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2. Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

Author

Antczak, P., Birtel, J., Bergmann, C., Cetiner, M., Dahmer-Heath, M., Drube, J., Gerß, J., Haffner, D., Illig, T., Kamp-Becker, I., Klopp, N., Kollmann, S., König, J., Konrad, M., Liebau, M.C., Nittel, C., Okorn, C., Omran, H., Pape, L., Pennekamp, P., Schäfer, F., Schermer, B., Storf, H., Vasseur, J., Weber, S., Wohlgemuth, K., Ziegler, W., Gimpel, C., Göbel, J., Schlevogt, B., König, Jens Christian, Karsay, Rebeka, Gerß, Joachim, Schlingmann, Karl-Peter, Dahmer-Heath, Mareike, Telgmann, Anna-Katharina, Kollmann, Sabine, Ariceta, Gema, Gillion, Valentine, Bockenhauer, Detlef, Bertholet-Thomas, Aurélia, Mastrangelo, Antonio, Boyer, Olivia, Lilien, Marc, Decramer, Stéphane, Schanstra, Joost. P., Pohl, Martin, Schild, Raphael, Weber, Stefanie, Hoefele, Julia, Drube, Jens, Cetiner, Metin, Hansen, Matthias, Thumfart, Julia, Tönshoff, Burkhard, Habbig, Sandra, Liebau, Max Christoph, Bald, Martin, Bergmann, Carsten, Pennekamp, Petra, and Konrad, Martin

Published
2022
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3. In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation

Author

Llamas, E., Koyuncu, S., Lee, H.J., Wehrmann, M., Gutierrez-Garcia, R., Dunken, N., Charura, N., Torres-Montilla, S., Schlimgen, E., Mandel, A.M., Theile, E.B., Grossbach, J., Wagle, P, Lackmann, J.W., Schermer, B., Benzing, T., Beyer, A, Pulido, P, Rodriguez-Concepcion, Manuel, Zuccaro, A, Vilchez, D, Llamas, E., Koyuncu, S., Lee, H.J., Wehrmann, M., Gutierrez-Garcia, R., Dunken, N., Charura, N., Torres-Montilla, S., Schlimgen, E., Mandel, A.M., Theile, E.B., Grossbach, J., Wagle, P, Lackmann, J.W., Schermer, B., Benzing, T., Beyer, A, Pulido, P, Rodriguez-Concepcion, Manuel, Zuccaro, A, and Vilchez, D

Abstract

In humans, aggregation of polyglutamine repeat (polyQ) proteins causes disorders such as Huntington’s disease. Although plants express hundreds of polyQ-containing proteins, no pathologies arising from polyQ aggregation have been reported. To investigate this phenomenon, we expressed an aggregation-prone fragment of human huntingtin (HTT) with an expanded polyQ stretch (Q69) in Arabidopsis thaliana plants. In contrast to animal models, we find that Arabidopsis sp. suppresses Q69 aggregation through chloroplast proteostasis. Inhibition of chloroplast proteostasis diminishes the capacity of plants to prevent cytosolic Q69 aggregation. Moreover, endogenous polyQ-containing proteins also aggregate on chloroplast dysfunction. We find that

Published
2023

4. Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

Author

König, Jens Christian, primary, Karsay, Rebeka, additional, Gerß, Joachim, additional, Schlingmann, Karl-Peter, additional, Dahmer-Heath, Mareike, additional, Telgmann, Anna-Katharina, additional, Kollmann, Sabine, additional, Ariceta, Gema, additional, Gillion, Valentine, additional, Bockenhauer, Detlef, additional, Bertholet-Thomas, Aurélia, additional, Mastrangelo, Antonio, additional, Boyer, Olivia, additional, Lilien, Marc, additional, Decramer, Stéphane, additional, Schanstra, Joost. P., additional, Pohl, Martin, additional, Schild, Raphael, additional, Weber, Stefanie, additional, Hoefele, Julia, additional, Drube, Jens, additional, Cetiner, Metin, additional, Hansen, Matthias, additional, Thumfart, Julia, additional, Tönshoff, Burkhard, additional, Habbig, Sandra, additional, Liebau, Max Christoph, additional, Bald, Martin, additional, Bergmann, Carsten, additional, Pennekamp, Petra, additional, Konrad, Martin, additional, Antczak, P., additional, Birtel, J., additional, Bergmann, C., additional, Cetiner, M., additional, Dahmer-Heath, M., additional, Drube, J., additional, Gerß, J., additional, Haffner, D., additional, Illig, T., additional, Kamp-Becker, I., additional, Klopp, N., additional, Kollmann, S., additional, König, J., additional, Konrad, M., additional, Liebau, M.C., additional, Nittel, C., additional, Okorn, C., additional, Omran, H., additional, Pape, L., additional, Pennekamp, P., additional, Schäfer, F., additional, Schermer, B., additional, Storf, H., additional, Vasseur, J., additional, Weber, S., additional, Wohlgemuth, K., additional, Ziegler, W., additional, Gimpel, C., additional, Göbel, J., additional, and Schlevogt, B., additional

Published
2022
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5. CALINCA - a novel pipeline for the identification of lncRNAs in podocyte disease

Author

Talyan, S., Filipów, S., Ignarski, M., Smieszek, M., Chen, H., Kühne, L., Butt, L., Göbel, H., Hoyer-Allo, K.J.R., Koehler, F.C., Altmüller, J., Brinkkötter, P., Schermer, B., Benzing, T., Kann, M., Müller, R.U., and Dieterich, C.

Subjects
urogenital system, Technology Platforms, urologic and male genital diseases, female genital diseases and pregnancy complications
Abstract

Diseases of the renal filtration unit-the glomerulus-are the most common cause of chronic kidney disease. Podocytes are the pivotal cell type for the function of this filter and focal-segmental glomerulosclerosis (FSGS) is a classic example of a podocytopathy leading to proteinuria and glomerular scarring. Currently, no targeted treatment of FSGS is available. This lack of therapeutic strategies is explained by a limited understanding of the defects in podocyte cell biology leading to FSGS. To date, most studies in the field have focused on protein-coding genes and their gene products. However, more than 80% of all transcripts produced by mammalian cells are actually non-coding. Here, long non-coding RNAs (lncRNAs) are a relatively novel class of transcripts and have not been systematically studied in FSGS to date. The appropriate tools to facilitate lncRNA research for the renal scientific community are urgently required due to a row of challenges compared to classical analysis pipelines optimized for coding RNA expression analysis. Here, we present the bioinformatic pipeline CALINCA as a solution for this problem. CALINCA automatically analyzes datasets from murine FSGS models and quantifies both annotated and de novo assembled lncRNAs. In addition, the tool provides in-depth information on podocyte specificity of these lncRNAs, as well as evolutionary conservation and expression in human datasets making this pipeline a crucial basis to lncRNA studies in FSGS.

Published
2021

6. mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy.

Author

Schlingmann, K.P., Jouret, F., Shen, K., Nigam, A., Arjona, F.J., Dafinger, C., Houillier, P., Jones, D.P., Kleinerüschkamp, F., Oh, J., Godefroid, N., Eltan, M., Güran, T., Burtey, S., Parotte, M.C., König, J., Braun, A., Bos, C., Ibars Serra, M., Rehmann, H., Zwartkruis, F.J., Renkema, K.Y., Klingel, K., Schulze-Bahr, E., Schermer, B., Bergmann, C., Altmüller, J., Thiele, H., Beck, B.B., Dahan, K., Sabatini, D., Liebau, M.C., Vargas-Poussou, R., Knoers, N.V.A.M., Konrad, M., Baaij, J.H.F. de, Schlingmann, K.P., Jouret, F., Shen, K., Nigam, A., Arjona, F.J., Dafinger, C., Houillier, P., Jones, D.P., Kleinerüschkamp, F., Oh, J., Godefroid, N., Eltan, M., Güran, T., Burtey, S., Parotte, M.C., König, J., Braun, A., Bos, C., Ibars Serra, M., Rehmann, H., Zwartkruis, F.J., Renkema, K.Y., Klingel, K., Schulze-Bahr, E., Schermer, B., Bergmann, C., Altmüller, J., Thiele, H., Beck, B.B., Dahan, K., Sabatini, D., Liebau, M.C., Vargas-Poussou, R., Knoers, N.V.A.M., Konrad, M., and Baaij, J.H.F. de

Abstract

01 november 2021, Item does not contain fulltext, BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

Published
2021

7. A fast and simple clearing and swelling protocol for 3D in-situ imaging of the kidney across scales

Author

Unnersjö-Jess, D., Butt, L., Höhne, M., Witasp, A., Kühne, L., Hoyer, P. F., Patrakka, J., Brinkkötter, P. T., Wernerson, A., Schermer, B., Benzing, T., Scott, L., Brismar, H., Blom, H., Unnersjö-Jess, D., Butt, L., Höhne, M., Witasp, A., Kühne, L., Hoyer, P. F., Patrakka, J., Brinkkötter, P. T., Wernerson, A., Schermer, B., Benzing, T., Scott, L., Brismar, H., and Blom, H.

Abstract

In recent years, many light-microscopy protocols have been published for visualization of nanoscale structures in the kidney. These protocols present researchers with new tools to evaluate both foot process anatomy and effacement, as well as protein distributions in foot processes, the slit diaphragm and in the glomerular basement membrane. However, these protocols either involve the application of different complicated super resolution microscopes or lengthy sample preparation protocols. Here, we present a fast and simple, five-hour long procedure for three-dimensional visualization of kidney morphology on all length scales. The protocol combines optical clearing and tissue expansion concepts to produce a mild swelling, sufficient for resolving nanoscale structures using a conventional confocal microscope. We show that the protocol can be applied to visualize a wide variety of pathologic features in both mouse and human kidneys. Thus, our fast and simple protocol can be beneficial for conventional microscopic evaluation of kidney tissue integrity both in research and possibly in future clinical routines., QC 20211215

Published
2021
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11. Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics.

Author

Schell C., Puelles V.G., Lagies S., Schlimpert M., Kammerer B., Handschin C., Huber T.B., Brinkkoetter P.T., Bork T., Salou S., Liang W., Mizi A., Ozel C., Koehler S., Hagmann H.H., Ising C., Kuczkowski A., Schnyder S., Abed A., Schermer B., Benzing T., Kretz O., Schell C., Puelles V.G., Lagies S., Schlimpert M., Kammerer B., Handschin C., Huber T.B., Brinkkoetter P.T., Bork T., Salou S., Liang W., Mizi A., Ozel C., Koehler S., Hagmann H.H., Ising C., Kuczkowski A., Schnyder S., Abed A., Schermer B., Benzing T., and Kretz O.

Abstract

The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo, we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1alpha, Drp1, or Tfam, respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS). Glomerular podocytes form the third and most outer layer of the kidney filtration barrier responsible for restricting the passage of proteins into the urine. Brinkkoetter et al. show that podocyte metabolism primarily relies on anaerobic glycolysis and the fermentation of glucose to lactate.Copyright © 2019 The Authors

Published
2019

12. Characterisation of the Hamamatsu photomultipliers for the KM3NeT Neutrino Telescope

Author

Aiello, S. Akrame, S.E. Ameli, F. Anassontzis, E.G. Andre, M. Androulakis, G. Anghinolfi, M. Anton, G. Ardid, M. Aublin, J. Avgitas, T. Baars, M. Bagatelas, C. Barbarino, G. Baret, B. Barrios-Martí, J. Belias, A. Berbee, E. Berg, A.V.D. Bertin, V. Biagi, S. Biagioni, A. Biernoth, C. Bormuth, R. Boumaaza, J. Bourret, S. Bouwhuis, M. Bozza, C. Branzaş, H. Briukhanova, N. Bruijn, R. Brunner, J. Buis, E. Buompane, R. Busto, J. Calvo, D. Capone, A. Caramete, L. Celli, S. Chabab, M. Cherubini, S. Chiarella, V. Chiarusi, T. Circella, M. Cocimano, R. Coelho, J.A.B. Coleiro, A. Molla, M.C. Coniglione, R. Coyle, P. Creusot, A. Cuttone, G. D'Onofrio, A. Dallier, R. Sio, C.D. Palma, I.D. Díaz, A.F. Distefano, C. Domi, A. Donà, R. Donzaud, C. Dornic, D. Dörr, M. Durocher, M. Eberl, T. Eijk, D.V. Bojaddaini, I.E. Elsaesser, D. Enzenhöfer, A. Ferrara, G. Fusco, L.A. Gal, T. Garufi, F. Gauchery, S. Geißelsöder, S. Gialanella, L. Giorgio, E. Giuliante, A. Gozzini, S.R. Ruiz, R.G. Graf, K. Grasso, D. Grégoire, T. Grella, G. Hallmann, S. Haren, H.V. Heid, T. Heijboer, A. Hekalo, A. Hernández-Rey, J.J. Hofestädt, J. Illuminati, G. James, C.W. Jongen, M. Jongewaard, B. De Jong, M. De Jong, P. Kadler, M. Kalaczyński, P. Kalekin, O. Katz, U.F. Chowdhury, N.R.K. Kieft, G. Kießling, D. Koffeman, E.N. Kooijman, P. Kouchner, A. Kreter, M. Kulikovskiy, V. Lahmann, R. Breton, R.L. Leone, F. Leonora, E. Levi, G. Lincetto, M. Lonardo, A. Longhitano, F. Lotze, M. Loucatos, S. Maggi, G. Mańczak, J. Mannheim, K. Margiotta, A. Marinelli, A. Markou, C. Martin, L. Martínez-Mora, J.A. Martini, A. Marzaioli, F. Mele, R. Melis, K.W. Migliozzi, P. Migneco, E. Mijakowski, P. Miranda, L.S. Mollo, C.M. Morganti, M. Moser, M. Moussa, A. Muller, R. Musumeci, M. Nauta, L. Navas, S. Nicolau, C.A. Nielsen, C. Organokov, M. Orlando, A. Panagopoulos, V. Papalashvili, G. Papaleo, R. Pǎvǎlaş, G.E. Pellegrini, G. Pellegrino, C. Pérez Romero, J. Perrin-Terrin, M. Piattelli, P. Pikounis, K. Pisanti, O. Poirè, C. Polydefki, G. Poma, G.E. Popa, V. Post, M. Pradier, T. Pühlhofer, G. Pulvirenti, S. Quinn, L. Raffaelli, F. Randazzo, N. Razzaque, S. Real, D. Resvanis, L. Reubelt, J. Riccobene, G. Richer, M. Rovelli, A. Salvadori, I. Samtleben, D.F.E. Sánchez Losa, A. Sanguineti, M. Santangelo, A. Sapienza, P. Schermer, B. Sciacca, V. Seneca, J. Sgura, I. Shanidze, R. Sharma, A. Simeone, F. Sinopoulou, A. Spisso, B. Spurio, M. Stavropoulos, D. Steijger, J. Stellacci, S.M. Strandberg, B. Stransky, D. Stüven, T. Taiuti, M. Tatone, F. Tayalati, Y. Tenllado, E. Thakore, T. Timmer, P. Trovato, A. Tsagkli, S. Tzamariudaki, E. Tzanetatos, D. Valieri, C. Vallage, B. Elewyck, V.V. Versari, F. Viola, S. Vivolo, D. Volkert, M. De Waardt, L. Wilms, J. De Wolf, E. Zaborov, D. Zornoza, J.D. Zuniga, J.

Subjects
Physics::Instrumentation and Detectors, Astrophysics::Instrumentation and Methods for Astrophysics
Abstract

The Hamamatsu R12199-02 3-inch photomultiplier tube is the photodetector chosen for the first phase of the KM3NeT neutrino telescope. About 7000 photomultipliers have been characterised for dark count rate, timing spread and spurious pulses. The quantum efficiency, the gain and the peak-to-valley ratio have also been measured for a sub-sample in order to determine parameter values needed as input to numerical simulations of the detector. © 2018 The Author(s).

Published
2018

14. Introducing positive discrimination in predictive models

Author

Verwer, S.E., Calders, T., Custers, B., Schermer, B., Zarsky, T., Custers, B., Calders, T., Schermer, B., and Zarsky, T.

Subjects
Cognitive science, Reverse engineering, History, business.industry, Bayesian probability, Probabilistic logic, Latent variable, Machine learning, computer.software_genre, Naive Bayes classifier, Software Science, Probability distribution, Artificial intelligence, Latent variable model, business, computer, Independence (probability theory)
Abstract

In this chapter we give three solutions for the discrimination-aware classification problem that are based upon Bayesian classifiers. These classifiers model the complete probability distribution by making strong independence assumptions. First we discuss the necessity of having discrimination-free classification for probabilistic models. Then we will show three ways to adapt a Naive Bayes classifier in order to make it discrimination-free. The first technique is based upon setting different thresholds for the different communities. The second technique will learn two different models for both communities, while the third model describes how we can incorporate our belief of how discrimination was added to the decisions in the training data as a latent variable. By explicitly modeling the discrimination, we can reverse engineer decisions. Since all three models can be seen as ways to introduce positive discrimination, we end the chapter with a reflection on positive discrimination.

Published
2013

15. Characterisation of the Hamamatsu photomultipliers for the KM3NeT Neutrino Telescope

Author

Aiello, S., Akrame, S.E., Amélineau, F., Anassontzis, E.G., Andre, M., Androulakis, G., Anghinolfi, Anton, G., Ardid, M., Aublin, J., Avgitas, T., Baars, M., Bagatelas, C., Barbarino, G., Baret, B., Barrios-Martí, J., Belias, A., Berbee, E., van den Berg, A., Bertin, V., Biagi, S., Biagioni, A., Biernoth, C., Bormuth, R., Boumaaza, J., Bourret, S., Bouwhuis, M., Bozza, C., Brânzas, H., Briukhanova, N., Bruijn, R., Brunner, J., Buis, E., Buompane, R, Busto, J., Calvo, D., Capone, A., Caramete, L., Celli, S., Chabab, M., Cherubini, S., Chiarella, V., Chiarusi, T., Circella, M., Cocimano, R., Coelho, J.A.B., Coleiro, A., Molla, M.C., Coniglione, R., Coyle, P., Creusot, A., Cuttone, G., D’Onofrio, A., Dallier, R., De Sio, C., Di Palma, I., Díaz, A.F., Distefano, C., Domi, A., Donà, R., Donzaud, C., Dornic, D., Dörr, M., Durocher, M., Eberl, T., Van Eijk, D., El Bojaddaini, I., Elsaesser, D., Enzenhöfer, A., Ferrara, G., Fusco, L.A., Gal, T., Garufi, F., Gauchery, S., Geißelsöder, S., Gialanella, L., Giorgio, E., Giuliante, A., Gozzini, S.R., Gracia-Ruiz, R., Graf, K., Grasso, D., Grégoire, T., Grella, G., Hallmann, S., van Haren, H., Heid, T., Heijboer, A., Hekalo, A., Hernandez-Rey, J.J., Hofestädt, J., Illuminati, G., James, C.W., Jongen, M., Jongewaard, B., de Jong, M., de Jong, P., Kadler, M., Kalaczynski, P., Kalekin, O., Katz, U.F., Khan Chowdhury, N.R., Kieft, G., Kießling, D., Koffeman, E.N., Kooijman, P., Kouchner, A., Kreter, M., Kulikovskiy, V., Lahmann, R., Le Breton, A., Leone, F., Leonora, E., Levi, G., Lincetto, M., Lonardo, A., Longhitano, F., Lotze, M., Loucatos, S., Maggi, G., Manczak, J., Mannheim, K., Margiotta, A., Marinelli, A., Markou, C., Martin, L., Martínez-Mora, J.A., Martini, A., Marzaioli, F., Mele, R., Melis, K.W., Migliozzi, P., Migneco, E., Mijakowski, P., Mollo, C.M., Morganti, M., Moser, M., Moussa, A., Muller, R., Musumeci, M., Nauta, L., Navas, S., Nicolau, C.A., Nielsen, C., Organokov, M., Orlando, A., Panagopoulos, V., Papalashvili, G., Papaleo, R., Pavalas, G.E., Pellegrini, G., Pellegrino, C., Pérez Romero, J., Perrin-Terrin, M., Piattelli, P., Pikounis, K., Pisanti, O., Poirè, C., Polydefki, G., Poma, G.E., Popa, V., Post, M., Pradier, T., Pühlhofer, G., Pulvirenti, S., Quinn, L., Raffaelli, F., Randazzo, N., Razzaque, S., Real, D., Resvanis, L., Reubelt, J., Riccobene, G., Richer, M., Rovelli, A., Salvadori, I., Samtleben, D.F.E., Sánchez-Losa, A., Sanguineti, M., Santangelo, A., Sapienza, P., Schermer, B., Sciacca, V., Seneca, J., Sgura, I., Shanidze, R., Sharma, A., Simeone, F., Sinopoulou, A., Spisso, B., Spurio, M., Stavropoulos, D., Steijger, J., Stellacci, S.M., Strandberg, B., Stransky, D., Stüven, T., Taiuti, M., Tatone, F., Tayalati, Y., Tenllado, E., Thakore, T., Timmer, P., Trovato, A., Tsagkli, S., Tzamariudaki, E., Tzanetatos, D., Valieri, C., Vallage, B., Van Elewyck, V., Versari, F., Viola, S., Vivolo, D., Volkert, M., de Waardt, L., Wilms, J., de Wolf, E., Zaborov, D., Zornoza, J.D., Zúñiga, J., Aiello, S., Akrame, S.E., Amélineau, F., Anassontzis, E.G., Andre, M., Androulakis, G., Anghinolfi, Anton, G., Ardid, M., Aublin, J., Avgitas, T., Baars, M., Bagatelas, C., Barbarino, G., Baret, B., Barrios-Martí, J., Belias, A., Berbee, E., van den Berg, A., Bertin, V., Biagi, S., Biagioni, A., Biernoth, C., Bormuth, R., Boumaaza, J., Bourret, S., Bouwhuis, M., Bozza, C., Brânzas, H., Briukhanova, N., Bruijn, R., Brunner, J., Buis, E., Buompane, R, Busto, J., Calvo, D., Capone, A., Caramete, L., Celli, S., Chabab, M., Cherubini, S., Chiarella, V., Chiarusi, T., Circella, M., Cocimano, R., Coelho, J.A.B., Coleiro, A., Molla, M.C., Coniglione, R., Coyle, P., Creusot, A., Cuttone, G., D’Onofrio, A., Dallier, R., De Sio, C., Di Palma, I., Díaz, A.F., Distefano, C., Domi, A., Donà, R., Donzaud, C., Dornic, D., Dörr, M., Durocher, M., Eberl, T., Van Eijk, D., El Bojaddaini, I., Elsaesser, D., Enzenhöfer, A., Ferrara, G., Fusco, L.A., Gal, T., Garufi, F., Gauchery, S., Geißelsöder, S., Gialanella, L., Giorgio, E., Giuliante, A., Gozzini, S.R., Gracia-Ruiz, R., Graf, K., Grasso, D., Grégoire, T., Grella, G., Hallmann, S., van Haren, H., Heid, T., Heijboer, A., Hekalo, A., Hernandez-Rey, J.J., Hofestädt, J., Illuminati, G., James, C.W., Jongen, M., Jongewaard, B., de Jong, M., de Jong, P., Kadler, M., Kalaczynski, P., Kalekin, O., Katz, U.F., Khan Chowdhury, N.R., Kieft, G., Kießling, D., Koffeman, E.N., Kooijman, P., Kouchner, A., Kreter, M., Kulikovskiy, V., Lahmann, R., Le Breton, A., Leone, F., Leonora, E., Levi, G., Lincetto, M., Lonardo, A., Longhitano, F., Lotze, M., Loucatos, S., Maggi, G., Manczak, J., Mannheim, K., Margiotta, A., Marinelli, A., Markou, C., Martin, L., Martínez-Mora, J.A., Martini, A., Marzaioli, F., Mele, R., Melis, K.W., Migliozzi, P., Migneco, E., Mijakowski, P., Mollo, C.M., Morganti, M., Moser, M., Moussa, A., Muller, R., Musumeci, M., Nauta, L., Navas, S., Nicolau, C.A., Nielsen, C., Organokov, M., Orlando, A., Panagopoulos, V., Papalashvili, G., Papaleo, R., Pavalas, G.E., Pellegrini, G., Pellegrino, C., Pérez Romero, J., Perrin-Terrin, M., Piattelli, P., Pikounis, K., Pisanti, O., Poirè, C., Polydefki, G., Poma, G.E., Popa, V., Post, M., Pradier, T., Pühlhofer, G., Pulvirenti, S., Quinn, L., Raffaelli, F., Randazzo, N., Razzaque, S., Real, D., Resvanis, L., Reubelt, J., Riccobene, G., Richer, M., Rovelli, A., Salvadori, I., Samtleben, D.F.E., Sánchez-Losa, A., Sanguineti, M., Santangelo, A., Sapienza, P., Schermer, B., Sciacca, V., Seneca, J., Sgura, I., Shanidze, R., Sharma, A., Simeone, F., Sinopoulou, A., Spisso, B., Spurio, M., Stavropoulos, D., Steijger, J., Stellacci, S.M., Strandberg, B., Stransky, D., Stüven, T., Taiuti, M., Tatone, F., Tayalati, Y., Tenllado, E., Thakore, T., Timmer, P., Trovato, A., Tsagkli, S., Tzamariudaki, E., Tzanetatos, D., Valieri, C., Vallage, B., Van Elewyck, V., Versari, F., Viola, S., Vivolo, D., Volkert, M., de Waardt, L., Wilms, J., de Wolf, E., Zaborov, D., Zornoza, J.D., and Zúñiga, J.

Abstract

The Hamamatsu R12199-02 3-inch photomultiplier tube is the photodetector chosen for the first phase of the KM3NeT neutrino telescope. About 7000 photomultipliers have been characterised for dark count rate, timing spread and spurious pulses. The quantum efficiency, the gain and the peak-to-valley ratio have also been measured for a sub-sample in order to determine parameter values needed as input to numerical simulations of the detector.

Published
2018

16. Open brief aan Tweede Kamer: Onvoldoende waarborgen in nieuwe nationale veiligheidswet

Author

Arnbak, A., Bos, H., van Buuren, J., Dommering, E., Donders, Y., van Eeten, M., van Eijk, N., Eijkman, Q., Etalle, S., Gerards, J., de Goede, M., de Graaf, B., Hijzen, C., Hildebrandt, M., Hoepman, J.-H., van der Hof, S., van den Hoven, J., van den Hoven van Genderen, R., Jacobs, B., van Kempen, P.H., Leenes, R., Lodder, A., van Ommeren, F.J., Oskamp, A., Schmidt, A., Schermer, B., Smits, J., Zuiderveen Borgesius, F., Zwenne, G.-J., IViR (FdR), Institute of Interdisciplinary Studies, ACIL (FdR), Faculteit der Rechtsgeleerdheid, Information Law, Transnational Configurations, Conflict and Governance (AISSR, FMG), and FdR overig onderzoek

Published
2016

17. Characterisation of the Hamamatsu photomultipliers for the KM3NeT Neutrino Telescope

Author

Aiello, S., primary, Akrame, S.E., additional, Ameli, F., additional, Anassontzis, E. G., additional, Andre, M., additional, Androulakis, G., additional, Anghinolfi, M., additional, Anton, G., additional, Ardid, M., additional, Aublin, J., additional, Avgitas, T., additional, Baars, M., additional, Bagatelas, C., additional, Barbarino, G., additional, Baret, B., additional, Barrios-Martí, J., additional, Belias, A., additional, Berbee, E., additional, Berg, A. van den, additional, Bertin, V., additional, Biagi, S., additional, Biagioni, A., additional, Biernoth, C., additional, Bormuth, R., additional, Boumaaza, J., additional, Bourret, S., additional, Bouwhuis, M., additional, Bozza, C., additional, Brânzaş, H., additional, Briukhanova, N., additional, Bruijn, R., additional, Brunner, J., additional, Buis, E., additional, Buompane, R., additional, Busto, J., additional, Calvo, D., additional, Capone, A., additional, Caramete, L., additional, Celli, S., additional, Chabab, M., additional, Cherubini, S., additional, Chiarella, V., additional, Chiarusi, T., additional, Circella, M., additional, Cocimano, R., additional, Coelho, J.A.B., additional, Coleiro, A., additional, Molla, M. Colomer, additional, Coniglione, R., additional, Coyle, P., additional, Creusot, A., additional, Cuttone, G., additional, D'Onofrio, A., additional, Dallier, R., additional, Sio, C. De, additional, Palma, I. Di, additional, Díaz, A.F., additional, Distefano, C., additional, Domi, A., additional, Donà, R., additional, Donzaud, C., additional, Dornic, D., additional, Dörr, M., additional, Durocher, M., additional, Eberl, T., additional, Eijk, D. van, additional, Bojaddaini, I. El, additional, Elsaesser, D., additional, Enzenhöfer, A., additional, Ferrara, G., additional, Fusco, L.A., additional, Gal, T., additional, Garufi, F., additional, Gauchery, S., additional, Geißelsöder, S., additional, Gialanella, L., additional, Giorgio, E., additional, Giuliante, A., additional, Gozzini, S.R., additional, Ruiz, R. Gracia, additional, Graf, K., additional, Grasso, D., additional, Grégoire, T., additional, Grella, G., additional, Hallmann, S., additional, Haren, H. van, additional, Heid, T., additional, Heijboer, A., additional, Hekalo, A., additional, Hernández-Rey, J.J., additional, Hofestädt, J., additional, Illuminati, G., additional, James, C.W., additional, Jongen, M., additional, Jongewaard, B., additional, de Jong, M., additional, de Jong, P., additional, Kadler, M., additional, Kalaczyński, P., additional, Kalekin, O., additional, Katz, U.F., additional, Chowdhury, N.R. Khan, additional, Kieft, G., additional, Kießling, D., additional, Koffeman, E.N., additional, Kooijman, P., additional, Kouchner, A., additional, Kreter, M., additional, Kulikovskiy, V., additional, Lahmann, R., additional, Breton, R. Le, additional, Leone, F., additional, Leonora, E., additional, Levi, G., additional, Lincetto, M., additional, Lonardo, A., additional, Longhitano, F., additional, Lotze, M., additional, Loucatos, S., additional, Maggi, G., additional, Mańczak, J., additional, Mannheim, K., additional, Margiotta, A., additional, Marinelli, A., additional, Markou, C., additional, Martin, L., additional, Martínez-Mora, J.A., additional, Martini, A., additional, Marzaioli, F., additional, Mele, R., additional, Melis, K.W., additional, Migliozzi, P., additional, Migneco, E., additional, Mijakowski, P., additional, Miranda, L. S., additional, Mollo, C.M., additional, Morganti, M., additional, Moser, M., additional, Moussa, A., additional, Muller, R., additional, Musumeci, M., additional, Nauta, L., additional, Navas, S., additional, Nicolau, C.A., additional, Nielsen, C., additional, Organokov, M., additional, Orlando, A., additional, Panagopoulos, V., additional, Papalashvili, G., additional, Papaleo, R., additional, Păvălaş, G.E., additional, Pellegrini, G., additional, Pellegrino, C., additional, Pérez Romero, J., additional, Perrin-Terrin, M., additional, Piattelli, P., additional, Pikounis, K., additional, Pisanti, O., additional, Poirè, C., additional, Polydefki, G., additional, Poma, G.E., additional, Popa, V., additional, Post, M., additional, Pradier, T., additional, Pühlhofer, G., additional, Pulvirenti, S., additional, Quinn, L., additional, Raffaelli, F., additional, Randazzo, N., additional, Razzaque, S., additional, Real, D., additional, Resvanis, L., additional, Reubelt, J., additional, Riccobene, G., additional, Richer, M., additional, Rovelli, A., additional, Salvadori, I., additional, Samtleben, D.F.E., additional, Sánchez Losa, A., additional, Sanguineti, M., additional, Santangelo, A., additional, Sapienza, P., additional, Schermer, B., additional, Sciacca, V., additional, Seneca, J., additional, Sgura, I., additional, Shanidze, R., additional, Sharma, A., additional, Simeone, F., additional, Sinopoulou, A., additional, Spisso, B., additional, Spurio, M., additional, Stavropoulos, D., additional, Steijger, J., additional, Stellacci, S.M., additional, Strandberg, B., additional, Stransky, D., additional, Stüven, T., additional, Taiuti, M., additional, Tatone, F., additional, Tayalati, Y., additional, Tenllado, E., additional, Thakore, T., additional, Timmer, P., additional, Trovato, A., additional, Tsagkli, S., additional, Tzamariudaki, E., additional, Tzanetatos, D., additional, Valieri, C., additional, Vallage, B., additional, Elewyck, V. Van, additional, Versari, F., additional, Viola, S., additional, Vivolo, D., additional, Volkert, M., additional, de Waardt, L., additional, Wilms, J., additional, de Wolf, E., additional, Zaborov, D., additional, Zornoza, J.D., additional, and Zúñiga, J., additional

Published
2018
Full Text
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19. Legal Aspects of Sweetie 2.0

Author

Schermer, B. W., Ilina Georgieva, Simone Van der Hof, Bert-Jaap Koops, and TILT

Subjects
ComputingMilieux_LEGALASPECTSOFCOMPUTING
Published
2016

21. Privacy Expectations of Social Media Users: The Role of Informed Consent in Privacy Policies

Author

Custers, B.H.M., Hof, S. van der, and Schermer, B.

Abstract

Social media process (sometimes large amounts of) personal data of their users, usually on the basis of informed consent. In this article, a comparison is made between, on the one hand, existing practices of social media regarding informed consent for using personal data of users and, on the other hand, user expectations with regard to privacy and informed consent. The comparison is made on the basis of a set of criteria for informed consent distilled from an analytical bibliography. Next, the privacy policies of a selection of eight social network sites and user generated content sites are analyzed using this set of criteria for informed consent. User expectations regarding these criteria were derived from survey results of a large EU-wide online survey (N = 8,621, 26 countries) on the awareness, values, and attitudes of social media users regarding privacy. We find that not all privacy policy criteria are important to users, but most criteria that are important to users can be found in most privacy policies.

Published
2014

24. From data minimization to data minimummization

Author

van der Sloot, B., Custers, B., Calders, T., Schermer, B., Zarsky, T., and IViR dp01 (IViR, FdR)

Subjects
Knowledge extraction, Risk analysis (engineering), Computer science, Data quality, Profiling (information science), Data mining, Minification, computer.software_genre, computer, Kochen–Specker theorem
Abstract

Data mining and profiling offer great opportunities, but also involve risks related to privacy and discrimination. Both problems are often addressed by implementing data minimization principles, which entail restrictions on gathering, processing and using data. Although data minimization can sometimes help to minimize the scale of damage that may take place in relation to privacy and discrimination, for example when a data leak occurs or when data are being misused, it has several disadvantages as well. Firstly, the dataset loses a rather large part of its value when personal and sensitive data are filtered from it. Secondly, by deleting these data, the context in which the data were gathered and had a certain meaning is lost. This chapter will argue that this loss of contextuality, which is inherent to data mining as such but is aggravated by the use of data minimization principles, gives rise to or aggravates already existing privacy and discrimination problems. Thus, an opposite approach is suggested, namely that of data minimummization, which requires a minimum set of data being gathered, stored and clustered when used in practice. This chapter argues that if the data minimummization principle is not realized, this may lead to quite some inconveniences; on the other hand, if the principle is realized, new techniques can be developed that rely on the context of the data, which may provide for innovative solutions. However, this is far from a solved problem and it requires further research.

Published
2013

27. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia

Author

Scha&#776, fer, T., Senderek, J., Olbrich, H., Becker, C., Benzing, T., Kelehan, P., Kirschner, J., Walz, G., Gretz, N., Grimm, T., Lynch, S. A., Bergmann, C., Neuhaus, T. J., Nu&#776, rnberg, P., Omran, H., Kra&#776, nzlin, B., Schermer, B., Kispert, A., Frank, V., rnberg, G., Zentgraf, H., Zerres, K., Fliegauf, M., Lienkamp, S., Stallmach, T., Bru&#776, chle, N. O., Lohaus, C., Girschick, G., Schmedding, I., University of Zurich, and Bergmann, C

Subjects
2716 Genetics (clinical), 1311 Genetics, 10036 Medical Clinic, 610 Medicine & health
Published
2008

28. Der Kreuzgang des Domes in Monreale

Author

Schermer, B. (Birgitt), Poeschke, J. (Joachim), and Universitäts- und Landesbibliothek Münster

Subjects
Sculpture and related arts, ddc:730, Monreale, Kreuzgang, Skulptur, Kapitell, Ornamentik, Romanik, Italien, Sizilien
Abstract

Das Benediktinerkloster in Monreale wurde um 1174 von Wilhelm II. gegründet. Die prachtvolle Architektur des Gebäudekomplexes entstand, ohne diesbezüglich auf eine ausgeprägte Bautradition im normannischen Königreich zurückgreifen zu können. Die stilistische Einordnung der Skulptur des Kreuzgangs, die im Zentrum der Arbeit steht, führt zu der These, daß ein Großteil der Kapitelle in der Nachfolge des Nicolaus von Ferrara entstand. Aus Norditalien migrierte Künstler waren für die antikisierenden Tendenzen und z.T. stilbildenden Innovationen der Kapitellplastik verantwortlich. Auf dieser Beobachtung basiert eine Revision der Chronologie sizilianischer Bauskulptur des späten 12. Jahrhunderts, in der die Bauskulptur des Doms in Cefalù als Reflex der Monrealer beurteilt wird. Auch wird anhand der Ornamentik ein Konnex zu frühgotischen Werken Frankreichs aufgezeigt. Die Entwicklung des spezifischen Stils der Monrealer Skulptur innerhalb der Bauhütte wird nachvollzogen und ihre Bedeutung für die süditalienische Skulptur der folgenden Jahrzehnte aufgezeigt.

Published
2003

30. Transcriptional profiling reveals progeroid Ercc1(-/Delta) mice as a model system for glomerular aging

Author

Schermer, B, Bartels, V, Frommolt, P, Habermann, B, Braun, F, Schultze, JL, Roodbergen, M (Marianne), Hoeijmakers, Jan, Schumacher, Bjorn, Nurnberg, P, Dollé, Martijn, Benzing, T, Muller, RU, Kurschat, CE, Schermer, B, Bartels, V, Frommolt, P, Habermann, B, Braun, F, Schultze, JL, Roodbergen, M (Marianne), Hoeijmakers, Jan, Schumacher, Bjorn, Nurnberg, P, Dollé, Martijn, Benzing, T, Muller, RU, and Kurschat, CE

Abstract

Background: Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1(-/Delta) progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. Results: In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1(-/Delta) mice showed cluster formation between young WT and Ercc1(-/Delta) as well as old WT and Ercc1(-/Delta) samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1(-/Delta) mice (p < 0.0001). GO term enrichment analysis reveal Conclusion: Beyond insulin signaling, we find chemokine and cytokine signaling as well as modifiers of extracellular matrix composition to be subject to major changes in the aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1(-/Delta) mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies.

Published
2013

31. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling

Author

Chaki, M., Airik, R., Ghosh, A.K., Giles, R.H., Chen, R., Slaats, G.G., Wang, H, Hurd, T.W., Zhou, W., Cluckey, A., Gee, H.Y., Ramaswami, G., Hong, C.J., Hamilton, B.A., Cervenka, I., Ganji, R.S., Bryja, V., Arts, H.H., Reeuwijk, J. van, Oud, M.M., Letteboer, S.J., Roepman, R., Husson, H., Ibraghimov-Beskrovnaya, O., Yasunaga, T., Walz, G., Eley, L., Sayer, J.A., Schermer, B., Liebau, M.C., Benzing, T., Le Corre, S., Drummond, I., Janssen, S., Allen, S.J., Natarajan, S., O'Toole, J.F., Attanasio, M., Saunier, S., Antignac, C., Koenekoop, R.K., Ren, H., Lopez, I., Nayir, A., Stoetzel, C., Dollfus, H., Massoudi, R., Gleeson, J.G., Andreoli, S.P., Doherty, D.G., Lindstrad, A., Golzio, C., Katsanis, N., Pape, L., Abboud, E.B., Al-Rajhi, A.A., Lewis, R.A., Omran, H., Lee, E.Y., Wang, S., Sekiguchi, J.M., Saunders, R., Johnson, C.A., Garner, E., Vanselow, K., Andersen, J.S., Shlomai, J., Nurnberg, G., Nurnberg, P., Levy, S., Smogorzewska, A., Otto, E.A., Hildebrandt, F., Chaki, M., Airik, R., Ghosh, A.K., Giles, R.H., Chen, R., Slaats, G.G., Wang, H, Hurd, T.W., Zhou, W., Cluckey, A., Gee, H.Y., Ramaswami, G., Hong, C.J., Hamilton, B.A., Cervenka, I., Ganji, R.S., Bryja, V., Arts, H.H., Reeuwijk, J. van, Oud, M.M., Letteboer, S.J., Roepman, R., Husson, H., Ibraghimov-Beskrovnaya, O., Yasunaga, T., Walz, G., Eley, L., Sayer, J.A., Schermer, B., Liebau, M.C., Benzing, T., Le Corre, S., Drummond, I., Janssen, S., Allen, S.J., Natarajan, S., O'Toole, J.F., Attanasio, M., Saunier, S., Antignac, C., Koenekoop, R.K., Ren, H., Lopez, I., Nayir, A., Stoetzel, C., Dollfus, H., Massoudi, R., Gleeson, J.G., Andreoli, S.P., Doherty, D.G., Lindstrad, A., Golzio, C., Katsanis, N., Pape, L., Abboud, E.B., Al-Rajhi, A.A., Lewis, R.A., Omran, H., Lee, E.Y., Wang, S., Sekiguchi, J.M., Saunders, R., Johnson, C.A., Garner, E., Vanselow, K., Andersen, J.S., Shlomai, J., Nurnberg, G., Nurnberg, P., Levy, S., Smogorzewska, A., Otto, E.A., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

Published
2012

32. Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics

Author

Dafinger, C, Liebau, M C, Elsayed, S M, Hellenbroich, Y, Boltshauser, E, Korenke, G C, Fabretti, F, Janecke, A R, Ebermann, I, Nürnberg, G, Nürnberg, P, Zentgraf, H, Koerber, F, Addicks, K, Elsobky, E, Benzing, T, Schermer, B, Bolz, H J, Dafinger, C, Liebau, M C, Elsayed, S M, Hellenbroich, Y, Boltshauser, E, Korenke, G C, Fabretti, F, Janecke, A R, Ebermann, I, Nürnberg, G, Nürnberg, P, Zentgraf, H, Koerber, F, Addicks, K, Elsobky, E, Benzing, T, Schermer, B, and Bolz, H J

Abstract

Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.

Published
2011

33. Inhibition of the production of endothelium-derived hyperpolarizing factor by cannabinoid receptor agonists

Author

Fleming, I, Schermer, B, Popp, R, and Busse, R

Subjects
Male, Polyunsaturated Alkamides, Swine, Receptors, Drug, Arachidonic Acids, Biological Factors, Cytochrome P-450 Enzyme System, Piperidines, Vasoconstriction, Papers, cardiovascular system, Cyclic AMP, Animals, Pyrazoles, Calcium, Female, Dronabinol, Rabbits, Rimonabant, Receptors, Cannabinoid, Cells, Cultured, Endocannabinoids
Abstract

1. The endogenous cannabinoid, anandamide, has been reported to induce an 'endothelium-derived hyperpolarizing factor (EDHF)-like' relaxation in vitro. We therefore investigated the effects of cannabinoid CB1 receptor agonists; HU 210, delta9-tetrahydrocannabinol (delta9-THC) and anandamide, and a CB1 antagonist/inverse agonist, SR 141716A, on nitric oxide (NO) and EDHF-mediated relaxation in precontracted rings of porcine coronary, rabbit carotid and mesenteric arteries. 2. In rings of mesenteric artery HU 210 and delta9-THC induced endothelium- and cyclo-oxygenase-independent relaxations which were sensitive to SR 141716A. Anandamide (0.03-30 microM) induced a slowly developing, endothelium-independent relaxation which was abolished by diclofenac and was therefore mediated by cyclo-oxygenase product(s). None of the CB1 agonists tested affected the tone of precontracted rings of rabbit carotid or porcine coronary artery. 3. In endothelium-intact segments, HU 210, delta9-THC and anandamide did not affect NO-mediated responses but under conditions of continuous NO synthase/cyclo-oxygenase blockade, significantly inhibited acetylcholine and bradykinin-induced relaxations which are attributed to the production of EDHF. The effects of HU 210 and delta9-THC were not observed when experiments were performed in the presence of SR 141716A suggesting the involvement of the CB1 receptor. 4. In a patch clamp bioassay of EDHF production, HU 210 decreased the EDHF-mediated hyperpolarization of detector smooth muscle cells when applied to the donor segment but was without effect on the membrane potential of detector cells. The inhibition of EDHF production was unrelated to alterations in Ca2+ -signalling or cytochrome P450 activity. 5. These results suggest that the activation of endothelial CB1 receptors appears to be negatively coupled to the production of EDHF.

Published
1999

39. 14-3-3 interacts with regulator of G protein signaling proteins and modulates their activity.

Author

Benzing, T, Yaffe, M B, Arnould, T, Sellin, L, Schermer, B, Schilling, B, Schreiber, R, Kunzelmann, K, Leparc, G G, Kim, E, and Walz, G

Abstract

Regulator of G protein signaling (RGS) proteins function as GTPase-activating proteins (GAPs) that stimulate the inactivation of heterotrimeric G proteins. We have recently shown that RGS proteins may be regulated on a post-translational level (Benzing, T., Brandes, R., Sellin, L., Schermer, B., Lecker, S., Walz, G., and Kim, E. (1999) Nat. Med. 5, 913-918). However, mechanisms controlling the GAP activity of RGS proteins are poorly understood. Here we show that 14-3-3 proteins associate with RGS7 and RGS3. Binding of 14-3-3 is mediated by a conserved phosphoserine located in the Galpha-interacting portion of the RGS domain; interaction with 14-3-3 inhibits the GAP activity of RGS7, depends upon phosphorylation of a conserved residue within the RGS domain, and results in inhibition of GAP function. Collectively, these data indicate that phosphorylation-dependent binding of 14-3-3 may act as molecular switch that controls the GAP activity keeping a substantial fraction of RGS proteins in a dormant state.

Published
2000
Full Text
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40. Sustainable Development and Human Rights: An Indivisible Bond

Author

Hirsch Ballin, E., Cleiren, T., Karin Arts, Ms, Berger, Donders, Y., Gerards, J., Hamburger, A., Heerts, T., Hoeven, R., Jägers, N., Lawson, R., Monteiro, M., Myjer, E., Opschoor, H., Schermer, B., Tahir, N., Verrijn Stuart, H., and Academic staff unit

Abstract

See https://aiv-advies.nl/b08

41. The Nephrocystin Protein Complex Interacts with the Transport Protein PACS-1 and Localizes to Primary Cilia in Kidney Cells.

Author

Schermer, B., Höpker, K., Blauka, A., Hacki, M., Köttgen, M., Huber, T. B., Rapka, M., Walz, G., and Benzing, T.

Subjects
*GENETIC mutation, *PROTEIN kinase CK2, *CASEINS, *PROTEINS, *KIDNEY diseases
Abstract

Objective: Juvenile nephronophthisis type 1 is caused by mutations of NPHP1, the gene encoding for nephrocystin. We have recently shown that nephrocystin is a scaffolding protein and recruits signal transduction components into a specialized protein complex, the nephrocystin protein complex. Results: Here we show that nephrocystin interacts with PACS-1, a transport protein of the trans-Golgi network (TGN). Interaction was mediated by the furin-binding region of PACS-1 and a cluster of acidic residues in nephrocystin. Interestingly, this acidic cluster in nephrocystin contains three critical serine residues representing casein kinase 2 phosphorylation sites. Mutation of these residues to alanine abrogated the interaction whereas phosphorylation promoted PACS-1 binding. In vivo phosphoproteomics analysis of immunoprecipitated nephrocystin revealed phosphorylation at these critical serine residues. Using specific antisera and proteomics technology we identified additional components of this complex and could show that the nephrocystin protein complex localizes to primary cilia of kidney cells. Targeting to cilia requires correct packaging of cargo molecules into vesicles derived from the TGN. Binding of PACS-1 lead to the targeting of nephrocystin-interacting proteins to the TGN suggesting that the nephrocystin/PACS-1 interaction may serve to recruit cargo molecules to the TGN, a prerequisite for correct packaging into cilia cargo vesicles. Conclusions: Our data reveal a novel role for the nephrocystin protein complex in recruitment of attached proteins into the TGN and suggest a functional link between nephrocystin/PACS-1-mediated targeting to TGN and subsequent localization to cilia of proteins involved in the pathogenesis of cystic kidney disease. [ABSTRACT FROM AUTHOR]

Published
2004

42. A Proteomics and Systems Biology Approach to Signaling Networks in Kidney Disease.

Author

Schermer, B., Höpker, K., Yaffe, M. B., Gerke, P., Walz, G., and Benzing, T.

Subjects
*CELLULAR signal transduction, *KIDNEY diseases, *PATHOLOGICAL physiology, *AMINO acids, *PROTEIN kinase C, *PROTEOMICS
Abstract

Objective: The kidney has to rely on multiple intracellular signal transduction pathways to successfully fulfill its specialized tasks. All kidney pathologies ultimately disrupt these intracellular signaling pathways to cause renal disease. Signaling pathways are interconnected in a network of multifunctional, redundant and non-redundant molecules to elicit a set of phenotypic responses that subsequently impact function at the cell, tissue, and organ level. Basic principle is that the interaction of several pathways in the network can exhibit a new emergent state as a consequence of their interactions. It is this property of biological systems that makes signaling networks difficult to model and to fully understand. Therefore, to develop a molecular understanding of the complex pathophysiology underlying kidney diseases and to design new treatment strategies a systems-level, network-biology approach should be applied to the signaling networks governing the relevant cell responses. Results: To attack signaling networks in kidney diseases we have developed and improved a phosphopeptide library-based proteomic screening technology and used this technique for a systems-biology approach to polarity signal transduction. We generated a normalized mouse embryonic kidney cDNA library and constructed arrays of >2,000 small cDNA pools comprising >200,000 independent clones for high-throughput in vitro expression cloning. Oriented phosphopeptide libraries biased to resemble the basophilic kinase motif of atypical protein kinase C were immobilized and screened together with their nonphosphorylated counterparts against these 200,000 in vitro translated polypeptides. This technique allowed the identification of novel phospho-serine binding domains involved in polarity signaling. We have identified more than 50 unknown proteins binding to aPKC targets, a huge number of additional ones are waiting to be sequenced. Data from this proteomics screen will be used to integrate the information in a systems biology-based prediction of kinase networks controlling cell polarity. Conclusions: Our integrative approach, which is applicable to other cellular programs of kidney cells, will provide a better understanding of basic principles in signal transduction both in the healthy and diseased kidney and will certainly identify critical regulatory nodes for therapeutic manipulation. [ABSTRACT FROM AUTHOR]

Published
2004

43. Phosphorylation Regulates Binding of PDZ Domains to NEPH Proteins at the Glomerular Slit Diaphragm.

Author

Huber, T. B., Reinhardt, C., Stegmann, C., Schermer, B., Müller, R. U., Zahn, A., Schmidts, M., Beyerle, J., Gödel, M., Walz, G., and Benzing, T.

Subjects
PHOSPHORYLATION, GLOMERULAR filtration rate, KIDNEY function tests, KIDNEY diseases, CHRONIC kidney failure
Abstract

Objective: Diseases of the glomerular filter of the kidney are a leading cause of end-stage renal failure. Recent studies have emphasized the critical role of the slit diaphragm of podocytes for the sizeselective filtration barrier of the kidney and revealed novel aspects of the mechanisms leading to proteinuria, both in inherited and acquired diseases. Several critical structural protein components of the slit diaphragm have been identified. We have recently shown that these slit diaphragm proteins, in addition to their structural functions, participate in common signaling pathways. Results: Here we demonstrate that the immunoglobulin superfamily and slit diaphragm proteins of the NEPH family bind to the PDZ domain proteins Zonula occludens 1 (ZO-1) and Densin. This interaction was mediated by the first PDZ domain of ZO-1 and a single PDZ domain in Densin and involved the conserved PDZ domain binding motif present in the carboxyl terminus of the three known NEPH family members. Both deletion of the PDZ binding motif of NEPH1 as well as threonine-to-glutamate mutation of the threonine within the binding motif abrogated binding of Densin/ZO-1, suggesting that phosphorylation may regulate this interaction. Indeed, phosphorylation abrogated binding of Densin as well as ZO-1 as demonstrated by in vitro interaction studies and fluorescence polarization measurements. Conclusions: It is reasonable to speculate that the slit diaphragm protein complex is highly dynamic. Protein components of the complex are endocytosed, recycled and returned back to the cell surface. Our data now suggest that NEPH molecules that have to enter or leave the complex are phosphorylated on critical threonine residues disabling binding to ZO-1 and Densin. Dephosphorylation of NEPHs will then promote binding and allows recruitment of these proteins into the slit diaphragm protein complex. We propose that regulated phosphorylation/dephosphorylation of NEPH proteins contributes to the dynamic assembly of proteins at the slit diaphragm. [ABSTRACT FROM AUTHOR]

Published
2004

44. Molecular Basis of Hereditary Nephrotic Syndrome: Direct Binding of Cholesterol and Targeting of Nephrin to Lipid Rafts Are Disrupted in Disease-Causing Podocin Mutations.

Author

Huber, T. B., Reinhardt, C., Simons, M., Sernetz, L., Schermer, B., Petraschka, D., Gundlach, E., Beyerle, J., Gödel, M., Walz, G., and Benzing, T.

Subjects
NEPHROTIC syndrome, KIDNEY diseases, GENETIC disorders, PROTEINURIA, EPITHELIAL cells
Abstract

Objective: Hereditary nephrotic syndrome is a heterogeneous disease, characterized by heavy proteinuria and renal failure. Mutations of NPHS1 or NPHS2, the genes encoding for nephrin and podocin, lead to early onset of heavy proteinuria, and rapid progression to end-stage renal disease, suggesting that both proteins are essential for the integrity of the glomerular filter. We have previously shown that the stomatin protein family member podocin binds nephrin to recruit nephrin into lipid rafts at the insertion site of the slit diaphragm of podocytes, the visceral glomerular epithelial cells of the kidney. Here we investigate the structural requirements for nephrin targeting and the pathomechanisms of different disease-causing podocin mutations. Results: We show that podocin forms homo-oligomers that directly interact with cholesterol at the plasma membrane. Binding of cholesterol as well as multimerization and lipid raft recruitment of podocin is strictly dependent on the integrity of the PHB domain of podocin. The association of podocin with specialized lipid raft microdomains of the plasma membrane was a prerequisite for recruitment of nephrin into rafts. In contrast to the wild-type protein, disease- causing mutations of podocin (R138Q and R138X) failed to recruit nephrin into rafts either because these mutants were retained in the endoplasmic reticulum and did not interact with cholesterol (R138Q), or because they failed to associate with rafts (R138X) despite their presence in the plasma membrane. None of the mutants did augment nephrin signaling, suggesting that lipid raft targeting facilitates nephrin signaling. Conclusions: Our findings demonstrate that the failure of mutant podocin to recruit nephrin into lipid rafts may be essential for the pathogenesis of NPHS2. These data elucidate the structural requirements for podocin-mediated augmentation of nephrin signaling and are beginning to provide a molecular understanding of the basis of hereditary nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Published
2004

45. Characterisation of the Hamamatsu photomultipliers for the KM3NeT Neutrino Telescope

Author

Carmelo Pellegrino, F. Garufi, S.E. Akrame, A. Martini, U. Katz, Stavroula Tsagkli, D. van Eijk, T. Stüven, Rosanna Cocimano, A. Orlando, M. Anghinolfi, Piotr Kalaczyński, Vladimir Kulikovskiy, P. Timmer, Luigi Antonio Fusco, Maurizio Spurio, L. de Waardt, A.J. Heijboer, Rezo Shanidze, R. Gracia Ruiz, M. Jongen, F. Versari, J. Manczak, B. Schermer, Alessia Capone, P.M. Kooijman, J. Brunner, T. Gal, E. Migneco, B. Spisso, M. Richer, C. Distefano, Raffaele Buompane, Robert Lahmann, Lucio Gialanella, J. Seneca, E. Buis, Els Koffeman, D. F. E. Samtleben, A. Hekalo, A. Trovato, D. Tzanetatos, P. Migliozzi, Cristiano Bozza, E. Berbee, I. Di Palma, G. Ferrara, B. Jongewaard, Antonio F. Díaz, D. Zaborov, Paolo Sapienza, H. van Haren, S. Geißelsöder, Sebastiano Aiello, G. Pühlhofer, T. Avgitas, Fabio Longhitano, M. Taiuti, G. E. Poma, Francesco Simeone, G. Polydefki, R. Donà, L. Nauta, S. Loucatos, B. Vallage, G. Grella, G. Maggi, Carlos Maximiliano Mollo, P. Mijakowski, Tommaso Chiarusi, M. Perrin-Terrin, Matteo Sanguineti, Robert Muller, Massimiliano Lincetto, Alessandro Lonardo, S. Bourret, J. Barrios-Martí, Giuseppe Levi, Silvia Celli, V. Sciacca, M. Dörr, Thierry Pradier, Carlo Alessandro Nicolau, G. Riccobene, S.F. Biagi, E. A. De Wolf, G.E. Păvălaş, Emanuele Leonora, O. Kalekin, Michel André, C. Poirè, Corinne Donzaud, A. Marinelli, R. Coniglione, A. Sánchez Losa, I. El Bojaddaini, V. Bertin, A. Belias, A.M. van den Berg, V. Van Elewyck, Kay Graf, Karel Melis, J.D. Zornoza, E. Tenllado, C. De Sio, Antoine Kouchner, Mohamed Chabab, Antonio D'Onofrio, J. Hofestädt, Michael Moser, L. S. Miranda, Fabio Marzaioli, F. Raffaelli, M.C. Bouwhuis, Matthias Kadler, Daniele Vivolo, Jörn Wilms, Richard Dallier, H. Brânzaş, Giulia Illuminati, Alba Domi, D. Calvo, Jihad Boumaaza, Andrea Santangelo, R. Bormuth, Diego Real, R. Le Breton, M. Baars, I. Sgura, M. Colomer Molla, Salvatore Viola, Soebur Razzaque, Sara Pulvirenti, Thomas Eberl, P. Piattelli, M. Lotze, A. Sharma, Ofelia Pisanti, M. Volkert, Vitaliano Chiarella, G. Kieft, S. Navas, Jose Busto, A. Enzenhöfer, J. Reubelt, T. Heid, Mario Musumeci, D. Kießling, T. Grégoire, L. K. Resvanis, P. de Jong, C. Biernoth, V. Popa, T. Thakore, N. Randazzo, J. Zúñiga, D. Stavropoulos, M. Organokov, C. Nielsen, N. R. Khan Chowdhury, B. Strandberg, Damien Dornic, Jos Steijger, V. Panagopoulos, Simona Maria Stellacci, J. Aublin, A. Rovelli, Abdelilah Moussa, M. de Jong, R. Mele, J.A. Martínez-Mora, Alexis Coleiro, Michael Kreter, Dario Grasso, Fabrizio Ameli, Steffen Hallmann, Joao A B Coelho, Francesca Tatone, R. Bruijn, Emidio Giorgio, E. G. Anassontzis, C. Bagatelas, M. Ardid, J. Pérez Romero, Dominik Elsaesser, L. Quinn, L. Martin, I. Salvadori, C. W. James, Annarita Margiotta, Gisela Anton, Bruny Baret, S. R. Gozzini, M. Post, K. Pikounis, A. Creusot, N. Briukhanova, C. Markou, E. Tzamariudaki, Claudia Valieri, Riccardo Papaleo, A. Giuliante, G. C. Barbarino, J.J. Hernández-Rey, Yahya Tayalati, M. Durocher, G. Androulakis, Silvio Cherubini, S. Gauchery, L. Caramete, G. Papalashvili, D. Stransky, M. Circella, Karl Mannheim, Andrea Biagioni, G. Pellegrini, A. Sinopoulou, M. Morganti, P. Coyle, Giacomo Cuttone, Francesco Leone, AstroParticule et Cosmologie (APC (UMR_7164)), Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Physique des Particules de Marseille (CPPM), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Aix Marseille Université (AMU), Laboratoire de physique subatomique et des technologies associées (SUBATECH), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Département de Physique des Particules (ex SPP) (DPP), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, KM3NeT, Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Aiello, S., Akrame, S. E., Ameli, F., Anassontzis, E. G., Andre, M., Androulakis, G., Anghinolfi, M., Anton, G., Ardid, M., Aublin, J., Avgitas, T., Baars, M., Bagatelas, C., Barbarino, G., Baret, B., Barrios-Martí, J., Belias, A., Berbee, E., Berg, A. Van Den, Bertin, V., Biagi, S., Biagioni, A., Biernoth, C., Bormuth, R., Boumaaza, J., Bourret, S., Bouwhuis, M., Bozza, C., Branzaş, H., Briukhanova, N., Bruijn, R., Brunner, J., Buis, E., Buompane, R., Busto, J., Calvo, D., Capone, A., Caramete, L., Celli, S., Chabab, M., Cherubini, S., Chiarella, V., Chiarusi, T., Circella, M., Cocimano, R., Coelho, J. A. B., Coleiro, A., Molla, M. Colomer, Coniglione, R., Coyle, P., Creusot, A., Cuttone, G., D'Onofrio, A., Dallier, R., Sio, C. De, Palma, I. Di, Díaz, A. F., Distefano, C., Domi, A., Donà, R., Donzaud, C., Dornic, D., Dörr, M., Durocher, M., Eberl, T., Eijk, D. Van, Bojaddaini, I. El, Elsaesser, D., Enzenhöfer, A., Ferrara, G., Fusco, L. A., Gal, T., Garufi, F., Gauchery, S., Geißelsöder, S., Gialanella, L., Giorgio, E., Giuliante, A., Gozzini, S. R., Ruiz, R. Gracia, Graf, K., Grasso, D., Grégoire, T., Grella, G., Hallmann, S., Haren, H. Van, Heid, T., Heijboer, A., Hekalo, A., Hernández-Rey, J. J., Hofestädt, J., Illuminati, G., James, C. W., Jongen, M., Jongewaard, B., De Jong, M., De Jong, P., Kadler, M., Kalaczyński, P., Kalekin, O., Katz, U. F., Chowdhury, N. R. Khan, Kieft, G., Kießling, D., Koffeman, E. N., Kooijman, P., Kouchner, A., Kreter, M., Kulikovskiy, V., Lahmann, R., Breton, R. Le, Leone, F., Leonora, E., Levi, G., Lincetto, M., Lonardo, A., Longhitano, F., Lotze, M., Loucatos, S., Maggi, G., Mańczak, J., Mannheim, K., Margiotta, A., Marinelli, A., Markou, C., Martin, L., Martínez-Mora, J. A., Martini, A., Marzaioli, F., Mele, R., Melis, K. W., Migliozzi, P., Migneco, E., Mijakowski, P., Miranda, L. S., Mollo, C. M., Morganti, M., Moser, M., Moussa, A., Muller, R., Musumeci, M., Nauta, L., Navas, S., Nicolau, C. A., Nielsen, C., Organokov, M., Orlando, A., Panagopoulos, V., Papalashvili, G., Papaleo, R., Pǎvǎlaş, G. E., Pellegrini, G., Pellegrino, C., Pérez Romero, J., Perrin-Terrin, M., Piattelli, P., Pikounis, K., Pisanti, O., Poirè, C., Polydefki, G., Poma, G. E., Popa, V., Post, M., Pradier, T., Pühlhofer, G., Pulvirenti, S., Quinn, L., Raffaelli, F., Randazzo, N., Razzaque, S., Real, D., Resvanis, L., Reubelt, J., Riccobene, G., Richer, M., Rovelli, A., Salvadori, I., Samtleben, D. F. E., Sánchez Losa, A., Sanguineti, M., Santangelo, A., Sapienza, P., Schermer, B., Sciacca, V., Seneca, J., Sgura, I., Shanidze, R., Sharma, A., Simeone, F., Sinopoulou, A., Spisso, B., Spurio, M., Stavropoulos, D., Steijger, J., Stellacci, S. M., Strandberg, B., Stransky, D., Stüven, T., Taiuti, M., Tatone, F., Tayalati, Y., Tenllado, E., Thakore, T., Timmer, P., Trovato, A., Tsagkli, S., Tzamariudaki, E., Tzanetatos, D., Valieri, C., Vallage, B., Elewyck, V. Van, Versari, F., Viola, S., Vivolo, D., Volkert, M., De Waardt, L., Wilms, J., De Wolf, E., Zaborov, D., Zornoza, J. D., Zuniga, J., Centre Tecnològic de Vilanova i la Geltrú, Universitat Politècnica de Catalunya. LAB - Laboratori d'Aplicacions Bioacústiques, Mollo, Carlos Maximiliano, Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Département de Physique des Particules (ex SPP) (DPhP), KM3NeT (IHEF, IoP, FNWI), IHEF (IoP, FNWI), ATLAS (IHEF, IoP, FNWI), Akrame, S.E., Anassontzis, E.G., Coelho, J.A.B., Díaz, A.F., Fusco, L.A., Gozzini, S.R., Hernández-Rey, J.J., James, C.W., Katz, U.F., Chowdhury, N.R. Khan, Koffeman, E.N., Martínez-Mora, J.A., Melis, K.W., Miranda, L.S., Mollo, C.M., Nicolau, C.A., Pǎvǎlaş, G.E., Poma, G.E., Samtleben, D.F.E., Stellacci, S.M., and Zornoza, J.D.

Subjects
Astrofísica, Tubs, PROTOTYPE, Physics::Instrumentation and Detectors, Física::Física de partícules [Àrees temàtiques de la UPC], Particle detectors, High Tech Systems & Materials, Astrophysics, 01 natural sciences, Neutrino detector, Photon detectors for UV, visible and IR photons (vacuum), Large detector systems, Neutrino detectors, Instrumentation, KM3NeT, Photon detectors for UV, Mathematical Physics, photoelectron: yield, Physics, photomultiplier, Industrial Innovation, Peak-to-valley ratios, Detector, Astrophysics::Instrumentation and Methods for Astrophysics, Particle physics, Photodetectors, efficiency: quantum, Cherenkov counters, Cherenkov detectors, Large detector systems for particle and astroparticle physics, Dark count rate, Quantum efficiency, Física nuclear, Optoelectrònica, performance, Cherenkov detector, Cherenkov detectors, Large detector systems for particle and astroparticle physics, Neutrino detectors, Photon detectors for UV, visible and IR photons (vacuum), Instrumentation, Mathematical Physics, Photomultiplier, Fotònica, Phase (waves), Photodetector, Partícules (Física nuclear), Optics, Photo multiplier tube, 0103 physical sciences, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Optoelectronics, 010306 general physics, numerical calculations, Particles (Nuclear physics), Astroparticle physics, 010308 nuclear & particles physics, business.industry, Herenkov detectors, visible and IR photons (vacuum), Photomultipliers, Photonics, FISICA APLICADA, Large detector systems for particle and astroparticle physic, Òptica -- Aparells i instruments, Neutrino telescopes, Photon detectors for UV,visible and IR photons (vacuum), business, Telescopes
Abstract

[EN] The Hamamatsu R12199-02 3-inch photomultiplier tube is the photodetector chosen for the first phase of the KM3NeT neutrino telescope. About 7000 photomultipliers have been characterised for dark count rate, timing spread and spurious pulses. The quantum eÿciency, the gain and the peak-to-valley ratio have also been measured for a sub-sample in order to determine parameter values needed as input to numerical simulations of the detector., The authors acknowledge the financial support of the funding agencies: Agence Nationale de la Recherche (contract ANR-15-CE31-0020), Centre National de la Recherche Scientifique (CNRS), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cite (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02), France; 'Helmholtz Alliance for Astroparticle Physics' funded by the Initiative and Networking Fund of the Helmholtz Association, Germany; The General Secretariat of Research and Technology (GSRT), Greece; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Italy; Agence de l'Oriental and CNRST, Morocco; Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; National Authority for Scientific Research (ANCS), Romania; Plan Estatal de Investigacion (refs. FPA2015-65150-C3-1-P, -2-P and -3-P, (MINECO/FEDER)), Severo Ochoa Centre of Excellence and MultiDark Consolider (MINECO), and Prometeo and Grisolia programs (Generalitat Valenciana), Spain.

Published
2018

46. Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics

Author

Andreas R. Janecke, Solaf M. Elsayed, Francesca Fabretti, Peter Nürnberg, Ezzat Elsobky, Georg Christoph Korenke, Friederike Koerber, Klaus Addicks, Max C. Liebau, Inga Ebermann, Hanno J. Bolz, Thomas Benzing, Eugen Boltshauser, Claudia Dafinger, Hanswalter Zentgraf, Bernhard Schermer, Yorck Hellenbroich, Gudrun Nürnberg, University of Zurich, and Schermer, B

Subjects
Male, DNA Mutational Analysis, Golgi Apparatus, Kinesins, 610 Medicine & health, 2700 General Medicine, Biology, Microtubules, Retina, Joubert syndrome, Motor protein, Consanguinity, Mice, Cerebellar Diseases, Microtubule, Cerebellum, Gene duplication, medicine, Animals, Humans, Abnormalities, Multiple, Hedgehog Proteins, Tissue Distribution, Eye Abnormalities, RNA, Small Interfering, Genetics, Chromosomes, Human, Pair 15, Brief Report, Cilium, General Medicine, Kidney Diseases, Cystic, medicine.disease, Phenotype, Hedgehog signaling pathway, Pedigree, Cell biology, 10036 Medical Clinic, Kinesin, Drosophila, Signal Transduction
Abstract

Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.

Published
2011

47. A Comparative Analysis of Anti-Discrimination and Data Protection Legislations

Author

Serge Gutwirth, Katja de Vries, Raphael Gellert, Paul De Hert, Custers, B., Calders, T., Schermer, B., Zarsky, T., University of Brussels - European Criminal Law, Metajuridica, Law Science Technology and Society, and Fundamental rights centre

Subjects
antidiscrimination, Political science, Negative liberty, Data Protection Act 1998, Fundamental rights, Indirect discrimination, privacy, Data protection, Law and economics
Abstract

The make a comparison between European anti-discrimination law and data protection law. Both the differences and the overlap are discussed. They show that both rights have the same structure and increasingly turn to the same mode of operation in the information society, even though their content is far from identical. They show that this is because both rights are grounded in the notion of negative freedom as evidenced by I. Berlin, and thus aim at safeguarding the autonomy of the citizen in the information society. Finally, they analyze two cases where both rights apply, and draw conclusions on how to best articulate the two tools. Departing from the ECJ's Huber case where Germany was condemned for discriminatory processing of personal data and which suggests that there is a strong kin between data protection and discrimination issues, this chapter is an attempt to further compare the two fundamental rights (i.e., non-discrimination, and data protection). Beyond their place in the EU legal order, their respective object or scope, this chapter will contend that these two human rights increasingly turn to the same mode of operation, including, inter alia, reliance upon administrative structures and procedures, or the endowment of citizens with a bundle of individual rights. We will argue that this similarity can be understood in the light of their nature as regulatory human rights, that is, embodying the logic of negative freedom (cf. Berlin). The final section will examine situations of overlap between the rights, building upon the Huber and Test-Achats cases. This will lead to final conclusions on how to best articulate these rights.

Published
2013

48. A Mammalian microRNA Expression Atlas Based on Small RNA Library Sequencing

Author

Astrid Novosel, Markus Landthaler, Julia Schliwka, Sabina Chiaretti, Miklós Palkovits, Roberto Di Lauro, Nicola Iovino, Mirabela Rusu, Roman-Ulrich Müller, Giuseppe Macino, James W. Nagle, Andreas Bosio, Mihaela Zavolan, Peter Wernet, Alice O. Kamphorst, Charles E. Rogler, Chris Sander, Veit Hornung, James J. Russo, Wayne Tam, Thomas Benzing, Alexei A. Aravin, Uta Fuchs, Thomas Tuschl, Pablo Landgraf, Sébastien Pfeffer, Alain Sewer, Hans Ingo Trompeter, Jason M. Inman, Ruchi Choksi, Amanda J. Rice, Arndt Borkhardt, Robert L. Sheridan, Valerio Fulci, Carolina Lin, Leandro C. Hermida, Michael J. Brownstein, Ute Bissels, Bernhard Schermer, Daniela Frezzetti, Minchen Chien, Grace Teng, Jingyue Ju, Quang Phan, Gunther Hartmann, F. Nina Papavasiliou, Robin Foà, Nicholas D. Socci, David B. Weir, Gabriella De Vita, Peter Lichter, Landgraf, P, Rusu, M, Sheridan, R, Sewer, A, Iovino, N, Aravin, A, Pfeffer, S, Rice, A, Kamphorst, Ao, Landthaler, M, Lin, C, Socci, Nd, Hermida, L, Fulci, V, Chiaretti, S, Foa, R, Schliwka, J, Fuchs, U, Novosel, A, Muller, Ru, Schermer, B, Bissels, U, Inman, J, Phan, Q, Chien, M, Weir, Db, Choksi, R, DE VITA, Gabriella, Frezzetti, D, Trompeter, Hi, Hornung, V, Teng, G, Hartmann, G, Palkovits, M, DI LAURO, Roberto, Wernet, P, Macino, G, Rogler, Ce, Nagle, Jw, Ju, J, Papavasiliou, Fn, Benzing, T, Lichter, P, Tam, W, Brownstein, Mj, Bosio, A, Borkhardt, A, Russo, Jj, Sander, C, Zavolan, M, Tuschl, T., Institut de biologie moléculaire des plantes (IBMP), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Small RNA, moleneuro, molimmuno, rna, Molecular Sequence Data, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Genome, General Biochemistry, Genetics and Molecular Biology, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, IsomiR, Mirtron, Sequence Homology, Nucleic Acid, microRNA, Animals, Humans, Cell Lineage, RNA, Messenger, MOLIMMUNO, Conserved Sequence, Phylogeny, MOLENEURO, Gene Library, 030304 developmental biology, Genetics, Regulation of gene expression, 0303 health sciences, Base Sequence, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, RNA, Hematopoietic Stem Cells, Rats, Gene expression profiling, MicroRNAs, Gene Expression Regulation, Hematologic Neoplasms, 030220 oncology & carcinogenesis
Abstract

SummaryMicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. In order to identify miRNAs and to assess their expression patterns, we sequenced over 250 small RNA libraries from 26 different organ systems and cell types of human and rodents that were enriched in neuronal as well as normal and malignant hematopoietic cells and tissues. We present expression profiles derived from clone count data and provide computational tools for their analysis. Unexpectedly, a relatively small set of miRNAs, many of which are ubiquitously expressed, account for most of the differences in miRNA profiles between cell lineages and tissues. This broad survey also provides detailed and accurate information about mature sequences, precursors, genome locations, maturation processes, inferred transcriptional units, and conservation patterns. We also propose a subclassification scheme for miRNAs for assisting future experimental and computational functional analyses.

Published
2007

49. The podocytes' inflammatory responses in experimental GN are independent of canonical MYD88-dependent toll-like receptor signaling.

Author

Schömig T, Diefenhardt P, Plagmann I, Trinsch B, Merz T, Crispatzu G, Unnersjö-Jess D, Nies J, Pütz D, Sierra Gonzalez C, Schermer B, Benzing T, Brinkkoetter PT, and Brähler S

Subjects
Animals, Mice, Adaptor Proteins, Signal Transducing metabolism, Inflammation pathology, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Proteinuria metabolism, Toll-Like Receptors metabolism, Glomerulonephritis pathology, Podocytes metabolism
Abstract

Podocytes form the kidney filtration barrier and continuously adjust to external stimuli to preserve their integrity even in the presence of inflammation. It was suggested that canonical toll-like receptor signaling, mediated by the adaptor protein MYD88, plays a crucial role in initiating inflammatory responses in glomerulonephritis (GN). We explored the influence of podocyte-intrinsic MYD88 by challenging wild-type (WT) and podocyte-specific Myd88 knockout (MyD88 pko ) mice, with a model of experimental GN (nephrotoxic nephritis, NTN). Next-generation sequencing revealed a robust upregulation of inflammatory pathways and changes in cytoskeletal and cell adhesion proteins in sorted podocytes from WT mice during disease. Unchallenged MyD88 pko mice were healthy and showed no proteinuria, normal kidney function and lacked morphological changes. During NTN, MyD88 pko exhibited a transient increase in proteinuria in comparison to littermates, while histological damage, podocyte ultrastructure in STED imaging and frequencies of infiltrating immune cells by flow cytometry were unchanged. MYD88-deficiency led to subtle changes in the podocyte transcriptome, without a significant impact on the overall podocyte response to inflammation, presumably through MYD88-independent signaling pathways. In conclusion, our study reveals a comprehensive analysis of podocyte adaptation to an inflammatory environment on the transcriptome level, while MYD88-deficiency had only limited impact on the course of GN suggesting additional signaling through MYD88-independent signaling., (© 2024. The Author(s).)

Published
2024
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50. In vivo characterization of a podocyte-expressed short podocin isoform.

Author

Butt L, Unnersjö-Jess D, Reilly D, Hahnfeldt R, Rinschen MM, Bozek K, Schermer B, Benzing T, and Höhne M

Subjects
Humans, Animals, Mice, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, RNA, Messenger metabolism, Podocytes metabolism, Nephrotic Syndrome genetics, Nephrotic Syndrome metabolism
Abstract

The most common genetic causes of steroid-resistant nephrotic syndrome (SRNS) are mutations in the NPHS2 gene, which encodes the cholesterol-binding, lipid-raft associated protein podocin. Mass spectrometry and cDNA sequencing revealed the existence of a second shorter isoform in the human kidney in addition to the well-studied canonical full-length protein. Distinct subcellular localization of the shorter isoform that lacks part of the conserved PHB domain suggested a physiological role. Here, we analyzed whether this protein can substitute for the canonical full-length protein. The short isoform of podocin is not found in other organisms except humans. We therefore analysed a mouse line expressing the equivalent podocin isoform (podocin Δexon5 ) by CRISPR/Cas-mediated genome editing. We characterized the phenotype of these mice expressing podocin Δexon5 and used targeted mass spectrometry and qPCR to compare protein and mRNA levels of podocin wildtype and podocin Δexon5 . After immunolabeling slit diaphragm components, STED microscopy was applied to visualize alterations of the podocytes' foot process morphology.Mice homozygous for podocin Δexon5 were born heavily albuminuric and did not survive past the first 24 h after birth. Targeted mass spectrometry revealed massively decreased protein levels of podocin Δexon5 , whereas mRNA abundance was not different from the canonical form of podocin. STED microscopy revealed the complete absence of podocin at the podocytes' slit diaphragm and severe morphological alterations of podocyte foot processes. Mice heterozygous for podocin Δexon5 were phenotypically and morphologically unaffected despite decreased podocin and nephrin protein levels.The murine equivalent to the human short isoform of podocin cannot stabilize the lipid-protein complex at the podocyte slit diaphragm. Reduction of podocin levels at the site of the slit diaphragm complex has a detrimental effect on podocyte function and morphology. It is associated with decreased protein abundance of nephrin, the central component of the filtration-slit forming slit diaphragm protein complex., (© 2023. The Author(s).)

Published
2023
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