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48 results on '"Hildebrandt P"'

3. Author Correction: MerMAIDs: a family of metagenomically discovered marine anion-conducting and intensely desensitizing channelrhodopsins

Author

Oppermann, Johannes, Fischer, Paul, Silapetere, Arita, Liepe, Bernhard, Rodriguez-Rozada, Silvia, Flores-Uribe, José, Schiewer, Enrico, Keidel, Anke, Vierock, Johannes, Kaufmann, Joel, Broser, Matthias, Luck, Meike, Bartl, Franz, Hildebrandt, Peter, Wiegert, J. Simon, Béjà, Oded, Hegemann, Peter, and Wietek, Jonas

Published
2024
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4. Host-pathogen interactions in the Plasmodium-infected mouse liver at spatial and single-cell resolution

Author

Franziska Hildebrandt, Miren Urrutia Iturritza, Christian Zwicker, Bavo Vanneste, Noémi Van Hul, Elisa Semle, Jaclyn Quin, Tales Pascini, Sami Saarenpää, Mengxiao He, Emma R. Andersson, Charlotte L. Scott, Joel Vega-Rodriguez, Joakim Lundeberg, and Johan Ankarklev

Subjects
Science
Abstract

Abstract Upon infecting its vertebrate host, the malaria parasite initially invades the liver where it undergoes massive replication, whilst remaining clinically silent. The coordination of host responses across the complex liver tissue during malaria infection remains unexplored. Here, we perform spatial transcriptomics in combination with single-nuclei RNA sequencing over multiple time points to delineate host-pathogen interactions across Plasmodium berghei-infected liver tissues. Our data reveals significant changes in spatial gene expression in the malaria-infected tissues. These include changes related to lipid metabolism in the proximity to sites of Plasmodium infection, distinct inflammation programs between lobular zones, and regions with enrichment of different inflammatory cells, which we term ‘inflammatory hotspots’. We also observe significant upregulation of genes involved in inflammation in the control liver tissues of mice injected with mosquito salivary gland components. However, this response is considerably delayed compared to that observed in P. berghei-infected mice. Our study establishes a benchmark for investigating transcriptome changes during host-parasite interactions in tissues, it provides informative insights regarding in vivo study design linked to infection and offers a useful tool for the discovery and validation of de novo intervention strategies aimed at malaria liver stage infection.

Published
2024
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5. Systematic review and meta-analysis of ex-post evaluations on the effectiveness of carbon pricing

Author

Niklas Döbbeling-Hildebrandt, Klaas Miersch, Tarun M. Khanna, Marion Bachelet, Stephan B. Bruns, Max Callaghan, Ottmar Edenhofer, Christian Flachsland, Piers M. Forster, Matthias Kalkuhl, Nicolas Koch, William F. Lamb, Nils Ohlendorf, Jan Christoph Steckel, and Jan C. Minx

Subjects
Science
Abstract

Abstract Today, more than 70 carbon pricing schemes have been implemented around the globe, but their contributions to emissions reductions remains a subject of heated debate in science and policy. Here we assess the effectiveness of carbon pricing in reducing emissions using a rigorous, machine-learning assisted systematic review and meta-analysis. Based on 483 effect sizes extracted from 80 causal ex-post evaluations across 21 carbon pricing schemes, we find that introducing a carbon price has yielded immediate and substantial emission reductions for at least 17 of these policies, despite the low level of prices in most instances. Statistically significant emissions reductions range between –5% to –21% across the schemes (–4% to –15% after correcting for publication bias). Our study highlights critical evidence gaps with regard to dozens of unevaluated carbon pricing schemes and the price elasticity of emissions reductions. More rigorous synthesis of carbon pricing and other climate policies is required across a range of outcomes to advance our understanding of “what works” and accelerate learning on climate solutions in science and policy.

Published
2024
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6. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Gupta, Yask, Friedman, David J., McNulty, Michelle T., Khan, Atlas, Lane, Brandon, Wang, Chen, Ke, Juntao, Jin, Gina, Wooden, Benjamin, Knob, Andrea L., Lim, Tze Y., Appel, Gerald B., Huggins, Kinsie, Liu, Lili, Mitrotti, Adele, Stangl, Megan C., Bomback, Andrew, Westland, Rik, Bodria, Monica, Marasa, Maddalena, Shang, Ning, Cohen, David J., Crew, Russell J., Morello, William, Canetta, Pietro, Radhakrishnan, Jai, Martino, Jeremiah, Liu, Qingxue, Chung, Wendy K., Espinoza, Angelica, Luo, Yuan, Wei, Wei-Qi, Feng, Qiping, Weng, Chunhua, Fang, Yilu, Kullo, Iftikhar J., Naderian, Mohammadreza, Limdi, Nita, Irvin, Marguerite R., Tiwari, Hemant, Mohan, Sumit, Rao, Maya, Dube, Geoffrey K., Chaudhary, Ninad S., Gutiérrez, Orlando M., Judd, Suzanne E., Cushman, Mary, Lange, Leslie A., Lange, Ethan M., Bivona, Daniel L., Verbitsky, Miguel, Winkler, Cheryl A., Kopp, Jeffrey B., Santoriello, Dominick, Batal, Ibrahim, Pinheiro, Sérgio Veloso Brant, Oliveira, Eduardo Araújo, Simoes e Silva, Ana Cristina, Pisani, Isabella, Fiaccadori, Enrico, Lin, Fangming, Gesualdo, Loreto, Amoroso, Antonio, Ghiggeri, Gian Marco, D’Agati, Vivette D., Magistroni, Riccardo, Kenny, Eimear E., Loos, Ruth J. F., Montini, Giovanni, Hildebrandt, Friedhelm, Paul, Dirk S., Petrovski, Slavé, Goldstein, David B., Kretzler, Matthias, Gbadegesin, Rasheed, Gharavi, Ali G., Kiryluk, Krzysztof, Sampson, Matthew G., Pollak, Martin R., and Sanna-Cherchi, Simone

Published
2023
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9. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome

Author

Barry, Alexandra, McNulty, Michelle T., Jia, Xiaoyuan, Gupta, Yask, Debiec, Hanna, Luo, Yang, Nagano, China, Horinouchi, Tomoko, Jung, Seulgi, Colucci, Manuela, Ahram, Dina F., Mitrotti, Adele, Sinha, Aditi, Teeninga, Nynke, Jin, Gina, Shril, Shirlee, Caridi, Gianluca, Bodria, Monica, Lim, Tze Y., Westland, Rik, Zanoni, Francesca, Marasa, Maddalena, Turudic, Daniel, Giordano, Mario, Gesualdo, Loreto, Magistroni, Riccardo, Pisani, Isabella, Fiaccadori, Enrico, Reiterova, Jana, Maringhini, Silvio, Morello, William, Montini, Giovanni, Weng, Patricia L., Scolari, Francesco, Saraga, Marijan, Tasic, Velibor, Santoro, Domenica, van Wijk, Joanna A. E., Milošević, Danko, Kawai, Yosuke, Kiryluk, Krzysztof, Pollak, Martin R., Gharavi, Ali, Lin, Fangmin, Simœs e Silva, Ana Cristina, Loos, Ruth J. F., Kenny, Eimear E., Schreuder, Michiel F., Zurowska, Aleksandra, Dossier, Claire, Ariceta, Gema, Drozynska-Duklas, Magdalena, Hogan, Julien, Jankauskiene, Augustina, Hildebrandt, Friedhelm, Prikhodina, Larisa, Song, Kyuyoung, Bagga, Arvind, Cheong, II, Hae, Ghiggeri, Gian Marco, Vachvanichsanong, Prayong, Nozu, Kandai, Lee, Dongwon, Vivarelli, Marina, Raychaudhuri, Soumya, Tokunaga, Katsushi, Sanna-Cherchi, Simone, Ronco, Pierre, Iijima, Kazumoto, and Sampson, Matthew G.

Published
2023
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10. Speos: an ensemble graph representation learning framework to predict core gene candidates for complex diseases

Author

Florin Ratajczak, Mitchell Joblin, Marcel Hildebrandt, Martin Ringsquandl, Pascal Falter-Braun, and Matthias Heinig

Subjects
Science
Abstract

Abstract Understanding phenotype-to-genotype relationships is a grand challenge of 21st century biology with translational implications. The recently proposed “omnigenic” model postulates that effects of genetic variation on traits are mediated by core-genes and -proteins whose activities mechanistically influence the phenotype, whereas peripheral genes encode a regulatory network that indirectly affects phenotypes via core gene products. Here, we develop a positive-unlabeled graph representation-learning ensemble-approach based on a nested cross-validation to predict core-like genes for diverse diseases using Mendelian disorder genes for training. Employing mouse knockout phenotypes for external validations, we demonstrate that core-like genes display several key properties of core genes: Mouse knockouts of genes corresponding to our most confident predictions give rise to relevant mouse phenotypes at rates on par with the Mendelian disorder genes, and all candidates exhibit core gene properties like transcriptional deregulation in disease and loss-of-function intolerance. Moreover, as predicted for core genes, our candidates are enriched for drug targets and druggable proteins. In contrast to Mendelian disorder genes the new core-like genes are enriched for druggable yet untargeted gene products, which are therefore attractive targets for drug development. Interpretation of the underlying deep learning model suggests plausible explanations for our core gene predictions in form of molecular mechanisms and physical interactions. Our results demonstrate the potential of graph representation learning for the interpretation of biological complexity and pave the way for studying core gene properties and future drug development.

Published
2023
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11. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Yask Gupta, David J. Friedman, Michelle T. McNulty, Atlas Khan, Brandon Lane, Chen Wang, Juntao Ke, Gina Jin, Benjamin Wooden, Andrea L. Knob, Tze Y. Lim, Gerald B. Appel, Kinsie Huggins, Lili Liu, Adele Mitrotti, Megan C. Stangl, Andrew Bomback, Rik Westland, Monica Bodria, Maddalena Marasa, Ning Shang, David J. Cohen, Russell J. Crew, William Morello, Pietro Canetta, Jai Radhakrishnan, Jeremiah Martino, Qingxue Liu, Wendy K. Chung, Angelica Espinoza, Yuan Luo, Wei-Qi Wei, Qiping Feng, Chunhua Weng, Yilu Fang, Iftikhar J. Kullo, Mohammadreza Naderian, Nita Limdi, Marguerite R. Irvin, Hemant Tiwari, Sumit Mohan, Maya Rao, Geoffrey K. Dube, Ninad S. Chaudhary, Orlando M. Gutiérrez, Suzanne E. Judd, Mary Cushman, Leslie A. Lange, Ethan M. Lange, Daniel L. Bivona, Miguel Verbitsky, Cheryl A. Winkler, Jeffrey B. Kopp, Dominick Santoriello, Ibrahim Batal, Sérgio Veloso Brant Pinheiro, Eduardo Araújo Oliveira, Ana Cristina Simoes e Silva, Isabella Pisani, Enrico Fiaccadori, Fangming Lin, Loreto Gesualdo, Antonio Amoroso, Gian Marco Ghiggeri, Vivette D. D’Agati, Riccardo Magistroni, Eimear E. Kenny, Ruth J. F. Loos, Giovanni Montini, Friedhelm Hildebrandt, Dirk S. Paul, Slavé Petrovski, David B. Goldstein, Matthias Kretzler, Rasheed Gbadegesin, Ali G. Gharavi, Krzysztof Kiryluk, Matthew G. Sampson, Martin R. Pollak, and Simone Sanna-Cherchi

Subjects
Science
Abstract

Abstract African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Published
2023
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12. Mammalian maxilloturbinal evolution does not reflect thermal biology

Author

Quentin Martinez, Jan Okrouhlík, Radim Šumbera, Mark Wright, Ricardo Araújo, Stan Braude, Thomas B. Hildebrandt, Susanne Holtze, Irina Ruf, and Pierre-Henri Fabre

Subjects
Science
Abstract

Abstract The evolution of endothermy in vertebrates is a major research topic in recent decades that has been tackled by a myriad of research disciplines including paleontology, anatomy, physiology, evolutionary and developmental biology. The ability of most mammals to maintain a relatively constant and high body temperature is considered a key adaptation, enabling them to successfully colonize new habitats and harsh environments. It has been proposed that in mammals the anterior nasal cavity, which houses the maxilloturbinal, plays a pivotal role in body temperature maintenance, via a bony system supporting an epithelium involved in heat and moisture conservation. The presence and the relative size of the maxilloturbinal has been proposed to reflect the endothermic conditions and basal metabolic rate in extinct vertebrates. We show that there is no evidence to relate the origin of endothermy and the development of some turbinal bones by using a comprehensive dataset of µCT-derived maxilloturbinals spanning most mammalian orders. Indeed, we demonstrate that neither corrected basal metabolic rate nor body temperature significantly correlate with the relative surface area of the maxilloturbinal. Instead, we identify important variations in the relative surface area, morpho-anatomy, and complexity of the maxilloturbinal across the mammalian phylogeny and species ecology.

Published
2023
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13. Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes

Author

Ryan P. Hildebrandt, Kathryn R. Moss, Aleksandra Janusz-Kaminska, Luke A. Knudson, Lance T. Denes, Tanvi Saxena, Devi Prasad Boggupalli, Zhuangyue Li, Kun Lin, Gary J. Bassell, and Eric T. Wang

Subjects
Science
Abstract

Abstract RNA binding proteins (RBPs) act as critical facilitators of spatially regulated gene expression. Muscleblind-like (MBNL) proteins, implicated in myotonic dystrophy and cancer, localize RNAs to myoblast membranes and neurites through unknown mechanisms. We find that MBNL forms motile and anchored granules in neurons and myoblasts, and selectively associates with kinesins Kif1bα and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs associate with these kinesins, implicating a motor-RBP specificity code. MBNL and kinesin perturbation leads to widespread mRNA mis-localization, including depletion of Nucleolin transcripts from neurites. Live cell imaging and fractionation reveal that the unstructured carboxy-terminal tail of MBNL1 allows for anchoring at membranes. An approach, termed RBP Module Recruitment and Imaging (RBP-MRI), reconstitutes kinesin- and membrane-recruitment functions using MBNL-MS2 coat protein fusions. Our findings decouple kinesin association, RNA binding, and membrane anchoring functions of MBNL while establishing general strategies for studying multi-functional, modular domains of RBPs.

Published
2023
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14. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome

Author

Alexandra Barry, Michelle T. McNulty, Xiaoyuan Jia, Yask Gupta, Hanna Debiec, Yang Luo, China Nagano, Tomoko Horinouchi, Seulgi Jung, Manuela Colucci, Dina F. Ahram, Adele Mitrotti, Aditi Sinha, Nynke Teeninga, Gina Jin, Shirlee Shril, Gianluca Caridi, Monica Bodria, Tze Y. Lim, Rik Westland, Francesca Zanoni, Maddalena Marasa, Daniel Turudic, Mario Giordano, Loreto Gesualdo, Riccardo Magistroni, Isabella Pisani, Enrico Fiaccadori, Jana Reiterova, Silvio Maringhini, William Morello, Giovanni Montini, Patricia L. Weng, Francesco Scolari, Marijan Saraga, Velibor Tasic, Domenica Santoro, Joanna A. E. van Wijk, Danko Milošević, Yosuke Kawai, Krzysztof Kiryluk, Martin R. Pollak, Ali Gharavi, Fangmin Lin, Ana Cristina Simœs e Silva, Ruth J. F. Loos, Eimear E. Kenny, Michiel F. Schreuder, Aleksandra Zurowska, Claire Dossier, Gema Ariceta, Magdalena Drozynska-Duklas, Julien Hogan, Augustina Jankauskiene, Friedhelm Hildebrandt, Larisa Prikhodina, Kyuyoung Song, Arvind Bagga, Hae Cheong, Gian Marco Ghiggeri, Prayong Vachvanichsanong, Kandai Nozu, Dongwon Lee, Marina Vivarelli, Soumya Raychaudhuri, Katsushi Tokunaga, Simone Sanna-Cherchi, Pierre Ronco, Kazumoto Iijima, and Matthew G. Sampson

Subjects
Science
Abstract

Abstract Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations—eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

Published
2023
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15. Author Correction: MerMAIDs: a family of metagenomically discovered marine anion-conducting and intensely desensitizing channelrhodopsins

Author

Johannes Oppermann, Paul Fischer, Arita Silapetere, Bernhard Liepe, Silvia Rodriguez-Rozada, José Flores-Uribe, Enrico Schiewer, Anke Keidel, Johannes Vierock, Joel Kaufmann, Matthias Broser, Meike Luck, Franz Bartl, Peter Hildebrandt, J. Simon Wiegert, Oded Béjà, Peter Hegemann, and Jonas Wietek

Subjects
Science
Published
2024
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16. QuasAr Odyssey: the origin of fluorescence and its voltage sensitivity in microbial rhodopsins

Author

Arita Silapetere, Songhwan Hwang, Yusaku Hontani, Rodrigo G. Fernandez Lahore, Jens Balke, Francisco Velazquez Escobar, Martijn Tros, Patrick E. Konold, Rainer Matis, Roberta Croce, Peter J. Walla, Peter Hildebrandt, Ulrike Alexiev, John T. M. Kennis, Han Sun, Tillmann Utesch, and Peter Hegemann

Subjects
Science
Abstract

The authors present an in-depth investigation of excited state dynamics and molecular mechanism of the voltage sensing in microbial rhodopsins. Using a combination of spectroscopic investigations and molecular dynamics simulations, the study proposes the voltage-modulated deprotonation of the chromophore as the key event in the voltage sensing. Thus, molecular constraints that may further improve the fluorescence quantum yield and the voltage sensitivity are presented.

Published
2022
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20. Identification of 22 susceptibility loci associated with testicular germ cell tumors

Author

Pluta, John, Pyle, Louise C., Nead, Kevin T., Wilf, Rona, Li, Mingyao, Mitra, Nandita, Weathers, Benita, D’Andrea, Kurt, Almstrup, Kristian, Anson-Cartwright, Lynn, Benitez, Javier, Brown, Christopher D., Chanock, Stephen, Chen, Chu, Cortessis, Victoria K., Ferlin, Alberto, Foresta, Carlo, Gamulin, Marija, Gietema, Jourik A., Grasso, Chiara, Greene, Mark H., Grotmol, Tom, Hamilton, Robert J., Haugen, Trine B., Hauser, Russ, Hildebrandt, Michelle A. T., Johnson, Matthew E., Karlsson, Robert, Kiemeney, Lambertus A., Lessel, Davor, Lothe, Ragnhild A., Loud, Jennifer T., Loveday, Chey, Martin-Gimeno, Paloma, Meijer, Coby, Nsengimana, Jérémie, Quinn, David I., Rafnar, Thorunn, Ramdas, Shweta, Richiardi, Lorenzo, Skotheim, Rolf I., Stefansson, Kari, Turnbull, Clare, Vaughn, David J., Wiklund, Fredrik, Wu, Xifeng, Yang, Daphne, Zheng, Tongzhang, Wells, Andrew D., Grant, Struan F. A., Rajpert-De Meyts, Ewa, Schwartz, Stephen M., Bishop, D. Timothy, McGlynn, Katherine A., Kanetsky, Peter A., and Nathanson, Katherine L.

Published
2021
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22. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

Author

Lawrenson, Kate, Li, Qiyuan, Kar, Siddhartha, Seo, Ji-Heui, Tyrer, Jonathan, Spindler, Tassja J, Lee, Janet, Chen, Yibu, Karst, Alison, Drapkin, Ronny, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Australian Ovarian Cancer Study Group, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Chen, Anne, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, James, Paul, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kruger Kjaer, Susanne, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Nevanlinna, Heli, McNeish, Ian, and Menon, Usha

Subjects
Australian Ovarian Cancer Study Group, Cell Line, Tumor, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Homeodomain Proteins, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Protein Binding, Quantitative Trait Loci, Female, Nuchal Cord, Genetic Association Studies, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Neoplasms, Glandular and Epithelial, Gene Expression Regulation, Neoplastic, Carcinoma, Ovarian Epithelial, Rare Diseases, Prevention, Ovarian Cancer, Biotechnology, Human Genome, Cancer, Genetics, 2.1 Biological and endogenous factors
Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P

Published
2015

25. Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome

Author

Arrondel, Christelle, Missoury, Sophia, Snoek, Rozemarijn, Patat, Julie, Menara, Giulia, Collinet, Bruno, Liger, Dominique, Durand, Dominique, Gribouval, Olivier, Boyer, Olivia, Buscara, Laurine, Martin, Gaëlle, Machuca, Eduardo, Nevo, Fabien, Lescop, Ewen, Braun, Daniela A., Boschat, Anne-Claire, Sanquer, Sylvia, Guerrera, Ida Chiara, Revy, Patrick, Parisot, Mélanie, Masson, Cécile, Boddaert, Nathalie, Charbit, Marina, Decramer, Stéphane, Novo, Robert, Macher, Marie-Alice, Ranchin, Bruno, Bacchetta, Justine, Laurent, Audrey, Collardeau-Frachon, Sophie, van Eerde, Albertien M., Hildebrandt, Friedhelm, Magen, Daniella, Antignac, Corinne, van Tilbeurgh, Herman, and Mollet, Géraldine

Published
2019
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27. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Author

Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex V., Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., and Sefiani, Abdelaziz

Published
2019
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30. Odd skipped-related 1 identifies a population of embryonic fibro-adipogenic progenitors regulating myogenesis during limb development

Author

Vallecillo-García, Pedro, Orgeur, Mickael, vom Hofe-Schneider, Sophie, Stumm, Jürgen, Kappert, Verena, Ibrahim, Daniel M., Börno, Stefan T., Hayashi, Shinichiro, Relaix, Frédéric, Hildebrandt, Katrin, Sengle, Gerhard, Koch, Manuel, Timmermann, Bernd, Marazzi, Giovanna, Sassoon, David A., Duprez, Delphine, and Stricker, Sigmar

Published
2017
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31. Generation of a μ-1,2-hydroperoxo FeIIIFeIII and a μ-1,2-peroxo FeIVFeIII Complex

Author

Stephan Walleck, Thomas Philipp Zimmermann, Henning Hachmeister, Christian Pilger, Thomas Huser, Sagie Katz, Peter Hildebrandt, Anja Stammler, Hartmut Bögge, Eckhard Bill, and Thorsten Glaser

Subjects
Science
Abstract

Iron coordination complexes can be used to gain insight on biologically relevant iron-oxygen compounds generated in iron metalloenzymes. Here, the authors characterise a μ-1,2-hydroperoxo FeIIIFeIII and a μ-1,2-peroxo FeIVFeIII, and study their reactivity in C-H activation.

Published
2022
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32. Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver

Author

Franziska Hildebrandt, Alma Andersson, Sami Saarenpää, Ludvig Larsson, Noémi Van Hul, Sachie Kanatani, Jan Masek, Ewa Ellis, Antonio Barragan, Annelie Mollbrink, Emma R. Andersson, Joakim Lundeberg, and Johan Ankarklev

Subjects
Science
Abstract

Global transcriptional differences across lobular units in the liver remain unknown. Here the authors perform spatial transcriptomics of liver tissue to delineate transcriptional differences in physical space, confirm lobular zonation along transcriptional gradients and suggest the presence of previously uncharacterized structures within liver tissue.

Published
2021
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33. Identification of 22 susceptibility loci associated with testicular germ cell tumors

Author

John Pluta, Louise C. Pyle, Kevin T. Nead, Rona Wilf, Mingyao Li, Nandita Mitra, Benita Weathers, Kurt D’Andrea, Kristian Almstrup, Lynn Anson-Cartwright, Javier Benitez, Christopher D. Brown, Stephen Chanock, Chu Chen, Victoria K. Cortessis, Alberto Ferlin, Carlo Foresta, Marija Gamulin, Jourik A. Gietema, Chiara Grasso, Mark H. Greene, Tom Grotmol, Robert J. Hamilton, Trine B. Haugen, Russ Hauser, Michelle A. T. Hildebrandt, Matthew E. Johnson, Robert Karlsson, Lambertus A. Kiemeney, Davor Lessel, Ragnhild A. Lothe, Jennifer T. Loud, Chey Loveday, Paloma Martin-Gimeno, Coby Meijer, Jérémie Nsengimana, David I. Quinn, Thorunn Rafnar, Shweta Ramdas, Lorenzo Richiardi, Rolf I. Skotheim, Kari Stefansson, Clare Turnbull, David J. Vaughn, Fredrik Wiklund, Xifeng Wu, Daphne Yang, Tongzhang Zheng, Andrew D. Wells, Struan F. A. Grant, Ewa Rajpert-De Meyts, Stephen M. Schwartz, D. Timothy Bishop, Katherine A. McGlynn, Peter A. Kanetsky, Katherine L. Nathanson, and The Testicular Cancer Consortium

Subjects
Science
Abstract

Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

Published
2021
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34. Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome

Author

Christelle Arrondel, Sophia Missoury, Rozemarijn Snoek, Julie Patat, Giulia Menara, Bruno Collinet, Dominique Liger, Dominique Durand, Olivier Gribouval, Olivia Boyer, Laurine Buscara, Gaëlle Martin, Eduardo Machuca, Fabien Nevo, Ewen Lescop, Daniela A. Braun, Anne-Claire Boschat, Sylvia Sanquer, Ida Chiara Guerrera, Patrick Revy, Mélanie Parisot, Cécile Masson, Nathalie Boddaert, Marina Charbit, Stéphane Decramer, Robert Novo, Marie-Alice Macher, Bruno Ranchin, Justine Bacchetta, Audrey Laurent, Sophie Collardeau-Frachon, Albertien M. van Eerde, Friedhelm Hildebrandt, Daniella Magen, Corinne Antignac, Herman van Tilbeurgh, and Géraldine Mollet

Subjects
Science
Abstract

The biosynthesis of N6-threonylcarbamoylated adenosine 37 in tRNA (t6A) involves the YRDC enzyme and the KEOPS complex. Here, the authors report mutations in YRDC and the KEOPS component GON7 in Galloway-Mowat syndrome and determine the crystal structure of a GON7-containg subcomplex that suggests a role in KEOPS complex stability.

Published
2019
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35. MerMAIDs: a family of metagenomically discovered marine anion-conducting and intensely desensitizing channelrhodopsins

Author

Johannes Oppermann, Paul Fischer, Arita Silapetere, Bernhard Liepe, Silvia Rodriguez-Rozada, José Flores-Uribe, Enrico Schiewer, Anke Keidel, Johannes Vierock, Joel Kaufmann, Matthias Broser, Meike Luck, Franz Bartl, Peter Hildebrandt, J. Simon Wiegert, Oded Béjà, Peter Hegemann, and Jonas Wietek

Subjects
Science
Abstract

Abstract Channelrhodopsins (ChRs) are algal light-gated ion channels widely used as optogenetic tools for manipulating neuronal activity. ChRs desensitize under continuous bright-light illumination, resulting in a significant decline of photocurrents. Here we describe a metagenomically identified family of phylogenetically distinct anion-conducting ChRs (designated MerMAIDs). MerMAIDs almost completely desensitize during continuous illumination due to accumulation of a late non-conducting photointermediate that disrupts the ion permeation pathway. MerMAID desensitization can be fully explained by a single photocycle in which a long-lived desensitized state follows the short-lived conducting state. A conserved cysteine is the critical factor in desensitization, as its mutation results in recovery of large stationary photocurrents. The rapid desensitization of MerMAIDs enables their use as optogenetic silencers for transient suppression of individual action potentials without affecting subsequent spiking during continuous illumination. Our results could facilitate the development of optogenetic tools from metagenomic databases and enhance general understanding of ChR function.

Published
2019
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36. Domain-interface dynamics of CFTR revealed by stabilizing nanobodies

Author

Maud Sigoillot, Marie Overtus, Magdalena Grodecka, Daniel Scholl, Abel Garcia-Pino, Toon Laeremans, Lihua He, Els Pardon, Ellen Hildebrandt, Ina Urbatsch, Jan Steyaert, John R. Riordan, and Cedric Govaerts

Subjects
Science
Abstract

The leading cause of cystic fibrosis is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). Here authors we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein.

Published
2019
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37. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Author

Najim Lahrouchi, Aman George, Ilham Ratbi, Ronen Schneider, Siham C. Elalaoui, Shahida Moosa, Sanita Bharti, Ruchi Sharma, Mones Abu-Asab, Felix Onojafe, Najlae Adadi, Elisabeth M. Lodder, Fatima-Zahra Laarabi, Yassine Lamsyah, Hamza Elorch, Imane Chebbar, Alex V. Postma, Vassilios Lougaris, Alessandro Plebani, Janine Altmueller, Henriette Kyrieleis, Vardiella Meiner, Helen McNeill, Kapil Bharti, Stanislas Lyonnet, Bernd Wollnik, Alexandra Henrion-Caude, Amina Berraho, Friedhelm Hildebrandt, Connie R. Bezzina, Brian P. Brooks, and Abdelaziz Sefiani

Subjects
Science
Abstract

Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.

Published
2019
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38. Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis

Author

Sumeda Nandadasa, Caroline M. Kraft, Lauren W. Wang, Anna O’Donnell, Rushabh Patel, Heon Yung Gee, Kay Grobe, Timothy C. Cox, Friedhelm Hildebrandt, and Suneel S. Apte

Subjects
Science
Abstract

Ciliogenesis is a complex process requiring hundreds of molecules, although few secreted proteins have been implicated. Here, the authors show that the secreted metalloproteases ADAMTS9 and ADAMTS20 intracellularly regulate ciliogenesis from unique periciliary vesicles with proteolytic activity.

Published
2019
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39. Structural snapshot of a bacterial phytochrome in its functional intermediate state

Author

Andrea Schmidt, Luisa Sauthof, Michal Szczepek, Maria Fernandez Lopez, Francisco Velazquez Escobar, Bilal M. Qureshi, Norbert Michael, David Buhrke, Tammo Stevens, Dennis Kwiatkowski, David von Stetten, Maria Andrea Mroginski, Norbert Krauß, Tilman Lamparter, Peter Hildebrandt, and Patrick Scheerer

Subjects
Science
Abstract

Phytochromes are photoreceptors that are present in plants, bacteria and fungi. Here the authors present crystal structures of the phytochrome Agp2 from Agrobacterium fabrum in the parent Pfr state as well as a functional Meta-F intermediate and discuss mechanistic implications for photoconversion.

Published
2018
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40. Embryos and embryonic stem cells from the white rhinoceros

Author

Thomas B. Hildebrandt, Robert Hermes, Silvia Colleoni, Sebastian Diecke, Susanne Holtze, Marilyn B. Renfree, Jan Stejskal, Katsuhiko Hayashi, Micha Drukker, Pasqualino Loi, Frank Göritz, Giovanna Lazzari, and Cesare Galli

Subjects
Science
Abstract

The Southern (SWR) and Northern (NWR) are two subspecies of the White Rhinoceros with the NWR being almost extinct. Here, using assisted reproduction technology, the authors produce and cryopreserve SWR purebred and NWR-SWR hybrid embryos developed to the blastocyst stage, and also generate embryonic stem cell lines, in an attempt to save genes of the NWR.

Published
2018
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41. Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment

Author

Shazia Ashraf, Hiroki Kudo, Jia Rao, Atsuo Kikuchi, Eugen Widmeier, Jennifer A. Lawson, Weizhen Tan, Tobias Hermle, Jillian K. Warejko, Shirlee Shril, Merlin Airik, Tilman Jobst-Schwan, Svjetlana Lovric, Daniela A. Braun, Heon Yung Gee, David Schapiro, Amar J. Majmundar, Carolin E. Sadowski, Werner L. Pabst, Ankana Daga, Amelie T. van der Ven, Johanna M. Schmidt, Boon Chuan Low, Anjali Bansal Gupta, Brajendra K. Tripathi, Jenny Wong, Kirk Campbell, Kay Metcalfe, Denny Schanze, Tetsuya Niihori, Hiroshi Kaito, Kandai Nozu, Hiroyasu Tsukaguchi, Ryojiro Tanaka, Kiyoshi Hamahira, Yasuko Kobayashi, Takumi Takizawa, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Naonori Kumagai, Kazumoto Iijima, Henry Fehrenbach, Jameela A. Kari, Sherif El Desoky, Sawsan Jalalah, Radovan Bogdanovic, Nataša Stajić, Hildegard Zappel, Assel Rakhmetova, Sharon-Rose Wassmer, Therese Jungraithmayr, Juergen Strehlau, Aravind Selvin Kumar, Arvind Bagga, Neveen A. Soliman, Shrikant M. Mane, Lewis Kaufman, Douglas R. Lowy, Mohamad A. Jairajpuri, Richard P. Lifton, York Pei, Martin Zenker, Shigeo Kure, and Friedhelm Hildebrandt

Subjects
Science
Abstract

Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome.

Published
2018
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42. Odd skipped-related 1 identifies a population of embryonic fibro-adipogenic progenitors regulating myogenesis during limb development

Author

Pedro Vallecillo-García, Mickael Orgeur, Sophie vom Hofe-Schneider, Jürgen Stumm, Verena Kappert, Daniel M. Ibrahim, Stefan T. Börno, Shinichiro Hayashi, Frédéric Relaix, Katrin Hildebrandt, Gerhard Sengle, Manuel Koch, Bernd Timmermann, Giovanna Marazzi, David A. Sassoon, Delphine Duprez, and Sigmar Stricker

Subjects
Science
Abstract

Fibro-adipogenic progenitors (FAPs) form part of interstitial muscle connective tissue (MCT) in adults but the origin of this non-myogenic lineage is unclear. Here, the authors show that Odd skipped related 1 (Osr1) in mice marks embryonic MCT, giving rise to FAPs, and loss of Osr1 in the limb causes muscle defects.

Published
2017
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43. Redox-dependent substrate-cofactor interactions in the Michaelis-complex of a flavin-dependent oxidoreductase

Author

Tobias Werther, Stefan Wahlefeld, Johannes Salewski, Uwe Kuhlmann, Ingo Zebger, Peter Hildebrandt, and Holger Dobbek

Subjects
Science
Abstract

Due to their transient nature, enzyme-substrate complexes are difficult to characterize structurally. Here, the authors capture the reactive reduced form of xenobiotic reductase A bound to its substrate and show that the oxidation state of the flavin cofactor affects the interaction of the substrate with the enzyme.

Published
2017
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44. Compositional diversity of rehabilitated tropical lands supports multiple ecosystem services and buffers uncertainties

Author

Thomas Knoke, Carola Paul, Patrick Hildebrandt, Baltazar Calvas, Luz Maria Castro, Fabian Härtl, Martin Döllerer, Ute Hamer, David Windhorst, Yolanda F. Wiersma, Giulia F. Curatola Fernández, Wolfgang A. Obermeier, Julia Adams, Lutz Breuer, Reinhard Mosandl, Erwin Beck, Michael Weber, Bernd Stimm, Wolfgang Haber, Christine Fürst, and Jörg Bendix

Subjects
Science
Abstract

Land use becomes more diverse when it considers uncertain interactions of multiple ecosystem services. Here, Knoke and colleagues show that uncertainty plays a larger role if ecosystem services are optimized only for a single service, or if services correlate.

Published
2016
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45. FAT1 mutations cause a glomerulotubular nephropathy

Author

Heon Yung Gee, Carolin E. Sadowski, Pardeep K. Aggarwal, Jonathan D. Porath, Toma A. Yakulov, Markus Schueler, Svjetlana Lovric, Shazia Ashraf, Daniela A. Braun, Jan Halbritter, Humphrey Fang, Rannar Airik, Virginia Vega-Warner, Kyeong Jee Cho, Timothy A. Chan, Luc G. T. Morris, Charles ffrench-Constant, Nicholas Allen, Helen McNeill, Rainer Büscher, Henriette Kyrieleis, Michael Wallot, Ariana Gaspert, Thomas Kistler, David V. Milford, Moin A. Saleem, Wee Teik Keng, Stephen I. Alexander, Rudolph P. Valentini, Christoph Licht, Jun C. Teh, Radovan Bogdanovic, Ania Koziell, Agnieszka Bierzynska, Neveen A. Soliman, Edgar A. Otto, Richard P. Lifton, Lawrence B. Holzman, Nicholas E. S. Sibinga, Gerd Walz, Alda Tufro, and Friedhelm Hildebrandt

Subjects
Science
Abstract

Steroid-sensitive nephrotic syndrome (SRNS) can cause CKD and necessitate kidney transplant. Here the authors identify FAT1 mutations by homozygosity mapping and whole-exome sequencing in families with SRNS and provide functional mouse and zebrafish evidence that FAT1 is required for normal glomerular and tubular function and that FAT1 mutations can cause SRNS.

Published
2016
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46. Compositional diversity of rehabilitated tropical lands supports multiple ecosystem services and buffers uncertainties.

Author

Knoke T, Paul C, Hildebrandt P, Calvas B, Castro LM, Härtl F, Döllerer M, Hamer U, Windhorst D, Wiersma YF, Curatola Fernández GF, Obermeier WA, Adams J, Breuer L, Mosandl R, Beck E, Weber M, Stimm B, Haber W, Fürst C, and Bendix J

Abstract

High landscape diversity is assumed to increase the number and level of ecosystem services. However, the interactions between ecosystem service provision, disturbance and landscape composition are poorly understood. Here we present a novel approach to include uncertainty in the optimization of land allocation for improving the provision of multiple ecosystem services. We refer to the rehabilitation of abandoned agricultural lands in Ecuador including two types of both afforestation and pasture rehabilitation, together with a succession option. Our results show that high compositional landscape diversity supports multiple ecosystem services (multifunction effect). This implicitly provides a buffer against uncertainty. Our work shows that active integration of uncertainty is only important when optimizing single or highly correlated ecosystem services and that the multifunction effect on landscape diversity is stronger than the uncertainty effect. This is an important insight to support a land-use planning based on ecosystem services.

Published
2016
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47. Afforestation or intense pasturing improve the ecological and economic value of abandoned tropical farmlands.

Author

Knoke T, Bendix J, Pohle P, Hamer U, Hildebrandt P, Roos K, Gerique A, Sandoval ML, Breuer L, Tischer A, Silva B, Calvas B, Aguirre N, Castro LM, Windhorst D, Weber M, Stimm B, Günter S, Palomeque X, Mora J, Mosandl R, and Beck E

Subjects
Conservation of Natural Resources methods, Ecuador, Forestry methods, Trees growth & development, Conservation of Natural Resources economics, Ecosystem, Forestry economics, Pinus growth & development
Abstract

Increasing demands for livelihood resources in tropical rural areas have led to progressive clearing of biodiverse natural forests. Restoration of abandoned farmlands could counter this process. However, as aims and modes of restoration differ in their ecological and socio-economic value, the assessment of achievable ecosystem functions and benefits requires holistic investigation. Here we combine the results from multidisciplinary research for a unique assessment based on a normalization of 23 ecological, economic and social indicators for four restoration options in the tropical Andes of Ecuador. A comparison of the outcomes among afforestation with native alder or exotic pine, pasture restoration with either low-input or intense management and the abandoned status quo shows that both variants of afforestation and intense pasture use improve the ecological value, but low-input pasture does not. Economic indicators favour either afforestation or intense pasturing. Both Mestizo and indigenous Saraguro settlers are more inclined to opt for afforestation.

Published
2014
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48. ATP-induced electron transfer by redox-selective partner recognition.

Author

Hennig SE, Goetzl S, Jeoung JH, Bommer M, Lendzian F, Hildebrandt P, and Dobbek H

Subjects
Binding Sites, Calorimetry, Cell Respiration, Chromatography, Crystallization, Crystallography, X-Ray, Electron Spin Resonance Spectroscopy, Electron Transport, Electrons, Ions, Ligands, Models, Molecular, Nucleotides chemistry, Oxygen chemistry, Protein Structure, Tertiary, Spectrophotometry, Thermoanaerobacter enzymology, Adenosine Triphosphatases chemistry, Adenosine Triphosphate chemistry, Oxidation-Reduction, Vitamin B 12 chemistry
Abstract

Thermodynamically unfavourable electron transfers are enabled by coupling to an energy-supplying reaction. How the energy is transduced from the exergonic to the endergonic process is largely unknown. Here we provide the structural basis for an energy transduction process in the reductive activation of B12-dependent methyltransferases. The transfer of one electron from an activating enzyme to the cobalamin cofactor is energetically uphill and relies on coupling to an ATPase reaction. Our results demonstrate that the key to coupling is, besides the oxidation state-dependent complex formation, the conformational gating of the electron transfer. Complex formation induces a substitution of the ligand at the electron-accepting Co ion. Addition of ATP initiates electron transfer by provoking conformational changes that destabilize the complex. We show how remodelling of the electron-accepting Co(2+) promotes ATP-dependent electron transfer; an efficient strategy not seen in other electron-transferring ATPases.

Published
2014
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