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144 results on '"Spielmann, Nadine"'

1. X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes

Author

Hasenbein, Tim P., Hoelzl, Sarah, Smith, Zachary D., Gerhardinger, Chiara, Gonner, Marion O. C., Aguilar-Pimentel, Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Dragano, Nathalia R. V., da Silva-Buttkus, Patricia, Garrett, Lillian, Hölter, Sabine M., Kraiger, Markus, Östereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Spielmann, Nadine, Wurst, Wolfgang, Gailus-Durner, Valerie, Fuchs, Helmut, Hrabě de Angelis, Martin, Meissner, Alexander, Engelhardt, Stefan, Rinn, John L., and Andergassen, Daniel

Published
2024
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3. Single-cell, whole-embryo phenotyping of mammalian developmental disorders

Author

Huang, Xingfan, Henck, Jana, Qiu, Chengxiang, Sreenivasan, Varun KA, Balachandran, Saranya, Amarie, Oana V, Hrabě de Angelis, Martin, Behncke, Rose Yinghan, Chan, Wing-Lee, Despang, Alexandra, Dickel, Diane E, Duran, Madeleine, Feuchtinger, Annette, Fuchs, Helmut, Gailus-Durner, Valerie, Haag, Natja, Hägerling, Rene, Hansmeier, Nils, Hennig, Friederike, Marshall, Cooper, Rajderkar, Sudha, Ringel, Alessa, Robson, Michael, Saunders, Lauren M, da Silva-Buttkus, Patricia, Spielmann, Nadine, Srivatsan, Sanjay R, Ulferts, Sascha, Wittler, Lars, Zhu, Yiwen, Kalscheuer, Vera M, Ibrahim, Daniel M, Kurth, Ingo, Kornak, Uwe, Visel, Axel, Pennacchio, Len A, Beier, David R, Trapnell, Cole, Cao, Junyue, Shendure, Jay, and Spielmann, Malte

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Mice, Cell Nucleus, Developmental Disabilities, Embryo, Mammalian, Gain of Function Mutation, Genotype, Loss of Function Mutation, Models, Genetic, Mutation, Phenotype, Single-Cell Gene Expression Analysis, Disease Models, Animal, General Science & Technology
Abstract

Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

Published
2023

4. EchoVisuAL: Efficient Segmentation of Echocardiograms Using Deep Active Learning

Author

Galter, Isabella, Schneltzer, Elida, Marr, Carsten, Consortium, IMPC, Spielmann, Nadine, Hrabě de Angelis, Martin, Goos, Gerhard, Series Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Yap, Moi Hoon, editor, Kendrick, Connah, editor, Behera, Ardhendu, editor, Cootes, Timothy, editor, and Zwiggelaar, Reyer, editor

Published
2024
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6. Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice

Author

Oestereicher, Manuela A., Wotton, Janine M., Ayabe, Shinya, Bou About, Ghina, Cheng, Tsz Kwan, Choi, Jae-Hoon, Clary, Dave, Dew, Emily M., Elfertak, Lahcen, Guimond, Alain, Haseli Mashhadi, Hamed, Heaney, Jason D., Kelsey, Lois, Keskivali-Bond, Piia, Lopez Gomez, Federico, Marschall, Susan, McFarland, Michael, Meziane , Hamid, Munoz Fuentes, Violeta, Nam , Ki-Hoan, Nichtová, Zuzana, Pimm, Dale, Bower, Lynette, Prochazka, Jan, Rozman, Jan, Santos, Luis, Stewart, Michelle, Tanaka, Nobuhiko, Ward, Christopher S., Willett, Amelia M. E., Wilson, Robert, Braun, Robert E., Dickinson, Mary E., Flenniken, Ann M., Herault, Yann, Lloyd, K. C. Kent, Mallon, Ann-Marie, McKerlie, Colin, Murray, Stephen A., Nutter, Lauryl M. J., Sedlacek, Radislav, Seong, Je Kyung, Sorg, Tania, Tamura, Masaru, Wells, Sara, Schneltzer, Elida, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, White, Jacqueline K., and Spielmann, Nadine

Published
2023
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8. Knockout mouse models as a resource for the study of rare diseases

Author

da Silva-Buttkus, Patricia, Spielmann, Nadine, Klein-Rodewald, Tanja, Schütt, Christine, Aguilar-Pimentel, Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Garrett, Lillian, Gerlini, Raffaele, Kraiger, Markus, Leuchtenberger, Stefanie, Östereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Stöger, Claudia, Hölter, Sabine M., Seisenberger, Claudia, Marschall, Susan, Fuchs, Helmut, Gailus-Durner, Valerie, and Hrabě de Angelis, Martin

Published
2023
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11. Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain

Author

Aguilar-Pimental, Juan A., Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Da Silva-Buttkus, Patricia, Dragano, Nathalia, Kraiger, Markus, Lengger, Christoph, Leuchtenberger, Stefanie, Marschall, Susan, Oestereicher, Manuela A., Rathkolb, Birgit, Sanz-Moreno, Adrián, Seisenberger, Claudia, Spielmann, Nadine, Stoeger, Claudia, Kumar, Vivek, Keskivali, Piia, King, Ruairidh, Haselimashhadi, Hamed, Bezginov, Alexandr, Norris, Clare, Taylor, Sarah, Pimm, Dale, Kelsey, Lois, Berberovic, Zorana, Qu, Dawei, D'Souza, Abigail, Bradaschia, Vivian, Eskandarian, Mohammed, Shang, Xueyuan, Duffin, Kyle, Roberton, Kyle, Xu, Catherine, Baguinat, Gloria, Laurin, Valerie, Lan, Qing, Sleep, Gillian, Lintott, Lauri, Gertsenstein, Marina, Tondat, Sandra, Cruz, Maribelle, Miller, David, Sorg, Tania, Riet, Fabrice, Tolentino, Heather, Tolentino, Todd, Schuchbauer, Mike, Hockenbury, Nichole, Beeman, Karrie, Pedroia, Sheryl, Salazar, Jason, Heffner, Mollie, Hsu, Joanne, Fletcher, Colin, Vanzanten, Maya, Golini, Elisabetta, Seavitt, John R., Lanza, Denise G., Lorenzo, Isabel, Gaspero, Angelina, Rios, Amanda, Garrett, Lillian, Trümbach, Dietrich, Lee, Donghyung, Mandillo, Silvia, Samaco, Rodney, Flenniken, Ann M., Stewart, Michelle, White, Jacqueline K., McKerlie, Colin, Nutter, Lauryl M.J., Vukobradovic, Igor, Veeraragavan, Surabi, Yuva, Lisa, Heaney, Jason D., Dickinson, Mary E., Meziane, Hamid, Hérault, Yann, Wells, Sara, Lloyd, K.C. Kent, Bower, Lynette, Lanoue, Louise, Clary, Dave, Zimprich, Annemarie, Gailus-Durner, Valerie, Fuchs, Helmut, Brown, Steve D.M., Chesler, Elissa J., Wurst, Wolfgang, Hrabě de Angelis, Martin, and Hölter, Sabine M.

Published
2024
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12. AOX delays the onset of the lethal phenotype in a mouse model of Uqcrh (complex III) disease

Author

Jacobs, Howard T., Szibor, Marten, Rathkolb, Birgit, da Silva-Buttkus, Patricia, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Dragano, Nathalia, Garrett, Lillian, Gerlini, Raffaele, Hölter, Sabine M., Klein-Rodewald, Tanja, Kraiger, Markus, Leuchtenberger, Stefanie, Marschall, Susan, Östereicher, Manuela A., Pfannes, Kristina, Sanz-Moreno, Adrián, Seisenberger, Claudia, Spielmann, Nadine, Stoeger, Claudia, Wurst, Wolfgang, Fuchs, Helmut, Hrabě de Angelis, Martin, and Gailus-Durner, Valérie

Published
2023
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13. Soft windowing application to improve analysis of high-throughput phenotyping data

Author

Haselimashhadi, Hamed, Mason, Jeremy C, Munoz-Fuentes, Violeta, López-Gómez, Federico, Babalola, Kolawole, Acar, Elif F, Kumar, Vivek, White, Jacqui, Flenniken, Ann M, King, Ruairidh, Straiton, Ewan, Seavitt, John Richard, Gaspero, Angelina, Garza, Arturo, Christianson, Audrey E, Hsu, Chih-Wei, Reynolds, Corey L, Lanza, Denise G, Lorenzo, Isabel, Green, Jennie R, Gallegos, Juan J, Bohat, Ritu, Samaco, Rodney C, Veeraragavan, Surabi, Kim, Jong Kyoung, Miller, Gregor, Fuchs, Helmult, Garrett, Lillian, Becker, Lore, Kang, Yeon Kyung, Clary, David, Cho, Soo Young, Tamura, Masaru, Tanaka, Nobuhiko, Soo, Kyung Dong, Bezginov, Alexandr, About, Ghina Bou, Champy, Marie-France, Vasseur, Laurent, Leblanc, Sophie, Meziane, Hamid, Selloum, Mohammed, Reilly, Patrick T, Spielmann, Nadine, Maier, Holger, Gailus-Durner, Valerie, Sorg, Tania, Hiroshi, Masuya, Yuichi, Obata, Heaney, Jason D, Dickinson, Mary E, Wolfgang, Wurst, Tocchini-Valentini, Glauco P, Lloyd, Kevin C Kent, McKerlie, Colin, Seong, Je Kyung, Yann, Herault, de Angelis, Martin Hrabé, Brown, Steve DM, Smedley, Damian, Flicek, Paul, Mallon, Ann-Marie, Parkinson, Helen, and Meehan, Terrence F

Subjects
Biological Sciences, Genetics, Animals, Genetic Association Studies, Humans, Mice, Phenotype, Population Health, Software, Mathematical Sciences, Information and Computing Sciences, Bioinformatics, Biological sciences, Information and computing sciences, Mathematical sciences
Abstract

MotivationHigh-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors.ResultsHere we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.Availability and implementationThe method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.Supplementary informationSupplementary data are available at Bioinformatics online.

Published
2020

14. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Swan, Anna L, Schütt, Christine, Rozman, Jan, del Mar Muñiz Moreno, Maria, Brandmaier, Stefan, Simon, Michelle, Leuchtenberger, Stefanie, Griffiths, Mark, Brommage, Robert, Keskivali-Bond, Piia, Grallert, Harald, Werner, Thomas, Teperino, Raffaele, Becker, Lore, Miller, Gregor, Moshiri, Ala, Seavitt, John R, Cissell, Derek D, Meehan, Terrence F, Acar, Elif F, Lelliott, Christopher J, Flenniken, Ann M, Champy, Marie-France, Sorg, Tania, Ayadi, Abdel, Braun, Robert E, Cater, Heather, Dickinson, Mary E, Flicek, Paul, Gallegos, Juan, Ghirardello, Elena J, Heaney, Jason D, Jacquot, Sylvie, Lally, Connor, Logan, John G, Teboul, Lydia, Mason, Jeremy, Spielmann, Nadine, McKerlie, Colin, Murray, Stephen A, Nutter, Lauryl MJ, Odfalk, Kristian F, Parkinson, Helen, Prochazka, Jan, Reynolds, Corey L, Selloum, Mohammed, Spoutil, Frantisek, Svenson, Karen L, Vales, Taylor S, Wells, Sara E, White, Jacqueline K, Sedlacek, Radislav, Wurst, Wolfgang, Lloyd, KC Kent, Croucher, Peter I, Fuchs, Helmut, Williams, Graham R, Bassett, JH Duncan, Gailus-Durner, Valerie, Herault, Yann, Mallon, Ann-Marie, Brown, Steve DM, Mayer-Kuckuk, Philipp, and Hrabe de Angelis, Martin

Subjects
Biological Sciences, Genetics, Aging, Osteoporosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Musculoskeletal, Animals, Bone Density, Female, Gene Expression Regulation, Gene Ontology, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Male, Mice, Mice, Transgenic, Mutation, Osteoblasts, Osteoclasts, Phenotype, Promoter Regions, Genetic, Protein Interaction Maps, Sex Characteristics, Transcriptome, IMPC Consortium, Developmental Biology
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Published
2020

16. Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice

Author

Xie, Kan, Fuchs, Helmut, Scifo, Enzo, Liu, Dan, Aziz, Ahmad, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, da Silva-Buttkus, Patricia, Calzada-Wack, Julia, Cho, Yi-Li, Deng, Yushuang, Edwards, A. Cole, Garrett, Lillian, Georgopoulou, Christina, Gerlini, Raffaele, Hölter, Sabine M., Klein-Rodewald, Tanja, Kramer, Michael, Leuchtenberger, Stefanie, Lountzi, Dimitra, Mayer-Kuckuk, Phillip, Nover, Lena L., Oestereicher, Manuela A., Overkott, Clemens, Pearson, Brandon L., Rathkolb, Birgit, Rozman, Jan, Russ, Jenny, Schaaf, Kristina, Spielmann, Nadine, Sanz-Moreno, Adrián, Stoeger, Claudia, Treise, Irina, Bano, Daniele, Busch, Dirk H., Graw, Jochen, Klingenspor, Martin, Klopstock, Thomas, Mock, Beverly A., Salomoni, Paolo, Schmidt-Weber, Carsten, Weiergräber, Marco, Wolf, Eckhard, Wurst, Wolfgang, Gailus-Durner, Valérie, Breteler, Monique M. B., Hrabě de Angelis, Martin, and Ehninger, Dan

Published
2022
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17. Co-expression of prepulse inhibition and schizophrenia genes in the mouse and human brain

Author

Garrett, Lillian, primary, Trümbach, Dietrich, additional, Lee, Dongyhung, additional, Mandillo, Silvia, additional, Samaco, Rodney, additional, Flenniken, Ann M., additional, Stewart, Michelle, additional, Aguilar-Pimental, Juan A., additional, Amarie, Oana V., additional, Becker, Lore, additional, Calzada-Wack, Julia, additional, Da Silva-Buttkus, Patricia, additional, Dragano, Nathalia, additional, Kraiger, Markus, additional, Lengger, Christoph, additional, Leuchtenberger, Stefanie, additional, Marschall, Susan, additional, Oestereicher, Manuela A., additional, Rathkolb, Birgit, additional, Sanz-Moreno, Adrián, additional, Seisenberger, Claudia, additional, Spielmann, Nadine, additional, Stoeger, Claudia, additional, Kumar, Vivek, additional, Keskivali, Piia, additional, King, Ruairidh, additional, Haselimashhadi, Hamed, additional, Bezginov, Alexandr, additional, Norris, Clare, additional, Taylor, Sarah, additional, Pimm, Dale, additional, Kelsey, Lois, additional, Berberovic, Zorana, additional, Qu, Dawei, additional, D'Souza, Abigail, additional, Bradaschia, Vivian, additional, Eskandarian, Mohammed, additional, Shang, Xueyuan, additional, Duffin, Kyle, additional, Roberton, Kyle, additional, Xu, Catherine, additional, Baguinat, Gloria, additional, Laurin, Valerie, additional, Lan, Qing, additional, Sleep, Gillian, additional, Lintott, Lauri, additional, Gertsenstein, Marina, additional, Tondat, Sandra, additional, Cruz, Maribelle, additional, Miller, David, additional, Sorg, Tania, additional, Riet, Fabrice, additional, Tolentino, Heather, additional, Tolentino, Todd, additional, Schuchbauer, Mike, additional, Hockenbury, Nichole, additional, Beeman, Karrie, additional, Pedroia, Sheryl, additional, Salazar, Jason, additional, Heffner, Mollie, additional, Hsu, Joanne, additional, Fletcher, Colin, additional, Vanzanten, Maya, additional, Golini, Elisabetta, additional, Seavitt, John R., additional, Lanza, Denise G., additional, Lorenzo, Isabel, additional, Gaspero, Angelina, additional, Rios, Amanda, additional, White, Jacqueline K., additional, McKerlie, Colin, additional, Nutter, Lauryl M.J., additional, Vukobradovic, Igor, additional, Veeraragavan, Surabi, additional, Yuva, Lisa, additional, Heaney, Jason D., additional, Dickinson, Mary E., additional, Meziane, Hamid, additional, Hérault, Yann, additional, Wells, Sara, additional, Lloyd, K.C.Kent, additional, Bower, Lynette, additional, Lanoue, Louise, additional, Clary, Dave, additional, Zimprich, Annemarie, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Brown, Steve D.M., additional, Chesler, Elissa J., additional, Wurst, Wolfgang, additional, Hrabě de Angelis, Martin, additional, and Hölter, Sabine M., additional

Published
2024
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18. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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19. Creld1 regulates myocardial development and function

Author

Beckert, Vera, Rassmann, Sebastian, Kayvanjoo, Amir Hossein, Klausen, Christina, Bonaguro, Lorenzo, Botermann, Dominik Simon, Krause, Melanie, Moreth, Kristin, Spielmann, Nadine, da Silva-Buttkus, Patricia, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabě, Händler, Kristian, Ulas, Thomas, Aschenbrenner, Anna C., Mass, Elvira, and Wachten, Dagmar

Published
2021
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20. Publisher Correction: Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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21. In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria

Author

Lucienne, Marie, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Garrett, Lillian, Hölter, Sabine M., Mayer-Kuckuk, Philipp, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Busch, Dirk H., Klopstock, Thomas, Schmidt-Weber, Carsten, Wolf, Eckhard, Wurst, Wolfgang, Forny, Merima, Mathis, Déborah, Fingerhut, Ralph, Froese, D. Sean, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabě, and Baumgartner, Matthias R.

Published
2020
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22. Characterising a homozygous two‐exon deletion in UQCRH: comparing human and mouse phenotypes

Author

Vidali, Silvia, Gerlini, Raffaele, Thompson, Kyle, Urquhart, Jill E, Meisterknecht, Jana, Aguilar‐Pimentel, Juan Antonio, Amarie, Oana V, Becker, Lore, Breen, Catherine, Calzada‐Wack, Julia, Chhabra, Nirav F, Cho, Yi‐Li, da Silva‐Buttkus, Patricia, Feichtinger, René G, Gampe, Kristine, Garrett, Lillian, Hoefig, Kai P, Hölter, Sabine M, Jameson, Elisabeth, Klein‐Rodewald, Tanja, Leuchtenberger, Stefanie, Marschall, Susan, Mayer‐Kuckuk, Philipp, Miller, Gregor, Oestereicher, Manuela A, Pfannes, Kristina, Rathkolb, Birgit, Rozman, Jan, Sanders, Charlotte, Spielmann, Nadine, Stoeger, Claudia, Szibor, Marten, Treise, Irina, Walter, John H, Wurst, Wolfgang, Mayr, Johannes A, Fuchs, Helmut, Gärtner, Ulrich, Wittig, Ilka, Taylor, Robert W, Newman, William G, Prokisch, Holger, Gailus‐Durner, Valerie, and Hrabě de Angelis, Martin

Published
2021
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23. Comparative Phenotyping of Mice Reveals Canonical and Noncanonical Physiological Functions of TRα and TRβ.

Author

Hönes, Georg Sebastian, Geist, Daniela, Wenzek, Christina, Pfluger, Paul Thomas, Müller, Timo Dirk, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, Dragano, Natalia, Garrett, Lillian, Hölter, Sabine Maria, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Wolf, Eckhard, Wurst, Wolfgang, Fuchs, Helmut, Gailus-Durner, Valerie, and Angelis, Martin Hrabe de

Subjects
ACTION spectrum, THYROID hormone receptors, MICE, MUSCLE metabolism, KNOCKOUT mice
Abstract

Thyroid hormone (TH) effects are mediated through TH receptors (TRs), TRα1, TRβ1, and TRβ2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. The aim of this study was to attribute physiological effects to the TR isoforms and their canonical and noncanonical signaling. We conducted multiparameter phenotyping in male and female TR knockout mice (TRαKO, TRβKO), mice with disrupted canonical signaling due to mutations in the TR DNA binding domain (TRαGS, TRβGS), and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRβ with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRβ), and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization, or increased anxiety-related behavior were only observed in TRαKO but not TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRβ knockout models alongside their DNA binding–deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRβ play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Canonical and Noncanonical Contribution of Thyroid Hormone Receptor Isoforms Alpha and Beta to Cardiac Hypertrophy and Heart Rate in Male Mice.

Author

Geist, Daniela, Hönes, Georg Sebastian, Grund, Susanne Camilla, Pape, Janina, Siemes, Devon, Spangenberg, Philippa, Tolstik, Elen, Dörr, Stefanie, Spielmann, Nadine, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Mittag, Jens, Engel, Daniel Robert, Führer, Dagmar, Lorenz, Kristina, and Moeller, Lars Christian

Subjects
THYROID hormone receptors, CARDIAC hypertrophy, HEART beat, MICE, POLYMERASE chain reaction
Abstract

Background: Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). The aim of this study was to determine in vivo which TH receptor (TR)—α or β—and which mode of TR action—canonical gene expression or DNA-binding independent noncanonical action—mediate these effects. Methods: We compared global TRα and TRβ knockout mice (TRαKO; TRβKO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRβGS). Hearts were studied with echocardiography at baseline and after 7 weeks of T3 treatment. Gene expression was measured with real-time polymerase chain reaction. Heart rate was recorded with radiotelemetry transmitters for 7 weeks in untreated, hypothyroid, and T3-treated mice. Results: T3 induced ventricular hypertrophy in WT and TRβKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRαKO mice, demonstrating that TRβ could compensate for absence of TRα. Conclusions: T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRβ could substitute for canonical but not noncanonical TRα action. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Comparative phenotyping of mice reveals canonical and noncanonical physiological functions of TRα and TRβ

Author

Hönes, Georg Sebastian, primary, Geist, Daniela, additional, Wenzek, Christina, additional, Pfluger, Paul T, additional, Müller, Timo D, additional, Amarie, Oana V, additional, Becker, Lore, additional, Dragano, Nathalia, additional, Garrett, Lillian, additional, Hölter, Sabine M, additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Spielmann, Nadine, additional, Treise, Irina, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, de Angelis, Martin H, additional, Führer, Dagmar, additional, and Moeller, Lars C, additional

Published
2023
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27. Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice

Author

Geist, Daniela, primary, Hönes, Georg Sebastian, additional, Grund, Susanne Camilla, additional, Pape, Janina, additional, Siemes, Devon, additional, Spangenberg, Philippa, additional, Tolstik, Elen, additional, Dörr, Stefanie, additional, Spielmann, Nadine, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, Hrabe de Angelis, Martin, additional, Mittag, Jens, additional, Engel, Daniel Robert, additional, Führer, Dagmar, additional, Lorenz, Kristina, additional, and Moeller, Lars Christian, additional

Published
2023
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28. Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

Author

Auffenberg, Eva, Hedrich, Ulrike B.S., Barbieri, Raffaella, Miely, Daniela, Groschup, Bernhard, Wuttke, Thomas V., Vogel, Niklas, Luhrs, Philipp, Zanardi, Ilaria, Bertelli, Sara, Spielmann, Nadine, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabe, Pusch, Michael, Dichgans, Martin, Lerche, Holger, Gavazzo, Paola, Plesnila, Nikolaus, and Freilinger, Tobias

Subjects
Cerebral cortex -- Physiological aspects -- Health aspects, Neural oscillations -- Health aspects -- Genetic aspects, Migraine -- Models -- Genetic aspects -- Physiological aspects, Neural transmission -- Health aspects -- Genetic aspects, Health care industry
Abstract

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated [Na.sup.+] channel [Na.sub.V]1.1 predominantly expressed in inhibitory interneurons. Homozygous [Scn1a.sup.L1649Q] knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous [Scn1a.sup.L1649Q] knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired [Na.sup.+]*-channel inactivation and increased ramp [Na.sup.+] currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using [K.sup.+]-sensitive electrodes revealed an increase in extracellular [K.sup.+] in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous [Scn1a.sup.L1649Q] knock-in mice was partially rescued by GS967, a blocker of persistent [Na.sup.+] currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD., Introduction With a prevalence of 10% to 15% in the general population, migraine is one of the most common neurological diseases (1, 2) and is rated as one of the [...]

Published
2021
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31. Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction

Author

Spielmann, Nadine, primary, Schenkl, Christina, additional, Komlódi, Tímea, additional, da Silva-Buttkus, Patricia, additional, Heyne, Estelle, additional, Rohde, Jana, additional, Amarie, Oana V., additional, Rathkolb, Birgit, additional, Gnaiger, Erich, additional, Doenst, Torsten, additional, Fuchs, Helmut, additional, Gailus-Durner, Valérie, additional, de Angelis, Martin Hrabě, additional, and Szibor, Marten, additional

Published
2022
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33. Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors

Author

Bayindir‐Buchhalter, Irem, Wolff, Gretchen, Lerch, Sarah, Sijmonsma, Tjeerd, Schuster, Maximilian, Gronych, Jan, Billeter, Adrian T, Babaei, Rohollah, Krunic, Damir, Ketscher, Lars, Spielmann, Nadine, Hrabe de Angelis, Martin, Ruas, Jorge L, Müller‐Stich, Beat P, Heikenwalder, Mathias, Lichter, Peter, Herzig, Stephan, and Vegiopoulos, Alexandros

Published
2018
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35. Knockout mouse models as a resource for rare diseases studies

Author

Silva-Buttkus, Patricia da, primary, Spielmann, Nadine, additional, Klein-Rodewald, Tanja, additional, Schütt, Christine, additional, Aguilar-Pimentel, Antonio, additional, Amarie, Oana V., additional, Becker, Lore, additional, Calzada-Wack, Julia, additional, Garrett, Lillian, additional, Gerlini, Raffaele, additional, Kraiger, Markus, additional, Leuchtenberger, Stefanie, additional, Östereicher, Manuela A., additional, Rathkolb, Birgit, additional, Sanz-Moreno, Adrián, additional, Stöger, Claudia, additional, Hölter, Sabine M., additional, Seisenberger, Claudia, additional, Marschall, Susan, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, and de Angelis, Martin Hrabě, additional

Published
2022
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37. Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

Author

Xie, Kan, primary, Fuchs, Helmut, additional, Scifo, Enzo, additional, Liu, Dan, additional, Aziz, Ahmad, additional, Aguilar-Pimentel, Juan Antonio, additional, Amarie, Oana Veronica, additional, Becker, Lore, additional, da Silva-Buttkus, Patricia, additional, Calzada-Wack, Julia, additional, Cho, Yi-Li, additional, Deng, Yushuang, additional, Cole Edwards, A., additional, Garrett, Lillian, additional, Georgopoulou, Christina, additional, Gerlini, Raffaele, additional, Hölter, Sabine M., additional, Klein-Rodewald, Tanja, additional, Kramer, Michael, additional, Leuchtenberger, Stefanie, additional, Lountzi, Dimitra, additional, Mayer-Kuckuk, Phillip, additional, Nover, Lena L., additional, Oestereicher, Manuela A., additional, Overkott, Clemens, additional, Pearson, Brandon L., additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Russ, Jenny, additional, Schaaf, Kristina, additional, Spielmann, Nadine, additional, Sanz-Moreno, Adrián, additional, Stoeger, Claudia, additional, Treise, Irina, additional, Bano, Daniele, additional, Busch, Dirk H., additional, Graw, Jochen, additional, Klingenspor, Martin, additional, Klopstock, Thomas, additional, Mock, Beverly A., additional, Salomoni, Paolo, additional, Schmidt-Weber, Carsten, additional, Weiergräber, Marco, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Gailus-Durner, Valérie, additional, Breteler, Monique M.B., additional, de Angelis, Martin Hrabě, additional, and Ehninger, Dan, additional

Published
2022
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38. Post-synaptic scaffold protein TANC2 in psychiatric and somatic disease risk

Author

Garrett, Lillian, primary, Da Silva-Buttkus, Patricia, additional, Rathkolb, Birgit, additional, Gerlini, Raffaele, additional, Becker, Lore, additional, Sanz-Moreno, Adrian, additional, Seisenberger, Claudia, additional, Zimprich, Annemarie, additional, Aguilar-Pimentel, Antonio, additional, Amarie, Oana V., additional, Cho, Yi-Li, additional, Kraiger, Markus, additional, Spielmann, Nadine, additional, Calzada-Wack, Julia, additional, Marschall, Susan, additional, Busch, Dirk, additional, Schmitt-Weber, Carsten, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, Hölter, Sabine M., additional, and Hrabě de Angelis, Martin, additional

Published
2022
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39. Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy

Author

Raj Murthi, Sarala, Petry, Andreas, Shashikadze, Bachuki, Stöckl, Jan B., Schmid, Manuel, Santamaria, Gianluca, Klingel, Karin, Kračun, Damir, Chen, Xinpei, Bauer, Sabine, Schmitt, Joachim P., Flenkenthaler, Florian, Gorham, Josh, Toepfer, Christopher N., Potěšil, David, Hruška, Pavel, Zdráhal, Zbyněk, Mayer, Zsuzsanna, Klop, Mathieu, Lehmann, Luisa, Qin, Yishi, Papanakli, Laura, Spielmann, Nadine, Moretti, Alessandra, Fröhlich, Thomas, Ewert, Peter, Holdenrieder, Stefan, Seidman, Jonathan G., Seidman, Christine E., Görlach, Agnes, and Wolf, Cordula M.

Published
2025
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40. Angiotensin II response in afferent arterioles of mice lacking either the endothelial or neuronal isoform of nitric oxide synthase

Author

Patzak, Andreas, Steege, Andreas, Lai, En Yin, Brinkmann, Jan Ole, Kupsch, Eckehardt, Spielmann, Nadine, Gericke, Adrian, Skalweit, Angela, Stegbauer, Johannes, Persson, Pontus B., and Seeliger, Erdmann

Subjects
Renin-angiotensin system -- Research, Vascular endothelium -- Research, Microcirculation -- Research, Renal artery -- Research, Biological sciences
Abstract

The aim of the study is to evaluate the impact of nitric oxide (NO) produced by endothelial NO synthase (eNOS) and neuronal NOS (nNOS) on the angiotensin II response in afferent arterioles (Af). Dose responses were assessed for angiotensin II in microperfused Af of mice homozygous for disruption of the eNOS gene [eNOS(-/-)], or nNOS gene [nNOS(-/-)], and their wild-type controls, eNOS(+/+) and nNOS(+/+). Angiotensin II at [10.sup.-8] and [10.sup.-6] mol/1 reduced the lumen to 69% and 68% in eNOS(+/+), and to 59% and 50% in nNOS(+/+). [N.sup.G]-nitro-L-arginine methyl ester (L-NAME) did not change basal arteriolar diameters, but augmented angiotensin II contraction, reducing diameters to 23% and 13% in eNOS(+/+), and 7% and 10% in nNOS(+/+) at [10.sup.-8] and [10.sup.-6] mol/l. The response to angiotensin II was enhanced in nNOS(-/-) mice (41% and 25% at [10.sup.-8] and [10.sup.-6] mol/l) and even more enhanced in eNOS(-/-) mice (12% and 9%) compared with nNOS(+/+) and eNOS(+/+). L-NAME led to complete constriction of Af in these groups. Mediato-lumen ratios of Af did not differ between controls and gene-deficient mice. mRNA expression of angiotensin II receptor types IA and 1B and type 2 also did not differ. The results reveal that angiotensin II-induced release of NO from both eNOS and nNOS significantly contributes to the control of Af. Results also suggest that eNOS-derived NO is of greater importance than nNOS-derived NO in this isolated arteriolar preparation. renin-angiotensin system; eNOS knockout; nNOS knockout; [N.sup.G]nitro-L-arginine methyl ester; renal hemodynamics; juxtaglomerular apparatus

Published
2008

41. Genome-wide linkage scan for submaximal exercise heart rate in the HERITAGE family study

Author

Spielmann, Nadine, Leon, Arthur S., Rao, D.C., Rice, Treva, Skinner, James S., Rankinen, Tuomo, and Bouchard, Claude

Subjects
Exercise -- Health aspects, Exercise -- Research, Heart beat -- Genetic aspects, Heart beat -- Measurement, Heart beat -- Research, Human genome -- Research, Biological sciences
Abstract

The purpose of this study was to identify regions of the human genome linked to submaximal exercise heart rates in the sedentary state and in response to a standardized 20-wk endurance training program in blacks and whites of the HERITAGE Family Study. A total of 701 polymorphic markers covering the 22 autosomes were used in the genome-wide linkage scan, with 328 sibling pairs from 99 white nuclear families and 102 pairs from 115 black family units. Steady-state heart rates were measured at the relative intensity of 60% maximal oxygen uptake (HR60) and at the absolute intensity of 50 W (HR50). Baseline phenotypes were adjusted for age, sex, and baseline body mass index (BMI) and training responses (posttraining minus baseline, [DELTA]) were adjusted for age, sex, baseline BMI, and baseline value of the phenotype. Two analytic strategies were used, a multipoint variance components and a regression-based multipoint linkage analysis. In whites, promising linkages (LOD > 1.75) were identified on 18q21-q22 for baseline HR50 (LOD = 2.64; P = 0.0002) and [DELTA]HR60 (LOD = 2.10; P = 0.0009) and on chromosome 2q33.3 for [DELTA]HR50 (LOD = 2.13; P = 0.0009). In blacks, evidence of promising linkage for baseline HR50 was detected with several markers within the chromosomal region 10q24-q25.3 (peak LOD = 2.43, P = 0.0004 with D10S597). The most promising regions for fine mapping in the HERITAGE Family Study were found on 2q33 for HR50 training response in whites, on 10q25-26 for baseline HR60 in blacks, and on 18q21-22 for both baseline HR50 and [DELTA]HR60 in whites. exercise training; linkage; quantitative trait loci; genotype

Published
2007

43. Claudin-12 is not required for blood–brain barrier tight junction function

Author

Castro Dias, Mariana, Coisne, Caroline, Engelhardt, Britta, Aguilar-Pimentel, Antonio, Adler, Thure, Busch, Dirk H, Spielmann, Nadine, Moreth, Kristin, Hans, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Baden, Pascale, Radc, Ildiko, Neff, Frauke, Calzada-Wack, Julia, Rathkolb, Birgit, Wolf, Eckhard, Klopstock, Thomas, Wurst, Wolfgang, Beckers, Johannes, Östereicher, Manuela, Miller, Gregor, Enzmann, Gaby, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gailus-Durner, Valérie, Fuchs, Helmut, Garrett, Lillian, Becker, Lore, Hölter, Sabine M, Consortium, German Mouse Clinic, Hrabě de Angelis, Martin, and Deutsch, Urban

Subjects
Male, 0301 basic medicine, endocrine system diseases, urologic and male genital diseases, lcsh:RC346-429, 0302 clinical medicine, Claudin-12, Gene Knock-In Techniques, Experimental autoimmune encephalomyelitis, Tight junction, General Medicine, ddc, 3. Good health, Cell biology, medicine.anatomical_structure, Neurology, Blood-Brain Barrier, Paracellular transport, Female, tissues, Cell type, Encephalomyelitis, Autoimmune, Experimental, Central nervous system, 610 Medicine & health, Mice, Transgenic, Biology, Blood–brain barrier, digestive system, Tight Junctions, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Animals, ddc:610, Claudin, lcsh:Neurology. Diseases of the nervous system, Neuroinflammation, Blood–brain Barrier, Experimental Autoimmune Encephalomyelitis, Research, Endothelial Cells, medicine.disease, digestive system diseases, Mice, Inbred C57BL, 030104 developmental biology, Claudins, 570 Life sciences, biology, 030217 neurology & neurosurgery
Abstract

Background The blood–brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Complex and continuous tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB, with claudin-5 being its dominant TJs protein. However, claudin-5 deficient mice still display ultrastructurally normal TJs, suggesting the contribution of other claudins or tight-junction associated proteins in establishing BBB junctional complexes. Expression of claudin-12 at the BBB has been reported, however the exact function and subcellular localization of this atypical claudin remains unknown. Methods We created claudin-12-lacZ-knock-in C57BL/6J mice to explore expression of claudin-12 and its role in establishing BBB TJs function during health and neuroinflammation. We furthermore performed a broad standardized phenotypic check-up of the mouse mutant. Results Making use of the lacZ reporter allele, we found claudin-12 to be broadly expressed in numerous organs. In the CNS, expression of claudin-12 was detected in many cell types with very low expression in brain endothelium. Claudin-12lacZ/lacZ C57BL/6J mice lacking claudin-12 expression displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis. Determining the precise localization of claudin-12 at the BBB was prohibited by the fact that available anti-claudin-12 antibodies showed comparable detection and staining patterns in tissues from wild-type and claudin-12lacZ/lacZ C57BL/6J mice. Conclusions Our present study thus shows that claudin-12 is not essential in establishing or maintaining BBB TJs integrity. Claudin-12 is rather expressed in cells that typically lack TJs suggesting that claudin-12 plays a role other than forming classical TJs. At the same time, in depth phenotypic screening of clinically relevant organ functions of claudin-12lacZ/lacZ C57BL/6J mice suggested the involvement of claudin-12 in some neurological but, more prominently, in cardiovascular functions.

Published
2019
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44. Soft windowing application to improve analysis of high-throughput phenotyping data

Author

Haselimashhadi, Hamed, primary, Mason, Jeremy C, additional, Munoz-Fuentes, Violeta, additional, López-Gómez, Federico, additional, Babalola, Kolawole, additional, Acar, Elif F, additional, Kumar, Vivek, additional, White, Jacqui, additional, Flenniken, Ann M, additional, King, Ruairidh, additional, Straiton, Ewan, additional, Seavitt, John Richard, additional, Gaspero, Angelina, additional, Garza, Arturo, additional, Christianson, Audrey E, additional, Hsu, Chih-Wei, additional, Reynolds, Corey L, additional, Lanza, Denise G, additional, Lorenzo, Isabel, additional, Green, Jennie R, additional, Gallegos, Juan J, additional, Bohat, Ritu, additional, Samaco, Rodney C, additional, Veeraragavan, Surabi, additional, Kim, Jong Kyoung, additional, Miller, Gregor, additional, Fuchs, Helmult, additional, Garrett, Lillian, additional, Becker, Lore, additional, Kang, Yeon Kyung, additional, Clary, David, additional, Cho, Soo Young, additional, Tamura, Masaru, additional, Tanaka, Nobuhiko, additional, Soo, Kyung Dong, additional, Bezginov, Alexandr, additional, About, Ghina Bou, additional, Champy, Marie-France, additional, Vasseur, Laurent, additional, Leblanc, Sophie, additional, Meziane, Hamid, additional, Selloum, Mohammed, additional, Reilly, Patrick T, additional, Spielmann, Nadine, additional, Maier, Holger, additional, Gailus-Durner, Valerie, additional, Sorg, Tania, additional, Hiroshi, Masuya, additional, Yuichi, Obata, additional, Heaney, Jason D, additional, Dickinson, Mary E, additional, Wolfgang, Wurst, additional, Tocchini-Valentini, Glauco P, additional, Lloyd, Kevin C Kent, additional, McKerlie, Colin, additional, Seong, Je Kyung, additional, Yann, Herault, additional, de Angelis, Martin Hrabé, additional, Brown, Steve D M, additional, Smedley, Damian, additional, Flicek, Paul, additional, Mallon, Ann-Marie, additional, Parkinson, Helen, additional, and Meehan, Terrence F, additional

Published
2019
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45. In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria

Author

Lucienne, Marie, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V, Becker, Lore, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Garrett, Lillian, Hölter, Sabine M, Mayer-Kuckuk, Philipp, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Busch, Dirk H, Klopstock, Thomas, Schmidt-Weber, Carsten, Wolf, Eckhard, Wurst, Wolfgang, Forny, Merima, Mathis, Déborah, Fingerhut, Ralph, Froese, D Sean, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabě, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, Lucienne, Marie, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V, Becker, Lore, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Garrett, Lillian, Hölter, Sabine M, Mayer-Kuckuk, Philipp, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Busch, Dirk H, Klopstock, Thomas, Schmidt-Weber, Carsten, Wolf, Eckhard, Wurst, Wolfgang, Forny, Merima, Mathis, Déborah, Fingerhut, Ralph, Froese, D Sean, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabě, and Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826

Abstract

Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term. Here, we report a hemizygous mouse model which combines a knock-in (ki) missense allele of Mut with a knock-out (ko) allele (Mut-ko/ki mice) that was fed a 51%-protein diet from day 12 of life, constituting a bespoke model of MMAuria. Under this diet, mutant mice developed a pronounced metabolic phenotype characterized by drastically increased blood levels of MMA and C3 compared to their littermate controls (Mut-ki/wt). With this bespoke mouse model, we performed a standardized phenotypic screen to assess the whole-body impairments associated with this strong metabolic condition. We found that Mut-ko/ki mice show common clinical manifestations of MMAuria, including pronounced failure to thrive, indications of mild neurological and kidney dysfunction, and degenerative morphological changes in the liver, along with less well described symptoms such as cardiovascular and hematological abnormalities. The analyses also reveal so far unknown disease characteristics, including low bone mineral density, anxiety-related behaviour and ovarian atrophy. This first phenotypic screening of a MMAuria mouse model confirms its relevance to human disease, reveals new alterations associated with MUT deficiency, and suggests a series of quantifiable readouts that can be used to evaluate potential treatment strategies.

Published
2019

46. Saliva: diagnostics and therapeutic perspectives

Author

Spielmann, Nadine and Wong, David T.

Subjects
Proteome, Dental Caries Susceptibility, Gene Expression Profiling, Risk Assessment, Article, Treatment Outcome, Neoplasms, Biomarkers, Tumor, Disease Progression, Metabolome, Humans, Saliva, Biomarkers, Periodontal Diseases
Abstract

For the past two decades, salivary diagnostic approaches have been developed to monitor oral diseases such as periodontal diseases and to assess caries risk. Recently, the combination of emerging biotechnologies and salivary diagnostics has extended the range of saliva-based diagnostics from the oral cavity to the whole physiological system as most compounds found in blood are also present in saliva. Accordingly saliva can reflect the physiological state of the body, including emotional, endocrinal, nutritional and metabolic variations and provides a source for the monitoring of oral and also systemic health. This review presents the current status of saliva diagnostics and delves into their applications to the discovery of biomarkers for cancer detection and therapeutic applications. Translating scientific findings of nucleic acids, proteins and metabolites in body fluids to clinical applications is a cumbersome and challenging journey. Our research group is pursuing the biology of salivary analytes and the development of technologies in order to detect distinct biomarkers with high sensitivity and specificity. The avenue of saliva diagnostics incorporating transcriptomic, proteomic and metabolomic findings will enable us to connect salivary molecular analytes to monitor therapies, therapeutic outcomes, and finally disease progression in cancer.

Published
2010

47. Heart rate variability in relation to the menstrual cycle in trained and untrained women

Author

Spielmann, Nadine, Patzak, Andreas, Friederich, Niklaus, and Wolff, Roland

Subjects
Ausdauertraining, Cardiac autonomic control, 796 Sport, Herzfrequenzvariabilität, 50 Sport, Spiele, menstrual cycle, YB 9004, Menstruationszyklus, endurance training, ZX 9520, ddc:796, heart rate variability (HRV), Vegetative Kontrolle des Herzens
Abstract

Einleitung: Es wird angenommen, dass die zyklusbedingten, hormonellen Änderungen die vegetative Ansteuerung des Herzens bei normotensiven Frauen beeinflussen. Die Herzfrequenzvariabilität (HRV) stellt einen der am häufigsten untersuchten, nicht-invasiven Parameter des Herz-Kreislauf-Systems dar. Deshalb war es das Ziel dieser Studie, den Verlauf der HRV Parameter bei ausdauertrainierten als auch untrainierten normotensiven Frauen in Abhängigkeit vom Menstruationszyklus zu untersuchen. Methode: Normotensive, untrainierte als auch trainierte Frauen nahmen an der Studie teil. Die Athletinnen absolvierten individuell abgestimmte Trainingspläne (>5h/Woche) während der Studie. Die HRV Messungen wurden in den folgenden fünf Zyklusphasen aufgezeichnet: In der Menstruation (M), der Mitte der Follikel- (MidF), der Ovulations- (O), der Mitte der Luteal- (MidL) und der Pre-Menstruationsphase (PreM). Die Basaltemperatur als auch die Hormonanalysen des Luteinisierenden (LH) und des Follikelstimulierenden Hormons (FSH), des β-17 Östrogens (E2) und des Progesterons (P) dienten der Verifizierung der Zyklusphasen. Die HRV Messungen wurden bei Spontanatmung im Liegen (20 min) wie auch während eines Orthosthase Tests aufgezeichnet. Parameter der Zeit als auch der Frequenzdomäne für Kurzzeitmessungen wurden ausgewertet. Resultate: Alle Frauen hatten einen normotensiven Menstruationszyklus mit typischen hormonellen Schwankungen und einem signifikanten Verlauf (p, Introduction: The autonomic control of the heart is assumed to be affected by endogenous hormonal fluctuations in normal ovulatory females. Analyzing heart rate variability (HRV) had become a tool for the noninvasive measurement of cardiac autonomic control. The purpose of the present study was to investigate the course of the HRV parameters in moderately active as well as in long time endurance trained women during the menstrual cycle. Methods: Normal ovulatory females, untrained and trained were enrolled. Female athletes were involved in individually different training patterns (>5h/week) during the study. HRV recordings were obtained during five different menstrual cycle phases: menstruation (M), middle of follicular (MidF), ovulation (O), middle of luteal (MidL) and pre menstruation phase (PreM). Phases were verified by basal body temperature and analysis of luteinizing hormone (LH), follicular stimulation hormone (FSH), β-17 estrogen (E2) and progesterone (P). HRV measurements took place at subjects’ spontaneous breathing frequency in supine position (20 min) as well as during an orthostatic test. Parameters of short-term recording were calculated in time and frequency domain. Results: All women had normal ovulatory menstrual cycles including typical endogenous hormonal fluctuations; levels of LH, FSH, E2 and P were significantly different (p

Published
2005

48. Contribution of adenosine receptors in the control of arteriolar tone and adenosine-angiotensin II interaction

Author

Lai, En Yin, Patzak, Andreas, Steege, Andreas, Mrowka, Ralf, Brown, Russell, Spielmann, Nadine, Persson, Pontus B., Fredholm, Bertil B., Persson, A. Erik G., Lai, En Yin, Patzak, Andreas, Steege, Andreas, Mrowka, Ralf, Brown, Russell, Spielmann, Nadine, Persson, Pontus B., Fredholm, Bertil B., and Persson, A. Erik G.

Abstract

Adenosine (Ado) mediates vasoconstriction via A(1)-Ado receptors and vasodilation via A(2)-Ado receptors in the kidney. It interacts with angiotensin II (Ang II), which is important for renal hemodynamics and tubuloglomerular feedback (TGF). The aim was to investigate the function of Ado receptors in the Ado -Ang II interaction in mouse microperfused, afferent arterioles. Ado (10(-11)-10(-4) mol/l) caused a biphasic response: arteriolar diameters were reduced (-7%) at Ado 10(-11)-10(-9) mol/l and returned to control values at higher concentrations. Treatment with Ang II (10(-10) mol/l) transformed the response into a concentration-dependent constriction. N-6-cyclopentyladenosine (A(1)-Ado receptor agonist) reduced diameters (12% at 10(-6) mol/l). Application of CGS21680 (10(-12)-10(-4) mol/l, A(2A) receptor agonist) increased the diameter by 13%. Pretreatment with ZM241385 (A(2A)-Ado receptor antagonist) alone or in combination with MRS1706 (A(2B)-Ado receptor antagonist) resulted in a pure constriction upon Ado, whereas 8-cyclopentyltheophylline (CPT) (A(1)-Ado receptor antagonist) inhibited the constrictor response. Afferent arterioles of mice lacking A(1)-Ado receptor did not show constriction upon Ado. Treatment with Ado (10(-8) mol/l) increased the response upon Ang II, which was blocked by CPT. Ado (10(-5) mol/l) did not influence the Ang II response, but an additional blockade of A(2)-Ado receptors enhanced it. The action of Ado on constrictor A(1)-Ado receptors and dilatory A(2)-Ado receptors modulates the interaction with Ang II. Both directions of Ado-Ang II interaction, which predominantly leads to an amplification of the contractile response, are important for the operation of the TGF.

Published
2006
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49. Heart rate variability in relation to the menstrual cycle in trained and untrained women

Author

Patzak, Andreas, Friederich, Niklaus, Wolff, Roland, Spielmann, Nadine, Patzak, Andreas, Friederich, Niklaus, Wolff, Roland, and Spielmann, Nadine

Abstract

Einleitung: Es wird angenommen, dass die zyklusbedingten, hormonellen Änderungen die vegetative Ansteuerung des Herzens bei normotensiven Frauen beeinflussen. Die Herzfrequenzvariabilität (HRV) stellt einen der am häufigsten untersuchten, nicht-invasiven Parameter des Herz-Kreislauf-Systems dar. Deshalb war es das Ziel dieser Studie, den Verlauf der HRV Parameter bei ausdauertrainierten als auch untrainierten normotensiven Frauen in Abhängigkeit vom Menstruationszyklus zu untersuchen. Methode: Normotensive, untrainierte als auch trainierte Frauen nahmen an der Studie teil. Die Athletinnen absolvierten individuell abgestimmte Trainingspläne (>5h/Woche) während der Studie. Die HRV Messungen wurden in den folgenden fünf Zyklusphasen aufgezeichnet: In der Menstruation (M), der Mitte der Follikel- (MidF), der Ovulations- (O), der Mitte der Luteal- (MidL) und der Pre-Menstruationsphase (PreM). Die Basaltemperatur als auch die Hormonanalysen des Luteinisierenden (LH) und des Follikelstimulierenden Hormons (FSH), des β-17 Östrogens (E2) und des Progesterons (P) dienten der Verifizierung der Zyklusphasen. Die HRV Messungen wurden bei Spontanatmung im Liegen (20 min) wie auch während eines Orthosthase Tests aufgezeichnet. Parameter der Zeit als auch der Frequenzdomäne für Kurzzeitmessungen wurden ausgewertet. Resultate: Alle Frauen hatten einen normotensiven Menstruationszyklus mit typischen hormonellen Schwankungen und einem signifikanten Verlauf (p, Introduction: The autonomic control of the heart is assumed to be affected by endogenous hormonal fluctuations in normal ovulatory females. Analyzing heart rate variability (HRV) had become a tool for the noninvasive measurement of cardiac autonomic control. The purpose of the present study was to investigate the course of the HRV parameters in moderately active as well as in long time endurance trained women during the menstrual cycle. Methods: Normal ovulatory females, untrained and trained were enrolled. Female athletes were involved in individually different training patterns (>5h/week) during the study. HRV recordings were obtained during five different menstrual cycle phases: menstruation (M), middle of follicular (MidF), ovulation (O), middle of luteal (MidL) and pre menstruation phase (PreM). Phases were verified by basal body temperature and analysis of luteinizing hormone (LH), follicular stimulation hormone (FSH), β-17 estrogen (E2) and progesterone (P). HRV measurements took place at subjects’ spontaneous breathing frequency in supine position (20 min) as well as during an orthostatic test. Parameters of short-term recording were calculated in time and frequency domain. Results: All women had normal ovulatory menstrual cycles including typical endogenous hormonal fluctuations; levels of LH, FSH, E2 and P were significantly different (p

Published
2005

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