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3. Nitric-acid hydrolysis of Miscanthus giganteus to sugars fermented to bioethanol

Author

Yang, F, Afzal, W, Cheng, K, Liu, N, Pauly, M, Bell, AT, Liu, Z, and Prausnitz, JM

Subjects
Miscanthus giganteus, dilute-nitric-acid hydrolysis, two-step process, fermentation, analysis with NMR, Biotechnology, Genetics, Chemical Engineering
Abstract

Miscanthus giganteus (M. giganteus) is a promising feedstock for the production of bioethanol or biochemicals. Using only dilute nitric acid, this work describes a two-step process for hydrolyzing hemicellulose and cellulose to fermentable sugars. Primary variables were temperature and reaction time. The solid-to-liquid mass ratio was 1:8. No enzymes were used. In the first step, M. giganteus was contacted with 0.5 wt.% nitric acid at temperatures between 120 and 160°C for 5 to 40 min. The second step used 0.5 or 0.75 wt.% nitric acid at temperatures between 180 and 210°C for less than 6 min. Under selected conditions, almost all hemicellulose and 58% cellulose were transferred to the liquid phase. Small amounts of degradation products were observed. The xylose solution obtained from the nitric-acid hydrolysis was fermented for 96 h and the glucose solution for 48 h to yield 0.41 g ethanol/g xylose and 0.46 g ethanol/g glucose. To characterize residual solids and the liquor from both steps, nuclear-magneticresonance (NMR) spectroscopy was performed for each fraction. The analytical data indicate that the liquid phase from Steps 1 and 2 contain little lignin or lignin derivatives.

Published
2015

4. An Arabidopsis gene regulatory network for secondary cell wall synthesis

Author

Taylor-Teeples, M, Lin, L, de Lucas, M, Turco, G, Toal, TW, Gaudinier, A, Young, NF, Trabucco, GM, Veling, MT, Lamothe, R, Handakumbura, PP, Xiong, G, Wang, C, Corwin, J, Tsoukalas, A, Zhang, L, Ware, D, Pauly, M, Kliebenstein, DJ, Dehesh, K, Tagkopoulos, I, Breton, G, Pruneda-Paz, JL, Ahnert, SE, Kay, SA, Hazen, SP, and Brady, SM

Subjects
Plant Biology, Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Biotechnology, Genetics, 1.1 Normal biological development and functioning, Arabidopsis, Arabidopsis Proteins, Cell Wall, DNA, Plant, E2F Transcription Factors, Feedback, Gene Expression Regulation, Developmental, Gene Expression Regulation, Plant, Gene Regulatory Networks, Iron Deficiencies, Organ Specificity, Promoter Regions, Genetic, Reproducibility of Results, Salinity, Time Factors, Transcription Factors, Xylem, General Science & Technology
Abstract

The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here we present a protein-DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.

Published
2015

5. Prevention and treatment of Clostridium perfringens epsilon toxin intoxication in mice with a neutralizing monoclonal antibody (c4D7) produced in Nicotiana benthamiana

Author

Garcia, JP, Beingesser, J, Bohorov, O, Bohorova, N, Goodman, C, Kim, D, Pauly, M, Velasco, J, Whaley, K, Zeitlin, L, Roy, CJ, and Uzal, FA

Subjects
Emerging Infectious Diseases, Biotechnology, Prevention, Biodefense, Infectious Diseases, Foodborne Illness, Vaccine Related, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Bacterial Toxins, Cytokines, Female, Lethal Dose 50, Male, Mice, Mice, Inbred BALB C, Tobacco, Epsilon toxin, Monoclonal antibody, Nicotiana benthamiana, Preventive, Therapeutic, Pharmacology and Pharmaceutical Sciences, Toxicology
Abstract

Epsilon toxin (ETX), produced by Clostridium perfringens types B and D, is among the most lethal toxins known. ETX is a potential bioterrorism threat that was listed as a Category B agent by the U.S. Centers for Disease Control until 2012 and it still remains a toxin of interest for several government agencies. We produced a monoclonal antibody (MAb) against ETX (ETX MAb c4D7) in Nicotiana benthamiana and characterized its preventive and therapeutic efficacy in mice. The ETX preparation used was highly lethal for mice (LD50 = 1.6 μg/kg) and resulted in a mean time from inoculation to death of 18 and 180 min when administered intravenously or intraperitoneally, respectively. High lethal challenge resulted in dramatic increases of a variety of pro-inflammatory cytokines in serum, while lower, but still lethal doses, did not elicit such responses. ETX MAb c4D7 was highly effective prophylactically (ED50 = 0.3 mg/kg; ED100 = 0.8 mg/kg) and also provided protection when delivered 15-30 min post-ETX intoxication. These data suggest that ETX MAb c4D7 may have use as a pre- and post-exposure treatment for ETX intoxication.

Published
2014

7. Two-step delignification of miscanthus to enhance enzymatic hydrolysis: Aqueous ammonia followed by sodium hydroxide and oxidants

Author

Liu, Z, Padmanabhan, S, Cheng, K, Xie, H, Gokhale, A, Afzal, W, Na, H, Pauly, M, Bell, AT, and Prausnitz, JM

Subjects
Energy, Chemical Sciences, Engineering, Physical Chemistry, Chemical Engineering, Resources Engineering and Extractive Metallurgy, Physical Chemistry (incl. Structural)
Abstract

Pretreatment of miscanthus is essential for enzymatic production of sugars to yield bioethanol. A two-step process using 10 wt % aqueous ammonia in the first step is followed by 1 wt % sodium hydroxide (with or without oxygen or 1 wt % hydrogen peroxide) in the second step. The first step retains about 90% of the cellulose and about 67% of the hemicellulose in the solid while removing about 62% of the lignin. Both steps together achieve 83-90% delignification. Subsequent enzymatic conversion to fermentable sugars is close to 90% after 96 h. While an oxidant does not significantly increase delignification, it has a favorable effect on saccharification of the recovered solid. Infrared spectroscopy, X-ray diffraction, and two-dimensional nuclear magnetic resonance spectroscopy provide data concerning the chemical composition of the recovered solid. Inclusion of an oxidant to the pretreatment breaks β-O-4′- linked aryl ether bonds of the remaining lignin in the recovered solid. © 2013 American Chemical Society.

Published
2014

11. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Denomme-Pichon A. -S., Bruel A. -L., Duffourd Y., Safraou H., Thauvin-Robinet C., Tran Mau-Them F., Philippe C., Vitobello A., Jean-Marcais N., Moutton S., Thevenon J., Faivre L., Matalonga L., de Boer E., Gilissen C., Hoischen A., Kleefstra T., Pfundt R., de Vries B. B. A., Willemsen M. H., Vissers L. E. L. M., Jackson A., Banka S., Clayton-Smith J., Benetti E., Fallerini C., Renieri A., Ciolfi A., Dallapiccola B., Pizzi S., Radio F. C., Tartaglia M., Ellwanger K., Graessner H., Haack T. B., Zurek B., Havlovicova M., Macek M., Ryba L., Schwarz M., Votypka P., Lopez-Martin E., Posada M., Mencarelli M. A., Rooryck C., Trimouille A., Verloes A., Abbott K. M., Kerstjens M., Martin E. L., Maystadt I., Morleo M., Nigro V., Pinelli M., Riess O., Agathe J. -M. D. S., Santen G. W. E., Thauvin C., Torella A., Vissers L., Zguro K., Boer E. D., Cohen E., Danis D., Gao F., Horvath R., Johari M., Johanson L., Li S., Morsy H., Nelson I., Paramonov I., te Paske I. B. A. W., Robinson P., Savarese M., Steyaert W., Topf A., van der Velde J. K., Vandrovcova J., Ossowski S., Demidov G., Sturm M., Schulze-Hentrich J. M., Schule R., Xu J., Kessler C., Wayand M., Synofzik M., Wilke C., Traschutz A., Schols L., Hengel H., Lerche H., Kegele J., Heutink P., Brunner H., Scheffer H., Hoogerbrugge N., 't Hoen P. A. C., Sablauskas K., de Voer R. M., Kamsteeg E. -J., van de Warrenburg B., van Os N., Paske I. T., Janssen E., Steehouwer M., Yaldiz B., Brookes A. J., Veal C., Gibson S., Maddi V., Mehtarizadeh M., Riaz U., Warren G., Dizjikan F. Y., Shorter T., Straub V., Bettolo C. M., Manera J. D., Hambleton S., Engelhardt K., Alexander E., Peyron C., Pelissier A., Beltran S., Gut I. G., Laurie S., Piscia D., Papakonstantinou A., Bullich G., Corvo A., Fernandez-Callejo M., Hernandez C., Pico D., Lochmuller H., Gumus G., Bros-Facer V., Rath A., Hanauer M., Lagorce D., Hongnat O., Chahdil M., Lebreton E., Stevanin G., Durr A., Davoine C. -S., Guillot-Noel L., Heinzmann A., Coarelli G., Bonne G., Evangelista T., Allamand V., Ben Yaou R., Metay C., Eymard B., Atalaia A., Stojkovic T., Turnovec M., Thomasova D., Kremlikova R. P., Frankova V., Liskova P., Dolezalova P., Parkinson H., Keane T., Freeberg M., Thomas C., Spalding D., Robert G., Costa A., Patch C., Hanna M., Houlden H., Reilly M., Efthymiou S., Cali E., Magrinelli F., Sisodiya S. M., Rohrer J., Muntoni F., Zaharieva I., Sarkozy A., Timmerman V., Baets J., de Vries G., De Winter J., Beijer D., de Jonghe P., Van de Vondel L., De Ridder W., Weckhuysen S., Mutarelli M., Varavallo A., Banfi S., Musacchia F., Piluso G., Ferlini A., Selvatici R., Gualandi F., Bigoni S., Rossi R., Neri M., Aretz S., Spier I., Sommer A. K., Peters S., Oliveira C., Pelaez J. G., Matos A. R., Jose C. S., Ferreira M., Gullo I., Fernandes S., Garrido L., Ferreira P., Carneiro F., Swertz M. A., Johansson L., van der Vries G., Neerincx P. B., Ruvolo D., Kerstjens Frederikse W. S., Zonneveld-Huijssoon E., Roelofs-Prins D., van Gijn M., Kohler S., Metcalfe A., Drunat S., Heron D., Mignot C., Keren B., Lacombe D., Capella G., Valle L., Holinski-Feder E., Laner A., Steinke-Lange V., Cilio M. -R., Carpancea E., Depondt C., Lederer D., Sznajer Y., Duerinckx S., Mary S., Macaya A., Cazurro-Gutierrez A., Perez-Duenas B., Munell F., Jarava C. F., Maso L. B., Marce-Grau A., Colobran R., Hackman P., Udd B., Hemelsoet D., Dermaut B., Schuermans N., Poppe B., Verdin H., Osorio A. N., Depienne C., Roos A., Cordts I., Deschauer M., Striano P., Zara F., Riva A., Iacomino M., Uva P., Scala M., Scudieri P., Basak A. N., Claeys K., Boztug K., Haimel M., W. E G., Ruivenkamp C. A. L., Natera de Benito D., Thompson R., Polavarapu K., Grimbacher B., Zaganas I., Kokosali E., Lambros M., Evangeliou A., Spilioti M., Kapaki E., Bourbouli M., Balicza P., Molnar M. J., De la Paz M. P., Sanchez E. B., Delgado B. M., Alonso Garcia de la Rosa F. J., Schrock E., Rump A., Mei D., Vetro A., Balestrini S., Guerrini R., Chinnery P. F., Ratnaike T., Schon K., Maver A., Peterlin B., Munchau A., Lohmann K., Herzog R., Pauly M., May P., Beeson D., Cossins J., Furini S., Afenjar A., Goldenberg A., Masurel A., Phan A., Dieux-Coeslier A., Fargeot A., Guerrot A. -M., Toutain A., Molin A., Sorlin A., Putoux A., Jouret B., Laudier B., Demeer B., Doray B., Bonniaud B., Isidor B., Gilbert-Dussardier B., Leheup B., Reversade B., Paul C., Vincent-Delorme C., Neiva C., Poirsier C., Quelin C., Chiaverini C., Coubes C., Francannet C., Colson C., Desplantes C., Wells C., Goizet C., Sanlaville D., Amram D., Lehalle D., Genevieve D., Gaillard D., Zivi E., Sarrazin E., Steichen E., Schaefer E., Lacaze E., Jacquemin E., Bongers E., Kilic E., Colin E., Giuliano F., Prieur F., Laffargue F., Morice-Picard F., Petit F., Cartault F., Feillet F., Baujat G., Morin G., Diene G., Journel H., Perthus I., Lespinasse J., Alessandri J. -L., Amiel J., Martinovic J., Delanne J., Albuisson J., Lambert L., Perrin L., Ousager L. B., Van Maldergem L., Pinson L., Ruaud L., Samimi M., Bournez M., Bonnet-Dupeyron M. N., Vincent M., Jacquemont M. -L., Cordier-Alex M. -P., Gerard-Blanluet M., Willems M., Spodenkiewicz M., Doco-Fenzy M., Rossi M., Renaud M., Fradin M., Mathieu M., Holder-Espinasse M. H., Houcinat N., Hanna N., Leperrier N., Chassaing N., Philip N., Boute O., Van Kien P. K., Parent P., Bitoun P., Sarda P., Vabres P., Jouk P. -S., Touraine R., El Chehadeh S., Whalen S., Marlin S., Passemard S., Grotto S., Bellanger S. A., Blesson S., Nambot S., Naudion S., Lyonnet S., Odent S., Attie-Bitach T., Busa T., Drouin-Garraud V., Layet V., Bizaoui V., Cusin V., Capri Y., Alembik Y., Unión Europea. Comisión Europea. H2020, Unión Europea. Comisión Europea. 7 Programa Marco, Instituto de Salud Carlos III, Instituto Nacional de Bioinformatica (España), Ministry of Health (República Checa), Ministry of Education, Youth and Sports (República Checa), Denomme-Pichon, A. -S., Bruel, A. -L., Duffourd, Y., Safraou, H., Thauvin-Robinet, C., Tran Mau-Them, F., Philippe, C., Vitobello, A., Jean-Marcais, N., Moutton, S., Thevenon, J., Faivre, L., Matalonga, L., de Boer, E., Gilissen, C., Hoischen, A., Kleefstra, T., Pfundt, R., de Vries, B. B. A., Willemsen, M. H., Vissers, L. E. L. M., Jackson, A., Banka, S., Clayton-Smith, J., Benetti, E., Fallerini, C., Renieri, A., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Ellwanger, K., Graessner, H., Haack, T. B., Zurek, B., Havlovicova, M., Macek, M., Ryba, L., Schwarz, M., Votypka, P., Lopez-Martin, E., Posada, M., Mencarelli, M. A., Rooryck, C., Trimouille, A., Verloes, A., Abbott, K. M., Kerstjens, M., Martin, E. L., Maystadt, I., Morleo, M., Nigro, V., Pinelli, M., Riess, O., Agathe, J. -M. D. S., Santen, G. W. E., Thauvin, C., Torella, A., Vissers, L., Zguro, K., Boer, E. D., Cohen, E., Danis, D., Gao, F., Horvath, R., Johari, M., Johanson, L., Li, S., Morsy, H., Nelson, I., Paramonov, I., te Paske, I. B. A. W., Robinson, P., Savarese, M., Steyaert, W., Topf, A., van der Velde, J. K., Vandrovcova, J., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Schule, R., Xu, J., Kessler, C., Wayand, M., Synofzik, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Lerche, H., Kegele, J., Heutink, P., Brunner, H., Scheffer, H., Hoogerbrugge, N., 't Hoen, P. A. C., Sablauskas, K., de Voer, R. M., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., Paske, I. T., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Maddi, V., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Manera, J. D., Hambleton, S., Engelhardt, K., Alexander, E., Peyron, C., Pelissier, A., Beltran, S., Gut, I. G., Laurie, S., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Fernandez-Callejo, M., Hernandez, C., Pico, D., Lochmuller, H., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Lagorce, D., Hongnat, O., Chahdil, M., Lebreton, E., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Ben Yaou, R., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Liskova, P., Dolezalova, P., Parkinson, H., Keane, T., Freeberg, M., Thomas, C., Spalding, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Efthymiou, S., Cali, E., Magrinelli, F., Sisodiya, S. M., Rohrer, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., de Vries, G., De Winter, J., Beijer, D., de Jonghe, P., Van de Vondel, L., De Ridder, W., Weckhuysen, S., Mutarelli, M., Varavallo, A., Banfi, S., Musacchia, F., Piluso, G., Ferlini, A., Selvatici, R., Gualandi, F., Bigoni, S., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Ruvolo, D., Kerstjens Frederikse, W. S., Zonneveld-Huijssoon, E., Roelofs-Prins, D., van Gijn, M., Kohler, S., Metcalfe, A., Drunat, S., Heron, D., Mignot, C., Keren, B., Lacombe, D., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Cilio, M. -R., Carpancea, E., Depondt, C., Lederer, D., Sznajer, Y., Duerinckx, S., Mary, S., Macaya, A., Cazurro-Gutierrez, A., Perez-Duenas, B., Munell, F., Jarava, C. F., Maso, L. B., Marce-Grau, A., Colobran, R., Hackman, P., Udd, B., Hemelsoet, D., Dermaut, B., Schuermans, N., Poppe, B., Verdin, H., Osorio, A. N., Depienne, C., Roos, A., Cordts, I., Deschauer, M., Striano, P., Zara, F., Riva, A., Iacomino, M., Uva, P., Scala, M., Scudieri, P., Basak, A. N., Claeys, K., Boztug, K., Haimel, M., W. E, G., Ruivenkamp, C. A. L., Natera de Benito, D., Thompson, R., Polavarapu, K., Grimbacher, B., Zaganas, I., Kokosali, E., Lambros, M., Evangeliou, A., Spilioti, M., Kapaki, E., Bourbouli, M., Balicza, P., Molnar, M. J., De la Paz, M. P., Sanchez, E. B., Delgado, B. M., Alonso Garcia de la Rosa, F. J., Schrock, E., Rump, A., Mei, D., Vetro, A., Balestrini, S., Guerrini, R., Chinnery, P. F., Ratnaike, T., Schon, K., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., May, P., Beeson, D., Cossins, J., Furini, S., Afenjar, A., Goldenberg, A., Masurel, A., Phan, A., Dieux-Coeslier, A., Fargeot, A., Guerrot, A. -M., Toutain, A., Molin, A., Sorlin, A., Putoux, A., Jouret, B., Laudier, B., Demeer, B., Doray, B., Bonniaud, B., Isidor, B., Gilbert-Dussardier, B., Leheup, B., Reversade, B., Paul, C., Vincent-Delorme, C., Neiva, C., Poirsier, C., Quelin, C., Chiaverini, C., Coubes, C., Francannet, C., Colson, C., Desplantes, C., Wells, C., Goizet, C., Sanlaville, D., Amram, D., Lehalle, D., Genevieve, D., Gaillard, D., Zivi, E., Sarrazin, E., Steichen, E., Schaefer, E., Lacaze, E., Jacquemin, E., Bongers, E., Kilic, E., Colin, E., Giuliano, F., Prieur, F., Laffargue, F., Morice-Picard, F., Petit, F., Cartault, F., Feillet, F., Baujat, G., Morin, G., Diene, G., Journel, H., Perthus, I., Lespinasse, J., Alessandri, J. -L., Amiel, J., Martinovic, J., Delanne, J., Albuisson, J., Lambert, L., Perrin, L., Ousager, L. B., Van Maldergem, L., Pinson, L., Ruaud, L., Samimi, M., Bournez, M., Bonnet-Dupeyron, M. N., Vincent, M., Jacquemont, M. -L., Cordier-Alex, M. -P., Gerard-Blanluet, M., Willems, M., Spodenkiewicz, M., Doco-Fenzy, M., Rossi, M., Renaud, M., Fradin, M., Mathieu, M., Holder-Espinasse, M. H., Houcinat, N., Hanna, N., Leperrier, N., Chassaing, N., Philip, N., Boute, O., Van Kien, P. K., Parent, P., Bitoun, P., Sarda, P., Vabres, P., Jouk, P. -S., Touraine, R., El Chehadeh, S., Whalen, S., Marlin, S., Passemard, S., Grotto, S., Bellanger, S. A., Blesson, S., Nambot, S., Naudion, S., Lyonnet, S., Odent, S., Attie-Bitach, T., Busa, T., Drouin-Garraud, V., Layet, V., Bizaoui, V., Cusin, V., Capri, Y., Alembik, Y., and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Exome reanalysis, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Developmental disorder, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology and Life Sciences, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], ClinVar, Rare diseases, All institutes and research themes of the Radboud University Medical Center, Medicine and Health Sciences, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences], Exome reanalysi, Genetics (clinical)
Abstract

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M. Sí

Published
2023
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17. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Author

Gehlen, J., Giel, A.S., Köllges, R., Haas, S.L., Zhang, R., Trcka, J., Sungur, A., Renziehausen, F., Bornholdt, D., Jung, D., Hoyer, P.D., Nordenskjöld, A., Tibboel, D., Vlot, J., Spaander, M.C., Smigiel, R., Patkowski, D., Roeleveld, N., Rooij, I.A.L.M. van, Blaauw, I. de, Hölscher, A., Pauly, M., Leutner, A., Fuchs, J., Niethammer, J., Melissari, M.T., Jenetzky, E., Zwink, N., Thiele, H., Hilger, A.C., Hess, T., Trautmann, J., Marks, M., Baumgarten, M., Bläss, G., Landén, M., Fundin, B., Bulik, C.M., Pennimpede, T., Ludwig, M., Ludwig, K.U., Mangold, E., Heilmann-Heimbach, S., Moebus, S., Herrmann, B.G., Alsabeah, K., Burgos, C.M., Lilja, H.E., Azodi, S., Stenström, P., Arnbjörnsson, E., Frybova, B., Lebensztejn, D.M., Debek, W., Kolodziejczyk, E., Kozera, K., Kierkus, J., Kaliciński, P., Stefanowicz, M., Socha-Banasiak, A., Kolejwa, M., Piaseczna-Piotrowska, A., Czkwianianc, E., Nöthen, M.M., Grote, P., Rygl, M., Reinshagen, K., Spychalski, N., Ludwikowski, B., Hubertus, J., Heydweiller, A., Ure, B., Muensterer, O.J., Aubert, O., Gosemann, J.H., Lacher, M., Degenhardt, P., Boemers, T.M., Mokrowiecka, A., Małecka-Panas, E., Wöhr, M., Knapp, M., Seitz, G., Klein, A., Oracz, G., Brosens, E., Reutter, H., Schumacher, J., Gehlen, J., Giel, A.S., Köllges, R., Haas, S.L., Zhang, R., Trcka, J., Sungur, A., Renziehausen, F., Bornholdt, D., Jung, D., Hoyer, P.D., Nordenskjöld, A., Tibboel, D., Vlot, J., Spaander, M.C., Smigiel, R., Patkowski, D., Roeleveld, N., Rooij, I.A.L.M. van, Blaauw, I. de, Hölscher, A., Pauly, M., Leutner, A., Fuchs, J., Niethammer, J., Melissari, M.T., Jenetzky, E., Zwink, N., Thiele, H., Hilger, A.C., Hess, T., Trautmann, J., Marks, M., Baumgarten, M., Bläss, G., Landén, M., Fundin, B., Bulik, C.M., Pennimpede, T., Ludwig, M., Ludwig, K.U., Mangold, E., Heilmann-Heimbach, S., Moebus, S., Herrmann, B.G., Alsabeah, K., Burgos, C.M., Lilja, H.E., Azodi, S., Stenström, P., Arnbjörnsson, E., Frybova, B., Lebensztejn, D.M., Debek, W., Kolodziejczyk, E., Kozera, K., Kierkus, J., Kaliciński, P., Stefanowicz, M., Socha-Banasiak, A., Kolejwa, M., Piaseczna-Piotrowska, A., Czkwianianc, E., Nöthen, M.M., Grote, P., Rygl, M., Reinshagen, K., Spychalski, N., Ludwikowski, B., Hubertus, J., Heydweiller, A., Ure, B., Muensterer, O.J., Aubert, O., Gosemann, J.H., Lacher, M., Degenhardt, P., Boemers, T.M., Mokrowiecka, A., Małecka-Panas, E., Wöhr, M., Knapp, M., Seitz, G., Klein, A., Oracz, G., Brosens, E., Reutter, H., and Schumacher, J.

Abstract

Item does not contain fulltext, Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.

Published
2022

18. Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsed/refractory acute lymphoblastic leukemia

Author

Burke, M. J., Ziegler, D. S., Bautista, F., Attarbaschi, A., Gore, L., Locatelli, Franco, M. O'Brien, M., Pauly, M., Kormany, W. N., Tian, S., Morris, C. L., Baruchel, A., Locatelli F. (ORCID:0000-0002-7976-3654), Burke, M. J., Ziegler, D. S., Bautista, F., Attarbaschi, A., Gore, L., Locatelli, Franco, M. O'Brien, M., Pauly, M., Kormany, W. N., Tian, S., Morris, C. L., Baruchel, A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed and/or refractory ALL. Methods: Patients aged 1–21 years (n = 24) received 4-week induction therapy with carfilzomib at dose levels of 27 mg/m2 (n = 3), 36 mg/m2 (n = 7), 45 mg/m2 (n = 4), and 56 mg/m2 (n = 10) in combination with VXLD. Patients achieving stable disease were offered further consolidation chemotherapy. Analyses were based on the safety evaluable population. Results: Following dose escalation of carfilzomib, the recommended phase 2 carfilzomib dose was identified as 56 mg/m2. Grade ≥3 hematological adverse events were common (83%, 20/24 patients), and serious treatment-emergent adverse events occurred in 58% (14/24) of patients. At the end of induction, CR/CR with incomplete platelet recovery (CRp)/CR with incomplete blood count recovery (CRi) was identified in 50% of patients (n = 12/24). By the end of consolidation, cumulative CR/CRp/CRi was identified in 58% of patients (n = 14/24). Conclusion: These data support the use of carfilzomib in pediatric patients with relapsed and/or refractory ALL.

Published
2022

19. Dendroclimatology using stable isotopes from subfossil tree-rings

Author

Pauly, M.

Abstract

The overall goal of this PhD dissertation is to develop multi-centennial stable isotope chronologies in annual rings of subfossil pine trees (Pinus sylvestris) from sites in (1) Switzerland (Binz) and (2) the southern French Alps (barbers), as well as (3) decadal records from subfossil New Zealand kauri trees (Agathis australis). After establishing these three chronologies, this dissertation explored the following objectives: (1) detect any potential climatic signal contained within the developed δ18O and δ13C records,(2) identify any probable diagenetic biases impacting the inter- and intra- tree stable isotope correlations (e.g. wood decay), (3) develop a technique to estimate sourcewater δ18O (precipitation) from dual stable isotope models, and (4) reconstruct high frequency climate variability across the Late Glacial. The oldest chronology was developed from 27 Swiss subfossil pine trees, covering ~14,050 – 12,795 cal BP; described in the Chapter 6 paper. The tree-ring δ18O record was compared to ice core del18O (NGRIP) to investigate whether Greenland Stadial “events”, which are often discernible in European lake records, are also recorded in the Swiss plateau during the summer growing season. Two examples of δ18Otree extreme depletions did parallel known North Atlantic ‘cool periods’ (GI-1c, GS-1), while another LG oscillation (GI-1b) is not clearly expressed in δ18Otree. The trees tended to record events more cohesively (higher population signal) during extreme δ18Otreedepletions in relatively wet conditions (high precipitation amount); likely due to the lack of stomata in influence on stable isotope fractionation in high humidity. Generally, this record was able to capture North Atlantic climate oscillations, but to a lesser degree than Greenland ice core δ18O, suggesting the “events” may be less extreme in the summer season. The GS-1 (Younger Dryas) cold reversal recorded in the Swiss pine trees was also documented in 7 pine trees from the southern French alps, as described in the Chapter 7 paper. A short chronology was developed during this interval, covering ~12 900 – 12 600 cal BP. Estimates of sourcewater δ18O (δ18OSW) recorded changes in air mass origin in southern France over the cooling event, indicating an ampli cation of both North Atlantic (depleted δ18OSW) as well as Mediterranean (high δ18OSW) originating storms. Higher magnitude and frequency of precipitation from both origins would likely have been due to the oscillating, southward moving polar front as Europe plunged into near-Glacial conditions. The youngest chronology was established using 6 kauri trees from New Zealand, covering ~13 020 – 11 850 cal BP at decadal resolution and a subset at annual resolution (~12 520 – 12 400 cal BP), as explained in the Chapter 8 paper. Whilst North Atlantic climate oscillations are occurring in Europe, the Southern Hemisphere is going through a gradual warming. The kauri trees recorded a signifcant climate downturn (~12 625 – 12 375 cal BP: low tree-ring growth, depleted δ18Otree, δ18OSW and δ13Ctree), undetected in Antarctic ice core data, which was characterised by sustained high precipitation, low temperature and high humidity. In conjunction with global climate model outputs, this research suggests this climate downturn may have been triggered by ocean circulation changes, resulting in a prolonged shift in hydroclimate conditions in New Zealand. Overall, the tree-ring chronologies presented in this dissertation from Switzerland, France and New Zealand demonstrate the potential to use subfossil trees to reconstruct hydroclimate variability during the Late Glacial using dual stable isotopes and sourcewater reconstructions. However, they tend to record high-frequency signals and often reflect unknown climate trends from other archives. On the one hand, this is related to the biological character of the “tree” archive, on the other hand, possible signal changes due to decomposition processes during and after embedding in the sediment are currently difficult to quantify. Das übergeordnete Ziel dieser Dissertation ist der Aufbau von Jahrring-Isotopenchronologien von Kohlenstoff (δ13C) und Sauerstoff (δ18O) spätglazialer Hölzer der Nord- und Südhemisphäre und die Extraktion und Interpretation möglicher Klimasignale. Dazu wurden (1) jährlich aufgelöste mehrhundertjährige Zeitreihen der stabilen Isotope in Jahrringen subfossiler Kiefernhölzer (Pinus sylvestris) von Fundorten in der Schweiz (Binz) und (2) den südfranzösischen Alpen (Barbiers) erstellt, und (3) eine etwas mehr als tausendjährige Jahrring-Isotopenchronologie von neuseeländischen Kauribäumen (Agathis australis) entwickelt. Anschließend wurden folgende Teilziele verfolgt: (1) ermitteln potenzieller Klimasignale in den erstellten Isotopendatensätzen, (2) identifizieren und beschreiben möglicher Signalstörungen infolge diagenetischer Veränderungen einzelner Hölzer durch Vergleiche der Isotopentrends gleichalter Bäume, sowie in Einzelbäumen, (3) Ableitung des Quellwasser-δ18O (Niederschlag) aus dualen (δ13C, δ18O) Isotopenmodellen, und (4) Erstellung und Interpretation von Rekonstruktionen der Klimavariabilität in den untersuchten Regionen und Zeitabschnitten. Die älteste der drei Isotopenchronologien wurde aus 27 Schweizer Kiefern entwickelt. Sie umfasst den Zeitraum ~ 14.050 - 12.795 cal BP (Kapitel 6). Der Jahrring Datensatz (del18Otree) wurde mit Eisbohrkern-δ18O Daten (NGRIP) verglichen, um zu testen, ob die während des Sommers in der Zellulose der Jahrringe festgelegten Isotopenverhältnisse des Schweizer Plateaus die grönländischen Klimaphasen ebenso widerspiegeln wie mitteleuropäische Seesedimente. Zwei extreme Einbrüche des δ18Otree zeigen Bezug zu GI-1c und GS-1, während z.B. GI-1b in δ18Otree nicht klar zum Ausdruck kommt. Einbrüche in δ18Otree können nicht ausschließlich in Verbindung mit extremen Kältephasen gebracht werden, sondern sie sind auch Ausdruck deutlich erhöhter Niederschläge. In solchen Phasen zeigensich δ18O-Zeitreihen der Einzelbäume deutlich kohäsiver (höheres Populationssignal), was wahrscheinlich auf den geringeren Einfluss der Stomata-Apertur der Nadeln auf die Isotopenfraktionierung bei hoher Luftfeuchtigkeit deutet. Im Allgemeinen kann δ18Otree Klimaschwankungen erfassen, jedoch in geringerem Maße als NGRIP δ18O. Die dort dokumentierten Kältephasen sind in der Sommersaison auf dem Schweizer Plateau eventuell weniger stark ausgeprägt. Anhand von 7 Kiefern aus den südfranzösischen Alpen wurden der Beginn (~ 12 900 - 12 600 cal BP) von GS-1 (Grönland) bzw. Jüngerer Dryas (Europa) untersucht (Kapitel 7). Aus δ18Otree Quellwasser- 18O abgeleitet, wodurch sich Veränderungen des Ursprungs feuchter Luftmassen in S-Frankreich zeigten. Eine erhöhte δ18Otree-Variabilität deutet auf ein Wechselspiel zwischen Nordatlantik (niedriges δ18O) und im Mittelmeerraum (hohes δ18O) hin, wahrscheinlich infolge starker Oszillationen einer generell nach Süden wandernden Polarfront. Die jüngste Chronologie wurde unter Verwendung von 6 Kauri-Bäumen aus Neuseeland erstellt. Der Zeitraum wurde ~ 13 020 - 11 850 cal BP ist in dekadischer Auflösung, ein kurzer Teilabschnitt in jährlicher Auflösung (~ 12 520 - 12 400 cal BP) untersucht (Kapitel 8). Anders als im nordatlantischen Raum erwärmt sich die südliche Hemisphäre im Spätglazial eher allmählich. Ein markanter Klimaabschwung (~ 12 625 - 12 375 cal BP) wurde allerdings von den Bäumen dokumentiert. Kennzeichnend waren hohe Niederschläge/Luftfeuchtigkeit und niedrige Temperaturen, möglicherweise ausgelöst durch Veränderungen der Ozeanzirkulation. Insgesamt zeigen die Jahrringisotope das gute Potenzial subfossiler Bäume zur Rekonstruktion der hydroklimatischen Variabilität des Spätglazials. Allerdings zeichnen sie eher hochfrequente Signale auf und spiegeln oft nicht bekannte Klimatrends anderer Archive wider. Dies hängt einerseits mit dem biologischen Charakter des Archivs „Baum“ zusammen, andererseits sind mögliche Signalveränderungen durch Zersetzungsprozesse während und nach der Einbettung im Sediment derzeit nur schwer zu quantifizieren. Insgesamt zeigen die Baumring-Chronologien in dieser Dissertation das Potenzial, subfossile Bäume zur Rekonstruktion der Variabilität des Hydroklimas während des späten Gletschers zu verwenden. Das übergeordnete Ziel dieser Dissertation ist der Aufbau von Jahrring-Isotopenchronologien von Kohlenstoff (δ13C) und Sauerstoff (δ18O) spätglazialer Hölzer der Nord- und Südhemisphäre und die Extraktion und Interpretation möglicher Klimasignale. Dazu wurden (1) jährlich aufgelöste mehrhundertjährige Zeitreihen der stabilen Isotope in Jahrringen subfossiler Kiefernhölzer (Pinus sylvestris) von Fundorten in der Schweiz (Binz) und (2) den südfranzösischen Alpen (Barbiers) erstellt, und (3) eine etwas mehr als tausendjährige Jahrring-Isotopenchronologie von neuseeländischen Kauribäumen (Agathis australis) entwickelt. Anschließend wurden folgende Teilziele verfolgt: (1) ermitteln potenzieller Klimasignale in den erstellten Isotopendatensätzen, (2) identifizieren und beschreiben möglicher Signalstörungen infolge diagenetischer Veränderungen einzelner Hölzer durch Vergleiche der Isotopentrends gleichalter Bäume, sowie in Einzelbäumen, (3) Ableitung des Quellwasser-δ18O (Niederschlag) aus dualen (δ13C, δ18O) Isotopenmodellen, und (4) Erstellung und Interpretation von Rekonstruktionen der Klimavariabilität in den untersuchten Regionen und Zeitabschnitten. Die älteste der drei Isotopenchronologien wurde aus 27 Schweizer Kiefern entwickelt. Sie umfasst den Zeitraum ~ 14.050 - 12.795 cal BP (Kapitel 6). Der Jahrring Datensatz (del18Otree) wurde mit Eisbohrkern-δ18O Daten (NGRIP) verglichen, um zu testen, ob die während des Sommers in der Zellulose der Jahrringe festgelegten Isotopenverhältnisse des Schweizer Plateaus die grönländischen Klimaphasen ebenso widerspiegeln wie mitteleuropäische Seesedimente. Zwei extreme Einbrüche des δ18Otree zeigen Bezug zu GI-1c und GS-1, während z.B. GI-1b in δ18Otree nicht klar zum Ausdruck kommt. Einbrüche in δ18Otree können nicht ausschließlich in Verbindung mit extremen Kältephasen gebracht werden, sondern sie sind auch Ausdruck deutlich erhöhter Niederschläge. In solchen Phasen zeigensich δ18O-Zeitreihen der Einzelbäume deutlich kohäsiver (höheres Populationssignal), was wahrscheinlich auf den geringeren Einfluss der Stomata-Apertur der Nadeln auf die Isotopenfraktionierung bei hoher Luftfeuchtigkeit deutet. Im Allgemeinen kann δ18Otree Klimaschwankungen erfassen, jedoch in geringerem Maße als NGRIP δ18O. Die dort dokumentierten Kältephasen sind in der Sommersaison auf dem Schweizer Plateau eventuell weniger stark ausgeprägt. Anhand von 7 Kiefern aus den südfranzösischen Alpen wurden der Beginn (~ 12 900 - 12 600 cal BP) von GS-1 (Grönland) bzw. Jüngerer Dryas (Europa) untersucht (Kapitel 7). Aus δ18Otree Quellwasser- 18O abgeleitet, wodurch sich Veränderungen des Ursprungs feuchter Luftmassen in S-Frankreich zeigten. Eine erhöhte δ18Otree-Variabilität deutet auf ein Wechselspiel zwischen Nordatlantik (niedriges δ18O) und im Mittelmeerraum (hohes δ18O) hin, wahrscheinlich infolge starker Oszillationen einer generell nach Süden wandernden Polarfront. Die jüngste Chronologie wurde unter Verwendung von 6 Kauri-Bäumen aus Neuseeland erstellt. Der Zeitraum wurde ~ 13 020 - 11 850 cal BP ist in dekadischer Auflösung, ein kurzer Teilabschnitt in jährlicher Auflösung (~ 12 520 - 12 400 cal BP) untersucht (Kapitel 8). Anders als im nordatlantischen Raum erwärmt sich die südliche Hemisphäre im Spätglazial eher allmählich. Ein markanter Klimaabschwung (~ 12 625 - 12 375 cal BP) wurde allerdings von den Bäumen dokumentiert. Kennzeichnend waren hohe Niederschläge/Luftfeuchtigkeit und niedrige Temperaturen, möglicherweise ausgelöst durch Veränderungen der Ozeanzirkulation. Insgesamt zeigen die Jahrringisotope das gute Potenzial subfossiler Bäume zur Rekonstruktion der hydroklimatischen Variabilität des Spätglazials. Allerdings zeichnen sie eher hochfrequente Signale auf und spiegeln oft nicht bekannte Klimatrends anderer Archive wider. Dies hängt einerseits mit dem biologischen Charakter des Archivs „Baum“ zusammen, andererseits sind mögliche Signalveränderungen durch Zersetzungsprozesse während und nach der Einbettung im Sediment derzeit nur schwer zu quantifizieren. Insgesamt zeigen die Baumring-Chronologien in dieser Dissertation das Potenzial, subfossile Bäume zur Rekonstruktion der Variabilität des Hydroklimas während des späten Gletschers zu verwenden. de

Published
2022

21. Correction: Solving unsolved rare neurological diseases—a Solve-RD viewpoint (European Journal of Human Genetics, (2021), 29, 9, (1332-1336), 10.1038/s41431-021-00901-1)

Author

Schule R., Timmann D., Erasmus C. E., Reichbauer J., Wayand M., Baets J., Balicza P., Chinnery P., Durr A., Haack T., Hengel H., Horvath R., Houlden H., Kamsteeg E. -J., Kamsteeg C., Lohmann K., Macaya A., Marce-Grau A., Maver A., Molnar J., Munchau A., Peterlin B., Riess O., Schols L., Stevanin G., Synofzik M., Timmerman V., van de Warrenburg B., van Os N., Vandrovcova J., Wilke C., Bevot A., Zuchner S., Beltran S., Laurie S., Matalonga L., Graessner H., Zurek B., Ellwanger K., Ossowski S., Demidov G., Sturm M., Schulze-Hentrich J. M., Heutink P., Brunner H., Scheffer H., Hoogerbrugge N., Hoischen A., 't Hoen P. A. C., Vissers L. E. L. M., Gilissen C., Steyaert W., Sablauskas K., de Voer R. M., Janssen E., de Boer E., Steehouwer M., Yaldiz B., Kleefstra T., Brookes A. J., Veal C., Gibson S., Wadsley M., Mehtarizadeh M., Riaz U., Warren G., Dizjikan F. Y., Shorter T., Topf A., Straub V., Bettolo C. M., Specht S., Clayton-Smith J., Banka S., Alexander E., Jackson A., Faivre L., Thauvin C., Vitobello A., Denomme-Pichon A. -S., Duffourd Y., Tisserant E., Bruel A. -L., Peyron C., Pelissier A., Gut I. G., Piscia D., Papakonstantinou A., Bullich G., Corvo A., Garcia C., Fernandez-Callejo M., Hernandez C., Pico D., Paramonov I., Lochmuller H., Gumus G., Bros-Facer V., Rath A., Hanauer M., Olry A., Lagorce D., Havrylenko S., Izem K., Rigour F., Davoine C. -S., Guillot-Noel L., Heinzmann A., Coarelli G., Bonne G., Evangelista T., Allamand V., Nelson I., Yaou R. B., Metay C., Eymard B., Cohen E., Atalaia A., Stojkovic T., Macek M., Turnovec M., Thomasova D., Kremlikova R. P., Frankova V., Havlovicova M., Kremlik V., Parkinson H., Keane T., Spalding D., Senf A., Robinson P., Danis D., Robert G., Costa A., Patch C., Hanna M., Reilly M., Muntoni F., Zaharieva I., Sarkozy A., de Jonghe P., Nigro V., Banfi S., Torella A., Musacchia F., Piluso G., Ferlini A., Selvatici R., Rossi R., Neri M., Aretz S., Spier I., Sommer A. K., Peters S., Oliveira C., Pelaez J. G., Matos A. R., Jose C. S., Ferreira M., Gullo I., Fernandes S., Garrido L., Ferreira P., Carneiro F., Swertz M. A., Johansson L., van der Velde J. K., van der Vries G., Neerincx P. B., Roelofs-Prins D., Kohler S., Metcalfe A., Verloes A., Drunat S., Rooryck C., Trimouille A., Castello R., Morleo M., Pinelli M., Varavallo A., De la Paz M. P., Sanchez E. B., Martin E. L., Delgado B. M., de la Rosa F. J. A. G., Ciolfi A., Dallapiccola B., Pizzi S., Radio F. C., Tartaglia M., Renieri A., Benetti E., Molnar M. J., Herzog R., Pauly M., Osorio A. N., de Benito D. N., Thompson R., Polavarapu K., Beeson D., Cossins J., Cruz P. M. R., Hackman P., Johari M., Savarese M., Udd B., Capella G., Valle L., Holinski-Feder E., Laner A., Steinke-Lange V., Schrock E., Rump A., Schule, R., Timmann, D., Erasmus, C. E., Reichbauer, J., Wayand, M., Baets, J., Balicza, P., Chinnery, P., Durr, A., Haack, T., Hengel, H., Horvath, R., Houlden, H., Kamsteeg, E. -J., Kamsteeg, C., Lohmann, K., Macaya, A., Marce-Grau, A., Maver, A., Molnar, J., Munchau, A., Peterlin, B., Riess, O., Schols, L., Stevanin, G., Synofzik, M., Timmerman, V., van de Warrenburg, B., van Os, N., Vandrovcova, J., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Graessner, H., Zurek, B., Ellwanger, K., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Heutink, P., Brunner, H., Scheffer, H., Hoogerbrugge, N., Hoischen, A., 't Hoen, P. A. C., Vissers, L. E. L. M., Gilissen, C., Steyaert, W., Sablauskas, K., de Voer, R. M., Janssen, E., de Boer, E., Steehouwer, M., Yaldiz, B., Kleefstra, T., Brookes, A. J., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Topf, A., Straub, V., Bettolo, C. M., Specht, S., Clayton-Smith, J., Banka, S., Alexander, E., Jackson, A., Faivre, L., Thauvin, C., Vitobello, A., Denomme-Pichon, A. -S., Duffourd, Y., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Garcia, C., Fernandez-Callejo, M., Hernandez, C., Pico, D., Paramonov, I., Lochmuller, H., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Nelson, I., Yaou, R. B., Metay, C., Eymard, B., Cohen, E., Atalaia, A., Stojkovic, T., Macek, M., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Havlovicova, M., Kremlik, V., Parkinson, H., Keane, T., Spalding, D., Senf, A., Robinson, P., Danis, D., Robert, G., Costa, A., Patch, C., Hanna, M., Reilly, M., Muntoni, F., Zaharieva, I., Sarkozy, A., de Jonghe, P., Nigro, V., Banfi, S., Torella, A., Musacchia, F., Piluso, G., Ferlini, A., Selvatici, R., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Velde, J. K., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Verloes, A., Drunat, S., Rooryck, C., Trimouille, A., Castello, R., Morleo, M., Pinelli, M., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Renieri, A., Benetti, E., Molnar, M. J., Herzog, R., Pauly, M., Osorio, A. N., de Benito, D. N., Thompson, R., Polavarapu, K., Beeson, D., Cossins, J., Cruz, P. M. R., Hackman, P., Johari, M., Savarese, M., Udd, B., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Schrock, E., and Rump, A.

Abstract

In the original publication of the article, consortium author lists were missing in the article. The details are given below

Published
2021

24. Testing contrasts of quantiles in general factorial designs

Author

Ditzhaus, M, Dobler, D, and Pauly, M

Subjects
right censoring, ddc: 610, permutation methods, median, main and interaction effects, 610 Medical sciences, Medicine
Abstract

As quantities of interest, we consider the median survival time and more general quantiles in the survival set-up with possibly right-censored observations. Using corresponding estimands, we formulate null hypotheses and determine confidence regions for these survival endpoints. A Wald-type statistic[for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

Published
2021
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25. Fisher transformation-based confidence intervals of correlation coefficients in meta-analyses

Author

Welz, T and Pauly, M

Subjects
meta-analysis, ddc: 610, Fisher transformation, 610 Medical sciences, Medicine, correlation coefficient, confidence intervals, Monte Carlo simulation
Abstract

Background: In the fields of Psychology and Sociology investigators often consider meta-analyses with Pearson correlation coefficients as effect measure of interest. A classical approach to construct confidence intervals for the main effect is the Hedges-Olkin-Vevea Fisher-z (HOVz) approach, which is[for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

Published
2021
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26. Bootstrap approaches for nonparametric factorial repeated measures designs with missing data

Author

Amro, L and Pauly, M

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Repeated measure designs and split plot plans are widely employed in scientific and medical research. The analysis of such designs is typically based on MANOVA models, requiring complete data, and certain assumption on the underlying parametric distribution such as normality or covariance matrix homogeneity.[for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

Published
2021
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27. Rank-Based Tests for Multivariate Data in Nonparametric Factorial Designs – Theory, R-package and Applications

Author

Friedrich, S, Konietschke, F, and Pauly, M

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

In many experiments in the life sciences several endpoints, potentially measured on different scales, are recorded per subject. Classical MANOVA models assume normally distributed errors and homogeneity of the covariance matrices, two assumptions that are often not met in practice. In particular, if[for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

Published
2021
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31. Kauri tree‐ring stable isotopes reveal a centennial climate downturn following the Antarctic Cold Reversal in New Zealand

Author

Pauly, M., Turney, C.s.m., Palmer, J.g., Büntgen, U., Brauer, A., Helle, G., Pauly, M., Turney, C.s.m., Palmer, J.g., Büntgen, U., Brauer, A., and Helle, G.

Abstract

The dynamics of the Late Glacial (LG) have been demonstrated by numerous records from the Northern Hemisphere (NH) and far fewer from the Southern Hemisphere (SH). SH paleoclimate records reveal a general warming trend, interrupted by a deglaciation pause (ACR: Antarctic Cold Reversal, ∼14,700 – 13,000 cal BP). Here we present decadal tree‐ring stable isotope chronologies (δ18O, δ13C) from New Zealand (NZ) subfossil kauri trees (n=6) covering the post‐ACR millennium from 13 020 – 11 850 cal BP. We find a distinct, simultaneous downturn (∼12 625 – 12 375 cal BP) in all tree‐ring proxies paralleling regional tree growth declines, suggesting a widespread climate deterioration. This downturn was characterised by sustained high precipitation, low temperatures and high relative humidity in NZ with incoming weather fronts from the South Ocean. Despite these promising results, questions remain about what drove the Kauri Downturn and how the hydroclimatic conditions were altered during this time period.

Published
2021
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32. Kauri Tree-Ring Stable Isotopes Reveal a Centennial Climate Downturn Following the Antarctic Cold Reversal in New Zealand

Author

Pauly, M, Turney, CSM, Palmer, JG, Büntgen, U, Brauer, A, Helle, G, Pauly, M, Turney, CSM, Palmer, JG, Büntgen, U, Brauer, A, and Helle, G

Abstract

The dynamics of the Late Glacial have been demonstrated by numerous records from the Northern Hemisphere and far fewer from the Southern Hemisphere (SH). SH paleoclimate records reveal a general warming trend, interrupted by a deglaciation pause Antarctic Cold Reversal (ACR; ∼14,700–13,000 cal BP). Here, we present decadal tree-ring stable isotope chronologies (δ18O, δ13C) from New Zealand (NZ) subfossil kauri trees (n = 6) covering the post-ACR millennium from 13,020 to 11,850 cal BP. We find a distinct, simultaneous downturn (∼12,625–12,375 cal BP) in all tree-ring proxies paralleling regional tree growth declines, suggesting a widespread climate deterioration. This downturn was characterized by sustained high precipitation, low temperatures, and high relative humidity in NZ with incoming weather fronts from the South Ocean. Despite these promising results, questions remain about what drove the Kauri Downturn and how the hydroclimatic conditions were altered during this time period.

Published
2021

38. Mutant K-ras2 in serum

Author

Andreyev, H J N, Benamouzig, R, Beranek, M, Clarke, P, Cunningham, D, Norman, A R, Giaretti, W, de Goeij, A F P M, Iacopetta, B J, Jullian, E, Krtolica, K, Lee, J Q, Wang, S T, Lees, N, Al-Mulla, F, Muller, O, Pauly, M, Pricolo, V, Russo, A, Troungos, C, Urosevic, N, and Ward, R

Published
2003

41. X-Shells

Author

Panetta, J., primary, Konaković-Luković, M., additional, Isvoranu, F., additional, Bouleau, E., additional, and Pauly, M., additional

Published
2019
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43. Glycoceramides

Author

Pauly, M. and Pauly, G.

Subjects
Sphingolipids -- Research, Dermatologic agents -- Research, Business, Pharmaceuticals and cosmetics industries
Abstract

Their role in epidermal physiology and their potential efficacy in treating dry skin Sphingolipids are functionally important components of the skin. The transitional epidermal layers (stratum granulosum and stratum corneum [...]

Published
1995

44. Lightweight conical components for rotational parabolic domes: geometric definition, structural behaviour, optimisation and digital fabrication

Author

Narváez Rodríguez, Roberto, Barrera Vera, José Antonio, Adriaenssens, S. (Coordinador), Gramazio, F. (Coordinador), Kohler, M. (Coordinador), Menges, A. (Coordinador), Pauly, M. (Coordinador), Adriaenssens, S., Gramazio, F., Kohler, M., Menges, A., Pauly, M., and Universidad de Sevilla. Departamento de Ingeniería Gráfica

Subjects
Rotational parabolic dome, Computational design, Archimedes, Design optimisation, Power diagram, Architectural geometry
Abstract

Although initially intended for academic purposes, the research shown in this paper was drawn towards the development of hollow lightweight conical com-ponents to materialise rotational parabolic domes. The starting point is a projec-tive interpretation of an Archimedean property of rotational paraboloid planar sections. This is used to discretise the parabolic surface with a set of tangent ellipses obtained via planar circle-packing algorithms. The ellipses are then mate-rialised with components composed of three truncated conical surfaces, which may be composed of several laminar materials. The geometry and economy of the material, the good structural behaviour, the simple solution for fabrication and assembly, and the tests on a full-scale prototype prove this component to be an efficient self-supporting system for wide-span structures against the use of solid boundary rings, not only for rotational parabolic domes, but also for a possible translation to other types of surfaces

Published
2016

48. Combined fitting of alternative and direct susceptibility curves of assembled nanostructures.

Author

Hillion, A., Pauly, M., Tamion, A., Tournus, F., Hillenkamp, M., Pichon, B. P., Begin-Colin, S., and Dupuis, V.

Subjects
*NANOSTRUCTURES, *CRYSTALLOGRAPHY, *MAGNETIC properties, *PARTICLE size distribution, *ANISOTROPY
Abstract

Experimental ac-susceptibility curves at different frequencies (0.1 Hz ≤ f ≤ 1 kHz) were performed on samples prepared by physical and chemical pathways. By combining the triple fit method and a careful analysis of ac-experimental curves, we demonstrate an unambiguous and consistent determination method of both the magnetic particle size distribution and anisotropy for diluted granular nanostructures of magnetic clusters. Specifically, we highlight the importance of the size distribution in the determination of the magnetic anisotropy constant as well as the low relevance of the deduced parameters by considering alternative measurements alone. [ABSTRACT FROM AUTHOR]

Published
2012
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49. Spaces for urban drama at the threshold between the Middle Ages and the early modern period

Author

Fray, Jean-Luc, Pauly, Michel, Pinhero, Magda, Scheutz, Martin, Fray, J ( Jean-Luc ), Pauly, M ( Michel ), Pinhero, M ( Magda ), Scheutz, M ( Martin ), Stercken, Martina, Fray, Jean-Luc, Pauly, Michel, Pinhero, Magda, Scheutz, Martin, Fray, J ( Jean-Luc ), Pauly, M ( Michel ), Pinhero, M ( Magda ), Scheutz, M ( Martin ), and Stercken, Martina

Published
2018

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