteins, Genetics, Regulation of gene expression, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, Gene Expression Profiling, Computational Biology, Molecular Sequence Annotation, Animal Development, Actin cytoskeleton, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell biology, Gene Expression Regulation, Neoplastic, Gene expression profiling, Actin Cytoskeleton, MicroRNAs, Gene Ontology, Female, Databases, Nucleic Acid, Prediction, Signal Transduction
Abstract

International audience; MiRNAs are key regulators of gene expression. By binding to many genes, they create a complex network of gene co-regulation. Here, using a network-based approach, we identified miRNA hub groups by their close connections and common targets. In one cluster containing three miRNAs, miR-612, miR-661 and miR-940, the annotated functions of the co-regulated genes suggested a role in small GTPase signalling. Although the three members of this cluster targeted the same subset of predicted genes, we showed that their overexpression impacted cell fates differently. miR-661 demonstrated enhanced phosphorylation of myosin II and an increase in cell invasion, indicating a possible oncogenic miRNA. On the contrary, miR-612 and miR-940 inhibit phosphorylation of myosin II and cell invasion. Finally, expression profiling in human breast tissues showed that miR-940 was consistently downregulated in breast cancer tissues M icroRNAs are a class of endogenous, small (19–25 nucleotides), single-stranded non-coding RNAs that regulate gene expression in all eukaryotic organisms. In metazoans, microRNAs most commonly bind to the 39 untranslated region (39UTR) of their mRNA target transcript and cause translational repression and/or mRNA degradation. Every microRNA is predicted to regulate from a dozen to thousands of genes, including transcription factors. This fine-tuning of protein expression is known to be involved in many physiological processes, such as development, apoptosis, signal transduction and even cancer progression 1,2. More than 2,000 mature human microRNAs are listed in the 20 th release of miRBase: http://www.mirbase.org (2014) (Date of access:19/08/2013), and some authors hypothesise that the majority of human genes are regulated by microRNAs 3. Since their discovery in 1993 4 , a fair understanding of their role in animal development and in the onset and progression of diseases 2 , as well as of their potential use in therapies 5 , has been gathered. However, the cooperative behaviour of microRNAs is still under investigation. A growing body of experimental evidence suggests that microRNAs can regulate genes through complementarity, meaning that microRNAs can act together to regulate individual genes or groups of genes involved in similar processes 6. For example, Hu and co-workers demonstrated that transducing a cocktail of precursor microRNAs (miR-21, miR-24 and miR-221) can result in more effective engraftment of transplanted cardiac progenitor cells 7. Consistent with these discoveries, Zhu et al. demonstrated that miR-21 and miR-221 coregulate 56 gene ontology (GO) processes 8. In the same study, the authors also showed that cotransfection of miR-1 and miR-21 increases H 2 O 2-induced myocardial apoptosis and oxidative stress. These recent findings support the idea of microRNA-mediated cooperative regulation but also argue for the use of systemic approaches, notably based on graph theory, to decipher individual and complementary roles of microRNAs. Some work has been conducted to use recent high-throughput experiment-derived data sets to infer microRNA synergistic relationships 9–12. Herein, we present a microRNA network based on target similarities among microRNAs to infer clusters of microRNAs. Clusters are defined as groups of microRNAs sharing a set of common targets, predicted by either DIANA-microT v3 13 or TargetScan v6.2 14. Some authors have used GO enrichment analysis as a confirmatory tool for their clustering approach 11. In our case, GO enrichment is not used to infer networks but as a way to estimate the probable metabolic pathway(s) a cluster of microRNAs could co-regulate. Moreover, the novelty of our approach is to consider not only clusters of microRNAs but also OPEN

Published
2015

36. Condensation of Helium in Aerogel and Athermal Dynamics of the Random-Field Ising Model

Author

Florence Despetis, Pierre-Etienne Wolf, Mathieu Melich, P. Spathis, Fabien Bonnet, Laurent Guyon, Geoffroy J. Aubry, Hélium : du fondamental aux applications (HELFA), Institut Néel (NEEL), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and HEVEPOR

Subjects
Phase transition, Materials science, FOS: Physical sciences, General Physics and Astronomy, chemistry.chemical_element, Non-equilibrium thermodynamics, Thermodynamics, helium, 02 engineering and technology, Condensed Matter::Disordered Systems and Neural Networks, 01 natural sciences, Random field ising model, Critical point (thermodynamics), 0103 physical sciences, [PHYS.COND.CM-DS-NN]Physics [physics]/Condensed Matter [cond-mat]/Disordered Systems and Neural Networks [cond-mat.dis-nn], silica aerogel, 010306 general physics, Porosity, Helium, Condensed matter physics, Aerogel, Disordered Systems and Neural Networks (cond-mat.dis-nn), disorder, Condensed Matter - Disordered Systems and Neural Networks, 021001 nanoscience & nanotechnology, 3. Good health, Condensed Matter::Soft Condensed Matter, out-of-equilibrium phase transition, liquid-vapor transition, hysteresis, chemistry, avalanches, Ising model, 0210 nano-technology, Random Field Ising Model, 64.60.Ht, 64.70.F-, 75.60.Ej, 67.25.bh
Abstract

High resolution measurements reveal that condensation isotherms of $^4$He in a silica aerogel become discontinuous below a critical temperature. We show that this behaviour does not correspond to an equilibrium phase transition modified by the disorder induced by the aerogel structure, but to the disorder-driven critical point predicted for the athermal out-of-equilibrium dynamics of the Random Field Ising Model. Our results evidence the key role of non-equilibrium effects in the phase transitions of disordered systems., 5 p + suppl. material

Published
2014

37. Human bone marrow mesenchymal stem cells regulate biased DNA segregation in response to cell adhesion asymmetry

Author

Séverine Lecourt, Xavier Gidrol, Laurent Guyon, Valérie Vanneaux, Gaëlle Letort, Jérôme Larghero, Audrey Cras, Delphine Freida, Manuel Thery, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Unité de Thérapie Cellulaire, Hopital St Louis, Laboratoire de physiologie cellulaire végétale (LPCV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), European Research Council [ERC-310472], Agence National pour la Recherche [ANR-05PRIB01103, ANR-10-IBHU-0002], Martin-Laffon, Jacqueline, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-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 Grenoble Alpes [2016-2019] (UGA [2016-2019]), Larghero, Jerome, Thery, Manuel, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA)

Subjects
Cell type, Cell division, Cellular differentiation, micropatterns, Bone Marrow Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Chromatids, Biology, General Biochemistry, Genetics and Molecular Biology, Chromosome segregation, 03 medical and health sciences, 0302 clinical medicine, Chromosome Segregation, Humans, Sister chromatids, human, Cell adhesion, lcsh:QH301-705.5, Mitosis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Metaphase, 030304 developmental biology, Genetics, mitosis, 0303 health sciences, mesenchymal stem cells, spatial distribution, Mesenchymal stem cell, Cell Differentiation, cell adhesion, DNA, Fibroblasts, Fibronectins, Cell biology, lcsh:Biology (General), Cell Division, 030217 neurology & neurosurgery
Abstract

International audience; Biased DNA segregation is a mitotic event in which the chromatids carrying the original template DNA strands and those carrying the template copies are not segregated randomly into the two daughter cells. Biased segregation has been observed in several cell types, but not in human mesenchymal stem cells (hMSCs), and the factors affecting this bias have yet to be identified. Here, we have investigated cell adhesion geometries as a potential parameter by plating hMSCs from healthy donors on fibronectin-coated micropatterns. On symmetric micropatterns, the segregation of sister chromatids to the daughter cells appeared random. In contrast, on asymmetric micropatterns, the segregation was biased. This sensitivity to asymmetric extracellular cues was reproducible in cells from all donors but was not observed in human skin-derived fibroblasts or in a fibroblastic cell line used as controls. We conclude that the asymmetry of cell adhesion is a major factor in the regulation of biased DNA segregation in hMSCs.

Published
2013

38. Resolution of strongly competitive product channels with optimal dynamic discrimination: Application to flavins

Author

Jean-Pierre Wolf, Jonathan Roslund, Véronique Boutou, Matthias Roth, François Courvoisier, Laurent Guyon, Herschel Rabitz, Department of Chemistry, Princeton University, Laboratoire de Spectrométrie Ionique et Moléculaire (LASIM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Group of Applied Physics [Geneva] (GAP), and University of Geneva [Switzerland]

Subjects
Field (physics), General Physics and Astronomy, Flavin mononucleotide, ddc:500.2, 02 engineering and technology, Flavin group, 01 natural sciences, Fluorescence, law.invention, chemistry.chemical_compound, Optics, law, Flavins, 0103 physical sciences, Ultraviolet light, Physical and Theoretical Chemistry, 010306 general physics, Quantum, ComputingMilieux_MISCELLANEOUS, [PHYS]Physics [physics], Pulse shaping, Molecular Structure, business.industry, Molecular biophysics, Fluorescence spectra, 021001 nanoscience & nanotechnology, Laser, chemistry, Quantum Theory, 0210 nano-technology, business, Biological system, Ultraviolet spectra
Abstract

Fundamental molecular selectivity limits are probed by exploiting laser-controlled quantum interferences for the creation of distinct spectral signatures in two flavin molecules, erstwhile nearly indistinguishable via steady-state methods. Optimal dynamic discrimination (ODD) uses optimally shaped laser fields to transiently amplify minute molecular variations that would otherwise go unnoticed with linear absorption and fluorescence techniques. ODD is experimentally demonstrated by combining an optimally shaped UV pump pulse with a time-delayed, fluorescence-depleting IR pulse for discrimination amongst riboflavin and flavin mononucleotide in aqueous solution, which are structurally and spectroscopically very similar. Closed-loop, adaptive pulse shaping discovers a set of UV pulses that induce disparate responses from the two flavins and allows for concomitant flavin discrimination of ∼16σ. Additionally, attainment of ODD permits quantitative, analytical detection of the individual constituents in a flavin mixture. The successful implementation of ODD on quantum systems of such high complexity bodes well for the future development of the field and the use of ODD techniques in a variety of demanding practical applications.

Published
2011

39. On the Efficiency of Infrared Filters in Optical Cryostats

Author

Laurent Guyon, Mathieu Melich, Roman E. Boltnev, Pierre-Etienne Wolf, Fabien Bonnet, Hélium : du fondamental aux applications (HELFA), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institute of Energy Problems of Chemical Physics, Russian Academy of Sciences [Moscow] (RAS), and ANR-06-BLAN-0098,HEVEPOR,Un système modèle pour les transitions de phase en milieu désordonné : l'adsorption de l'hélium dans les aérogels(2006)

Subjects
Cryostat, Materials science, Infrared, chemistry.chemical_element, 02 engineering and technology, Optical cryostat, 01 natural sciences, Upper and lower bounds, Optics, PACS numbers: 07.20.Mc, 44.40.+a, 07.57.-c, Thermal radiation, 0103 physical sciences, General Materials Science, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], [PHYS.COND.CM-DS-NN]Physics [physics]/Condensed Matter [cond-mat]/Disordered Systems and Neural Networks [cond-mat.dis-nn], 010306 general physics, Helium, Infrared cut-off filter, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], business.industry, Condensation, Aerogels, Aerogel, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Atomic and Molecular Physics, and Optics, Low temperature shutters, chemistry, Optoelectronics, Infrared filters, 0210 nano-technology, business
Abstract

8 pages; International audience; In an optical cryostat, the sample temperature is limited by the 300 K ther- mal radiation transmitted through the observation windows. As discussed in this pa- per, the corresponding heat load should be brought much below the μW level by using suitable cold IR filters. However, there are situations where one wants to di- rectly check the absence of IR heating by running the same experiment with the cold observation windows either open or totally blocked. We describe a particular example which is the study of helium condensation in a silica aerogel. On this aim, we devel- oped a simple and compact magnetic system able to move metallic shutters inside our optical cryostat. This allows us to set an upper bound of 1 μW for the effect of 300 K thermal radiation on our sample. We discuss the relevance of this result to the operation of optical dilution refrigerators.

Published
2011

40. Copper-free click chemistry for highly luminescent quantum dot conjugates: application to in vivo metabolic imaging

Author

David Bonnaffé, Philippe Delannoy, Francoise Vinet, Aurélie Cazet, Isabelle Texier, Laurent Guyon, Aude Bernardin, Laboratoire d'Electronique et des Technologies de l'Information (CEA-LETI), Université Grenoble Alpes (UGA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Azides, Luminescence, MESH: Membrane Glycoproteins, Biomedical Engineering, Pharmaceutical Science, MESH: Cricetinae, Bioengineering, Nanotechnology, CHO Cells, 010402 general chemistry, 01 natural sciences, Cricetulus, MESH: Cricetulus, MESH: CHO Cells, Cricetinae, Quantum Dots, Animals, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Copper-free click chemistry, Pharmacology, chemistry.chemical_classification, Membrane Glycoproteins, MESH: Molecular Imaging, 010405 organic chemistry, Biomolecule, MESH: Luminescence, Organic Chemistry, Cell Membrane, MESH: Quantum Dots, MESH: Azides, Cycloaddition, N-Acetylneuraminic Acid, 0104 chemical sciences, Molecular Imaging, MESH: Copper, chemistry, Quantum dot, Alkynes, Click chemistry, Surface modification, MESH: N-Acetylneuraminic Acid, Biological imaging, MESH: Alkynes, Copper, Biotechnology, MESH: Cell Membrane
Abstract

International audience; Quantum dots (QD) are inorganic nanocrystals with outstanding optical properties, specially suited for biological imaging applications. Their attachment to biomolecules in mild aqueous conditions for the design of bioconjugates is therefore highly desirable. 1,3-dipolar [3 + 2] cycloaddition between azides and terminal alkynes ("click chemistry") could represent an attractive QD functionalization method. Unfortunately, the use of the popular Cu(I)-catalyzed version of this reaction is not applicable for achieving this goal, since the presence of copper dramatically alters the luminescence properties of QD dispersions. We demonstrate here that copper-free click chemistry, between strained cyclooctyne functionalized QD and azido-biomolecules, leads to highly luminescent conjugates. In addition, we show that QD-cyclooctyne can be used at previously unreported low concentration (250 nM) for imaging the incorporation of azido-modified sialic acid in cell membrane glycoproteins.

Published
2010

41. Localization of fluorescence marked prostate tumor with time- resolved diffuse optical tomography

Author

Aurélie Laidevant, Mathieu Debourdeau, Jean-Marc Dinten, Ludovic Lecordier, Laurent Guyon, Lionel Hervé, and Jérôme Boutet

Subjects
Materials science, Fluorophore, genetic structures, business.industry, Ultrasound, Fluorescence, eye diseases, Imaging phantom, Diffuse optical imaging, chemistry.chemical_compound, medicine.anatomical_structure, Nuclear magnetic resonance, Optics, chemistry, Prostate, Femtosecond, medicine, business, Indocyanine green
Abstract

To increase prostate cancer diagnosis sensibility, we propose to add an optical modality to an US biopsy tool to localize fluorophore marked tumors. Optical signals are acquired on a time-resolved acquisition chain composed by a 770 nm femtosecond laser source and a four channels TCSPC device. The fluorescence concentration is reconstructed by using intensity and mean time of flight acquired from each time-resolved source-detector signal. Validation experiments are performed on a phantom mimicking prostate both on its optical and ultrasound properties with 10 μmol/L ICG 1 cm deep double fluorescent inclusions to simulate marked tumors. An exhaustive search algorithm succeeded in reconstructing the two distinct fluorescence dots with correct locations.

Published
2010

42. Bimodal ultrasound and fluorescence approach for prostate cancer diagnosis

Author

Didier Vray, Laurent Guyon, Philippe Peltie, Lionel Hervé, Mathieu Debourdeau, Jérôme Boutet, François Duboeuf, Laurent Saroul, and Jean-Marc Dinten

Subjects
Male, medicine.medical_specialty, Materials science, Biomedical Engineering, Imaging phantom, Biomaterials, Prostate cancer, Prostate, medicine, Image Processing, Computer-Assisted, Humans, Optical tomography, Ultrasonography, medicine.diagnostic_test, business.industry, Phantoms, Imaging, Ultrasound, Prostatic Neoplasms, Reconstruction algorithm, Signal Processing, Computer-Assisted, Equipment Design, medicine.disease, Atomic and Molecular Physics, and Optics, Diffuse optical imaging, Electronic, Optical and Magnetic Materials, medicine.anatomical_structure, Spectrometry, Fluorescence, Radiology, Tomography, business, Biomedical engineering
Abstract

Finding a way to combine ultrasound and fluorescence optical imaging on an endorectal probe may improve early detection of prostate cancer. The ultrasound provides morphological information about the prostate, while the optical system detects and locates fluorophore-marked tumors. A tissue-mimicking phantom, which is representative of prostate tissues both on its optical (absorption mu(a) and diffusion mu(s) (')) and its ultrasound properties, has been made by our team. A transrectal probe adapted to fluorescence diffuse optical tomography measurements was also developed. Measurements were taken on the prostate phantom with this probe based on a pulsed laser and a time-resolved detection system. A reconstruction algorithm was then used to help locate and quantify fluorescent inclusions of different concentrations at fixed depths.

Published
2010

43. Chi2 analysis for estimating the accuracy of optical properties derived from time resolved diffuse-reflectance

Author

Philippe Rizo, Jean-Marc Dinten, Anabela Da Silva, Anne Planat-Chrétien, and Laurent Guyon

Subjects
Physics, Elastic scattering, Diffusion equation, Photon, Chi-Square Distribution, business.industry, Scattering, Sensitivity and Specificity, Atomic and Molecular Physics, and Optics, Diffuse optical imaging, Photon counting, Photometry, Refractometry, Optics, Nephelometry and Turbidimetry, Attenuation coefficient, business, Absorption (electromagnetic radiation), Algorithms
Abstract

Weighted residuals and the reduced chi(2) (chi(R) (2)) value are investigated with regard to their relevance for assessing optical property estimates using the diffusion equation for time-resolved measurements in turbid media. It is shown and explained, for all photon counting experiments including lifetime estimation, why chi(R) (2) increases linearly with the number of photons when there is a model bias. Only when a sufficient number of photons has been acquired, chi(R) (2) is a pertinent value for assessing the accuracy of mu(a) and mu(s)' estimates. It was concluded that chi(R) (2) is of particular interest for cases of small interfiber separation, low-level scattering, strong absorption and incorrect measurement of instrument response function. It was also found that chi(R) (2) is less pertinent for judging mu(a) in case of air boundary effects.

Published
2009

44. Non-negative matrix factorization: a blind sources separation method to unmix fluorescence spectra

Author

Jerome Mars, Anne-Sophie Montcuquet, Lionel Hervé, Laurent Guyon, Jean-Marc Dinten, GIPSA - Signal Images Physique (GIPSA-SIGMAPHY), Département Images et Signal (GIPSA-DIS), Grenoble Images Parole Signal Automatique (GIPSA-lab), Université Stendhal - Grenoble 3-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Stendhal - Grenoble 3-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Grenoble Images Parole Signal Automatique (GIPSA-lab), Université Stendhal - Grenoble 3-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Stendhal - Grenoble 3-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Stendhal - Grenoble 3-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Stendhal - Grenoble 3-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Grenoble Images Parole Signal Automatique (GIPSA-lab), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Stendhal - Grenoble 3-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Stendhal - Grenoble 3-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), and Mars, Jerome

Subjects
Signal processing, [INFO.INFO-TS] Computer Science [cs]/Signal and Image Processing, 010501 environmental sciences, 01 natural sciences, Blind signal separation, Fluorescence spectroscopy, Multiplexing, Matrix decomposition, Non-negative matrix factorization, 03 medical and health sciences, Optics, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, 030304 developmental biology, 0105 earth and related environmental sciences, Physics, 0303 health sciences, business.industry, Hyperspectral imaging, Fluorescence, Autofluorescence, Biological system, Gradient descent, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Spectral unmixing
Abstract

International audience; Fluorescent imaging in diffusive media is an emerging modality for medical applications. Here, we use spectrally resolved measurements in order to separate several fluorescence sources. It is useful to filter parasite signal (such as the intrinsic biological tissues fluorescence, called autofluorescence) or enable the multiplexing of several fluorophores. A spectroscopic approach, based on the Non-negative Matrix Factorization (NMF) method, is explored to unmix overlapping spectra and thus isolate the specific fluorescence signals. This blind source separation method treats specific fluorescences (due to the various fluorophores) as different sources to separate; it only needs initial spectra, updated over iterations thanks to the classical gradient descent method. Fluorescence contributions of Alexa750 and ICG have been satisfactorily isolated on experimental data.

Published
2009

45. Time-resolved optical tissue characterisation: goodness of estimation

Author

Anne Planat-Chrétien, Jean-Marc Dinten, and Laurent Guyon

Subjects
Photon, Optics, Goodness of fit, Scattering, business.industry, Interval (mathematics), Function (mathematics), Statistical physics, Diffusion (business), business, Absorption (electromagnetic radiation), Diffuse optical imaging, Mathematics
Abstract

Statistical functions help judging optical parameters estimation (absorption µa and diffusion µs') at different experimental conditions. We show that the reduced X2 function is a powerful tool for judging goodness of fit and finding fitting interval, providing enough photons are acquired. Situations of small scattering or strong absorption, small interfiber distance, surface influence and fit boundaries influence with both infinite and semi-infinite diffusion model are analyzed together with the above statistical tools to judge the estimation.

Published
2009

46. Quantum Control of Tightly Competitive Product Channels

Author

Laurent Guyon, Jean-Pierre Wolf, Françoise Courvoisier, Herschel Rabitz, Véronique Boutou, Matthias Roth, Jonathan Roslund, Department of Chemistry, Princeton University, Laboratoire de Spectrométrie Ionique et Moléculaire (LASIM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), GAP, and Université de Genève (UNIGE)

Subjects
Field (physics), Flavin Mononucleotide, Computer science, Riboflavin, Process (computing), General Physics and Astronomy, Quantum control, Nanotechnology, ddc:500.2, Topology, 01 natural sciences, 010309 optics, Spectrometry, Fluorescence, Product (mathematics), 0103 physical sciences, Quantum Theory, Spectrophotometry, Ultraviolet, 010306 general physics, ComputingMilieux_MISCELLANEOUS
Abstract

Fundamental selectivity limits of quantum control are pushed by introducing laser driven optimal dynamic discrimination to create distinguishing excitations on two nearly identical flavin molecules. Even with modest spectral resources, significant specificity is achieved with optimal pulse shapes, which amplify small molecular differences to create distinct, identifying signals. Rather than being a hindrance, system complexity appears to aid the control process and augments control field capability, which bodes well for implementation of quantum control in a variety of demanding applications.

Published
2009

47. Time-resolved fluorescence tomography in cancer research: backward versus toward geometry

Author

Philippe Rizo, Lionel Hervé, Jérôme Boutet, Jean-Marc Dinten, Laurent Guyon, Mathieu Debourdeau, Anabela Da Silva, Philippe Peltie, and Nadia Djaker

Subjects
Fluorophore, Materials science, business.industry, Imaging phantom, Diffuse optical imaging, chemistry.chemical_compound, Optics, chemistry, Transmission (telecommunications), Reflection (physics), Tomography, Time-resolved spectroscopy, business, Reflection geometry
Abstract

Fluorescence Diffuse Optical Tomography is an optical non-invasive molecular technique for cancer imaging. Depending on the accessibility of the organ two main geometries might be considered, reflection or transmission. We will present first experimental and reconstruction comparison between these two geometries, on a laboratory time resolved bench. Both acquisitions were made using a fluorophore inclusion positioned in a liquid phantom, with breast comparable optical properties. We successfully reconstructed all fluorophore positions examined in both geometries. Reflection geometry suffers of many drawbacks that we have to deal with. We will present all challenges it implies, and also what are the advantages to use time resolved techniques in both geometries.

Published
2009

48. Probing helium interfaces with light scattering : from fluid mechanics to statistical physics

Author

Bernard Rousset, Sylvain Perraud, Pierre-Etienne Wolf, L. Puech, Thierry Lambert, Pierre Thibault, Fabien Bonnet, Laurent Guyon, Hélium : du fondamental aux applications (HELFA), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Service des Basses Températures (SBT ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-06-BLAN-0098, ANR-HEVEPOR, Collaboration CRYOLOOP, ANR-06-BLAN-0098,HEVEPOR,Un système modèle pour les transitions de phase en milieu désordonné : l'adsorption de l'hélium dans les aérogels(2006), Hélium : du fondamental aux applications (NEEL - HELFA), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)

Subjects
Physics - Classical Physics, 01 natural sciences, light scattering, Light scattering, 010305 fluids & plasmas, [SPI.MECA.MEFL]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Fluids mechanics [physics.class-ph], Superfluidity, Physics::Fluid Dynamics, porous media, atomization, General Materials Science, Statistical physics, Physics::Atomic Physics, [PHYS.MECA.MEFL]Physics [physics]/Mechanics [physics]/Fluid mechanics [physics.class-ph], [PHYS.COND.CM-SM]Physics [physics]/Condensed Matter [cond-mat]/Statistical Mechanics [cond-mat.stat-mech], vycor, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Classical Physics (physics.class-ph), Fluid mechanics, Surfaces and Interfaces, disorder, Refraction, 3. Good health, isotherms, [PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], Physics - Optics, Biotechnology, Materials science, capillarity, aerogel, Biophysics, FOS: Physical sciences, chemistry.chemical_element, Context (language use), helium, Condensed Matter - Soft Condensed Matter, 67.25.bf, 67.25.bh, 47.80.Jk, 47.55.-t, 67.25.dg, hoizontal diphasic flow, 0103 physical sciences, heat transfer, Physics::Atomic and Molecular Clusters, 010306 general physics, Condensed Matter - Statistical Mechanics, Helium, Statistical Mechanics (cond-mat.stat-mech), Scattering, Condensation, General Chemistry, condensation, chemistry, adsorption, desorption, Soft Condensed Matter (cond-mat.soft), Optics (physics.optics)
Abstract

We have investigated the formation of helium droplets in two physical situations. In the first one, droplets are atomised from superfluid or normal liquid by a fast helium vapour flow. In the second, droplets of normal liquid are formed inside porous glasses during the process of helium condensation. The context, aims, and results of these experiments are reviewed, with focus on the specificity of light scattering by helium. In particular, we discuss how, for different reasons, the closeness to unity of the index of refraction of helium allows in both cases to minimise the problem of multiple scattering and obtain results which it would not be possible to get using other fluids., 21 pages

Published
2009

50. Femtosecond pump-probe experiments on trapped flavin: Optical control of dissociation

Author

Jean-Pierre Wolf, Rodolphe Antoine, Michel Broyer, Thibault Tabarin, Véronique Boutou, Benoit Thuillier, Laurent Guyon, Philippe Dugourd, Laboratoire de Spectrométrie Ionique et Moléculaire (LASIM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Group of Applied Physics [Geneva] (GAP), and University of Geneva [Switzerland]

Subjects
Photodissociation, Light, Reaction mechanisms, General Physics and Astronomy, Flavin mononucleotide, ddc:500.2, 02 engineering and technology, Flavin group, 010402 general chemistry, Photochemistry, Radiation Dosage, 01 natural sciences, chemistry.chemical_compound, Fragmentation (mass spectrometry), Flavins, Mass spectra, Lumiflavin, Physical and Theoretical Chemistry, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Chemistry, Pump probe experiments, Dose-Response Relationship, Radiation, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Femtosecond, Mass spectrum, Ion trap, Atomic physics, 0210 nano-technology, Dissociation, Excitation
Abstract

International audience; Femtosecond pump-probe experiments are performed on flavin biomolecules isolated in an ion trap. Mass spectra of the photoinduced fragments show that the fragmentation pathways can be modified using two-color two-photon excitation. In particular, when an infrared probe pulse (810 nm) is added subsequent to the first excitation step (excitation of the S(1) state of flavin mononucleotide at 405 nm), branching ratios between lumichrome and lumiflavin production are inverted relative to the single excitation case.

Published
2008

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